India
India
United States
United States

Quick facts

English Clinical trial application language English
Yes Regulatory authority & ethics committee review may be conducted at the same time Yes
Yes Clinical trial registration required Yes
Yes In-country sponsor presence/representation required No
Under 18 Age of minors Determined at the State Level
Yes Specimens export allowed Yes

Regulatory Authority > Regulatory Authority

Last content review/update: March 24, 2022

Central Drugs Standard Control Organization

As set forth in the 2019-CTRules and the Hdbk-ClinTrial, the Central Drugs Standard Control Organization (CDSCO) is the regulatory authority responsible for clinical trial oversight, approval, and inspections in India. In accordance with the provisions of the 2019-CTRules, the Drugs Controller General of India (DCGI) heads CDSCO, and is responsible for granting permission for clinical trials to be conducted and for regulating the sale and importation of drugs for use in clinical trials. The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.

According to IND-59, CDSCO functions under the Directorate General of Health Services (DGHS), which is part of the Ministry of Health and Family Welfare (MOHFW). Per IND-59 and IND-47, as the Central Drug Authority, CDSCO is responsible for approving new drugs, conducting clinical trials, establishing drug standards, overseeing the quality of imported drugs, providing expert advice, and coordinating the state licensing authorities who regulate the manufacture, sale, and distribution of drugs.

Per the DCA-DCR, the Drugs Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC) advise the DCGI. IND-16 states that the DTAB, a statutory board, is composed of technical experts who advise the central and state governments on technical drug matters and on making rules. The DCC, a statutory committee, consists of central and state drug control officials who advise the central and state governments and the DTAB to ensure drug control measures are enforced throughout India.

In addition, as indicated in the Hdbk-ClinTrial, Subject Expert Committees (SECs) comprise experts representing the relevant therapeutic areas that are responsible for reviewing the submitted clinical trial applications, investigators’ brochures, and study protocols. The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with the specialization in relevant fields to evaluate scientific and technical drug-related issues. In accordance with the 2019-CTRules, with the approval of the MOHFW, Order13Jan20 establishes the terms of reference that CDSCO will use to constitute the SECs from the groups/panels of approximately 550 medical experts with specialization in relevant fields, including the existing members of the SECs from various government medical colleges and institutions. Refer to Scope of Assessment section for additional information on the therapeutic areas to be reviewed by the SECs. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Please note: India is party to the Nagoya Protocol on Access and Benefit-sharing (IND-29), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see IND-45.

Contact Information

According to IND-58, IND-70, and IND-71, CDSCO contact information is as follows:

Central Drugs Standard Control Organization
Directorate General of Health Services (DGHS)
Ministry of Health and Family Welfare
Government of India
FDA Bhavan, ITO, Kotla Road
New Delhi 110002
India
Phone: +91-11-23216367 (CDSCO) / 23236975 (DGHS)
Fax: +91-11-23236973
E-mail:
dci@nic.in

CDSCO Public Relations Office
Phone: 011-23216367 ext. 102 or 1 800 11 1454 (toll free)
Email:
startupinnov@cdsco.nic.in

Chapter I (2), Chapter II (3), Chapter V (19 and 21-22), Chapter XIII (100), Second Schedule (1), and Third Schedule (1)
DCA, 1940
Preface, 5.1, 5.2, and Appendix 8.3
Regulatory System
About Us
Last content review/update: January 19, 2023

This profile covers the role of the Department of Health & Human Services (HHS)’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct, 21CFR50, and 21CFR312. Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule (Pre2018-ComRule and RevComRule), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E. (Please note: ClinRegs does not provide information on state level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct, 21CFR50, and 21CFR312, the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92, the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLiP) develops good clinical practice and human subject protection policies, regulation, and guidance.

See USA-47 for a list of FDA clinical trials related guidance documents.

Office for Human Research Protections and Common Rule Agencies

Per USA-93, OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as an institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-65 for a list of US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-55 and USA-74, the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements Decision Charts consistent with the RevComRule, see USA-74. For more information about the RevComRule, see USA-66.

Per the RevComRule, the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule. Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements Decision Charts consistent with the Pre2018-ComRule, see USA-74.

See USA-54 for additional information regarding compliance with the Pre2018-ComRule and the RevComRule.

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50. However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Contact Information

Food & Drug Administration

As per USA-81, USA-90, and USA-91, the contact information for the FDA is as follows:

Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Telephone (general inquiries): (888) 463-6332

CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CDER Email: druginfo@fda.hhs.gov

Office for Human Research Protections

Per USA-82, the contact information for the OHRP is as follows:

Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Telephone: (866) 447-4777 or (240) 453-6900
Email (general inquiries): OHRP@hhs.gov

Department of Health & Human Services

According to USA-83, the contact information for the HHS is as follows:

US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775

Subpart A (312.1), Subpart B (312.20), and Subpart C (312.40)
Subpart A (50.1)
Subchapter V, Part A, Sec. 355
46.101
46.101
Transition Provision

Regulatory Authority > Scope of Assessment

Last content review/update: April 28, 2022

Overview

In accordance with the 2019-CTRules and the Hdbk-ClinTrial, the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organization (CDSCO), is responsible for reviewing and approving clinical trial applications for all new drugs, investigational new drugs (INDs), and imported drugs to be registered in India. Additionally, per the 2019-CTRules, the G-ICMR, and IND-31, the DCGI and a DCGI-registered ethics committee (EC) must approve a clinical trial application prior to the sponsor initiating the trial, except in the case of non-regulatory academic/research clinical trials that only require EC approval. Refer to the Scope of Review section for detailed information on non-regulatory academic/research clinical requirements.

As per the 2019-CTRules and the Hdbk-ClinTrial, the scope of the DCGI assessment includes a review of applications for IND and new drug clinical trials, global clinical trials (GCTs), and post marketing studies (Phases I-IV). Per Notice18Feb20, which clarifies information provided in IND-31, the 2019-CTRules are only applicable to new drugs and investigational new drugs. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules, amended by the 2022-CTRules-Amdt, defines a “new drug” as:

  • A drug, including active pharmaceutical ingredients or phytopharmaceutical drugs, that has not been used in the country to any significant extent
  • A drug that has already been approved by the DCGI and is now proposed to be marketed with modified or new claims
  • A fixed dose combination of two (2) or more drugs, individually approved for earlier specific claims, and which are now proposed to be combined for the first time in a fixed ratio, or, if the ratio of ingredients in an already marketed combination is proposed to be changed
  • A modified or sustained release form of a drug, or novel drug delivery system of any drug approved by the DCGI
  • A vaccine, recombinant Deoxyribonucleic Acid (r-DNA)-derived product, living modified organism, monoclonal antibody, cell or stem cell derived product, gene therapeutic product, or xenografts intended to be used as a drug

Per the 2019-CTRules and IND-31, the above listed drugs, excluding the modified/sustained drug forms and biological drug products, will be deemed new for four (4) years from the date of first approval. The modified/sustained drug forms and biological products including vaccines should always be viewed as new drugs. See also IND-6 for additional information on the revised definition of “new drug” under the 2019-CTRules.

The 2019-CTRules defines an IND as a new chemical or biological entity or a product having therapeutic indication but that has never been tested on human beings, and as also noted in IND-31, has not been approved as a drug for marketing in any country.

In addition, according to IND-31 and IND-13, the DCGI review and approval process may be conducted in parallel with the institutional or independent EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm that the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.) (See the Scope of Review section for more information.)

Clinical Trial Review Process

As specified in the 2019-CTRules, and according to IND-31, IND-17, and IND-18, upon receipt of a clinical trial application (see the 2019-CTRules for Form CT-04), the DCGI has 90 calendar days to evaluate the application for drugs developed outside India and 30 days for drugs discovered, researched, and manufactured in India. If the DCGI does not respond within 30 days to applications for drugs developed in India, the sponsor (applicant) may conclude that permission to conduct the trial has been granted.

The 2019-CTRules and IND-31 further specify that once the sponsor (applicant) obtains approval from the DCGI, he/she must still formally notify CDSCO via Form CT-4A (see the 2019-CTRules) prior to initiating the clinical trial.. The DCGI will then record the information provided on the form and it will become part of the official record known as the automatic approval of the DCGI. The DCGI grants permission to initiate a clinical trial via either Form CT-06 (see the 2019-CTRules) or as an automatic approval via Form CT-4A (see the 2019-CTRules). The DCGI’s permission must remain valid for two (2) years from the date of its issue, unless extended by the DCGI as noted in the 2019-CTRules and IND-31.

As delineated in the Hdbk-ClinTrial, CDSCO coordinates the clinical trial application process. Upon receipt of an application, a CDSCO official is responsible for conducting the initial administrative review. If the application is deemed complete, within four (4) weeks following receipt, the official forwards the application along with a summary of his/her evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review. If the proposal is not accepted by the SEC, the sponsor (applicant) may request additional consideration of the proposal by the Technical Committee. Otherwise, only the SEC’s recommendations are required for the DCGI (CDSCO) to issue a final decision to the Technical or Apex Committee.

Per the Hdbk-ClinTrial, SECs are usually comprised of six (6) experts representing various therapeutic areas, including pharmacologists/clinical pharmacologists, and medical specialists. However, Order13Jan20, issued in accordance with the 2019-CTRules, indicates that SECs will be comprised of eight (8) medical experts, specifically one (1) pharmacologist and seven (7) medical specialists. Per the Hdbk-ClinTrial, SECs are responsible for advising CDSCO with in-depth evaluations of non-clinical data (including pharmacological and toxicological data) and clinical trial data (Phases I-IV) provided by the sponsors (applicants) for approval. The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with specialization in relevant fields to evaluate scientific and technical drug-related issues. The committee/group may submit its recommendations within 60 days from the date of the request. Additionally, per Order13Jan20, SECs will evaluate and advise DCGI on proposals in various categories for the approval of new drug and clinical trial applications. These include the following: new drug substances of chemical and biological origin including vaccines and r-DNA derived products; subsequent approval of new drug and biological products including vaccines and r-DNA derived products already approved in the country; global clinical trials; fixed dose combinations of two (2) or more drugs to be introduced for the first time in the country; causality analysis, drug safety, or any other technical matter requiring expert advice in the opinion of the Ministry of Health and Family Welfare (MOHFW) or the DCGI. See Order13Jan20 for the complete terms of reference required to constitute SECs.

Once an SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor (applicant) clarification or modification and sends this feedback to the sponsor (applicant) within one (1) week of receipt. The sponsor (applicant) must submit a written reply to CDSCO within four (4) weeks of receiving the comments, and his/her comments will, in turn, be sent to the SEC for review.

Once the sponsor (applicant)’s response is received, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee within 15 days. In the case of a sponsor (applicant)’s request for reconsideration, CDSCO will review the resubmitted application and send it to the SEC again, or, to the Technical Committee per the sponsor (applicant)’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee within 15 days. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor (applicant) to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The Hdbk-ClinTrial and the 2019-CTRules further state that application reviews should be based on the following evaluation parameters:

  • Assessment of risk versus benefit to the patients
  • Innovation vis-à-vis existing therapeutic option
  • Unmet medical need in the country
  • Safety/dosage/investigational tests (e.g., pharmacogenetic tests)
  • Any additional information or study(ies) needed before marketing approval for inclusion in package insert/ summary product characteristic (SmPC) post marketing

In addition, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the protocol without agreement by the sponsor and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC approval letter. Similarly, the G-ICMR indicates that the EC must review and approve any protocol amendments, major deviations, or violations prior to those changes being implemented.

The 2019-CTRules further states that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

See IND-46 for additional information on conducting clinical trials in India. For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

(See the Submission Process, Submission Content, and Timeline of Review sections for detailed submission content and timeline requirements.)

Other Considerations

In addition, per the 2019-CTRules and IND-31, the DCGI, with the approval of the Central Government, may waive the requirement to conduct a local trial for a new drug already approved outside India. The waiver will be considered for applications submitted to conduct a trial with a new drug already approved in certain countries if the following conditions are met:

  • The new drug is approved and marketed in countries to be specified by the DCGI and no major unexpected serious adverse events have been reported, or
  • The DCGI has already granted permission to conduct a GCT with the new drug that is currently ongoing in India and this new drug has also been approved for marketing in one (1) of the countries to be specified by the DCGI, and
  • There is no probability or evidence, on the basis of existing knowledge, of any difference in the metabolism of the new drug by the Indian population, or any factor that may affect the pharmacokinetics, pharmacodynamics, and safety and efficacy of the new drug, and
  • The applicant has committed in writing to conducting a Phase IV clinical trial to establish the new drug’s safety and efficacy per the DCGI-approved formulation

Per the 2019-CTRules, the DCGI plans to issue periodic orders to specify the countries that may be eligible for this waiver. For countries that do not meet the waiver eligibility requirements, the 2019-CTRules states that these applications must be approved by the DCGI within 90 working days from the date of application receipt. Although the 2019-CTRules does not delineate the countries that may be eligible for a waiver, according to IND-18 and IND-19, the United States, the United Kingdom, the European Union, Canada, Australia, and Japan are the countries that will no longer be required to complete local clinical trials for already approved and marketed new drugs. Refer to the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India. See also IND-6 for additional information on local clinical trial waivers under the 2019-CTRules.

Chapter I (2), Chapter II (3), Chapter III (11), Chapter V (19-25, and 28), Chapter XIII (100-101), First Schedule (3), Second Schedule (1 and Table 1), Third Schedule (1 and Table 4), Fourth Schedule (7), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)
7.11, and Annexures I, II, and III
4.8 (Table 4.2), 7.0, and 7.1
4, 11.2, and Annexures I and II
Preface, 4.0, 5.0, 5.1, 5.2, 5.22, 8.2, and Appendix 8.3
1
Introduction
Clinical Trial of New drugs
2-3, 7, 10-11, 18, 22, 25, 31-33, 38, and 79
Revising New Drug Definition and Waivers of Local Clinical Trial Data
Last content review/update: January 19, 2023

Overview

In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

  • Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.
  • Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
  • Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:

  • A drug is involved as defined in the FDCAct
  • A clinical investigation is being conducted as defined in 21CFR312
  • The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.

Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if he/she intends to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312, if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials.

For research involving cellular and gene therapy, see the guidance documents at USA-80.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

  • Breakthrough Therapy - expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
  • Accelerated Approval - allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
  • Priority Review - a process by which the FDA’s goal is to take action on an application within six (6) months
  • Fast Track - facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process.

Subpart A (312.1-312.3), Subpart B (312.20-312.23 and 312.30), Subpart C (312.40-312.42 and 312.44-312.45), and Subpart E (312.85)
Subpart A (50.1)
Subpart A (56.102)
Subchapter V, Part A, Sec. 355
VIII
II-IV
III (C)

Regulatory Authority > Regulatory Fees

Last content review/update: March 24, 2022

As per the 2019-CTRules, IND-43, and IND-42, a sponsor (applicant) is responsible for a paying a fee to the Drugs Controller General of India (DCGI) to submit a clinical trial application.

The 2019-CTRules and IND-43 specify that Form CT-04 should be accompanied by one (1) of the following officially mandated fees:

  • 3,00,000 Rupees for Phase I (human) clinical trials
  • 2,00,000 Rupees for Phase II (exploratory) clinical trials
  • 2,00,000 Rupees for Phase III (confirmatory) clinical trials
  • 2,00,000 Rupees for Phase IV clinical trials
  • 50,000 Rupees for reconsideration of application for permission to conduct clinical trial

In addition, the 2019-CTRules states that no fee is required to be paid along with the clinical trial application if a trial is being conducted by an institution or an organization wholly or partially funded or owned by the Central Government of India or one of India’s state government institute(s).

See also IND-31 for additional information on CDSCO fee requirements.

Payment Instructions

As described in the 2019-CTRules and IND-43, payment must be made electronically via the Bank of Baroda, Kasturba Gandhi Marg, New Delhi-110001, any other Bank of Baroda branch, or any other bank approved by the Ministry of Health and Family Welfare (MOHFW) via the SBI ePay payment gateway. The payment should be credited to: Head of Account, 0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines per the 2019-CTRules, also known as the head of Fees & Fines, according to IND-42.

In addition, according to IND-43 and IND-42, electronic payment is made via the SUGAM portal (IND-59). Once the payment is submitted, the bank payment gateway will confirm that the payment was successful, and the user will be redirected to the online payment status page on the SUGAM portal to view the e-Challan (payment receipt).

IND-43 and IND-42 also specify that the online payment will take two (2) to three (3) days to be credited to the National Portal of India’s Payment & Account Office. Therefore, users are requested to initiate online payments at least three (3) days prior to submitting an application to the Central Drugs Standard Control Organization (CDSCO).

According to the 2019-CTRules, the sponsor must also submit a fee of 5,000 Rupees per product with an application for permission to manufacture or import the investigational product (IP) to be used in a clinical trial.

Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal.

(Note: Although the fees listed in IND-43 are correct, the SUGAM portal and associated documentation as well as CDSCO’s Pre-Screening Checklist (IND-32) have not yet been aligned with the 2019-CTRules in terms of referencing the new application form (CT-04). However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

Chapter V (21), Chapter XIII (102), Sixth Schedule, and Eighth Schedule (Form CT-04)
1 (INDs) and 3 (Global Clinical Trials)
1 and 6
Last content review/update: January 19, 2023

Food & Drug Administration

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct, FDARA, and USA-45, the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43, the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.

Title 1, Prescription Drug User Fee Amendments of 2017
Part C, Subpart 2 (379g and 379h)

Ethics Committee > Ethics Committee

Last content review/update: March 24, 2022

Overview

As delineated in the 2019-CTRules and IND-31, India has a decentralized process for the ethical review of clinical trial applications, and requires ethics committee (EC) approval for each trial site. Because there is no national EC in the country, ECs are based at either institutions/organizations, or function independently, and must meet the requirements set forth in the 2019-CTRules and the G-ICMR. Prior to initiating and throughout the duration of a trial, every trial site must be overseen by an EC registered with the Drugs Controller General of India (DCGI), also commonly referred to as the Central Licensing Authority.

In addition, the 2019-CTRules established a separate registration and monitoring system for ECs that oversee biomedical and health research studies. See the Scope of Review section for additional information on biomedical and research study requirements.

See also the Authorizing Body section for detailed registration requirements for ECs that oversee clinical trials and ECs that monitor biomedical and health research studies.

Ethics Committee Composition

Pursuant to the 2019-CTRules and the G-ICMR, an institutional/independent EC should be multidisciplinary and multi-sectorial, representing a mixed gender and age composition.

The 2019-CTRules and the G-ICMR state that an EC should appoint from among its members a chairperson (from outside the institution) and a member secretary (generally from inside the institution). The other members should represent a balance of affiliated and non-affiliated medical/non-medical and scientific/non-scientific persons, including the lay public. Per the 2019-CTRules and the G-ICMR, preferably 50% of the members should also be non-affiliated or from outside the institution.

As per the 2019-CTRules and the G-ICMR, the composition should include the following:

  • Chairperson from outside the institute (Vice Chairperson (optional))
  • One (1) to two (2) basic medical scientists (preferably one (1) pharmacologist)
  • One (1) to two (2) clinicians from various institutions
  • Legal expert(s) or retired judge
  • One (1) social scientist/representative of non-governmental voluntary agency
  • One (1) philosopher/ethicist/theologian
  • One (1) lay person from the community
  • Member secretary (Alternative Member secretary optional)
  • One (1) member whose primary area of interest/specialization is non-scientific
  • At least one (1) member independent of the institution/trial site

Additionally, per the 2019-CTRules, EC members are required to:

  • Be familiar with key clinical regulatory requirements as delineated in the 2019-CTRules and the G-ICMR that reference both the Declaration of Helsinki (IND-63) and the most recently updated International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (IND-41)
  • Have post-graduate qualifications and experience in their fields if representing basic medical scientists/clinicians
  • Represent the specific patient group as much as possible based on the research area requirement

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the 2019-CTRules and the G-ICMR, EC members should be made aware of their roles and responsibilities. The terms of reference should also include a statement on terms of appointment including duration and conditions; policy for removal/replacement; resignation procedure; meeting frequency; payment of processing fee to EC for review; honorariums to members and invited experts; maintenance of EC documentation and communication records, etc. Each committee should specify these terms in its own standard operating procedures (SOPs) that should be made available to each member.

In addition, per the 2019-CTRules and the G-ICMR, members should have no conflict of interest, and should voluntarily withdraw from the EC while making a decision on an application if a proposal evokes a conflict of interest. The G-ICMR indicates the term of membership is generally two (2) to three (3) years, and may be extended.

In terms of training, the G-ICMR also specifies each member must:

  • Provide a recent signed Curriculum Vitae (CV) and training certificates on human research protection and good clinical practice (GCP) guidelines, if applicable
  • Either be trained in human research protection and/or GCP at the time of induction into the EC, or undergo training and submit training certificates within six (6) months of appointment (or as per institutional policy)
  • Be willing to undergo training or update their skills/knowledge during their tenure as an EC member

Further, if required, the 2019-CTRules and the G-ICMR, state subject experts could also be invited to offer their views, which must be recorded; however, the experts would not have any voting rights. Only members independent of the trial and the trial sponsor should vote/provide opinions in study related matters. In addition, all records must be safely maintained after the completion or termination of the study for at least five (5) years from the date of the trial’s completion or termination (both hard and soft copies).

The G-ICMR specifies that all EC members should review all proposals. Members should be given at least one (1) week to review the proposal and related documents, except in the case of expedited reviews. The Member Secretary should screen the proposals for their completeness and categorize them into three (3) types according to risk level: exemption from review, expedited review, or full committee review. An investigator cannot decide that his/her protocol falls in the exempted category without an EC review. Per the 2019-CTRules and the G-ICMR, a minimum of five (5) members is required for the quorum.

For detailed EC procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, and IND-5. See also IND-27 and IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Chapters I, III-IV, and V (19-20 and 25); Third Schedule (1 and Table 1); and Eighth Schedule (Forms CT-01 and CT-02)
2.1, 2.8, 4.0-4.4, 4.10, Tables 4.1-4.3, Glossary, and Annex 1
Sections 1-4
32-33
Sections 1-4
Registration of Ethics Committees reviewing Biomedical & Health Research
Last content review/update: January 19, 2023

Overview

As indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval. The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens. See USA-65, USA-66, and USA-54, and the Regulatory Authority section for more information on the RevComRule and agency-specific compliance.

