Country Selection

United States

Regulatory Authority

Regulatory Authority

Regulatory authority(ies), relevant office/departments, oversight roles, contact information

Scope of Assessment

Regulatory review and approval processes, renewal, monitoring, appeals, termination

Regulatory Fees

Regulatory fees (e.g., applications, amendments, notifications, import) and payment instructions

Ethics Committee

Ethics Committee

Ethics review landscape, ethics committee composition, terms of reference, review procedures, meeting schedule

Scope of Review

Ethics committee review and approval processes, renewal, monitoring, termination

Ethics Committee Fees

Ethics review fees and payment instructions

Oversight of Ethics Committees

Authorization of ethics committees, registration, auditing, accreditation

Clinical Trial Lifecycle

Submission Process

Submission procedures for regulatory and ethics reviews

Submission Content

Essential elements of regulatory and ethics submissions and protocols

Timeline of Review

Regulatory and ethics review and approval timelines

Initiation, Agreements & Registration

Pre-trial approvals, agreements, clinical trial registration

Safety Reporting

Safety reporting definitions, responsibilities, timelines, reporting format, delivery

Progress Reporting

Interim/annual and final reporting requirements

Sponsorship

Definition of Sponsor

Sponsor role and responsibilities, contract research organizations, representatives

Site/Investigator Selection

Site and investigator criteria, foreign sponsor responsibilities, data and safety monitoring boards, multicenter studies

Insurance & Compensation

Insurance requirements, compensation (injury, participation), post-trial access

Risk & Quality Management

Protocol and regulatory compliance, auditing, monitoring, inspections, study termination/suspension

Data & Records Management

Electronic data processing systems and records storage/retention

Personal Data Protection

Responsible parties, data protection, obtaining consent

Informed Consent

Documentation Requirements

Obtaining and documenting informed consent/reconsent and consent waivers

Required Elements

Essential elements for informed consent form and other related materials

Participant Rights

Rights regarding participation, information, privacy, appeal, safety, welfare

Emergencies

Obtaining or waiving consent in emergencies

Vulnerable Populations

Definition of vulnerable populations and consent/protection requirements

Children/Minors

Definition of minors, consent/assent requirements, conditions for research

Pregnant Women, Fetuses & Neonates

Consent requirements and conditions for research on pregnant women, fetuses, and neonates

Prisoners

Consent requirements and conditions for research on prisoners

Mentally Impaired

Consent requirements and conditions for research on persons who are mentally impaired

Investigational Products

Definition of Investigational Product

Description of what constitutes an investigational product and related terms

Manufacturing & Import

Investigational product manufacturing and import approvals, licenses, and certificates

Quality Requirements

Investigator's Brochure and quality documentation

Labeling

Investigational product labeling, blinding, re-labeling, and package labeling

Product Management

Investigational product supply, storage, handling, disposal, return, record keeping

Specimens

Definition of Specimen

Description of what constitutes a specimen and related terms

Specimen Import & Export

Specimen import, export, material transfer agreements

Consent for Specimen

Consent for obtaining, storing, and using specimens, including genetic testing
Hide
«
United States

Quick Facts

Clinical trial application language
Regulatory authority & ethics committee review may be conducted at the same time
Clinical trial registration required
In-country sponsor presence/representation required
Specimens export allowed

Regulatory Authority

Last content review/update: January 5, 2024

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, the 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 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, including how to determine if research is exempt, 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, including how to determine if research is exempt, 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.

Other Considerations

Per USA-16, the US is a founding regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The US has adopted several ICH guidance documents, including the E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population (US-ICH-E11), E17 General Principles for Planning and Design of Multiregional Clinical Trials (US-ICH-E17), and E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) (US-ICH-GCPs), which are cited throughout this profile.

Contact Information

Food & Drug Administration

As per USA-81, USA-91, and USA-90, 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

CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@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

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

Scope of Assessment

Last content review/update: January 5, 2024

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

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. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

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.

II-IV
VIII
III (C)
Subchapter V, Part A, Sec. 355 and 356
Sec. 3210
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)

Regulatory Fees

Last content review/update: January 5, 2024

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.

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

Ethics Committee

Last content review/update: January 5, 2024

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 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule, 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.

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 the member 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 FDA 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 FWAs.

What is a Federalwide Assurance (FWA)?
Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
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

Scope of Review

Last content review/update: January 5, 2024

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the institutional 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.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

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

Per the FDA’s G-IRBReview, 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 the FDA’s G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP)’s 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, 46.107, 46.109-46.111, and 46.113-46.114
46.101-46.102, 46.104, 46.107, 46.109-46.111, and 46.113-46.114

Ethics Committee Fees

Last content review/update: January 5, 2024

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.

Oversight of Ethics Committees

Last content review/update: January 5, 2024

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).

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.

Assurance Process
What is an assurance of compliance with human subject protection regulations?; What is a Federalwide Assurance (FWA)?; and What are the key features of the Federalwide Assurance (FWA)?
Filing a New Registration for an Institutional Review Board (IRB) by an Institution or Organization (IORG)
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?
III
I, II, and III
Subchapter V, Part A, Sec. 355
Subpart B (56.106)
46.103
46.103-46.104
Subpart E (46.501-46.505)

Submission Process

Last content review/update: January 5, 2024

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 the G-PharmeCTD, which implements FDCAct requirements, 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 the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (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.

According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or 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

(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

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.

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)

Submission Content

Last content review/update: January 5, 2024

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-Doc 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-Doc.

The FDCAct, as amended by the FDORA, requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).

According to the 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 the 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, 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 USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

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.

Form FDA 1571
Clinical Trial e-Protocol Tool and Template Documents
VIII
3 and 6
Sections I and III
Subchapter V, Part A, Sec. 355
Sec. 3601
Subpart B (312.22-