Ethics Committee Composition

As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

  • One (1) primarily focused on scientific issues
  • One (1) focused on nonscientific issues
  • One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which he/she has a conflicting interest, except to provide EC requested information.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56, ECs must follow written procedures for the following:

  • Conducting initial and continuing reviews, and reporting findings and actions
  • Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
  • Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
  • Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, ECs must establish and follow written procedures for the following:

  • Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
  • Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
  • Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
  • Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS)Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.

21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.

See G-IRBProcs for detailed guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWA.

Subpart A (312.3), Subpart B (312.23), and Subpart C (312.40)
Subpart A (50.3)
Subpart A (56.101-56.103), Subpart B (56.107), Subpart C (56.108-56.109), and Subpart D (56.115)
46.101-46.103, 46.107-46.108, and 46.115
46.101-46.104, 46.107-46.108, and 46.115
Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
Definitions

Ethics Committee > Scope of Review

Last content review/update: March 24, 2022

Overview

The primary scope of information assessed by ethics committees (ECs) relates to maintaining and protecting the rights, safety, and well-being of all research participants, especially those in vulnerable populations, in accordance with the requirements set forth in the 2019-CTRules, the G-ICMR, the G-Children, the Declaration of Helsinki (IND-63), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (IND-41). (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these populations).

The 2019-CTRules and the G-ICMR also state that ECs must ensure an independent, timely, and competent review of all ethical aspects of the research protocols. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards. Per the G-Children, ECs providing opinions on studies involving children should also include members with pediatric expertise. The expert(s) may be permanent EC members or invited as subject experts to provide advice and be consulted on an ad hoc basis.

As delineated in the 2019-CTRules, ECs also have a continuing responsibility to monitor approved clinical trials and biomedical and health research studies to ensure ethical compliance throughout the study duration.

For all studies, the G-ICMR indicates that ECs must review and approve any protocol amendments, major deviations, or violations at regular intervals.

There is no stated expiration date for an EC approval in the 2019-CTRules or the G-ICMR. However, per the 2019-CTRules, in the event that an EC revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator as well as to the Drugs Controller General of India (DCGI). For detailed EC review procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, IND-5, and IND-27. See also IND-36 for the EC clinical trial application form, and IND-52 for other commonly used EC review forms.

Role in Clinical Trial Approval Process

As per the 2019-CTRules, the G-ICMR, and IND-31, the DCGI (also known as the Central Drugs Authority) and a DCGI-registered EC must approve a clinical trial application prior to the sponsor initiating the trial, except in the case of non-regulatory academic/research clinical trials that only require EC approval. According to IND-31 and IND-13, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules, the Hdbk-ClinTrial, and IND-31 specify that an EC must grant a separate approval for each trial site to be used, and the DCGI must be informed of each approval. A trial may only be initiated at each respective site after obtaining an EC approval for that site. The 2019-CTRules and IND-31 further state that if a site does not have an EC, it may obtain approval from another site’s EC provided that it is located within the same city or within a radius of 50 kilometers of the trial site. The DCGI should be notified of the EC’s approval within 15 working days of the approval being granted per the 2019-CTRules. Per the 2019-CTRules and IND-31, the EC of each site should notify the DCGI of its approval and provide a copy within 15 working days of making this decision. Refer to IND-36 for the Indian Council of Medical Research (ICMR)’s EC clinical trials application form. In addition, per the 2019-CTRules and IND-31, the EC should inform the DCGI about the academic trials it has approved and about cases where there could be an overlap between the clinical trial for academic and regulatory purposes. If the DCGI does not comment to the EC within 30 days from receiving EC notification, it should be presumed that DCGI permission is not required. See also IND-6 for additional information on academic trial approval requirements.

The 2019-CTRules and IND-31 state that an academic/research trial is intended to study a new indication or route of administration, or, new dose or dosage of an already approved drug formulation and does not require DCGI approval as long as the following conditions are met:

  • The trial is approved by the EC, and
  • The data generated is not intended for submission to the DCGI

IND-25 further explains that a drug import license is not required for EC-approved academic trials that will be using a permitted drug formulation with a new indication, a new route of administration, a new dose, or a new dosage form. See the Manufacturing & Import section for detailed information.

During a clinical trial, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the trial protocol without agreement by the sponsor and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC’s approval letter.

The 2019-CTRules further states that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should also be notified of administrative or logistic changes or minor amendments in the protocol within 30 days.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Biomedical and Health Research

According to the 2019-CTRules and the G-ICMR, biomedical and health research is defined as studies that include basic research, applied and operational research, or clinical research designed primarily to increase scientific knowledge about diseases and conditions (physical or socio-behavioral); their detection and cause; and evolving strategies for health promotion, prevention, or the amelioration of disease and rehabilitation.

As discussed in Notice15Sept19 and chapter IV of the 2019-CTRules, any institution or organization that intends to conduct biomedical and health research involving human participants is required to have an EC to review and oversee the conduct of such research before the study is initiated and throughout its duration. The EC must also be registered with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). According to IND-50, the DHR’s Office for Ethics Committee Registration was established to coordinate and monitor EC registrations and related activities to provide transparency, accountability, and structure to regulate and monitor biomedical and health research in India.

See also IND-28 for ICMR’s biomedical and health research conduct policies, and IND-6 for additional information on the regulation of biomedical and health research under the 2019-CTRules.

Multicenter Research

As delineated in the G-ICMR, in a multicenter research study, all of the participating study sites are required to obtain approval from their respective ECs. Each EC may conduct a separate review, or the ECs may decide to designate a main EC, with the others choosing to accept its decision. The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and issues arising with communication between committees.

Per the G-ICMR, in the event that sites choose to have separate EC reviews, the following requirements must be met:

  • The participating site ECs/Secretariats should establish communication with one another
  • If any EC does not grant approval for a study at a site, the reasons must be shared with other ECs and should be considered
  • The EC can suggest site-specific protocols and informed consent modifications as per local needs

A separate review may be requested for studies with a higher degree of risk, clinical trials, or intervention studies where conduct may vary depending on the site, or, for any other reason that requires closer review and attention. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review.

Per the G-ICMR, when the multicenter research study designates one (1) main EC, the nominated EC members that represent the participating sites may attend the meeting of the elected EC. The designated EC should also be located in India and be registered with the relevant authority (either the DCGI or the DHR depending on the type of study). In addition, the decision to conduct a common review is only applicable for ECs in India. In the case of international collaboration for research and approval by a foreign institution, the local participating study sites would be required to obtain approval from a local EC. Refer to the G-ICMR for detailed information on multicenter studies that use the common review practice and involve international collaborations.

The G-ICMR further notes that the local site requirements (e.g., informed consent, research implementation and its monitoring) may be performed by the local EC, which would require good communication and coordination between the researchers and the EC secretariats representing the participating sites.

Chapter I, Chapter III (7 and 11), Chapter IV (15-17), Chapter V (19-20, 25, and 28), and Third Schedule (1, 3, and Table 4)
3.1
7.11, and Annexures I, II, and III
1.0-1.1, 2.1, 2.3, 2.8-2.9, 4.0, 4.2, 4.7-4.8, 4.11, Tables 4.1-4.3, Glossary, and Annex 1
4, 11.2, and Annexures I and II
Preface, 4.0, 5.0-5.2, 8.2, and 8.3
Introduction
Introduction and Sections 1-4, and 6
2, 11, and 31-35
1.27 and 3.1
1-4
Registration of Ethics Committees reviewing Biomedical & Health Research
Regulations on Biomedical and Health Research (BHR) and Academic Trials
Last content review/update: January 19, 2023

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312, the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.

Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

Expedited Review

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

  • Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
  • Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
  • Under the RevComRule, research for which limited EC review is a condition of exemption

21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

  • Research eligible for expedited review
  • Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
  • Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Per USA-54, for secondary research that does not qualify for an exemption under the RevComRule, the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

  • Scholarly and journalistic activities
  • Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
  • Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
  • Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.

Other Considerations

An EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see G-ComRuleCnsstncy.

Definitions, Exemptions, IRB Review
III (D, F, and H)
Foreword, 1.27, 2, and 3
IV and V
Subpart A (312.3) and Subpart B (312.20 and 312.23)
Subpart A (56.102 and 56.103) and Subpart C (56.108-56.111 and 56.113-56.114)
46.101-46.102, 46.104, 46.107, 46.109-46.111, and 46.113-46.114
46.101-46.102, 46.107, 46.109-46.111, and 46.113-46.114

Ethics Committee > Ethics Committee Fees

Last content review/update: March 24, 2022

As indicated in the G-ICMR, the ethics committee (EC) may charge a reasonable fee to cover the expenses related to optimal functioning to conduct reviews. EC members may also be given reasonable compensation for their time attending EC meetings, and every institution should allocate adequate funds to ensure the smooth functioning of the EC.

4.14
Last content review/update: January 19, 2023

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

Ethics Committee > Oversight of Ethics Committees

Last content review/update: March 24, 2022

Overview

In accordance with the 2019-CTRules and IND-31, all ethics committees (ECs) that review drug clinical trials are required to register with the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), prior to reviewing and approving a clinical trial protocol.

As delineated in Notice15Sept19 and chapter IV of the 2019-CTRules, all ECs that review biomedical and health research studies are required to register with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). According to IND-50, the DHR’s Office for Ethics Committee Registration has been designated as the entity responsible for coordinating and monitoring registrations for ECs overseeing biomedical and health research in India. This office will receive applications for registration of ECs and will review and make decisions on EC registrations/re-registrations. See also IND-69 for an application submission checklist to re-register ECs. Refer to IND-49 and IND-48 for a list of ECs that have registered and re-registered respectively.

Registration, Auditing, and Accreditation

Registration Provisions for Clinical Trial Ethics Committees

As specified in the 2019-CTRules and Notice1Aug18, ECs that intend to review clinical trial research protocols must submit Form CT-01 via the SUGAM portal (IND-59) to register with the DCGI. The DCGI, in turn, will review the application within 45 working days from the date of receipt and, if satisfied with the information provided, grant the EC's registration request via Form CT-02. Per the 2019-CTRules and IND-53, the EC registration will remain valid for a period of five (5) years from the date of issue, unless suspended or cancelled sooner. The EC may apply for registration renewal via the SUGAM portal using Form CT-01 and should include all additional required documentation 90 days prior to the registration’s expiration date. The registration will remain in force until the DCGI passes a new registration order as long as the application is received within the specified 90-day deadline. Following the DCGI’s review of the application and inspection report, if any, and provided that there are no changes to the documentation included in the original application, the EC’s request for registration renewal will be granted within 45 working days from the date of application receipt. See also IND-42 and IND-43 for detailed fee requirements and online payment instructions via the SUGAM portal.

The 2019-CTRules also states that if the EC fails to comply with any of the registration conditions, the DCGI may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed necessary. The suspended or cancelled EC can appeal to the DCGI within the period specified in the show cause notice, and, after consideration, the DCGI may respond by taking one (1) or more of the following actions:

  • Withdraw the notice
  • Issue a warning to the EC describing the deficiency or defect observed during an inspection
  • Reject the results of the clinical trial
  • Suspend for a specified period or cancel the registration, or
  • Debar its members to oversee any future trial for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 60 working days. The Central Government may subsequently pass an order in response to the appeal within 60 working days from the date of the appeal filing.

The EC must also allow CDSCO officials to enter the committee premises to inspect any records, data, documents, or other materials related to a clinical trial. The EC must provide adequate replies to any queries raised by the inspecting authority in relation to the conduct of the trial as noted in the 2019-CTRules.

Registration Provisions for Biomedical and Health Research Ethics Committees

As explained in Notice15Sept19 and IND-51, ECs planning to review biomedical and health research studies are initially required to register on the DHR’s National Ethics Committee Registry for Biomedical and Health Research (NECRBHR) website (IND-51). The NECRBHR facilitates the receipt and processing of application submissions and assists the DHR’s Office of Ethics Committee Registration. An authorized signatory/responsible person must complete the EC Applicant Registration Form (IND-38) and submit it online on the NECRBHR website (IND-51). Once the NECRBHR verifies the application and approves the account registration, the applicant will receive an email that will allow him/her to login to the DHR’s NAITIK portal (IND-54) to submit an application electronically. See IND-66 for a checklist of NECRBHR registration requirements.

Per the 2019-CTRules, the EC must submit an application to the NECRBHR using Form CT-01 along with the required information and documentation specified in Table 1 of the Third Schedule of the 2019-CTRules. Upon receipt of the application, the DHR’s Office of Ethics Committee Registration (designated authority) must grant provisional registration to the EC for a period of two (2) years. Final registration will be granted to the EC on Form CT-03 when the DHR has completed its review of the application and the associated documentation. The final registration will remain valid for a period of five (5) years from the date of its issue, unless suspended or cancelled sooner.

The EC may also submit an application to request registration renewal using Form CT-01 along with the specified documentation at least 90 days prior to the final registration’s expiration date. The final registration will remain in force until the DHR completes its review of the renewal application provided that the following conditions are met:

  • The DHR does not require the EC to provide a new set of documents
  • There have been no changes in the submitted documents since the final registration was granted, and
  • The EC submits a certificate to the DHR validating that the documents have not changed

Following a review of the registration renewal application and further inquiry to confirm there have been no documentation changes, the DHR will renew the EC’s registration on Form CT-03 within 45 working days from the date of application receipt. The renewed registration will remain valid for five (5) years from the date of its issue, unless suspended or cancelled sooner.

The 2019-CTRules further states that if the EC fails to comply with any of the registration conditions, the DHR may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed appropriate. The suspended or cancelled EC can appeal to the DHR, and after consideration, the DHR may respond by taking one (1) or more of the following actions:

  • Issue a warning to the EC describing the deficiency or defect observed, which may adversely affect the rights or well-being of the study participants
  • Suspend the EC for a specified period or cancel the registration, or
  • Debar its members from overseeing any future biomedical health research for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 45 working days. In response to the appeal, as deemed necessary, and after giving the EC an opportunity to be heard, the Central Government may subsequently pass an order considered appropriate to the case.

(Note: The registration provisions for biomedical and health research ECs in Notice15Sept19 and IND-51 have not yet been aligned with the 2019-CTRules in terms of explaining the application submission process. The 2019-CTRules does not specify that the application submission process is electronic as is stated in Notice15Sept19 and IND-51. Further, only Notice15Sept19 and IND-51 specify that the DHR’s Office of Ethics Committee Registration is the designated authority. However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

Additional Provisions for Clinical Trial and Biomedical and Health Research Ethics Committees

In addition to requiring all ECs to register with the relevant regulatory authority (the DCGI or the DHR), the G-ICMR specifies that ECs should be encouraged to seek recognition, certification, and accreditation from established national and international bodies (e.g., the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), the Association for the Accreditation of Human Research Protection Programs (AAHRPP), CDSCO, and the Quality Council of India through National Accreditation Board for Hospitals and Healthcare Providers (NABH), etc.). Although voluntary, the G-ICMR states that these certifications and accreditations should be continually updated to help with quality assurance and quality improvement and ensure that ECs comply with best practices to protect research participants.

Chapter III (6, 8-11, and 14), Chapter IV, and Chapter V (19-20, and 25), Third Schedule (Table 1), and Eighth Schedule (Forms CT-01, CT-02, and CT-03)
4.1 and 4.15
32-33
1 and 6
Registration of Ethics Committees reviewing Biomedical & Health Research
Last content review/update: January 19, 2023

Overview

As delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).

Per the RevComRule, which took effect January 21, 2019, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.

Food & Drug Administration

According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

Per USA-54, institutions do not need to change an existing FWA because of the RevComRule. See USA-57 for more information on FWAs.

Per 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.

Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.

Subpart B (56.106)
Subpart E (46.501-46.505)
Subchapter V, Part A, Sec. 355
III
I, II, and III
46.103
46.103-46.104
Filing a New Registration for an Institutional Review Board (IRB) by an Institution or Organization (IORG)
Assurance Process
When must an IRB be registered?; How must an IRB be registered?; and Does registration mean that an IRB is in full compliance with the HHS regulations, 45 CFR part 46, or is otherwise meeting a particular standard of competence or expertise?

Clinical Trial Lifecycle > Submission Process

Last content review/update: March 24, 2022

Overview

In accordance with the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, India requires the sponsor (applicant) to obtain clinical trial authorization from the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), and the investigator to obtain ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. In addition, according to IND-31 and IND-13, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Per the 2019-CTRules and IND-31, non-regulatory academic/research clinical trials only require EC approval. See Scope of Review section for detailed information on non-regulatory academic/research clinical trial requirements.

See the Scope of Review section for additional information on EC protocol review requirements.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Delivery Information for Clinical Trial Application

As indicated in the Notice15Jan18, all clinical trial application submissions must be submitted electronically via CDSCO’s SUGAM portal (IND-59).

Clinical Trial Application Language Requirements

The DCA-DCR delineates that English should be used for specific documents included in the clinical trial application submission. For the informed consent form and patient information sheet, English and/or the vernacular language of the participant(s) should be used. English should also be used for the package inserts.

Chapter I (2), Chapter II (3), Chapter V (19-22, 25, and 28), Second Schedule (1), Third Schedule (1 and Tables 3 and 7), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)
Appendix VIII and Schedule D(II)
7.11 and Annexures I, II, and III
4.0-4.2, 4.8, and 4.10
4, 11.2, and Annexures I and II
5.0, 5.1, 5.2, and Appendix 8.3
Introduction
10-11 and 31-33
Last content review/update: January 19, 2023

Overview

As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to USA-41 and USA-94, paper submissions of INDs should be sent to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.

According to the G-PharmeCTD, which implements section 745A(a) of the FDCAct, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting CDER or CBER. See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, the G-eCTDTech, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs and USA-7, eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) (USA-44). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs, physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical media information.

The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

II-IV
I and III
I, II, and III (A, B, C, K, L, and M)
II and IV
I and II
Subchapter V, Part A, Sec. 355 (a and b) and Subchapter VII, Part D, Sec. 379k-1
Subpart A (312.1-312.3), Subpart B (312.20-312.23), and Subpart C (312.40 and 312.47)
Subpart A (56.102)

Clinical Trial Lifecycle > Submission Content

Last content review/update: March 24, 2022

As set forth in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, India requires the sponsor (applicant) to obtain clinical trial authorization from the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), and the investigator to obtain ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. In addition, according to IND-31 and IND-13, the DCGI review and approval process may be conducted in parallel as the EC review for each clinical trial site, except in the case of non-regulatory academic/research clinical trials that only require EC approval. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm that the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Regulatory Authority Requirements

As per the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35, specific documentation must be submitted to DCGI as part of the approval process for investigational new drugs (INDs). The data required will depend upon the type of application, phase of the study, stage in drug development process, and/or objective of the study. Information that may be required is included in the lists below.

  • Form CT-04 (the clinical trial application form including applicant name; sponsor nature/constitution and contact information; clinical trials site contact information and details; contact information for person responsible for compensation payment, if any; correspondence address; new drug/investigational new drug name(s) and details (i.e., therapeutic class, dosage form, composition, and indications); clinical trial phase; protocol number with date; and EC and investigator names) (See Form CT-04 in the 2019-CTRules for additional details)
  • Treasury Challan receipt demonstrating payment of corresponding fee or transaction ID
  • Chemical and pharmaceutical information
  • Animal pharmacology data
  • Animal toxicology data
  • Human clinical pharmacology data
  • Active ingredient information (for INDs and global clinical trials (GCTs))
  • Formulation data (for INDs and GCTs)
  • Therapeutic class (for INDs and GCTs)
  • Regulatory status in India and in other countries
  • Proposed study status in other participating countries and any approvals, withdrawals, discontinuation of approval, etc. (for GCTs)
  • Affidavit stating study has not been discontinued in any country (for GCTs)
  • Prescribing information
  • Testing protocol(s) for quality control testing
  • Clinical study protocol
  • Dosage form
  • Justification and schematic diagram/flow chart proposed study and design (for INDs and GCTs)
  • Number of patients globally (for GCTs) and number of patients to be enrolled from India (for INDs and GCTs)
  • Details of all sites selected and assessment for suitability of sites and investigators (with contact details)
  • EC registration status of the selected sites
  • Relevance of study, investigational drug, or any specific study aspects to the health care needs of India
  • Innovation vis-à-vis existing therapeutic options
  • Unmet medical need in the country (as applicable)
  • Any India-specific safety/dosage concerns/investigational tests to be done
  • Clinical study reports should be submitted per the International Conference on Harmonisation (ICH) Common Technical Document (CTD) (IND-68)
  • Protocol safety measures per toxicological studies; early clinical studies, approved product insert for marketed product, and published literature
  • Investigator’s Brochure (IB)
  • Investigational Medicinal Products Dossier (IMPD) (for (GCTs))
  • Affidavit stating the IB information is correct and based on facts (for GCTs)
  • Source of bulk drugs (for INDs)
  • Treasury Challan with Form CT-16 (import license application) (for GCTs)
  • Sponsor authorization letter (for GCTs)
  • Details of biological specimens to be exported and the online application for export no objection certificate (NOC) for biological samples on the SUGAM portal (IND-59) (for GCTs) (See IND-1 for the application form to request a NOC to export biological samples) (Refer to the Specimens topic for more information on specimen import/export)
  • Case Report Form (CRF)
  • Informed consent form (ICF) and patient information sheet (See Required Elements section for additional information)
  • Investigator(s) undertaking
  • EC approvals (if available)
  • Clinical study report(s)
  • Investigator list in India and site address

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.) See also IND-22 for details on the SUGAM portal approval process for global clinical trials and IND-31 for clinical trial FAQs.

The 2019-CTRules and the Hdbk-ClinTrial further note that the nature and extent of information to be included in the application may vary based on the application type, study phase, drug development process stage, and study objective. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.) Refer to the 2019-CTRules and IND-31 to obtain detailed submission requirements for applications to conduct a clinical trial using an already approved new drug with a new indication, a new dosage form/new route of administration, a modified release dosage form, or a new drug with an additional strength.

Ethics Committee Requirements

Each institutional EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements. However, per the G-ICMR, the requirements listed below are basically consistent and shared by all of the Indian ECs:

  • Cover letter to the Member Secretary
  • Type of review requested
  • Application form for initial review (IND-39)
  • Informed consent document (in English and the local language(s)) including translation and back translation certificates, if applicable
  • Case record form/questionnaire
  • Recruitment procedures (e.g., advertisement, notices) if applicable
  • Patient instruction card, diary, etc., if applicable
  • IB (as applicable for drugs, biological, or device trials)
  • Details of funding agency/sponsor and fund allocation, if applicable
  • Investigators’ Curriculum Vitaes (CVs)
  • Conflict of interest statement, if applicable
  • Good Clinical Practice (GCP) training certificate for investigators (preferably within last five (5) years)
  • Any other research ethics/other training evidence, if applicable as per EC standard operating procedures (SOPs)
  • List of ongoing research studies undertaken by the principal investigator, if applicable
  • Investigator’s undertaking statement with all participating investigator signatures
  • Regulatory permissions (as applicable)
  • Relevant administrative approvals (such as Health Ministry’s Screening Committee (HMSC) approval for international trials)
  • Institutional Committee for Stem Cell Research (IC-SCR) Registration (IND-72), if applicable
  • Memorandum of Understanding (MoU) in case of studies involving collaboration with other institutions, if applicable
  • Clinical trial agreement between the sponsors, investigator, and the head of the institution(s), if applicable
  • Clinical trial registration documentation (preferable)
  • Insurance policy (it is preferable to have the policy as well as the insurance certificate) for study participants indicating conditions of coverage, date of commencement and date of expiry of coverage of risk (if applicable)
  • Indemnity policy, clearly indicating the conditions of coverage, commencement date, and expiry date of risk coverage (if applicable)
  • Any additional document(s), as required by EC (such as other EC clearances for multicentric studies)
  • Protocol

The G-ICMR also specifies that investigators should submit research proposals as soft or hard copies to the Secretariat for review in the prescribed format and required documents as per EC SOPs.

Furthermore, the ICMR has prepared a generic application for initial review (IND-39) that may be used by the EC. The form is also included in the bulleted list above.

Clinical Protocol

As delineated in the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR, the clinical study protocol should include the following elements (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.):

  • Title page
  • Table of contents
  • Brief summary (G-ICMR)
  • Study rationale
  • Study objective
  • Study design and methodology
  • Study population
  • Justification of inclusion/exclusion of vulnerable populations (G-ICMR)
  • Participant eligibility and recruitment procedures
  • Study assessments
  • Study conduct stating the types of activities that would be included (e.g., medical history, type of physical examination, etc.)
  • Study treatment
  • Ethical consideration
  • Study monitoring and supervision
  • Investigational product management (See Investigational Products topic for detailed coverage of this subject)
  • Data analysis
  • Undertaking by the Investigator statement
  • Appendices

The G-ICMR also mentions the following requirements:

  • Study duration
  • Justification for placebo, benefit-risk assessment, plans to withdraw; if standard therapies are to be withheld, justification for the same
  • Informed consent procedure and sample of the patient/participant information sheet and Informed consent forms including audiovisual recording, if applicable, and Informed consent for stored samples
  • Plan to maintain the privacy and confidentiality of the study participants
  • Adverse events/adverse drug reactions
  • For research involving more than minimal risk, an account of management of risk or injury
  • Proposed compensation, reimbursement of incidental expenses and management of research related injury/illness during and after research period
  • Provision of ancillary care for unrelated illness during the duration of research
  • Account of storage and maintenance of all data collected during the trial
  • Plans for publication of results while maintaining confidentiality of participants’ personal information/identity

For detailed information on these elements, see the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR.

Chapter I (2), Chapter II (3), Chapter V (19-22, 25, and 28), Second Schedule (1, 3, and Tables 1-4), Third Schedule (1 and Tables 1-4, and 6-7), Fourth Schedule (Table 3), Sixth Schedule, and Eighth Schedule (Forms CT-04, CT-4A, CT-06, and CT-16)
4.0-4.2, 4.8, and 4.10
Preface, 3, 5.0, 5.1, 5.2, and Appendix 8.3 and 8.4
Introduction
10-11 and 31-33
1 (INDs) and 3 (Global Clinical Trials)
Last content review/update: January 19, 2023

Regulatory Authority Requirements

As specified in 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

  • Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
  • Table of contents
  • Introductory statement and general investigational plan
  • Investigator’s brochure (IB)
  • Protocols
  • Chemistry, manufacturing, and control data
  • Pharmacology and toxicology data
  • Previous human experience with the IP
  • Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
  • Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.

The G-RWDRWE states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE.

According to G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see G-PedStudyPlans.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.

As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • Clinical protocol
  • Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
  • Participant recruitment procedures
  • IB
  • Safety information
  • Participant payments and compensation
  • Investigator(s) current Curriculum Vitaes (CVs)
  • Additional required EC documentation
  • Risks to participants are minimized and are reasonable in relation to anticipated benefits
  • Participant selection is equitable
  • Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data

Per the RevComRule, which took effect January 21, 2019, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants.

See 21CFR56, the Pre2018-ComRule, the RevComRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

According to the US-ICH-GCPs, the clinical protocol should contain the following elements:

  • General information
  • Background information
  • Trial objectives and purpose
  • Trial design
  • Participant selection/withdrawal
  • Participant treatment
  • Efficacy assessment
  • Safety assessment
  • Statistics
  • Direct access to source data/documents
  • Quality control/quality assurance
  • Ethics
  • Data handling/recordkeeping
  • Financing/insurance
  • Publication policy
  • For complete protocol requirements, see section 6 of the US-ICH-GCPs.

Per the NIHNotice17-064, and provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

Clinical Trial e-Protocol Tool and Template Documents
Form FDA 1571
VIII
3 and 6
Sections I and III
Subpart B (312.22-312.23)
Subpart A (56.102) and Subpart C (56.111)
46.104, 46.109, and 46.111
46.109 and 46.111

Clinical Trial Lifecycle > Timeline of Review

Last content review/update: March 24, 2022

Overview

Based on the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, the Drugs Controller General of India’s (DCGI) review and approval of an application to conduct a clinical trial is dependent upon obtaining ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. In addition, according to IND-31 and IND-13, the DCGI review and approval process may be conducted at the same time as the EC review for each clinical trial site, except in the case of non-regulatory academic/research clinical trials that only require EC approval. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Regulatory Authority Approval

As set forth in the 2019-CTRules and the Hdbk-ClinTrial, the Central Drugs Standard Control Organization (CDSCO) is the regulatory authority responsible for clinical trial oversight, approval, and inspections in India. In accordance with the provisions of the 2019-CTRules, the DCGI heads CDSCO, and is responsible for granting permission for clinical trials to be conducted and for regulating the sale and importation of drugs for use in clinical trials. The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.

According to IND-59, CDSCO functions under the Directorate General of Health Services (DGHS), which is part of the Ministry of Health and Family Welfare (MOHFW). Per IND-59 and IND-47, as the Central Drug Authority, CDSCO is responsible for approving new drugs, conducting clinical trials, establishing drug standards, overseeing the quality of imported drugs, providing expert advice, and coordinating the state licensing authorities who regulate the manufacture, sale, and distribution of drugs.

As specified in the 2019-CTRules, and according to IND-31, IND-17, and IND-18, upon receipt of a clinical trial application (see the 2019-CTRules for Form CT-04), the DCGI has 90 calendar days to evaluate the application for drugs developed outside India and 30 days for drugs discovered, researched, and manufactured in India. If the DCGI does not respond within 30 days to applications for drugs developed in India, the sponsor (applicant) may conclude that permission to conduct the trial has been granted. Refer to the Scope of Assessment section for information on obtaining a waiver for an already approved drug.

Refer to the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India.

The 2019-CTRules and IND-31 further specify that once the sponsor (applicant) obtains approval, he/she must inform the Central Drugs Standard Control Organization (CDSCO) prior to initiating the clinical trial via Form CT-4A (see the 2019-CTRules). The DCGI will then record the information provided on the form and it will become part of the official record known as the automatic approval of the DCGI. The DCGI’s permission to initiate a clinical trial granted via either Form CT-06 (see the 2019-CTRules) or as an automatic approval via Form CT-4A must remain valid for two (2) years from the date of its issue, unless extended by the DCGI as noted in the 2019-CTRules and IND-31.

As delineated in the Hdbk-ClinTrial, CDSCO coordinates the clinical trial application process. Upon receipt of an application, a CDSCO official is responsible for conducting the initial administrative review. If the application is deemed complete, within four (4) weeks following receipt, the official forwards the application along with a summary of his/her evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review. If the proposal is not accepted by the SEC, the sponsor (applicant) may request additional consideration of the proposal by the Technical Committee. Otherwise, only the SEC’s recommendations are required for the DCGI (CDSCO) to issue a final decision to the Technical or Apex Committee.

Per the Hdbk-ClinTrial, SECs are comprised of experts representing various therapeutic areas that are responsible for advising CDSCO with in-depth evaluations of non-clinical data (including pharmacological and toxicological data) and clinical trial data (Phases I-IV) provided by the sponsors (applicants) for approval. The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with the specialization in relevant fields to evaluate scientific and technical drug-related issues. The committee/group may submit its recommendations within 60 days from the date of the request.

Once the SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor (applicant) clarification or modification and send this feedback to the sponsor (applicant) within one (1) week of receipt. The applicant must submit a written reply to CDSCO within four (4) weeks of receiving the comments, and his/her comments will, in turn, be sent to the SEC for review.

Once the sponsor (applicant)’s response is received, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee within 15 days. In the case of a sponsor (applicant)’s request for reconsideration, CDSCO will review the resubmitted application and send to the SEC again, or, to the Technical Committee per the sponsor (applicant)’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee within 15 days. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor (applicant) to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

See also IND-22 for details on the SUGAM portal (IND-59) approval process for global clinical trials, and IND-46 for additional information on conducting clinical trials in India.

Ethics Committee Approval

As per IND-9, the EC review and approval process, which occurs at the same time as the DCGI review and approval, generally takes from four (4) to six (6) weeks. Many study sites also have scientific review committees (SRCs) review the scientific justification of the study. Once the SRC approves the study, it is submitted to the EC for its review and approval.

The G-ICMR indicates that EC members should be given enough time (at least one (1) week) to review the proposal and related documents, except in the case of expedited review. While all EC members should review all submitted proposals, each EC may adopt different procedures for protocol review per their standard operating procedures.

Chapter I (2), Chapter II (3), Chapter V (19-25 and 28), Chapter XIII (100-101), First Schedule (3), Second Schedule (1 and Table 1), Third Schedule (1), and Eighth Schedule (Forms CT-04, CT-4A, and CT-06)
4.1, 4.2, 4.8, and 4.10
5.0, 5.1, 5.2, and Appendix 8.3
Introduction
Clinical Trial of New drugs
10-11, 18, 22, 25, 31-33, 38, and 79
India
Last content review/update: January 19, 2023

Overview

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines.

According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time.

Subpart A (312.1-312.3), Subpart B (312.20-312.23), Subpart C (312.40 and 312.42), and Subpart E (312.85)
Subpart A (56.102)
Subchapter V, Part A, Sec. 355
3.1.2

Clinical Trial Lifecycle > Initiation, Agreements & Registration

Last content review/update: March 24, 2022

Overview

As set forth in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, a clinical trial can only commence in India after the sponsor (applicant) receives permission from the Drugs Controller General of India (DCGI) and approval from the respective ethics committees (ECs). The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations. According to the 2019-CTRules and IND-31, non-regulatory clinical trials intended for academic/research purposes only require institutional EC approval. (See the Scope of Review section for additional details). There is no waiting period required following the sponsor (applicant)’s receipt of these approvals. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

In addition, per the 2019-CTRules and IND-31, the sponsor (applicant) is required to obtain approval from the DCGI to manufacture or import investigational products (IPs) and to obtain an import license for the shipment of IPs to be used in the trial. (See the Manufacturing & Import section for additional information.)

As stated in the 2019-CTRules, all investigators must possess appropriate qualifications, training, and experience, and should conduct the trials in compliance with the Good Clinical Practices (GCPs) and Good Laboratory Practices. (See GCLP for the G-ICMR for Good Clinical Laboratory Practices, IND-31 for additional laboratory requirement information, and IND-40 and IND-30 for international Good Laboratory Practice guidelines.)

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Clinical Trial Notifications

The 2019-CTRules and IND-31 specify that once the sponsor (applicant) obtains approval from CDSCO, he/she must still formally notify the agency via Form CT-4A (see the 2019-CTRules) prior to initiating the clinical trial. The DCGI will then record the information provided on the form and it will become part of the official record known as the automatic approval of the DCGI.

The 2019-CTRules further states that when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

As explained in the 2019-CTRules and IND-31, the EC should notify the DCGI about the academic trials it has approved and about cases where there could be an overlap between the clinical trial for academic and regulatory purposes. If the DCGI does not provide comments to the EC within 30 days from receiving EC notification, then it should be presumed that DCGI permission is not required.

Clinical Trial Agreement

According to the 2019-CTRules, the sponsor must have an agreement with the investigator, which is to be provided to the EC. Furthermore, the investigator must sign an undertaking to conduct the trial in accordance with the protocol, good clinical practice guidelines, and all applicable requirements, among other things. For more details, see Table 4 in the 2019-CTRules.

As per the 2019-CTRules, before the trial begins, the sponsor (applicant) must permit clinical trial site inspections by DCGI authorized officers.

Clinical Trial Registration

Per the 2019-CTRules, the G-ICMR, and IND-31, it is mandatory for all sponsors (applicants) to register their clinical trials, including academic trials, with the Indian Council of Medical Research (ICMR)’s Clinical Trials Registry - India (CTRI) (IND-57) before initiating a study. Refer to the Scope of Review and Submission Process sections for further information on academic trials.

According to IND-56, registrants are advised to factor in a minimum of 10-15 working days for trial review, verification, and validation and the submission must indicate “Not Yet Recruiting” for the trial’s status. A REF number is issued to those registrants who have successfully submitted a trial to CTRI.

In addition, per IND-10, the ICMR has agreed to adopt the United Nation’s recommendations to register and publicly disclose results from all funded or supported clinical trials. The ICMR, along with other participating healthcare bodies, plans to develop and implement policies that require all trials they fund, co-fund, sponsor, or support to be registered in a publicly available registry. All study results will also be released within specified timeframes on the registry or through scientific journal publications.

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements.

Chapter I (2), Chapter II (3), Chapter V (19-22, 25, and 28-29), Chapter VIII (52), Chapter IX (67), First Schedule (3), Second Schedule (1 and Table 4), Third Schedule (1, Table 1 and Table 4), Sixth Schedule, and Eighth Schedule (Forms CT-04, CT-4A, CT-06, CT-10, and CT-16)
7.11 and Annexures I, II, and III
4.1, 4.2, 4.8, and 4.10
4, 11.2, and Annexures I and II
5.0, 5.1, 5.2, and Appendix 8.3
10-11, 23-24, 32-33, 37, 64-67, and 71-75
1 (INDs), 2 (New Drugs), 5 (Test License), and 7 (New Drug Formulation)
Last content review/update: January 19, 2023

Overview

In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.

The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:

  • To conduct the trial in compliance with good clinical practice (GCP), with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC;
  • To comply with procedures for data recording/reporting;
  • To permit monitoring, auditing, and inspection; and
  • To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed.

The sponsor and the investigator/institution must sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA, 42CFR11, and USA-26, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78).

See 42CFR11, the NIHTrialInfo, USA-26, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

At what point is a human subject considered to be “enrolled” in an applicable clinical trial?
Form FDA 1572
1.17, 5.6.3, and 8.2.6
I (1)
Title VIII (Section 801)
113
NIH Policy, Purpose, and Scope
Subpart B (312.20-312.23), Subpart C (312.40), Subpart D (312.53), and Subpart F (312.110)
Subpart A (56.102)
Subparts A, B, and C

Clinical Trial Lifecycle > Safety Reporting

Last content review/update: March 24, 2022

Safety Reporting Definitions

In accordance with the 2019-CTRules, the G-ICMR, and IND-42, the following definitions provide a basis for a common understanding of India’s safety reporting requirements:

  • Adverse Event (AE) – Any untoward medical occurrence (including a symptom/disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a human participant not necessarily related to the treatment
  • Adverse Drug Reaction (ADR) – a noxious and unintended response at doses normally used or tested in humans (in cases of approved pharmaceutical products); a noxious and unintended response at any dose(s) (in cases of new unregistered pharmaceutical products); an untoward medical occurrence seemingly caused by overdosing, abuse/dependence and interactions with other medicinal products (in clinical trials)
  • Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – an AE or ADR that is associated with death, in-patient hospitalization (in case the study was being conducted on outpatients), prolongation of hospitalization (in case the study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening. Per IND-42, Important Medical Events may be considered SAEs when they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one (1) of the outcomes listed in this definition
  • Unexpected Adverse Drug Reaction – an ADR, the nature or severity of which is not described in the informed consent/information sheet or the applicable product information, such as an investigator’s brochure (IB) for the unapproved investigational product (IP) or package insert/summary of product characteristics for an approved product (G-ICMR)

Safety Reporting Requirements

As indicated in the 2019-CTRules, the G-ICMR, and IND-42, the investigator must report all SAEs/SADRs to the Drugs Controller General of India (DCGI), the sponsor or his/her representative, and the ethics committee (EC), within 24 hours of occurrence. Per the 2019-CTRules, in the event that the investigator fails to report any SAE/SADR within the stipulated period, he/she is required to provide reasons for the delay to the DCGI along with the SAE/SADR report for the DCGI’s approval. The sponsor (applicant) and the investigator must forward any SAE/SADR report, after due analysis, within 14 days of the occurrence to the DCGI, the EC Chairman, and the head of the institution where the trial is being conducted. Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.

In addition, per the G-ICMR, the investigator must submit a report to the DCGI on how the SAE/SADR was related to the research within 14 days. According to the 2019-CTRules, the investigator must also promptly report to the EC all changes in the clinical trial activities and all unanticipated problems involving risks to human research participants or others.

In the event of an SAE/SADR resulting in death, per the 2019-CTRules, the sponsor or his/her representative and the investigator must forward his/her SAE/SADR reports to the DCGI within 14 days of knowledge of this occurrence. The 2019-CTRules and IND-42 also indicate that the EC is also required to forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or his/her representative, to the DCGI within 30 days of the incident.

See Table 5 of the 2019-CTRules for details on the data elements required for reporting SAEs/SADRs that occur during a clinical trial.

See the Insurance & Compensation section for additional information on sponsor compensation requirements.

Form Completion & Delivery Requirements

As per Notice25Feb21, the investigator, the sponsor or his/her representative, and the EC must report all SAEs electronically via the SUGAM portal (IND-59). However, follow-up reports pertaining to SAE reports submitted prior to March 14, 2021, will continue to be accepted in paper form. Refer to IND-59 for the SUGAM user manual and video tutorials. See also IND-42 for instructions on how to submit SAE reports (referred to as Due Analysis Reports) via the SUGAM portal (IND-59).

The G-ICMR further states that the investigator may report SAEs/SADRs to the EC through email or fax communication (including on non-working days). Refer to IND-37 for the Indian Council of Medical Research (ICMR)'s EC Serious Adverse Event Reporting Format (Clinical Trials).

Chapter I (2), Chapter V (25), Chapter VI (42), and Third Schedule (2-3 and Tables 4-5)
2.6, 5.3, 7.1, and Glossary
Chapter 8
Last content review/update: January 19, 2023

Safety Reporting Definitions

In accordance with 21CFR312, the G-IND-Safety, 42CFR11, and USA-38, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):

  • Adverse Event (AE) – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
  • Adverse Reaction (AR) – Any AE caused by a drug. ARs are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
  • Serious Adverse Event/Serious Suspected Adverse Reaction (SAE/SSAR) – An AE/SAR that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
  • Suspected Adverse Reaction (SAR) – Any AE where there is a reasonable possibility that the drug caused the AE
  • Unexpected AE/Unexpected SAR – An AE or SAR that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
  • Life-threatening AE/Life-threatening SAR – An AE/SAR is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an AE/SAR that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS) does not define or use the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the G-IRBRpting, the Pre2018-ComRule, and the RevComRule for further information.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-IND-Safety, the investigator must comply with the following reporting requirements:

  • SAEs, whether or not considered drug related, must be reported immediately to the sponsor
  • Study endpoints that are SAEs must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
  • Non-serious AEs must be recorded and reported to the sponsor according to the protocol specified timetable
  • Report promptly to the institutional ethics committee (EC) (institutional review boards (IRBs) in the US) all unanticipated problems involving risk to human participants or others where AEs should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any SAR/AR that is both serious and unexpected. An AE must only be reported as a SAR if there is evidence to suggest a causal relationship between the drug and the AE.

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening SAR as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312 and the G-IND-Safety, the sponsor must also report the following:

  • Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
  • Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
  • Any clinically important increase in the rate of an SSAR over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar SAR and must analyze the significance of the SAR in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.

As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of AE/adverse drug reaction (ADR) information. The tables should consist of the following summarized data:

  • All SAEs/serious adverse drug reactions (SADRs)
  • Other AEs/ADRs that exceed a frequency of five (5) percent in any arm of the trial
  • All-cause mortalities

Per 42CFR11 and USA-70, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov (USA-78) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed AE/ADR reporting requirements.

Form Completion and Delivery Requirements

As per 21CFR312, the G-IND-Safety, and USA-38, the sponsor must submit each safety report in a narrative format on Form FDA 3500A (USA-75), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 (USA-76) (cover sheet).

As per the G-IND-Safety and USA-38, the submission must be identified as follows:

  • “IND safety report” for 15-day reports
  • “7-day IND safety report” for unexpected fatal or life-threatening SAR reports
  • “Follow-up IND safety report” for follow-up information

The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER)). Per USA-38, the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used.

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign SAR reports on CIOMS Form I (See USA-13 and USA-3) instead of Form FDA 3500A (USA-75). See USA-38 and USA-48 for additional information.

MedWatch for Industry FDA Form 3500A pdf (Form FDA 3500A - Mandatory Reporting and Instructions for Completing Form FDA 3500A)
Results Information
III-VIII and Appendix B
Regulatory Background and Guidance (I and II)
Subpart B (312.32) and Subpart D (312.64 and 312.66)
Subparts A (11.10) and Subpart C (11.44 and 11.48)
46.108-46.109, and 46.113
46.109 and 46.113

Clinical Trial Lifecycle > Progress Reporting

Last content review/update: March 24, 2022

As indicated in the 2019-CTRules, investigators and sponsors share responsibility for submitting clinical trial progress reports and final reports upon the trial’s completion.

Interim and Annual Progress Reports

As described in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI) requires the sponsor (applicant) to submit a six (6)-month status report for each clinical trial electronically via the Central Drugs Standard Control Organization (CDSCO)’s SUGAM portal (IND-59). The report should clarify whether the trial is ongoing, completed, or terminated. In the case of termination, detailed reasons for such termination must be communicated to the DCGI within 30 working days of the termination. In addition, per the 2019-CTRules, an ethics committee (EC) may periodically request study progress reports from the investigators.

As delineated in the 2019-CTRules, sponsors are required to submit an annual status report for the clinical trial to the DCGI.

The 2019-CTRules also specifies that in cases where trials have been prematurely discontinued for any reason, including a lack of commercial interest in pursuing the new drug application (NDA), the sponsor (applicant) should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of participants exposed to the drug, dose/duration of exposure, details of adverse drug reactions, if any, and the reason for the study’s discontinuation or non-pursuit of the NDA.

See IND-35 for a Checklist of Notification for Annual Status Report documentation requirements to be included in a global clinical trial application.

Final Report

The final report should comply with the format and content guidelines listed in the 2019-CTRules as follows:

  • Title page
  • Study synopsis (1 to 2 pages)
  • List of abbreviations and definitions
  • Table of contents
  • EC approval letter(s)
  • Study team introduction
  • Study objective
  • Investigational plan
  • Trial participants
  • Efficacy evaluation
  • Safety evaluation
  • Discussion and overall conclusion
  • List of references
  • Appendices

See the 2019-CTRules for more detailed information on preparing the final report.

See also IND-35 for a checklist of documentation requirements to be included in a global clinical trial application pertaining to end of clinical trial notification.

Chapter III (11), Chapter V (25), First Schedule (6), and Third Schedule (3 and Table 6)
36
Checklist of Notification for Annual Status Report; Checklist for Notification for End of GCT
Last content review/update: January 19, 2023

Interim and Annual Progress Reports

As per the US-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

  • Title, purpose, and description of patient population, and current status
  • Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
  • Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
  • Description of the general investigational plan for the coming year
  • Updated investigator’s brochure, if revised
  • Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
  • Brief summary of significant foreign marketing developments with the drug
  • A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:

  • Not less than once every 12 months for updated general trial registration information
  • Not later than 30 calendar days for any changes in overall recruitment status
  • Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Final Report

As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.

Additionally, per 42CFR11 and USA-70, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:

  • Participant flow
  • Demographic and baseline characteristics
  • Outcomes and statistical analysis
  • Adverse events
  • The protocol and statistical analysis plan
  • Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.

Subpart B (312.33) and Subpart D (312.64 and 312.66)
Subpart A (56.108)
Subpart C
NIH Policy and Purpose
4.10 and 4.13
Results Information and Updates and Other Required Information

Sponsorship > Definition of Sponsor

Last content review/update: March 24, 2022

As per the 2019-CTRules and the G-ICMR, a sponsor is defined as an individual, a company, or an institution that takes responsibility for the initiation, management, or financing of a clinical study. The G-ICMR further states that an investigator who independently initiates and takes full responsibility for a trial automatically assumes the role of a sponsor. The 2019-CTRules also indicates that the sponsor may appoint a contract research organization (CRO).

Chapter I (2)
4.0-4.2, 4.8, and 4.10
Last content review/update: January 19, 2023

As per 21CFR312, 21CFR50, and the US-ICH-GCPs, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312, 21CFR50, and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all of his/her obligations to a contract research organization (CRO).

Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs, although a sponsor may transfer all of his/her trial-related duties and functions to a CRO, he/she is ultimately responsible for the study data’s quality and integrity.

As indicated in 21CFR312, a sponsor may be either domestic or foreign.

Subpart A (312.3), Subpart D (312.52), and Subpart F (312.110)
Subpart A (50.3)
1.53, 1.54, and 5.2

Sponsorship > Site/Investigator Selection

Last content review/update: March 24, 2022

Overview

The 2019-CTRules states that the investigator should possess appropriate qualifications, training, and experience and have access to investigational and treatment facilities as relevant to the protocol. Prior to entering into an agreement with the investigator(s)/institution(s) to conduct a study, the sponsor should provide the involved parties with the protocol and an up-to-date investigator’s brochure and allow them sufficient time to review this documentation. The sponsor must also define and allocate all study-related duties and responsibilities to the respective identified person(s) and organization(s) prior to initiating the study.

In addition, per Notice2Dec19, the Central Drugs Standard Control Organization (CDSCO) is preparing a comprehensive database of clinical trial sites and investigators involved in the conduct of global clinical trials in different therapeutic categories by collecting information from various sources. The first phase includes an Excel spreadsheet of sites and investigators involved in global clinical trials (IND-26).

See also IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Foreign Sponsor Responsibilities

No information is currently available on foreign sponsor responsibilities.

Data and Safety Monitoring Board

No information is currently available on data and safety monitoring boards.

Multicenter Studies

As delineated in the G-ICMR, in the case of multicenter research studies, all of the participating study sites are required to obtain approval from their respective ECs. The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and communication issues. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review. Also, see the Scope of Review section for additional details.

Further, per the G-ICMR, if a multicenter trial is going to be conducted, the sponsor may organize a coordinating committee or select coordinating investigators. The sponsor must also conduct training for investigators in ethics, good clinical practices, standard operating procedures (SOPs), and study protocols.

Chapter III (11), Third Schedule (1, 3, and Table 4)
4.2.3, 4.8 (Table 4.2.3), and 4.10
Last content review/update: January 19, 2023

Overview

As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

  • Signed investigator’s statement (Form FDA 1572 (USA-77))
  • Curriculum vitae
  • Clinical protocol
  • Financial disclosure information

As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.

See G-InvstgtrResp for more information on investigator responsibilities.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50 and the G-DMCs, Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by the Department of Health & Human Services (HHS), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed HHS/NIH requirements.

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

In the event of multicenter clinical studies, also known as cooperative research studies, which are required to comply with the RevComRule, all federally-funded or sponsored institutions that are located in the US and engaged in multicenter research must use a single EC to review that study. See the Scope of Review section and G-CoopRes for additional information.

The US-ICH-GCPs indicates that in the event of a multicenter clinical trial, the sponsor must ensure that:

  • All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and given EC approval
  • The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
  • Investigator responsibilities are documented prior to the start of the trial
  • All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
  • Communication among investigators is facilitated

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

Data and Safety Monitoring
Form FDA 1572
1
1.25, 4.1, 5.5.2, 5.6, 5.23, and 8.2.6
I (3)
Subpart D (312.50 and 312.53)
Subpart B (50.24)
46.101, 46.103, 46.111, and 46.114
46.103 and 46.111

Sponsorship > Insurance & Compensation

Last content review/update: March 24, 2022

Insurance

The G-ICMR specifies that the sponsor should provide insurance coverage or a provision in the budget for possible compensation for trial-related injuries. The G-ICMR also states that it is preferable to have the insurance certificate and the policy for study participants. Further, the policy should explain the conditions of coverage, date of commencement, and expiration date for risk coverage (if applicable). In addition, institutional mechanisms must be established to allow for insurance coverage of trial-related or unrelated illnesses (ancillary care).

The 2019-CTRules states that the ethics committee (EC) also requires a copy of the insurance policy or details regarding compensation for participation and for serious adverse events (SAEs) occurring during the study as part of its submission review process. IND-60 provides a table of the different policy types available in India including the no fault compensation, the claims-made policy, and the premium rating policy. Regarding coverage limits, IND-60 further indicates there is no set rule for establishing coverage limits or minimums in India, however, the consensus in the insurance community is that a clinical trials liability policy should carry a minimum limit of $1 million and can have upper limits of $10 million through $20 million or more. See IND-60 for additional information on policy types and coverage limits.

With regard to indemnity coverage, the G-ICMR states that an indemnity policy must be included in the documentation for EC review. The policy should clearly indicate the conditions of coverage, date of commencement, and coverage expiration date, if applicable.

Compensation

Injury or Death

In accordance with the 2019-CTRules and the G-ICMR, the sponsor (applicant), is responsible for providing compensation to research participants and/or their legal heir(s) in the event of trial-related injuries, permanent disability, or death. Per the G-ICMR, in the event the investigator/institution becomes the sponsor in a clinical trial, it is the host institution’s responsibility to provide compensation for research-related injury or harm as determined by the ethics committee (EC).

Per the 2019-CTRules and the G-ICMR, the sponsor (applicant) must also ensure that participants who suffer any trial-related injuries be provided with free medical treatment for such injuries as long as required per the opinion of the investigator (and the EC per the G-ICMR), or until such time it is established that the injury is not related to the clinical trial, whichever is earlier. Per the 2019-CTRules, if the sponsor or his/her representative fails to provide medical management, the Drugs Controller General of India (DCGI), after a hearing, must issue a written order to suspend or cancel the study or restrict the sponsor including his/her representative to conduct any further clinical trial or take any other action for such period deemed appropriate for this case.

The 2019-CTRules further notes that the sponsor (applicant) is responsible for compensating the research participant and/or his/her legal heir(s) if the trial-related injury, death, or permanent disability to a participant is specifically related to any of the following reasons:

  • Adverse effects of an IP
  • Any trial procedures involved in the study
  • A violation of the approved protocol, scientific misconduct, or negligence by the sponsor, his/her representative, or the investigator
  • Failure of the IP to provide the intended therapeutic effect where, the standard care, though available, was not provided to the participant per the protocol
  • Not providing the required standard care, though available to the participant per the protocol in the placebo-controlled trial
  • Adverse effects due to concomitant medication excluding standard care, necessitated as part of the approved protocol
  • Adverse effect on the child in-utero due to a parent’s participation in a trial
  • Any clinical trial procedures involved in the study leading to a serious adverse effect (SAE)/serious adverse drug reaction (SADR)

According to IND-31, compensation and medical management requirements are also applicable in the case of injury or death occurring during an academic trial.

In the case of a trial-related injury, the 2019-CTRules and IND-31 state that the sponsor (applicant) is required to provide complete medical management and compensation to the participant within 30 days of receiving an order from the DCGI. In the event of permanent injury or death, the sponsor (applicant) is required to provide compensation to the participant or to his/her legal representative(s) or guardian(s) within 30 days of receiving the DCGI’s order.

The 2019-CTRules explains that in the case of an SAE resulting in death, the DCGI must constitute an independent expert committee to review the incident and make its recommendations to the DCGI for the cause of death and to provide a quantum of compensation. The sponsor or his/her representative and the investigator must forward their reports, after due analysis, to the DCGI and the head of the institution where the trial was conducted within 14 days of the occurrence. The EC must forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or his/her representative within 30 days of receiving the investigator’s report. The DCGI, in turn, must forward the sponsor, investigator, and EC reports to the expert committee chairperson. Following its review, the expert committee must make its recommendations to the DCGI as to the cause of the SAE resulting in death and the quantum of compensation within 60 days from receiving the DCGI’s submission. The DCGI must then consider the expert committee’s recommendations and issue an order within 90 days to the sponsor or his/her representative specifying the quantum of compensation he/she is required to pay within 30 days of receiving the order.

In the case of an SAE/SADR resulting in permanent disability or any injury other than death, the 2019-CTRules indicates that the sponsor or his/her representative and the investigator must forward their reports, after due analysis, to the DCGI, the EC chairperson, and the head of the institution where the trial has been conducted within 14 days of the occurrence. The EC, after due analysis, must forward its report along with its opinion on financial compensation, if any, to the DCGI within 30 days of the event occurrence. The DCGI, in turn, must determine the cause of the injury and issue an order, with the option to constitute an independent expert committee, within 60 days of receipt of the report. The DCGI must issue an order within 90 days of receiving the report indicating the quantum of compensation to be paid by the sponsor or his/her representative within 30 days of receipt of this order.

In the case of an injury not being permanent in nature, per the 2019-CTRules, compensation should be commensurate with the participant’s loss of wages.

Per the 2019-CTRules, in the event that a sponsor or his/her representative fails to provide compensation to a research participant for trial-related injuries, or to his/her legal heir(s) in case of death, the DCGI must, after giving an opportunity to show cause why such an order should not be passed by a written order, suspend or cancel the clinical trial, or restrict the sponsor or his/her representative from conducting any further clinical trials in India or taking any other action deemed fit given the circumstances.

See the 2019-CTRules and the G-ICMR for detailed information on terms of compensation payment.

Trial Participation

The 2019-CTRules and IND-31 explain that the investigator may recommend the sponsor (applicant) provide post-trial access to the investigational product (IP) free of cost to the participant for such period as deemed necessary by the investigator and the EC. The sponsor must obtain DCGI approval to initiate this plan. The investigator’s recommendation will be based on the following conditions:

  • If the trial is being conducted for an indication for which no alternative therapy is available, and the IP has been determined to be beneficial
  • The participant and/or his/her legal representative(s) or guardian(s) has consented in writing to use the post-trial IP, and has certified and declared in writing, along with the investigator, that the sponsor must have no liability for post-trial use of the IP

See also IND-6 for additional information on post-trial access to IPs under the 2019-CTRules. In addition, the G-ICMR explains that participants may also be compensated for their time and other expenses (e.g., loss of wages, food supplies, and travel). The EC should approve all payments, reimbursement, and medical services provided. Per the G-ICMR, participants should not be required to pay for any expenses incurred beyond routine clinical care and those that are research related including patient work-ups, or interventions associated with treatment, and if applicable, participants may receive additional medical services at no further cost.

Chapter I (2), Chapter V (25 and 27), Chapter VI (39-40, and 42), Third Schedule (3, Table 1 and Table 3), and Seventh Schedule
2.5-2.7, 4.7, 4.8, Box 4.4(A), 7.1, and 7.16
12, 39-41, and 61
Post-Trial Access
Current Scenario of Liability and Indemnity in India and Other Countries
Last content review/update: January 19, 2023

Insurance

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

Injury or Death

According to the US-ICH-GCPs, the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).

As specified in 21CFR50, the Pre2018-ComRule, the RevComRule, and US-ICH-GCPs, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

Subpart B (50.25)
46.116
46.116
I (11)
4.8 and 5.8

Sponsorship > Risk & Quality Management

Last content review/update: March 24, 2022

Quality Assurance/Quality Control

In accordance with the 2019-CTRules and the G-ICMR, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, Good Clinical Practices, and all applicable laws and regulations.

Audit Requirements

As part of its QA system, the 2019-CTRules notes that investigator(s) may provide periodic study progress reports (PSUR), or regulatory officials or sponsor-designated authorized representatives may provide monitoring and internal audit reports to the ethics committee (EC) to support its recurring clinical trial reviews. An audit certificate may be issued, if available.

Furthermore, the 2019-CTRules requires the investigator to sign an undertaking where he/she agrees to maintain adequate and accurate records and to make those records available for audit or inspection by the sponsor, the EC, the Central Licensing Authority, or their authorized representatives, in accordance with regulatory provisions and the Good Clinical Practices (GCPs­) guidelines. The investigator must agree to fully cooperate with any study-related audit conducted by regulatory officials or authorized representatives of the sponsor.

See IND-35 for a checklist of PSUR documentation requirements to be included in a global clinical trial application, and IND-34 for the Drugs Controller General of India’s (DCGI) GCP Inspection Checklist.

Premature Study Termination/Suspension

Per the 2019-CTRules, in case of studies prematurely discontinued for any reason, including lack of commercial interest in pursuing the new drug application, the sponsor should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of patients exposed to the drug, dose and duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuation of the study or non-pursuit of the new drug application.

See IND-35 for a checklist of premature study termination documentation requirements to be included in a global clinical trial application.

Third Schedule
4.2.3, 4.10, and 6.1 (Table 6.1)
Last content review/update: January 19, 2023

Quality Assurance/Quality Control

Per the US-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

  • During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
  • Identify risks to critical trial processes and data
  • Evaluate the identified risks, against existing risk controls
  • Decide which risks to reduce and/or which risks to accept
  • Document quality management activities and communicate to those involved in or affected by these activities
  • Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
  • In the clinical study report, describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the US-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Monitoring Requirements

As part of its QA system, the US-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the US-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

According to the G-RiskMntrng, the FDA encourages sponsors to tailor monitoring plans to the needs of the trial. The agency also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

  • Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
  • Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring, see the G-RiskMntrng.

Premature Study Termination/Suspension

As delineated in 21CFR312 and the US-ICH-GCPs, if the sponsor determines the study presents an unreasonable and significant risk to the participants, he/she must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the Food & Drug Administration (FDA), all ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on his/her actions.

According to the US-ICH-GCPs, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

1.65, 5.0-5.2, 5.5, 5.18-5.19, 5.21, and 6.10
II and III
Subpart C (312.44) and Subpart D (312.56)

Sponsorship > Data & Records Management

Last content review/update: March 24, 2022

Electronic Data Processing System

No information is currently available on electronic data processing systems.

Records Management

Per the 2019-CTRules, the sponsor (applicant) must keep a record of new drugs manufactured and persons to whom the drugs have been supplied for clinical trial or bioavailability and bioequivalence study or for examination, testing, and analysis. In addition, the 2019-CTRules indicates that the licensed applicant must maintain records of any imported new drug or substance that indicates the quantity of drug imported, used, and disposed of in any manner including related documentation.

55 and 70
Last content review/update: January 19, 2023

Electronic Data Processing System

Per the US-ICH-GCPs, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the US-ICH-GCPs for additional information.

See G-eHealthRecords for guidance related to the use of electronic health records in clinical research.

Records Management

As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312, the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

In addition, the US-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Subpart D (312.57-312.58)
5.5 and 8

Sponsorship > Personal Data Protection

Last content review/update: March 24, 2022

Responsible Parties

For the purposes of data protection requirements, the ITAct, the ITActAmend, and the IT-SPDIRules delineate responsibilities of the “body corporate.” The body corporate as defined by the ITAct, the ITActAmend, and the IT-SPDIRules refers to any company including a firm, sole proprietorship, or other association of individuals engaged in commercial or professional activities. The IT-SPDIRules further explains that the body corporate or any person on its behalf is the entity responsible for collecting personal information, including sensitive personal data and information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well).

Data Protection

Data protection in India is currently regulated by the ITAct, the ITActAmend, and the IT-SPDIRules. Per the IT-SPDIRules, the “body corporate,” or any other person on its behalf, responsible for collecting, receiving, possessing, storing, dealing with, or handling provider information must provide a privacy policy for the handling of or dealing with this personal information including sensitive personal data or information. The IT-SPDIRules defines sensitive personal data or information as information relating to password(s); financial information; physical, physiological, and mental health condition(s); sexual orientation; medical records and history; and biometric information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well). The sponsor must ensure that this policy is available for view by the information providers under a lawful contract. The policy must be published on the sponsor’s or its representative’s website and provide the following:

  • Clear and easily accessible statements of its practices and policies
  • The type of personal information including sensitive personal data or information collected
  • The purpose of collection and usage of such information
  • Disclosure of information including sensitive personal data or information
  • Reasonable security practices and procedures

Please refer to the IT-SPDIRules for detailed requirements on implementing security practices and procedures and collecting, disclosing, and transferring sensitive personal data or information.

See also IND-65 for more detailed information on India’s data protection requirements.

Consent for Processing Personal Data

As set forth in the IT-SPDIRules, the body corporate or its representative must obtain consent in writing through letter, fax, or email from the provider of the sensitive personal data or information regarding the purpose of usage before collection of such information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well). The IT-SPDIRules states that while collecting information directly from the information provider, reasonable steps must be taken to ensure that the information provider receives details regarding the following:

  • The fact that the information is being collected
  • The purpose for which the information is being collected
  • The intended recipients of the information; and
  • The name and address of the agency that is collecting the information, and the agency that will retain the information
2 - 5
Chapter IX (43A)
Part II (22)
Last content review/update: January 19, 2023

Responsible Parties

As stated in USA-86, the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87, the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule) and Food & Drug Administration (FDA) (21CFR50 and 21CFR56) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)

Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.

Data Protection

According to the G-CertCnfdntlty, a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.

Consent for Processing Personal Data

Per USA-86, the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:

  • Documented institutional EC or privacy board approval
  • Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
  • Research on protected health information of decedents
  • Limited data sets with a data use agreement
  • Research use/disclosure with individual authorization
  • Accounting for research disclosures

See USA-86 for more information on these circumstances.

Introduction and Scope
Subpart A (160.103)
Subparts A and E

Informed Consent > Documentation Requirements

Last content review/update: March 24, 2022

Obtaining Consent

In all Indian clinical trials, a freely given, written informed consent is required to be obtained from each participant to comply with the requirements set forth in the 2019-CTRules, the G-ICMR, and the G-Children.

As per the 2019-CTRules and the G-ICMR, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) approval for the informed consent form (ICF) and the patient information sheet. This documentation must also be supplied to the Drugs Controller General of India (DCGI), prior to the trial’s initiation. The ICF and patient information sheet are ultimately integrated into one (1) document referred to as the ICF. (See the Required Elements section for details on what should be included in the form.)

The 2019-CTRules, the G-ICMR, and the G-Children, specify that investigator(s) should provide detailed study information to the research participant and/or his/her legal representative(s) or guardian(s). The ICF content should be briefly and clearly presented orally, and in writing, and in a manner that is easy to understand, commensurate with the comprehension level of the participants, and without coercion or unduly influencing a potential participant to enroll in the trial. Per the G-ICMR, the ICF language should not only be scientifically accurate and simple, but should also be sensitive to the participant’s social and cultural background. In addition, the participant and/or his/her legal representative(s) or guardian(s), should be given adequate time to consider whether to participate. The consent should also be given voluntarily and not be obtained under duress or coercion of any sort or by offering any inducements.

The G-ICMR also states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding (e.g., Braille for the visually impaired).

As delineated in the 2019-CTRules, investigator(s) must obtain an audio-video (AV) recording of the informed consent process for vulnerable participants in clinical trials of new chemical entity or new molecular entity, including the procedure of providing information to the participant and his/her understanding of the consent. This AV recording should be retained in the investigator’s files. In cases where clinical trials are conducted on anti-human immunodeficiency virus (HIV) and anti-leprosy drugs, the investigator(s) must only obtain an audio recording of the informed consent process. The investigator(s) is also required to retain the audio recording for his/her records.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Re-Consent

According to the G-ICMR and the G-Children, investigator(s) are required to renew the informed consent of each participant if there are any changes in the ICF related to the study conditions or research procedures, or if new information becomes available during the trial.

Per the G-ICMR and the G-Children, re-consent is applicable in cases in which a participant regains consciousness from an unconscious state and/or recovers his/her mental capacity to understand the research study. If such an event is expected, then procedures to address this circumstance should be explained clearly in the ICF.

The G-ICMR and the G-Children explain that re-consent is required in the following situations:

  • New information pertaining to the study becomes available that has implications for the participant(s) or that changes the benefit and risk ratio
  • A research participant who is unconscious regains consciousness or suffered loss of mental competence and regains the ability to understand the research implications
  • A child becomes an adult during the course of the study, or the legal representative(s) or guardian(s) have changed
  • Research requires a long-term follow up or an extension
  • There is a change in treatment modality, procedures, site visits, data collection methods, or tenure of participation which may impact a participant’s decision to continue in the research
  • There is possibility of identity disclosure through data presentation or photographs (this should be camouflaged adequately) in an upcoming publication
  • Future research may be carried out on stored biological samples if not anonymized

The partner/spouse may also be required to give additional re-consent in some of the above cases.

Language Requirements

As stated in the 2019-CTRules and the G-ICMR, the ICF should be written in English and/or in the vernacular language that the participant is able to understand.

Documenting Consent

The G-ICMR and the G-Children specify that the participant and/or the participant’s legal representative(s) or guardian(s) must sign and date the ICF. If the participant is incapable of giving an informed consent, his/her legal representative(s) or guardian(s) should sign and date the ICF. Where the participant is illiterate, and/or his/her legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Per the G-ICMR, if the participant and/or his/her legal representative(s) or guardian(s) cannot sign, a thumb impression must be obtained. In addition, the investigator(s) who administers the consent should also sign and date the ICF. As stated in the G-ICMR and the G-Children, when written consent as a signature or thumb impression is not possible, verbal consent may be taken with the EC’s approval, in the presence of an impartial witness who should sign and date the consent document, or through an AV recording. Per the G-ICMR, the ICF may also be administered and documented electronically, as long as the EC approves the process first.

As described in the G-ICMR, the following special situations may also arise in administering consent:

  • The gatekeeper’s (a group’s head/leader or the culturally appropriate authorities), may provide permission on the group’s behalf in writing or audio/video recording and be witnessed
  • Community consent is required for certain populations in order for participants to be permitted to participate in the research

According to the G-ICMR and the G-Children, a copy of the signed ICF and the patient information sheet should be given to the participant or his/her legal representative(s) or guardian(s). Per the G-Children, the investigator should also keep a signed copy of the ICF.

Waiver of Consent

As specified in the G-ICMR and the G-Children, the investigator(s) can apply to the EC for a waiver of consent if the research involves less than minimal risk to participants and the waiver will not adversely affect the rights and welfare of the participants. In addition, per the G-ICMR, the EC may grant a waiver of consent in the following situations:

  • Research cannot practically be carried out without the waiver and the waiver is scientifically justified
  • Retrospective studies, where the participants are de-identified or cannot be contacted
  • Research on anonymized biological samples/data
  • Certain types of public health studies/surveillance programs/program evaluation studies
  • Research on data available in the public domain, or
  • Research during humanitarian emergencies and disasters, when the participant may not be in a position to give consent. An attempt should be made to obtain the participant’s consent as soon as possible

The G-Children explains that following EC approval of the protocols listed below, the informed consent requirement for children may be waived:

  • When it is impractical to conduct research since confidentiality of personally identifiable information has to be maintained throughout the study (e.g., a study on the disease/burden of HIV/AIDS)
  • Research is carried out on publicly available information, documents, records, works, performances, reviews, quality assurance studies, archival materials or third-party interviews, etc.
  • Research on anonymized biological samples, leftover samples after clinical investigation/research, cell lines, or cell free derivatives (e.g., viral isolates, DNA or RNA from recognized institutions or qualified investigators, samples or data from repositories or registries, etc.) provided permission for future research on these samples has been taken in the previous ICF
  • In emergency situations when no surrogate consent can be taken
  • Retrospective studies, where the participants are de-identified or cannot be contacted

See the G-ICMR, IND-5, and IND-27 for additional information on informed consent requirements.

Chapter III (11) and Third Schedule (2-3 and Tables 1 and 3)
3.1
7.11 and Annexures I, II, and III
2.2, 4.4, 4.8, 5.0, 5.2-5.4, and 5.8
4, 11.2, and Annexures I and II
5
3-6
Last content review/update: January 19, 2023

Obtaining Consent

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E. The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND). Per the G-RevComRule-FDA, the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved informed consent form used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov (USA-78) and a docket folder on Regulations.gov (USA-79). According to the RevComRule, if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.

According to 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

As indicated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

Additionally, per the RevComRule, participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50, the Pre2018-ComRule, and the RevComRule, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.

See G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.

See USA-54 and USA-60 for additional information regarding informed consent.

Re-Consent

According to 21CFR50, the US-ICH-GCPs, and the G-IRBFAQs, the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.

The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.

Language Requirements

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s). As delineated in the G-ICInfoSheet, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language and at a level they can comprehend. The EC must review and approve all English and non-English language versions of consent documents. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available.

USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-ICInfoSheet and USA-63 for detailed information.

Documenting Consent

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.

Per 21CFR50, the Pre2018-ComRule, and the RevComRule, if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s).

According to the US-ICH-GCPs, where the participant is illiterate and/or the legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

  • The written ICF and any other written information to be provided to the participant is read and explained to the participant and the legal representative(s) and/or guardian(s)
  • The participant and the legal representative(s) and/or guardian(s), have orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Per the US-ICH-GCPs, before participating in the study, the participant or the legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

Waiver of Consent

Per the Pre2018-ComRule and the RevComRule, the EC may waive the requirement to obtain a signed ICF if it finds any of the following:

  • The ICF would risk a breach of confidentiality by linking the participant to the study
  • The research presents minimal risk and involves no procedures for which written consent is required outside of the study

The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.

The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s) and/or guardian(s) with a written statement regarding the research.

In addition, the Pre2018-ComRule states that for an EC to approve a general waiver or alteration of consent, the EC must find that:

  • The research involves no more than minimal risk
  • The research could not practicably be carried out without the requested waiver or alteration
  • If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
  • The waiver or alteration will not adversely affect the rights and welfare of the participants
  • Whenever appropriate, the participant or the legal representative(s) and/or guardian(s) will be provided with additional pertinent information after participation

Per G-MinRiskWaiver, the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.

Furthermore, the Pre2018-ComRule, the RevComRule, and G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.

Subpart B (50.20, 50.25, and 50.27)
Subparts B-D
Non-English Speaking Subjects
V (45)
III
46.116 and 46.117
46.116 and 46.117
IV
2.9, 4.8, 8.2, and 8.3
Broad Consent in the Revised Common Rule and Informed Consent

Informed Consent > Required Elements

Last content review/update: March 24, 2022

Per the 2019-CTRules, the G-ICMR, and the G-Children, the ICF should include the following statements or descriptions, as applicable (Note: The regulatory sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.) :

  • The study involves research and an explanation of its nature and purpose
  • The expected duration of the participant's participation
  • Any benefits reasonably expected from the research to the participant or others; if no benefit is expected, the participant should be made aware of this
  • The disclosure of specific appropriate alternative procedures or therapies available to the participant
  • The mechanism by which confidentiality of records identifying the participant will be maintained and who will have access to the participant’s medical records
  • An explanation about whom to contact for trial-related queries, participant rights, and in the event of any injury
  • The policy on compensation and/or medical treatment(s) available to the participant in the event of a trial-related injury, disability, or death
  • Participation is voluntary, the participant can withdraw from the study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled
  • Any reasonably foreseeable risks or discomforts to the participant resulting from his/her participation
  • Approximate number of participants enrolled in the study

Additional requirements listed in the G-ICMR and the G-Children include:

  • Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research (e.g., storage period of sample/data; probability of material being used for secondary purposes; whether material is to be shared with others; participant’s right to prevent use of his/her biological sample(s) at any time during or after the study; risk of discovery of biologically sensitive information and provisions to safeguard confidentiality)
  • Publication, if any, including photographs and pedigree charts
  • Payment/reimbursement for participation and incidental expenses depending on the type of study
  • Insurance coverage, if any, for research-related or other adverse events
  • If there is a possibility that the research could lead to any stigmatizing condition (e.g., HIV and genetic disorders, provision for pre-test and post-test counseling)
  • Post-research plan/benefit sharing for biological material research and/or if data leads to commercialization

Additional requirements listed in the 2019-CTRules include:

  • The procedures to be followed, including all invasive procedures
  • The investigational product (IP) may fail to achieve the intended therapeutic effect
  • In the case of a placebo-controlled trial, the placebo administered to the participant(s) must not have any therapeutic effect
  • The anticipated prorated payment, if any, to the participant for participating in the trial
  • The participant’s responsibilities in participating in the trial
  • Foreseeable circumstances under which the investigator(s) may remove the participant without his/her consent
  • The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
  • The participant and/or his/her legal representative(s) or guardian(s) will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue
  • The particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant), which are currently unforeseeable
  • Additional costs to the participant that may result from participating in the study
  • Any other pertinent information
  • Clinical trial treatment schedule(s) and the probability for random assignment to each treatment

See the Vulnerable Populations and Consent for Specimen sections for further information.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Second Schedule (1) and Third Schedule (2-3 and Tables 1 and 3-4)
3.1
7.11 and Annexures I, II, and III
2.2, 5.0-5.3, and 6.11
4, 11.2, and Annexures I and II
Last content review/update: January 19, 2023

Based on 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • The study purpose, procedures, and expected duration of the trial
  • Identification of any experimental procedures
  • Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
  • Any expected benefits to the participant
  • Disclosure of appropriate alternative procedures that might be advantageous to the participant
  • Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
  • Compensation and/or treatment available for the participant in the case of trial-related injury
  • Contact information for relevant individuals to contact in the event of a trial-related injury
  • That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of benefits to which he/she is otherwise entitled
  • Foreseeable circumstances under which the investigator may remove the participant without consent
  • Any expenses the participant needs to pay to participate in the trial
  • The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
  • Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
  • Approximate number of participants in the study

As per 21CFR50, for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

The RevComRule also requires the following statements to be included in the ICF:

  • Whether research results will be disclosed to participants
  • Whether or not the participant’s information or biospecimens will be used or distributed for future research
  • That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
  • Whether biospecimens research may include whole genome sequencing

Compensation Disclosure

The G-ICInfoSheet further states that when no system has been established to provide funds for compensation in case of injury, the preferred wording for the consent document is: “no funds have been set aside for” “[the cost] will be billed to you or your insurance,” or similar wording that explains the provisions or the process.

Subpart B (50.25)
46.116
46.116
4.8
Compensation v. Waiver of Subject's Rights

Informed Consent > Participant Rights

Last content review/update: March 24, 2022

Overview

In accordance with the 2019-CTRules and the G-ICMR, India’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-ICMR upholds the Declaration of Helsinki (IND-63). The 2019-CTRules, the G-ICMR, and the G-Children state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As stated in the 2019-CTRules, the G-ICMR, and the G-Children, the participant and/or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, he/she may withdraw from the research study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

Per the IT-SPDIRules, within the context of data protection legislation, the “body corporate” or its representative, must provide an option to the information provider to withhold his/her requested data or information prior to the collection of information including sensitive personal data or information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well). The information provider must, at any time, have the option to withdraw its consent given earlier to the sponsor or its representative. This withdrawal of consent must be sent in writing.

The Right to Information

As per the 2019-CTRules, the G-ICMR, and the G-Children, a potential research participant and/or his/her legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As described in the 2019-CTRules, the G-ICMR, and the G-Children, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The 2019-CTRules also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

The 2019-CTRules, the G-ICMR, and the G-Children state that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the investigator(s) and the ethics committee (EC) to address trial-related inquiries and/or to appeal against a violation of his/her rights.

The Right to Safety and Welfare

The G-ICMR clearly states that a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

See the G-ICMR and IND-27 for additional information on informed consent requirements.

Refer to the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

Chapter III (7 and 11), Chapter V (28) and Third Schedule (3)
3.1
1.0, 1.1, 2.2, 2.3, 4.0, 5.0-5.2, and 7.1
5
1 and 5
Last content review/update: January 19, 2023

Overview

In accordance with 21CFR50, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential participant and/or a legal representative(s) or guardian(s) must be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential research participant, and/or a legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information.

See G-eHealthRecords for guidance related to the use of electronic health records in clinical research.

The Right of Inquiry/Appeal

21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the research participant, and/or a legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The US-ICH-GCPs clearly states that a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

Subpart A (312.3)
Subpart A (50.1) and Subpart B (50.25)
46.103, 46.109, 46.116, and 46.117
46.116
Introduction, 1.27, 2.2, 2.3, 3.1, and 4.8
Informed Consent

Informed Consent > Emergencies

Last content review/update: March 24, 2022

The G-ICMR, and the G-Children make provisions to protect the rights of a research participant during the informed consent process when special circumstances complicate the procedure. The G-ICMR also upholds the Declaration of Helsinki (IND-63).

Emergencies

Per the G-Children, research involving children in emergency situations should only be carried out when it is scientifically justified and cannot be conducted outside this setting. The ethics committee(s) (EC) should review and approve these studies as well as the proposed timeframe in which formal consent will be obtained. If consent cannot be obtained in an emergency situation, deferred consent is suggested. Deferred consent involves giving minimum information verbally, followed by full details and formal consent later. If the legal representative(s) or guardian(s) are unavailable or unable to give consent, another individual, such as the participant’s doctor or a person nominated by the healthcare provider, can give consent. However, the doctor or a person nominated by the healthcare provider may not be involved in the research. It is recommended that a Data Safety Monitoring Board (DSMB) be strongly considered for these types of studies. See the Children/Minors section for additional pediatric informed consent requirements.

Moreover, per the G-Children, if a child’s legal representative(s) or guardian(s) refuses to give consent once their child is stabilized, he/she should not be included in the research, and no further research related procedures/data collection should be done. Additionally, the previously collected data obtained prior to the consent process should not be used without the legal representative(s)’s or guardian(s)’s permission.

See also IND-5 for additional information on consent requirements during medical emergencies.

3.1 and 6.5
Box 5.2, and 5.7-5.8
12
Last content review/update: January 19, 2023

21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmergencyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.

Medical Emergencies

As per the US-ICH-GCPs, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or a legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product (IP) could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) must approve the protocol in advance. The participant and/or the legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.

21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:

  • The participant is confronted by a life-threatening situation
  • Informed consent cannot be obtained due to an inability to communicate with the participant
  • Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
  • No alternative methods of approved or generally recognized therapy are available

Per 21CFR50 and the G-EmrgncyUse, if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50, 21CFR56, and the G-EmrgncyUse, the investigator must also notify the EC within five (5) working days.

21CFR56, the G-EmrgncyUse, and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.

Emergency Research

The G-ICEmergencyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.

21CFR50 and the G-ICEmergencyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:

  • The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
  • Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
  • Participation in the research holds out the prospect of direct benefit to the participants
  • The clinical investigation could not practicably be carried out without the waiver
  • The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
  • The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
  • Additional protections of the rights and welfare of the participants will be provided

See 21CFR50 and the G-ICEmergencyReqs for more details.

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance.

Military Operations

21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

1107
Subpart B (50.23 and 50.24)
Subpart A (56.102 and 56.104)
II (20), V (44), and Appendix B
III (18)
46.101(i)
4.8
Is it possible to obtain legally effective informed consent to research in an urgent or emergency care setting? and Is it possible to waive the informed consent requirement when conducting research in an emergency setting?

Informed Consent > Vulnerable Populations

Last content review/update: March 24, 2022

Overview

As set forth in the 2019-CTRules and the G-ICMR, in all clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The G-ICMR further describes vulnerable groups and individuals as those who may have an increased likelihood of incurring additional harm, as they may be relatively (or absolutely) incapable of protecting their own interests. According to the G-ICMR, vulnerable populations are characterized as individuals/communities with hierarchical relationships (e.g., prisoners, armed forces personnel, or staff and students at medical, nursing, or pharmacy academic institutions); economically and socially disadvantaged individuals (e.g., persons who are unemployed, abandoned, orphans, have language barriers, or cultural differences); persons below the poverty line; ethnic, religious, or sexual minority groups; tribal and marginalized communities; terminally ill patients or those suffering from stigmatizing or rare diseases; patients in emergency situations; institutionalized persons; homeless persons, nomads, or refugees; minors; women in special situations (e.g., pregnant or lactating women, those with poor decision-making powers, or poor access to healthcare); those with mental illness and cognitively impaired, differently abled, or mentally or physically disabled; or others incapable of personally giving consent.

See the G-ICMR for detailed safeguards that must be complied with when trials involving vulnerable populations are conducted. The G-ICMR also describes research principles that must be upheld during these trials and upholds the Declaration of Helsinki (IND-63).

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations. See also IND-5 for additional information on consent requirements for vulnerable populations.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

Terminally Ill Patients

Per the G-ICMR, terminally ill patients or patients seeking new treatments are vulnerable as they are ready to give consent for any intervention that could help them. The EC should carefully review protocols and recruitment procedures for these studies and comply with the following requirements:

  • Additional monitoring should be done to detect any adverse event as soon as possible
  • A benefit-risk assessment should be performed that considers the potential participant’s perception of benefits and risks
  • Post-trial access to the medication

Indigenous People

The G-ICMR states that research on tribal populations should only be conducted if it is of a specific therapeutic, diagnostic, and preventative nature with appropriate benefits to the tribal population. A competent administrative authority’s approval, such as the tribal welfare commissioner or the district collector, should be obtained prior to an investigator entering the area. Whenever possible, it is desirable to seek the help of government functionaries/local bodies or registered, non-governmental organizations who work closely with the tribal groups and have their confidence. The tribal leader, or other culturally appropriate authority may serve as the gatekeeper from whom permission to enter and interact should be obtained. A participant’s consent should be taken along as well as consulting with community elders and individuals who know the local language/dialect of the tribal population, and in the presence of appropriate witnesses. Additional precautions should be taken to avoid including children, pregnant women, and elderly people belonging to particularly vulnerable tribal groups. Benefit sharing with the tribal group should also be ensured for any research done using tribal knowledge that may have the potential for commercialization.

The Elderly

Permission to conduct clinical trials in geriatric patients must comply with the requirements listed in the Required Elements section. According to 2019-CTRules, geriatric patients should be included in Phase II and Phase III clinical trials at the sponsor’s recommendation, in the following circumstances:

  • The disease intended to be treated is typically a disease of aging
  • The population to be treated is known to include substantial numbers of geriatric patients
  • There is specific reason to expect that conditions common in the elderly are likely to be encountered
  • The new drug is likely to alter the geriatric patient’s response (with regard to safety or efficacy) compared with that of the non-geriatric patient

Persons in Dependent Groups

As indicated in the G-ICMR, while reviewing protocols involving participants who are engaged in subordinate or dependent relationships, the ethics committee (EC) must ensure the following:

  • Participant enrollment is specifically relevant to the research questions and is not merely a matter of convenience
  • Extra efforts are required to ensure the autonomy of these individuals is respected, and that they are able to freely decide to participate or deny consent and/or later withdraw from the study without fear of any negative repercussions on their care
  • Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol

Sexual Minorities and Sex Workers

Per the G-ICMR, sexual minorities and sex workers require additional protections as they are more vulnerable to privacy, confidentiality, stigma, discrimination, and exploitation issues during a research study. Research proposals should ensure the dignity of these participants is protected and that they have access to quality healthcare. Investigators should consult the community, if possible, prior to the proposal being finalized. It is also advised that a representative of the sexual minority group/lesbian/gay/bisexual and transgender (LGBT) community attend the ethics committee meeting as a special invitee/member.

First Schedule (3) and Third Schedule (3)
7.11 and Annexures I, II, and III
1.1, 2.9, 6.0-6.2, 6.6-6.7, and 6.9-6.10
4, 11.2, and Annexures I and II
1, 2, and 6
Last content review/update: January 19, 2023

Overview

As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants.

21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs, other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations.

The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

For more guidance documents related to vulnerable populations, see USA-64.

See the Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these vulnerable populations.

Subpart C (56.111)
46.107 and 46.111
46.111
1.61 and 3.1

Informed Consent > Children/Minors

Last content review/update: March 24, 2022

As per the G-ICMR, children are individuals who have not obtained the legal age of consent, which is 18.

As stated in the G-ICMR, the 2019-CTRules, and the G-Children, in the case of pediatric clinical trials, the participants are legally unable to provide written informed consent, and are dependent on their legal representative(s) or guardian(s) to assume responsibility for their participation in a research study.

However, as specified in the 2019-CTRules, all pediatric participants should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the informed consent form (ICF). In these studies, the following requirements should be complied with:

  • Written informed consent should be obtained from the legal representative(s) or guardian(s); however, all pediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand
  • Where appropriate, pediatric participants should additionally provide their assent to enroll in the study, and mature minors and adolescents should personally sign and date a separately designed written assent form
  • Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the investigator’s and legal representative(s)’s or guardian(s)’s opinion, a pediatric patient’s welfare would be jeopardized by his/her failing to participate in the study. In this situation, continued legal representative(s) or guardian(s) consent should be sufficient to allow participation in the study

The 2019-CTRules further specifies requirements for pediatric studies involving new drugs. These studies must take into account the following issues:

  • The timing of new drug pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments
  • If the new drug is for diseases predominantly or exclusively affecting pediatric patients, clinical trial data should be generated in the pediatric population except for initial safety and tolerability data, which will usually be obtained in adults, unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk
  • If the new drug is intended to treat serious or life-threatening diseases, occurring in both adults and pediatric patients, for which there are currently no or limited therapeutic options, the pediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit; in circumstances where this is not possible, lack of data should be justified in detail
  • If the new drug has a potential for use in pediatric patients, pediatric studies should be conducted
  • Pediatric studies should include clinical trials, relative bioequivalence comparisons between pediatric and adult formulations, and pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used
  • If the new drug is a major therapeutic advance for the pediatric population, studies should begin early in the drug development, and this data should be submitted with the new drug application

The reviewing ethics committee (EC) should also include members who are knowledgeable about pediatric, ethical, clinical, and psychosocial issues.

Refer to the 2019-CTRules for detailed pediatric study requirements.

Per the G-ICMR, the EC should also perform a benefit-risk assessment to determine whether there is a need to implement additional safeguards/protections to conduct a study involving children. The EC should consider the circumstances of the children to be enrolled in the study including their age, health status, and other factors and potential benefits to other children with the same disease or condition, or to society as a whole. In addition, the G-Children should be consulted for detailed EC assessment criteria to be used to evaluate research studies involving children.

Assent Requirements

As delineated in the G-ICMR, the 2019-CTRules, and the G-Children, if the pediatric participant has the capacity for assent, his/her affirmative assent is required to participate in a study according to their developmental level and decision-making capacity. Per the 2019-CTRules, mature minors and adolescents should personally sign and date a separately designed written assent form. According to the G-ICMR, mature minors are those from age seven (7) up to age 18.

The G-Children also explains that in addition to the children’s developmental level and capability of understanding, the assent process and form should also take into account their age, maturity, reading level, independence, autonomy as well as cultural and social factors. For children between ages seven (7) and 11, oral assent must be obtained in the presence of their legal representative(s) or guardian(s). For children between ages 12 and 18, written assent must be obtained.

A child’s dissent or refusal to participate must always be respected, and he/she must be informed in an understandable manner that he/she may withdraw his/her assent at any time during the study. The EC may also issue a waiver of assent in the following circumstances:

  • If the research has the potential to directly benefit the child, and this benefit is only available through this study
  • If the research involves children with intellectual and other developmental disabilities, they may not have the developmental level and intellectual capability to give assent

For details and guidance on preparing and using an assent form, see the G-Children.

First Schedule (3) and Third Schedule (2)
1.5, 2, 3.1-3.3, 4.1, and 6.1
6.5
Last content review/update: January 19, 2023

As set forth in 21CFR50 and 45CFR46-B-E, children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).

Per the Pre2018-ComRule and the RevComRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare.

As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).

For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:

  • The risk is justified by the anticipated benefit to the child
  • The anticipated benefit is greater than or equal to the available alternative approaches
  • Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians

For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:

  • The risk is slightly greater than minimal
  • The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
  • Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E, a study may only be conducted if the following applies:

  • The ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
  • The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)

Per the RevComRule, certain exemptions may apply to observational research involving children. See the RevComRule for details.

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60.

Assent Requirements

Per 21CFR50 and 45CFR46-B-E, when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:

  • The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
  • The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation

Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:

  • Trial involves no more than minimal risk
  • The waiver will not negatively affect the rights and welfare of the children/minors
  • The trial could not be implemented without the waiver
  • The children/minors will be given additional information after participation, whenever appropriate

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented.

21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

  • When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
  • Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable

Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.

Subpart A (50.3) and Subpart D
Subpart D
46.111
46.104 and 46.111
4.8.12
5, Appendix B, and Table B.2
How can the consent and parental permission processes be designed to facilitate understanding?; Can an electronic signature be used to document consent or parental permission?; Is a faxed copy of the signed consent or parental permission form acceptable to document informed consent?; Who must sign the informed consent or parental permission document?

Informed Consent > Pregnant Women, Fetuses & Neonates

Last content review/update: March 24, 2022

As per the 2019-CTRules and the G-ICMR, clinical studies involving pregnant or nursing women and fetuses require additional safeguards to ensure that the research assesses the risks to the women and the fetuses. The following conditions are required for research to be conducted involving pregnant or nursing women or fetuses.

Per the 2019-CTRules:

  • Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant or nursing women, fetuses, or nursing infants, and where the data generated from women who are not pregnant or nursing is unsuitable

Per the G-ICMR:

  • For studies related to pregnancy termination, only pregnant women who undergo Medical Termination of Pregnancy as per the Medical Termination of Pregnancy Act, 1971 can be included
  • The research should carry no more than minimal risk to the fetus or nursing infant and the research objective is to obtain new knowledge about the fetus, pregnancy, and lactation
  • Clinical trials involving pregnant or nursing women would be justified to ensure that these women are not deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines, or other agents that promise therapeutic or preventive benefits
  • Research related to prenatal diagnostic techniques in pregnant women should be limited to detecting fetal abnormalities or genetic disorders as per the Pre-Conception and Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994, amended in 2003, and not used to determine the sex of the fetus
  • Researchers must provide the ethics committee (EC) with proper justification for including pregnant and nursing women in trials designed to address the health needs of such women or their fetuses or nursing infants
  • If women of reproductive age are to be recruited, they should be informed of the potential risk to the fetus if they become pregnant, be asked to use an effective contraceptive method, and be told about the options available in case of failure of contraception
  • A woman who becomes pregnant must not automatically be removed from the study when there is no evidence showing potential harm to the fetus. The matter should be carefully reviewed, and she must be offered the option to withdraw or continue
  • If the female sexual partner of a male participant gets pregnant during his research participation, the EC should review the protocol and informed consent form (ICF) to determine if a plan exists to document this event, and both the pregnant partner and fetus must also be followed for the outcome and reported in the study results
  • Pregnant women have the right to participate in clinical research relevant to their healthcare needs (e.g., gestational diabetes, pregnancy-induced hypertension, and HIV)
  • Benefit-risk assessment must be done at all stages for both the mother and the fetus
  • Research involving pregnant women and fetuses must only take place when the objective is to obtain new knowledge directly relevant to the fetus, the pregnancy, or lactation
  • Women should not be encouraged to discontinue nursing for the sake of participation in research except in those studies where breastfeeding is harmful to the infant
  • Appropriate studies on animals and non-pregnant individuals should have been completed, if applicable
  • Researchers should not participate in decision-making regarding any termination of a pregnancy
  • No procedural changes, which will cause greater than minimal risk to the woman or fetus, will be introduced into the procedure for terminating the pregnancy solely in the interest of the trial
  • When research is planned on sensitive topics (e.g., domestic violence, genetic disorders, and/or rape) confidentiality should be strictly maintained and privacy protected

Fetuses and Neonates

As described in the G-Children, study protocols involving neonates should take into consideration that this group is the most vulnerable within the pediatric population in terms of the risk of long-term effects of interventions, including developmental effects. ECs reviewing such proposed protocols should have an advisory member with expertise in neonatal research/care. ECs should scrutinize all proposed research for potential risks and weigh them against the possible benefits and ensure a competent person(s) conducts a proper scientific review of the protocol. In addition, when possible, older children should be studied before conducting studies in younger children and infants.

The consent of one (1) parent is also required for neonate studies where research exposes them to no or minimal risk, or in studies that offer the prospect of direct benefit to the participant. However, for studies that do not offer the prospect of direct benefit or are high-risk, consent from both parents is required. Exceptions to this requirement include the following:

  • Only one (1) parent has legal responsibility for the care and custody of the child
  • One (1) parent is deceased, unknown, incompetent, or not available. In such cases, it is the duty of the investigators to provide adequate justification.

If one (1) of the parents is a minor, then consent should not be taken from her/him. If both parents are minors, then enrollment of such a baby should be avoided as much as possible. Investigator(s) should provide adequate justification to the EC to enroll such neonates for research. A legally acceptable representative should provide an informed consent in such situations.

First Schedule (3)
6.1
6.4 and 7.18
Last content review/update: January 19, 2023

As per 21CFR50 and 45CFR46-B-E, for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs, the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

Per the Pre2018-ComRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare.

All Department of Health & Human Services (HHS)-sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E.

Per the RevComRule, all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details.

Pregnant Women and Fetuses

As per 45CFR46-B-E, pregnant women and fetuses may participate in research if all of the following criteria are met:

  • Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
  • Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
  • Least possible risk involved for achieving the research objectives
  • Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
  • Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
  • All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
  • No inducements will be offered to terminate a pregnancy
  • Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
  • Participants will not be involved in determining the viability of a neonate

Neonates

45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:

  • Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
  • All individuals providing consent are fully informed about the foreseeable impact on the neonate

Neonates of uncertain viability may not be involved in research unless the ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:

  • Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
  • The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
  • Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.

Nonviable neonates may not be involved in research unless the following additional conditions are met:

  • Vital functions will not be maintained artificially
  • Research will not terminate the heartbeat or respiration
  • The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
  • Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.

Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E.

Subpart B (50.25)
Subparts B and D
46.111
46.104
4.8.10

Informed Consent > Prisoners

Last content review/update: March 24, 2022

As noted in the G-ICMR, prisoners are included in the description of vulnerable populations due to their diminished autonomy caused by dependency or being under a hierarchical system.

The G-ICMR specifies that during the review process, the ethics committee (EC) must ensure compliance with the following:

  • Enrolling participants is specifically pertinent to the research questions and is not merely a matter of convenience
  • Extra efforts are made to respect the autonomy of these individuals because they are in a hierarchical position and may not be in a position to disagree to participate for fear of authority
  • It is possible for the participant to deny consent and/or later withdraw from the study without any negative repercussions on her/his care
  • Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol
6.9
Last content review/update: January 19, 2023

21CFR56, 45CFR46-B-E, and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E, a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare.

45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:

  • The institution conducting the research has certified to the HHS Secretary that the research has been approved by the ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
  • Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research

Per the RevComRule, none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners.

See USA-62 for more information on prisoner research.

As per 45CFR46-B-E, ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:

  • The research under review represents one (1) of the permissible categories of research delineated in Subpart C
  • The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
  • Research risks are commensurate with those that would be accepted by non-prisoner volunteers
  • Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
  • Information is presented in a language understandable to the prisoner population
  • Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
  • As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact

See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.

Subpart C (56.111)
Subpart C
46.111
46.104 and 46.111
1.61

Informed Consent > Mentally Impaired

Last content review/update: March 24, 2022

The G-ICMR states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding. The G-ICMR also states that the presence of a mental disorder is not synonymous with incapacity of understanding or inability to provide informed consent. However, ethics committees (ECs) have special responsibilities when research is conducted on participants who are suffering from mental illness and/or cognitive impairment. ECs should exercise caution and require researchers to justify exceptions and their need to depart from the guidelines governing research. ECs should ensure that these exceptions are as minimal as possible and are clearly spelled out in the informed consent form. The G-ICMR also upholds the Declaration of Helsinki (IND-63).

As set forth in the MHA2017, every person, including a person with mental illness, must be deemed to have the capacity to make decisions regarding his/her mental healthcare or treatment providing he/she has the ability to engage in the following:

  • Understand the information that is relevant to make a decision on treatment, admission, or personal assistance
  • Appreciate any reasonably foreseeable consequence of a decision or lack of decision on the treatment, admission, or personal assistance, or
  • Communicate the decision by means of speech, expression, gesture, or any other means

Per MHA2017, information must be provided to a person with mental illness using simple and understandable language, sign language, visual aids, or any other means to enable him/her to understand the information. In the case in which a person makes a decision regarding his/her mental healthcare or treatment that is perceived by others as inappropriate or wrong, that by itself, must not be interpreted as the person not having the capacity to make such a decision, as long as the person has the capacity to meet the above stated requirements.

MHA2017 further delineates that every person with mental illness who is not a minor must have the right to appoint a nominated representative. The nomination must be made in writing on plain paper with the person’s signature or thumb impression. The person appointed as nominated representative must not be a minor, be competent to discharge the duties or perform the functions assigned to him/her under the MHA2017, and give his/her consent in writing to the mental health professional to discharge his/her duties and perform the functions assigned to him/her. A person who has appointed an individual as his/her nominated representative may revoke or alter the appointment at any time. The appointment of a nominated representative, or the inability of a person with mental illness to appoint a nominated representative, must not be construed as the lack of capacity of the person to make decisions about his/her mental healthcare or treatment. All persons with mental illness must have the capacity to make mental healthcare or treatment decisions but may require varying levels of support from their nominated representative to make decisions. When fulfilling his/her responsibilities, the nominated representative must have the right to give or withhold consent for research under circumstances.

Pursuant to MHA2017, professionals conducting research must obtain free and informed consent from all persons with mental illness for participation in any research that involves interviewing the person, or any research that involves psychological, physical, chemical, or medicinal interventions. In the case of research involving psychological, physical, chemical, or medicinal interventions to be conducted on a person who is unable to give free and informed consent, but does not resist participation in such research, permission to conduct such research must be obtained from the concerned State Authority. The State Authority may allow the research to proceed based on informed consent being obtained from the person’s nominated representative if the State Authority is satisfied that the following criteria are met:

  • The proposed research cannot be performed on persons who are capable of giving free and informed consent
  • The proposed research is necessary to promote the mental health of the population represented by the person
  • The purpose of the proposed research is to obtain knowledge relevant to the particular mental health needs of persons with mental illness
  • A full disclosure of the interests of the persons and organisations conducting the proposed research is made and there is no conflict of interest involved, and,
  • The proposed research follows all the national and international guidelines and regulations concerning the conduct of such research, and ethical approval has been obtained from the institutional EC where such research is to be conducted

A research-based study of the case notes of a person who is unable to give informed consent will be permitted so long as the anonymity of the person is secured. In addition, the person with mental illness or his/her nominated representative who gives informed consent for participation in any research under MHA2017 may withdraw consent at any time during the research period.

Third Schedule (2)
5.3-5.4, 6.3, 6.5, and 6.8
Chapter I (Section 4), Chapter IV (Sections 14 and 17), and Chapter XI (Section 99)
Last content review/update: January 19, 2023

In accordance with 21CFR56, the Pre2018-ComRule, and the US-ICH-GCPs, an ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent.

Per the Pre2018-ComRule and the RevComRule, this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence.

USA-60 further indicates that while the regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

Subpart C (56.111)
46.111
46.111
1.61
What should be considered in seeking informed consent from individuals with diminished decision-making capacity?

Investigational Products > Definition of Investigational Product

Last content review/update: March 24, 2022

As delineated in the 2019-CTRules, an investigational product (IP) is defined as the pharmaceutical formulation of an active ingredient or a placebo (including the comparator product) being tested or used as a reference in a clinical trial.

The 2019-CTRules further defines an investigational new drug as a new chemical or biological entity or a product having a therapeutic indication, but which has never been tested before on human participants.

Chapter I (2)
Last content review/update: January 19, 2023

As delineated in 21CFR312, an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.

Additionally, the US-ICH-GCPs defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Subpart A (312.3)
1.33

Investigational Products > Manufacturing & Import

Last content review/update: March 24, 2022

Overview

As specified in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI) is responsible for authorizing the manufacture or import of investigational products (IPs) in India. The DCGI approves the manufacture or import of IPs as part of the clinical trial application review and approval process.

The 2019-CTRules explains that applicants must apply to the DCGI using Form CT-10 to obtain permission to manufacture an IP for clinical trial purposes. After reviewing Form CT-10 and any supplemental information, the DCGI will either grant permission to manufacture the IP via Form CT-11 or reject the application, for reasons to be recorded in writing, within 90 working days from the date of application receipt. If applicable, the DCGI must inform the applicant of deficiencies in the application within 90 working days. If the applicant chooses to rectify the deficiencies within the specified period and provide the required information and documents, the DCGI must review the application again. Based on the review, the DCGI will either grant manufacturing permission to the applicant or reject the application within a period of 90 working days from the date the required information and documents were provided. In the case of rejection, the applicant may request the DCGI reconsider the application within a period of 60 working days from the rejection date along with payment of the specified fees in the 2019-CTRules and submission of the required information and documents. Refer to the 2019-CTRules for additional timeline information and the applicable forms.

Applicants who intend to manufacture an unapproved active pharmaceutical ingredient (API) to develop a pharmaceutical formulation for clinical trial purposes should submit to the DCGI either Form CT-12, if applying as a pharmaceutical formulation manufacturer, or Form CT-13, if applying as an API manufacturer, and any supplemental information. After reviewing the submission and conducting further inquiry, if needed, the DCGI will grant permission to the applicant to manufacture the unapproved API in Form CT-15 and permission to the manufacturer of the pharmaceutical formulation in Form CT-14 within 90 working days. If dissatisfied, the DCGI will reject the application, for reasons to be recorded in writing, within a period of 90 working days from the application submission date. Refer to the 2019-CTRules for additional timeline information and the applicable forms.

In addition, Notice18Feb20 clarifies information provided in IND-31 concerning where applications should be sent to obtain permission to manufacture trial batches of new drugs or IPs for testing and analysis, clinical trials, or bioavailability and bioequivalence (BA/BE) studies. For biological drugs, applications should be sent to CDSCO Headquarters (HQ) at FDA Bhavan, New Delhi; for drugs other than biologicals, applications should be sent to the appropriate zonal office/sub-zonal office for pure chemical testing, and the zonal office/sub-zonal office or CDSCO HQ for clinical trials or BA/BE studies. Furthermore, if the applicant obtains permission to manufacture new drugs/IPs for a clinical trial or BA/BE study, he/she should automatically consider the approval as permission to conduct other chemical/physical testing and analysis on these new drugs/IPs. Refer to IND-58 for detailed CDSCO HQ, zonal office/sub-zonal office contact information. Notice20Feb20 further specifies that applications sent to either CDSCO HQ or the appropriate zonal office/sub-zonal office will be processed within seven (7) working days of receipt.

Notice18Feb20 states that applicants must clearly mention the site where the product will be manufactured in their applications using the following statement: M/s. [name and address of the firm] having manufacturing premises for test and analysis at [name and address of the manufacturing site for test and analysis]. Refer to Notice18Feb20 for additional information.

Per Notice13Mar20, when the application is solely to conduct a clinical trial, the DCGI also requires the sponsor to submit the international non-proprietary name (INN) or generic name, drug category, dosage form, and data supporting IP stability in the intended container-closure system for the duration of the clinical trial. See the 2019-CTRules (Second Schedule, Table 1) for detailed data requirements. Additionally, for Phase III clinical trial batches, process validation data requirements may not be required; however, this requirement will vary depending on the IP’s complexity (biological, high tech, etc.).

If approved, the DCGI will grant permission for a period of three (3) years to both manufacturers of new drugs or investigational new drugs and manufacturers of unapproved APIs. In exceptional circumstances, the DCGI may extend the period of permission for an additional year. See the 2019-CTRules and IND-31 for more detailed information on manufacturing application submission requirements.

In addition, per the 2019-CTRules and IND-31, the sponsor (applicant) is required to obtain a license from the DCGI using Form CT-16 to import an IP (new drug or investigational new drug) for clinical trial purposes. Per the 2019-CTRules, the sponsor must also ensure that the imported IPs are manufactured in accordance with Good Manufacturing Practices (GMPs) as laid down in the DCA-DCR. Refer to Schedule M of the DCA-DCR to review the GMP requirements. See also the Second Schedule in the 2019-CTRules for the data requirements to be included in the DCGI’s import application.

The 2019-CTRules and IND-31 further state that the DCGI will grant an import license within 90 working days of receipt of the application. Once approved, the import license must remain valid for three (3) years from the date of issue, unless suspended or cancelled. In exceptional circumstances, the DCGI may extend the license for an additional year. (See the Submission Process, Submission Content, and Regulatory Fees sections for detailed clinical trial application requirements). See also IND-35 for a checklist of manufacturing and import related forms to be included in a global clinical trial application submission. According to the 2019-CTRules, the sponsor must submit a fee of 5,000 Indian National Rupees (INRs) per product with an application for permission to manufacture or import the IP to be used in a clinical trial. Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal (IND-59).

As explained in IND-25, the DCGI does not require a drug import license to be obtained when an ethics committee (EC) has granted approval for the conduct of an academic clinical trial that will be using a permitted drug formulation with a new indication, a new route of administration, a new dose, or a new dosage form. A copy of the EC approval for the trial must be provided to the Port office at the time of import along with a letter of undertaking that specifies the quantity of the drug being imported and states that it will be used exclusively for the academic clinical trial.

In addition, per the 2019-CTRules and IND-31, the DCGI will relax, abbreviate, omit, or defer clinical and non-clinical data requirements to import or manufacture new drugs already approved in other countries on a case-by-case basis for life threatening or serious/rare diseases and drugs intended to treat diseases of special relevance to the Indian population, unmet medical needs in India, and in disaster or special defense use (e.g., hemostatic and quick wound healing, enhancing oxygen carrying capacity, radiation safety, or drugs to combat chemical, nuclear, or biological conditions). This decision will vary depending on the specific clinical trial phase proposed and the clinical parameters related to the study drug.

Please note: India is party to the Nagoya Protocol on Access and Benefit-sharing (IND-29), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see IND-45.

Chapter V (25), Chapter VIII (52-54, 59-61, and 64), Chapter IX (67-70), Chapter X (75), Chapter XIII (101), Second Schedule (1 and Table 1), Sixth Schedule, Eighth Schedule (Forms CT-10, CT-11, CT-12, CT-13, CT-14, CT-15, and CT-16)
DCR, 1945
65 and 123
64-67, 71-75, and 79
1.6
1, 4, and 6
Foreword, Step 1, Step 2, and Step 5
Last content review/update: January 19, 2023

Manufacturing

According to 21CFR312 and USA-42, the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).

Per 21CFR312, sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312, unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.

Moreover, as stated in 21CFR312, a sponsor may ship an IP to the investigators named in the IND under the following conditions:

  • Thirty (30) days after the FDA receives the IND, or
  • FDA provides earlier authorization to ship the IP

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.

Import

As set forth in 21CFR312, the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:

  • The IP consignee is the IND sponsor, or
  • The consignee is a qualified investigator named in the IND, or
  • The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP
I-V
5.13
I-IX
210.2
Subpart B (312.22 and 312.23), Subpart C (312.40), and Subpart F (312.110)

Investigational Products > Quality Requirements

Last content review/update: March 24, 2022

Investigator's Brochure

The 2019-CTRules requires the Investigator’s Brochure (IB) to contain the version number, release date, and the following sections:

  • Contents
  • Summary
  • Introduction
  • Physical, Chemical, and Pharmaceutical Properties and Formulation
  • Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
  • Effects in humans (Pharmacokinetics and Product Metabolism in Humans, Safety and Efficacy, and Marketing Experience)
  • Summary of Data and Guidance for the Investigator

Refer to the 2019-CTRules for detailed content guidelines.

Per the 2019-CTRules, the licensee is responsible for ensuring the products are manufactured in accordance with the principles of Good Manufacturing Practice (GMP). (See the Product Management section for additional information on IP supply, storage, and handling requirements).

Additionally, per Notice13Mar20, when the application is solely to conduct a clinical trial, the DCGI also requires the sponsor to submit the international non-proprietary name (INN) or generic name, drug category, dosage form and data supporting IP stability in the intended container-closure system for the duration of the clinical trial (see the 2019-CTRules (Second Schedule, Table 1) for detailed data requirements). Additionally, for Phase III clinical trial batches, process validation data requirements may not be required; however, this requirement will vary depending on the IP’s complexity (biological, high tech, etc.).

Quality Documentation

As noted in the 2019-CTRules the applicant is required to provide the following:

  • A free sale certificate from country of origin
  • Certificate(s) of analysis of IP shipped

According to IND-8, the Central Drugs Standard Control Organization (CDSCO) increased the validation period of its World Health Organization (WHO) GMP certificate from two (2) to three (3) years to improve its ability to conduct business.

Further, per the 2019-CTRules, the submission of requirements related to pre-clinical/toxicological animal studies may be modified or relaxed in the case of new drugs approved or marketed for several years in other countries if the DCGI determines there is adequate published evidence regarding a drug’s safety.

See IND-35 for a checklist of GCT documentation requirements.

Chapter VIII (55 and 63), Chapter IX (70), Chapter X (75), Chapter XIII (101), Second Schedule (Table 1) and Third Schedule (Table 7), and Eighth Schedule (Forms CT-10, CT-12, and CT-16)
79
1
Last content review/update: January 19, 2023

Investigator's Brochure

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.

As specified in 21CFR312 and the US-ICH-GCPs, the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • A brief description of the drug substance and the formulation, including the structural formula, if known
  • A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
  • A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
  • A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
  • A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
  • Summary of data and guidance for the investigator

See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.

For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.

Quality Documentation

According to USA-39, submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA).

The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

312.23 and 312.120
2.12, 5.12, 7, and 8.2

Investigational Products > Labeling

Last content review/update: March 24, 2022

Per the 2019-CTRules and IND-31, the labeling of any new drug or investigational new drug product manufactured or imported for the purpose of conducting a clinical trial or for testing and analysis should include the following items:

  • The drug name or code number
  • Batch number or lot number
  • Manufacture date
  • Use before date
  • Storage conditions
  • Name of institution/organization/center where the clinical trial or testing and analysis is proposed to be conducted
  • Manufacturer name and address
  • Purpose for which the investigational product is being imported
Chapter VIII (66) and Chapter IX (73)
70
Last content review/update: January 19, 2023

Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312, which include the following:

  • The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
  • The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated

The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.

In addition, the US-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Subpart A (312.6)
5.13

Investigational Products > Product Management

Last content review/update: March 24, 2022

Supply, Storage, and Handling Requirements

According to the 2019-CTRules and IND-31, in the event that a new drug or investigational new drug manufactured for clinical trial or testing and analysis purposes is left over, remains unused, incurs damage, has an expired shelf life date, or has been found to be of sub-standard quality, the drug must be destroyed and the action taken should be recorded.

Per the 2019-CTRules, the investigational product (IP) section of the protocol submitted as part of the clinical trial application must include the following:

  • IP description and packaging (i.e., IP ingredients and formulation, and placebos used, if applicable)
  • Dosing required during study
  • Packaging, labeling, and blinding method
  • Method of assigning treatments to participants and identification code numbering system to be used
  • Storage conditions
  • Accountability (e.g., instructions for receipt, storage, dispensation, and return of IPs)
  • Policy and procedure for handling unused IPs

Record Requirements

No information is currently available on IP record requirements.

Chapter VIII (55) and Third Schedule (Tables 2 and 7)
68
Last content review/update: January 19, 2023

Supply, Storage, and Handling Requirements

As defined in the US-ICH-GCPs, the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Per 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • IP product quality and stability over the period of use
  • IP manufactured according to any applicable good manufacturing practices (GMPs)
  • Proper coding, packaging, and labeling of the IP(s)
  • Acceptable storage temperatures, conditions, and times for the IP
  • Timely delivery of the IP(s)

Refer to the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep for detailed sponsor-related IP requirements.

Record Requirements

According to 21CFR312, the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.

As per 21CFR312 and the US-ICH-GCPs, the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.

Subpart D (312.57, 312.59, and 312.62)
I-V
I-IX
5 and 7

Specimens > Definition of Specimen

Last content review/update: March 24, 2022

In India, per the G-XBiolMat, the G-ICMR, and the G-StemCellRes, a specimen is referred to as “human biological material,” “human biological sample,” “biological material,” or “biospecimen.” The G-XBiolMat defines a specimen as human material with the potential for use in biomedical research. According to the G-XBiolMat, the G-ICMR, and the G-StemCellRes, this material specifically includes:

  • Organs and parts of organs
  • Cells and tissue
  • Blood (e.g., cord blood and dried blood spots)
  • Gametes (e.g., sperm, ova, and oocytes)
  • Embryos and fetal tissue
  • Blastocysts
  • Somatic cells

(Note: The regulatory sources provide overlapping and unique elements so each of the items listed above will not necessarily be in each source.)

The G-XBiolMat definition also includes the following:

  • Sub-cellular structures and cell products
  • Wastes (e.g., urine, feces, sweat, hair, epithelial scales, nail clippings, placenta, etc.)
  • Cell lines from human tissues

As per the G-XBiolMat, these biological specimens or human material samples may be obtained from the following sources:

  • Patients following diagnostic or therapeutic procedures (e.g., dental, labor, etc.)
  • Autopsy specimens
  • Organ or tissue donation from living or dead persons
  • Fetal tissue
  • Body waste
  • Abandoned tissue
  • Tissue banks
Chapter III, Review Procedures, Section 3
15.0
Definition
Last content review/update: January 19, 2023

A specimen, referred to as patient specimen in 49CFR173, is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).

In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen.

Subpart F (73.1)
Subpart D (173.134)
46.102

Specimens > Specimen Import & Export

Last content review/update: March 24, 2022

Import/Export

As specified in the G-XBiolMat, the HumBiol-ImprtExprt, and IND-55, the applicable import/export guidelines for human biological materials/specimens in India are determined by whether the materials are to be used for biomedical research or for commercial purposes. According to IND-55, the G-XBiolMat should be followed to import/export human biological material for biomedical research purposes, and the HumBiol-ImprtExprt is to be used to import/export human biological samples for commercial purposes.

Biomedical Research

According to the G-XBiolMat, the following guidelines should be considered for requests to transfer biological material abroad for research/diagnostic purposes, and for requests to transfer biological material from abroad to Indian institutions for research purposes:

  • Exchange of material for diagnostic or therapeutic purposes for individual cases may be done without restriction, if this exchange is considered necessary by the doctor(s) in charge of the patient
  • Exchange of material from and to recognized laboratories such as the World Health Organization (WHO)’s Collaborating Centres may be allowed as part of routine activities relating to quality control, quality assurance, comparison with reference material, etc., without having to seek permission from any authority
  • Where exchange of material is envisioned as part of a collaborative research project, the project proposal as a whole must be routed through the appropriate authorities for evaluation and clearance (see International Research Collaboration section below for additional information)
  • The availability of facilities within India for carrying out certain investigations need not prevent collaboration with scientists in other countries from conducting the same investigations, including transfer of human material, if required
  • For the technology transfer/training of Indian scientists abroad/training of foreign scientists and students in India, and visits by foreign collaborators to their Indian partners’ laboratories to work with Indian material, there should be no restrictions on the visits of scientists to the laboratories concerned. However, any fieldwork to be undertaken in the community and other sensitive issues would have to be regulated according to the National Portal of India’s rules

International Research Collaboration

In the case of international research collaboration involving human biological material transfer, the G-XBiolMat and the G-ICMR indicate that the export of all biological materials is to be covered under existing Government of India and ethics guidelines. The G-ICMR further specifies that all biomedical and health research proposals relating to foreign assistance and/or collaboration should be submitted to the Indian Council of Medical Research (ICMR) for a technical review. Next, the ICMR submits the project to the Health Ministry’s Screening Committee (HMSC) for review and approval through its International Health Division that serves as the HMSC’s secretariat. Refer to IND-15 and IND-44 for detailed information on the HMSC.

Per the G-ICMR, the ethics committee (EC) may review research proposals requiring biological material transfer on a case-by-case basis. The exchange of human biological material from and to WHO Collaborating Centres for specific purposes, as well as for individual cases of diagnosis or therapeutic purposes, may not require permission. However, Indian participating center(s) must have appropriate regulatory approval and registration to receive foreign funds for research.

Per the G-ICMR and the G-IntlResProj, any research involving the exchange of biological materials with collaborative institutions outside India must sign an MTA. The MTA must justify the purpose and quantity of the sample being collected; the type of investigation(s) to be conducted using the material; the names/addresses of institution(s)/scientist(s) to whom the material is to be sent; and address confidentiality issues, data sharing, post-analysis handling of remaining biological materials, safety norms, etc. The G-ICMR also indicates that an appropriate memoranda of understanding (MoU) should be in place to safeguard mutual country interests and ensure compliance.

See IND-1 for the application form to request a no objection certificate (NOC) to export biological samples. Refer to the G-XBiolMat, the G-ICMR, the G-IntlResProj, and IND-27 for additional information.

Commercial Purposes

According to the HumBiol-ImprtExprt, per the Directorate General of Foreign Trade (DGFT) within India’s Ministry of Commerce and Industry, the import of human biological samples by Indian diagnostic laboratories/Indian clinical research centers for laboratory analysis/research and development testing, or, for exporting these materials to foreign laboratories, should be permitted by customs authorities at the port of entry/exit without prior approvals (import license/export permit) from any other government agency. In these cases, the concerned Indian company/agency should submit a statement that it is following all the applicable rules, regulations, and procedures for the safe transfer and disposal of biological samples being imported/exported. For more information, see the HumBiol-ImprtExprt.

Material Transfer Agreement

Per the G-XBiolMat, the collaborating partners (India and foreign) should enter into an MoU and/or material transfer agreement (MTA) for requests to transfer biological material abroad for research/diagnostic purposes, and for requests to transfer biological material from abroad to Indian institutions for research purposes.

3.8 and 11.4
Health Ministry’s Screening Committee (HMSC)
Definition, Transfer, Mechanism, and Exchange of Biological Material for Commercial Purposes
Section 11
Last content review/update: January 19, 2023

Import/Export

The import and export of human specimens, also known as patient/diagnostic specimens/substances or human biological materials in the United States (US), is governed by several federal agencies working cooperatively to ensure the safe transport of these materials. These agencies include, but are not limited to, the Department of Transportation (DOT)’s Pipeline and Hazardous Materials Safety Administration (PHMSA), the Centers for Disease Control and Prevention (CDC)’s Import Permit Program (IPP), the Department of Health & Human Services (HHS), the United States Postal Service (USPS), and the International Air Transport Association (IATA). The IATA has also adopted all of the hazardous materials requirements set forth in the Technical Instructions for the Safe Transport of Dangerous Goods by Air (USA-10) published biannually by the United Nations (UN)International Civil Aviation Organization (ICAO).

Infectious Specimens

Per 49CFR173, 42CFR73, 42CFR71, USA-21, USA-4, USA-11, and USA-31, DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Division 6.2 material (Category A or Category B), or a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use, and transfer of select agents and toxins per 42CFR73. See 42CFR71, 42CFR73, USA-31, and USA-73 for further information and permit applications for these import/transfer programs.

Additionally, the Department of Commerce (DOC)’s Bureau of Industry and Security is responsible for regulating the export of a wide range of infectious specimens that may require a DOC license. Refer to the Commerce Control List (CCL) in 15CFR774 and USA-30 to determine if a DOC export permit is required for specific specimens.

According to 49CFR173, USA-21, and USA-4, certain materials and specimens are exempt from the DOT’s PHMSA, IATA, and USPS requirements for import/export of infectious specimens. These include materials that do not contain infectious substances; non-infectious biological materials from humans, animals, or plants; and specimens for which there is a low probability that the sample is infectious. Exempt human or animal specimens are not subject to regulation as hazardous materials but are subject to specific packaging procedures that must be followed when shipped. Please refer to 49CFR173, USA-21, USA-4, and USA-11 for detailed DOT, IATA, and USPS shipping instructions.

NIH Specimen Requirements

The HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations. Researchers must also receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens to the NIH. Detailed instructions about how to proceed are outlined in USA-71.

Per USA-2, the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

Category 1
Subpart F (71.54)
Subpart F (73.1)
Subpart D (173.134)
C.5 and Appendix 4
346.1-346.3
Important Notice, Import Biological Materials to the NIH, Export Biological Materials from the NIH, and Biological Export Form

Sources > Requirements

(Legislation) Information Technology (Amendment) Act, 2008 (ITActAmend) (February 5, 2009)
Parliament of India
(Legislation) Information Technology Act, 2000 (ITAct) (Effective October 17, 2000)
Parliament of India
(Legislation) The Drugs and Cosmetics Act, 1940 and The Drugs and Cosmetics Rules, 1945 (DCA-DCR) (Amended through December 31, 2016)
Department of Health, Ministry of Health and Family Welfare
(Legislation) The Mental Healthcare Act, 2017 (MHA2017) (April 7, 2017)
Parliament of India
(Regulation) Information Technology (Reasonable Security Practices and Procedures and Sensitive Personal Data or Information) Rules, 2011 (IT-SPDIRules) (April 11, 2011)
Ministry of Communications and Information Technology
(Regulation) New Drugs and Clinical Trials (Amendment) Rules, 2022 (2022-CTRules-Amdt - Hindi and English) (Effective January 13, 2022)
Ministry of Health and Family Welfare
(Regulation) New Drugs and Clinical Trials Rules, 2019 (2019-CTRules - Hindi and English) (Effective March 19, 2019)
Ministry of Health and Family Welfare
(Guidance) Guidelines for International Collaboration/Research Projects in Health Research; MoUs & HMSC Procedure (G-IntlResProj) (Last Updated February 4, 2022)
Indian Council of Medical Research
(Guidance) Handbook for Applicants & Reviewers of Clinical Trials of New Drugs in India (Hdbk-ClinTrial) (January 2017)
Indian Council of Medical Research and Central Drugs Standard Control Organization
(Guidance) ICMR Guidelines for Good Clinical Laboratory Practices (GCLP) (2021)
Indian Council of Medical Research
(Guidance) National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (G-ICMR) (October 2017)
Indian Council of Medical Research
(Guidance) National Ethical Guidelines for Biomedical Research Involving Children (G-Children) (October 2017)
Indian Council of Medical Research
(Guidance) National Guidelines for Gene Therapy Product Development and Clinical Trials (G-GeneThrpy) (November 2019)
Indian Council of Medical Research, Central Drug Standards Control Organisation, and Ministry of Science and Technology
(Guidance) National Guidelines for Stem Cell Research (G-StemCellRes) (2017)
Indian Council of Medical Research, Ministry of Science and Technology
(Guidance) Office Memorandum: Guidelines for Exchange of Human Biological Material for Biomedical Research Purposes (G-XBiolMat) (November 19, 1997)
Ministry of Health and Family Welfare
(Notice) Import/Export Policy for Human Biological Samples for Commercial Purposes: Amendment Schedule–1 (Import Policy) and Schedule–2 (Export Policy) of ITC (HS), 2012 (HumBiol-ImprtExprt – Hindi and English) (August 4, 2016)
Ministry of Commerce and Industry
(Notice) Notice for Filing of Application for Clinical Trial, Marketing Authorization, Registration Certificate and Import License for r-DNA Derived Drugs in SUGAM Portal (Notice15Jan18) (January 15, 2018)
Central Drugs Standard Control Organization
(Notice) Notice Regarding Ethics Committee Registration through SUGAM Portal (Notice1Aug18) (August 1, 2018)
Central Drugs Standard Control Organization
(Notice) Notice Regarding Grant of Permission in Form CT-11/ CT-14/CT-15/ CT-17 Under New Drugs and Clinical Trials Rules 2019 (Notice20Feb20) (February 20, 2020)
Central Drugs Standard Control Organization
(Notice) Notice Regarding List of Approved Clinical Trial Sites and Investigators (Notice2Dec19) (December 2, 2019)
Central Drugs Standard Control Organization
(Notice) Notice Regarding Online Submission of SAE Reports in SUGAM Portal (Notice25Feb21) (Effective March 14, 2021)
Central Drugs Standard Control Organization
(Notice) Notice Regarding Process Validation Report Requirement for Permission to Conduct Clinical Trials/BA-BE Studies (Notice13Mar20) (March 13, 2020)
Central Drugs Standard Control Organization
(Notice) Notice Regarding Registration of Ethics Committees for Biomedical and Health Research Involving Human Participants (Notice15Sept19) (Effective September 15, 2019)
Central Drugs Standard Control Organization
(Notice) Notice Regarding the New Drugs and Clinical Trial Rules 2019 FAQs (Notice18Feb20) (February 18, 2020)
Central Drugs Standard Control Organization
(Order) Order Regarding Approved Subject Expert Committees (Order13Jan20) (January 13, 2020)
Central Drugs Standard Control Organization
(Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FDCAct) (June 25, 1938)
US Congress
(Legislation) FDA Reauthorization Act of 2017 (FDARA) (August 18, 2017)
US Congress
(Legislation) Food and Drug Administration Amendments Act of 2007 (FDAAA) (Effective October 1, 2007)
US Congress
(Legislation) Food and Drug Administration Modernization Act of 1997 (FDAMA) (November 21, 1997)
US Congress
(Legislation) Health Insurance Portability and Accountability Act of 1996 (HIPAA) (August 21, 1996)
US Congress
(Regulation) Code of Federal Regulations - Title 15, Part 774 - The Commerce Control List (15CFR774) (Up to Date as of January 10, 2023)
Bureau of Industry and Security, US Department of Commerce
(Regulation) Code of Federal Regulations - Title 21, Part 210 - Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General (21CFR210) (Up to Date as of January 10, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 312 - Investigational New Drug Application (21CFR312) (Up to Date as of January 10, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 50 - Protection of Human Subjects (21CFR50) (Up to Date as of January 10, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 21, Part 56 - Institutional Review Boards (21CFR56) (Up to Date as of January 10, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 11 - Clinical Trials Registration and Results Information Submission (42CFR11) (Up to Date as of January 12, 2023)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 71 - Foreign Quarantine (42CFR71) (Up to Date as of January 12, 2023)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 72 - Interstate Shipment of Etiologic Agents (42CFR72) (October 1, 2007)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 73 - Select Agents and Toxins (42CFR73) (Up to Date as of January 12, 2023)
Public Health Service, US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 160 - General Administrative Requirements (45CFR160) (Up to Date as of January 12, 2023)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 164 – Security and Privacy (45CFR164) (Up to Date as of January 12, 2023)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subpart A - Basic HHS Policy for Protection of Human Research Subjects (RevComRule) (Up to Date as of January 12, 2023)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subpart A - Basic HHS Policy for Protection of Human Research Subjects (Pre2018-ComRule) (Spanish – unofficial translation) (Revised January 15, 2009)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 45, Part 46, Subparts B through E (45CFR46-B-E) (Up to Date as of January 12, 2023)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 49, Part 173 - Shippers - General Requirements for Shipments and Packagings (49CFR173) (Up to Date as of January 12, 2023)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation
(Regulation) US Code - Title 10, Chapter 55: Medical and Dental Care (10USC55) (January 1, 2011)
US Congress
(Guidance) Approval of Research with Conditions: OHRP Guidance (G-OHRP-IRBApprvl) (November 10, 2010)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) eCTD Technical Conformance Guide (G-eCTDTech) (Version 1.8) (November 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Engagement of Institutions in Human Subjects Research (G-HHS-Inst-Engagemt) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs - Improving Human Subject Protection (G-IRBRpting) (January 2009)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND (G-IND-Determination) (September 2013)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees (G-DMCs) (March 2006)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry and Investigators: Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies (G-IND-Safety) (December 2012)
Food and Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry and Review Staff: Good Review Practice - Best Practices for Communication Between IND Sponsors and FDA During Drug Development (G-FDAComm) (December 2017)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Adaptive Designs for Clinical Trials of Drugs and Biologics (G-AdaptiveTrials) (November 2019)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Current Good Manufacturing Practice (CGMP) for Phase 1 Investigational Drugs (G-CGMP-Phase1) (July 2008)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (US-ICH-E11) (April 2018)
Food & Drug Administration, US Department of Health and Human Services
(Guidance) Guidance for Industry: E17 General Principles for Planning and Design of Multiregional Clinical Trials (US-ICH-E17) (July 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (US-ICH-GCPs) (March 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Enhancing the Diversity of Clinical Trial Populations - Eligibility Criteria, Enrollment Practices, and Trial Designs (G-CTDiversity) (November 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Investigator Responsibilities - Protecting the Rights, Safety, and Welfare of Study Subjects (G-InvstgtrResp) (October 2009)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (G-RiskMntrng) (August 2013)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Preparation of Investigational New Drug Products (Human and Animal) (G-INDPrep) (November 1992)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Providing Regulatory Submissions in Alternate Electronic Format (G-AltrntElecSubs) (Revision 1) (June 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (G-PharmeCTD) (Revision 7) (February 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Providing Regulatory Submissions to CBER in Electronic Format - Investigational New Drug Applications (INDs) (G-CBER-ElecINDs) (March 2002)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Special Protocol Assessment (G-SPA) (Revision 1) (April 2018)
Food & Drug Administration, US Department of Health and Human Services
(Guidance) Guidance for Industry: Use of Electronic Health Record Data in Clinical Investigations (G-eHealthRecords) (July 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans (G-PedStudyPlans) (July 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drug and Biological Products (G-RWDRWE) (September 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions - IRB Registration (G-IRBReg-FAQs) (July 2009)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: A Guide to Informed Consent (G-ICInfoSheet) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Cooperative Research (G-CoopRes) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Emergency Use of an Investigational Drug or Biologic (G-EmrgncyUse) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Institutional Review Boards Frequently Asked Questions (G-IRBFAQs) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Non-Local IRB Review (G-IRBReview) (January 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Payment and Reimbursement to Research Subjects (G-SbjctPayment) (January 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards and Clinical Investigators: Protection of Human Subjects: Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) Through an Expedited Review Procedure (G-IRBExpdtdRev) (November 1998)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Exception from Informed Consent Requirements for Emergency Research (G-ICEmergencyReqs) (Updated April 2013)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards, Investigators and Sponsors: Use of Electronic Informed Consent - Questions and Answers (G-ElectronicIC) (December 2016)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutions and IRBs: Institutional Review Board (IRB) Written Procedures (G-IRBProcs) (May 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for IRBs, Clinical Investigators, and Sponsors: FDA Institutional Review Board Inspections (G-IRBInspect) (January 2006)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review After Clinical Investigation Approval (G-IRBContRev) (February 2012)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Responsible Parties, Submitters of Certain Applications and Submissions to FDA, and FDA Staff: Civil Money Penalties Relating to the ClinicalTrials.gov Data Bank (G-DataBankPnlty) (August 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions - Statement of Investigator (Form FDA 1572) (G-1572FAQs) (May 2010)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Institutional Review Boards, and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (G-IC-IVDs) (April 2006)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Investigators, and Institutional Review Boards: Impact of Certain Provisions of the Revised Common Rule on FDA-Regulated Clinical Investigations (G-RevComRule-FDA) (October 2018)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Investigators, and Institutional Review Boards: IRB Waiver or Alteration of Informed Consent for Clinical Investigations Involving No More Than Minimal Risk to Human Subjects (G-MinRiskWaiver) (July 2017)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Sponsors, Sponsor-Investigators, Researchers, Industry, and Food and Drug Administration Staff: Certificates of Confidentiality (G-CertCnfdntlty) (September 2020)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance on Coded Private Information or Specimens Use in Research (G-SpecimensResrch) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) Informed Consent Requirements in Emergency Research (OPRR Letter, 1996) (G-HHS-Emrgncy) (Last Reviewed March 21, 2016)
US Department of Health & Human Services
(Guidance) Issues to Consider in the Research Use of Stored Data or Tissues (1996/1997) (G-StoredData-Tissues) (November 7, 1997)
Office for Protection from Research Risks, US Department of Health & Human Services
(Guidance) OHRP Guidance on Maintaining Consistency Regarding the Applicability of the 2018 or Pre-2018 Requirements (G-ComRuleCnsstncy) (November 12, 2020)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events: OHRP Guidance (G-HHS-AEReqs) (January 15, 2007)
Office for Human Research Protections, US Department of Health & Human Services
(Guidance) Transmitting Electronic Submissions Using eCTD Specifications (G-eCTDspecs) (Version 1.9) (June 14, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Policy) Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research (NOT-OD-16-094) (NIHNotice16-094) (Effective January 25, 2018)
National Institutes of Health, US Department of Health & Human Services
(Policy) NIH and FDA Release Protocol Template for Phase 2 and 3 IND/IDE Clinical Trials (NOT-OD-17-064) (NIHNotice17-064) (May 2, 2017)
National Institutes of Health and Food & Drug Administration, US Department of Health & Human Services
(Policy) NIH Policy for Data and Safety Monitoring (NIHDataSftyMntrng) (June 10, 1998)
National Institutes of Health, US Department of Health & Human Services
(Policy) NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (NIHTrialInfo) (Effective January 18, 2017)
National Institutes of Health, US Department of Health & Human Services
(Policy) Revision: Notice of Extension of Effective Date for Final NIH Policy on the Use of Single Institution Review Board for Multi-Site Research (NOT-OD-17-076) (NIHNotice17-076) (Effective January 25, 2018)
National Institutes of Health, US Department of Health & Human Services

Sources > Additional Resources

(Article) CDSCO Increases WHO GMP Certificate to Three Years for Ease of Doing Business (IND-8) (May 8, 2018)
Raghavan, Prabha; The Economic Times
(Article) Ethics Committees and the Changed Clinical Research Environment in India in 2016: A Perspective! (IND-13) (Jan-Mar 2017)
Davis, Sanish et al, Perspectives in Clinical Research
(Article) Health Ministry’s Screening Committee (Indian Council of Medical Research) (IND-15) (January 2015)
Seth, Sandeep; Journal of the Practice of Cardiovascular Sciences
(Article) Highlights of Indian Council of Medical Research National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (IND-5) (May-June 2019)
Mathur, Roli et al; Indian J Pharmacology 51(3): 214–221
(Article) India - Data Protection Overview (IND-65) (December 2021)
Chacko, Mathew and Misra, Aadya; OneTrust DataGuidance
(Article) India: The New Drugs And Clinical Trial Rules, 2019 (IND-17) (April 16, 2019)
Singh & Associates
(Article) India's Clinical-Trial Rules to Speed up Drug Approvals (IND-19) (April 3, 2019)
Vaidyanathan, Gayathri; Nature
(Article) India’s New Drugs and Clinical Trials Rules: An Industry Perspective (IND-6) (July 19, 2019)
Jain, Parveen and Chauhan, Rahul; Regulatory Focus
(Article) Medicines Regulation: Regulatory Systems in India (IND-16) (2017)
Gupta, M. et al; WHO Drug Information
(Article) New Clinical Trials Rules will Help Patients - Here's How (IND-18) (Last Updated April 8, 2019)
The Financial Express
(Article) Regulatory Timelines in the Asia-Pacific (IND-9) (August 22, 2016)
George Clinical; Pharmaphorum
(Article) UN Standards on Clinical Trials to be Implemented by ICMR (IND-10) (May 20, 2017)
Sabrang India
(Document) [Pre-Screening Checklist - Clinical Trial and New Drug Applications] (IND-32) (Date Unavailable)
Central Drugs Standard Control Organization
(Document) Additional FAQ on New Drugs and Clinical Trial Rules, 2019 (IND-25) (August 23, 2019)
Central Drugs Standard Control Organization
(Document) Checklist for Ethics Committee Registration for Biomedical and Health Research (IND-66) (Date Unavailable)
Ministry of Health and Family Welfare
(Document) Frequently Asked Questions (FAQs) on New Drugs and Clinical Trials (IND-31) (Date Unavailable)
Central Drugs Standard Control Organization
(Document) GCP Inspection Checklist (IND-34) (February 9, 2018)
Central Drugs Standard Control Organization
(Document) Global Clinical Trial (GCT) Application Checklist (IND-35) (Date Unavailable)
Central Drugs Standard Control Organization
(Document) Guidance for Investigators for Collaborative Biomedical Research in India (IND-44) (Date Unavailable)
National Institutes for Allergy and Infectious Diseases, National Institutes of Health
(Document) Handbook on National Ethical Guidelines for Biomedical and Health Research Involving Human Participants (IND-27) (2018)
Indian Council of Medical Research
(Document) ICMR Policy on Research Integrity and Publication Ethics (IND-28) (2019)
Indian Council of Medical Research
(Document) List of Approved Clinical Trial Sites & Investigators for Global Clinical Trials (IND-26) (December 2, 2019)
Central Drugs Standard Control Organization
(Document) Nagoya Protocol on Access and Benefit-sharing (IND-29) (2011)
Convention on Biological Diversity, United Nations
(Document) OECD Principles on Good Laboratory Practice (GLPs) (as revised in 1997) (IND-30) (1998) (OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring – Number 1)
Organisation for Economic Co-operation and Development
(Document) Re-Registration of Ethics Committee - Checklist for Application Submissions (IND-69) (February 8, 2013)
Central Drugs Standard Control Organization
(Document) SUGAM Portal Approval Process for Global Clinical Trials (IND-22) (Date Unavailable)
Central Drugs Standard Control Organization
(Document) User Manual For e-Governance Solution for CDSCO (IND-42) (Version 1.0) (Date Unavailable)
Centre for Development of Advanced Computing and Central Drugs Standard Control Organization
(Document) User Manual for SUGAM Online Payment (IND-43) (Version 1.1) (March 29, 2019)
Centre for Development of Advanced Computing and Central Drugs Standard Control Organization
(International Guidance) Declaration of Helsinki (IND-63) (October 19, 2013)
World Medical Association
(International Guidance) Handbook - Good Laboratory Practice (GLP): Quality Practices for Regulated Non-clinical Research and Development (IND-40) (2nd Edition) (2009)
World Health Organization
(International Guidance) ICH Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use (M4) (IND-68) (Step 5 Versions) (Modules range from 2002-2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) (IND-41) (Step 4 Version) (November 9, 2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(Webpage) Central Drugs Standard Control Organization - About Us (IND-47) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Central Drugs Standard Control Organization - Contact Us (IND-58) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Central Drugs Standard Control Organization - Public Relations Office (IND-71) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Clinical Trials Registry - India (IND-57) (Current as of March 24, 2022)
Indian Council of Medical Research
(Webpage) Clinical Trials Registry - India: Important Notice for all Trial Registrants (IND-56) (Current as of March 24, 2022)
Indian Council of Medical Research
(Webpage) Clinical Trials Toolkit India (IND-46) (Current as of March 24, 2022)
Clinical Development Services Agency (CDSA), MRC Clinical Trials Unit, University College London, and Translational Health Science and Technology Institute (THSTI)
(Webpage) Common Forms for Ethics Committee Review (IND-52) (Current as of March 24, 2022)
Indian Council of Medical Research
(Webpage) Country Profile: India (IND-45) (Current as of March 24, 2022)
Access and Benefit-sharing Clearing-house, Convention on Biological Diversity, United Nations
(Webpage) Department of Health Research - About Us (IND-50) (Current as of March 24, 2022)
Ministry of Health and Family Welfare
(Webpage) Ethics Committee Re-Registration Data (IND-48) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Ethics Committee Registration Data (IND-49) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Institutional Committee for Stem Cell Research (IC-SCR) Registration (IND-72) (Current as of March 24, 2022)
National Apex Committee for Stem Cell Research and Therapy
(Webpage) Liability and Indemnity in Clinical Trials and its Global Complexities (IND-60) (Last Updated December 12, 2018)
Institute of Good Manufacturing Practices India
(Webpage) NAITIK Portal (IND-54) (Current as of March 24, 2022)
National Ethics Committee Registry for Biomedical and Health Research, Ministry of Health and Family Welfare
(Webpage) National Ethics Committee Registry for Biomedical and Health Research (NECRBHR) (IND-51) (Last Updated January 31, 2020)
Department of Health Research, Ministry of Health and Family Welfare
(Webpage) Registration of Ethics Committees Reviewing Biomedical and Health Research with Department of Health Research (IND-53) (Current as of March 24, 2022)
Indian Council of Medical Research
(Webpage) SUGAM - Contact Us (IND-70) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) SUGAM Portal (IND-59) (Current as of March 24, 2022)
Central Drugs Standard Control Organization
(Webpage) Transfer of Biological Material (IND-55) (Last Updated April 29, 2020)
Indian Council of Medical Research
(Document) Announcement: Federal Websites that will Satisfy the Revised Common Rule’s Requirement to Post Clinical Trial Consent Forms (45 CFR 46.116(h)) (USA-12) (August 15, 2018)
US Department of Health & Human Services
(Document) Attachment D: FAQ's Terms and Recommendations on Informed Consent and Research Use of Biospecimens (USA-9) (July 20, 2011)
Office for Human Research Protections, US Department of Health & Human Services
(Document) Dangerous Goods Regulations (USA-21) (64th Edition) (Effective January 1, 2023)
International Air Transport Association, Montreal, CA and Geneva, Switzerland (Note: This document is available for purchase only.)
(Document) Ethical Conduct of Clinical Research Involving Children (USA-25) (2004)
Committee on Clinical Research Involving Children, Institute of Medicine
(Document) FDA Electronic Submissions Gateway (USA-7) (September 2017)
Food & Drug Administration, US Department of Health & Human Services
(Document) Getting Started: Creating an ESG Account (USA-8) (September 2017)
Food & Drug Administration, US Department of Health & Human Services
(Document) Manual of Policies and Procedures (MAPP 6030.1): IND Clinical Holds (USA-5) (Revised February 20, 2018)
Food & Drug Administration, US Department of Health & Human Services
(Document) NCI Best Practices for Biospecimen Resources (USA-2) (March 2016)
National Cancer Institute, National Institutes of Health, US Department of Health & Human Services
(Document) Publication 52: Hazardous, Restricted, and Perishable Mail - 346 Toxic Substances and Infectious Substances (Hazard Class 6) (USA-4) (July 2022)
United States Postal Service
(Document) Reporting Adverse Drug Reactions: Definitions of Terms and Criteria for Their Use (USA-3) (1999)
Council for International Organizations of Medical Sciences
(Document) Research Involving Private Information or Biospecimens (USA-1) (June 25, 2019)
National Institutes of Health, US Department of Health & Human Services
(Document) SOPP 8110: Submission of Regulatory Applications - Exempt from eCTD Requirements (USA-89) (Version 5) (Effective August 23, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Document) SOPP 8201: Administrative Processing of Clinical Holds for Investigational New Drug Applications (USA-15) (Version 6) (Effective December 11, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Document) Technical Instructions for the Safe Transport of Dangerous Goods by Air (USA-10) (Addendum No. 2) (2017/2018 Edition) (June 21, 2017)
International Civil Aviation Organization, United Nations
(Document) Transporting Infectious Substances Safely - Federal Register: Hazardous Materials: Infectious Substances; Harmonization with the United Nations Recommendations (USA-11) (Effective October 1, 2006)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation
(International Guidance) Best Practices: Recommendations for Repositories (USA-14) (Fourth Edition) (2018)
International Society for Biological and Environmental Repositories, Vancouver, CA
(Webpage) About OHRP (USA-93) (Last Reviewed February 12, 2016)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Assurance Process FAQs (USA-59) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Biologics Procedures (SOPPs) (USA-95) (FDA reviewed May 12, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) CDER Contact Information (USA-91) (FDA reviewed October 1, 2020)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) CDER Manual of Policies & Procedures | MAPP (USA-96) (FDA reviewed January 18, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Cellular & Gene Therapy Guidances (USA-80) (FDA reviewed November 4, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Certificate of Analysis for Investigational Drug (USA-67) (April 28, 2009)
Model Agreements & Guidelines International
(Webpage) Clinical Research (USA-29) (Current as of January 19, 2023)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Clinical Trial Informed Consent Form Posting (sec. 116(h) of the revised Common Rule) - Docket ID: HHS-OPHS-2018-0021 (USA-79) (Current as of January 19, 2023)
US Department of Health & Human Services
(Webpage) Clinical Trials Guidance Documents (USA-47) (FDA reviewed October 17, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) ClinicalTrials.gov - Frequently Asked Questions (USA-26) (Last Reviewed August 2022)
National Institutes of Health, US Department of Health & Human Services
(Webpage) ClinicalTrials.gov (USA-78) (Current as of January 19, 2023)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Commerce Control List (CCL) (USA-30) (Current as of January 19, 2023)
US Department of Commerce
(Webpage) Contact FDA (USA-81) (FDA reviewed November 10, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Contact OHRP (USA-82) (Last Reviewed February 10, 2022)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Contacts in the Center for Biologics Evaluation & Research (CBER) (USA-90) (FDA reviewed October 20, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Development & Approval Process - Drugs (USA-85) (FDA reviewed August 8, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Electronic Common Technical Document (eCTD) (USA-34) (FDA reviewed December 13, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Electronic Regulatory Submission and Review (USA-36) (FDA reviewed January 18, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Electronic Submission System - Welcome to the Electronic Submission System for FWAs and IRB Registrations (USA-28) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Electronic Submissions Gateway (USA-44) (FDA reviewed September 2, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review (USA-84) (FDA reviewed February 23, 2018)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA Overview Organization Chart (USA-33) (FDA reviewed January 12, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA's Role: ClinicalTrials.gov Information (USA-49) (FDA reviewed March 7, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Federal Policy for the Protection of Human Subjects ('Common Rule') (USA-65) (Last Reviewed December 13, 2022)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Federalwide Assurance (FWA) for the Protection of Human Subjects (USA-57) (Last Reviewed July 31, 2017)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Frequently Asked Questions: Human Subjects (USA-72) (Last Updated April 28, 2020)
National Institutes of Health, US Department of Health & Human Services
(Webpage) HHS – Contact Us (USA-83) (Last Reviewed September 21, 2022)
US Department of Health & Human Services
(Webpage) HHS and 16 Other Federal Departments and Agencies Issue a Final Rule to Delay for an Additional 6 Months the General Compliance Date of Revisions to the Common Rule While Allowing the Use of Three Burden-Reducing Provisions During the Delay Period (USA-55) (June 18, 2018)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Human Subject Regulations Decision Charts (USA-74) (Last Reviewed June 30, 2020)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Import Permit Applications (USA-73) (Last Reviewed September 18, 2020)
Centers for Disease Control and Prevention, US Department of Health & Human Services
(Webpage) Import Permit Program (USA-31) (Last Reviewed May 27, 2022)
Centers for Disease Control and Prevention, US Department of Health & Human Services
(Webpage) IND Application Reporting: Safety Reports (USA-38) (FDA reviewed October 19, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information (USA-39) (FDA reviewed February 25, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) IND Forms and Instructions (USA-40) (FDA reviewed March 31, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) (USA-41) (FDA reviewed June 27, 2017)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Informed Consent FAQs (USA-60) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Informed Consent of Subjects Who Do Not Speak English (USA-63) (November 9, 1995)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Initial IRB Registration (USA-58) (Last Reviewed March 15, 2016)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Investigational New Drug (IND) Application (USA-42) (FDA reviewed July 20, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Investigational New Drug Applications (IND) for CBER-Regulated Products (USA-52) (FDA reviewed October 14, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) IRB Registration Process FAQs (USA-61) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) IRBs and Assurances (USA-56) (Last Reviewed March 18, 2016)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) MedWatch Forms for FDA Safety Reporting (USA-48) (FDA reviewed September 15, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) National Institutes of Health - Division of Occupational Health and Safety - Biological Materials Shipping (USA-71) (Current as of January 19, 2023)
National Institutes of Health, US Department of Health & Human Services
(Webpage) New Drug Application (NDA) (USA-43) (FDA reviewed January 21, 2022)
Food & Drug Administration, US Department of Health & Human Service
(Webpage) NIH Clinical e-Protocol Writing Tool (USA-27) (Current as of January 19, 2023)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Office of Clinical Policy (USA-88) (FDA reviewed September 27, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Permits for Import or Export of Biological Materials (USA-68) (Last Updated June 26, 2019)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Prescription Drug User Fee Amendments (USA-45) (FDA reviewed October 27, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Prisoner Research FAQs (USA-62) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Regulatory Submissions in Electronic and Paper Format for CBER-Regulated Products (USA-94) (FDA reviewed December 22, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Research (USA-86) (Last Reviewed June 13, 2018)
US Department of Health & Human Services
(Webpage) Revised Common Rule Q&As (USA-54) (Last Reviewed December 1, 2021)
Office of Human Research Protections, US Department of Health & Human Services
(Webpage) Revised Common Rule (USA-66) (Last Reviewed January 19, 2017)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Submission of an Investigational New Drug Application (IND) to CBER (USA-53) (FDA reviewed May 19, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Submit Using eCTD (USA-35) (FDA reviewed November 2, 2021)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Summary of HHS/NIH Initiatives to Enhance Availability of Clinical Trial Information (USA-70) (September 15, 2016)
National Institutes of Health, US Department of Health & Human Services
(Webpage) The HIPAA Privacy Rule (USA-87) (Last Reviewed March 31, 2022)
US Department of Health & Human Services
(Webpage) Vulnerable Populations (USA-64) (Current as of January 19, 2023)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) What We Do (USA-92) (FDA reviewed March 28, 2018)
Food & Drug Administration, US Department of Health & Human Services

Sources > Forms

(Form) Application Form for Initial Review (IND-39) (Version 1) (Date Unavailable)
Indian Council of Medical Research
(Form) Application Format for the Obtaining of Export NOC of Biological Samples of Clinical Trial for Testing (Annexure) (IND-1) (July 20, 2012)
Central Drugs Standard Control Organization
(Form) EC Applicant Registration Form (IND-38) (Current as of March 24, 2022)
National Ethics Committee Registry for Biomedical and Health Research, Ministry of Health and Family Welfare
(Form) ICMR EC Application Form for Clinical Trials (Annexure 8) (IND-36) (Version 2.0) (Date Unavailable)
Indian Council of Medical Research
(Form) ICMR EC Serious Adverse Event Reporting Format (Clinical Trials) (Annexure 9) (IND-37) (Version 2.0) (Date Unavailable)
Indian Council of Medical Research
(Form) CIOMS Form I (USA-13) (Date Unavailable)
Council for International Organizations of Medical Sciences
(Form) Form FDA 1571 (04/19): Investigational New Drug Application (IND) (USA-76) (Expires March 31, 2022)
Food & Drug Administration, US Department of Health & Human Services
(Form) Form FDA 1572 (3/22): Statement of Investigator (USA-77) (Expires March 31, 2025)
Food & Drug Administration, US Department of Health & Human Services
(Form) Form FDA 3500A (11/22): MedWatch (USA-75) (Expires June 30, 2025)
Food & Drug Administration, US Department of Health & Human Services
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This message was reviewed on January 6, 2023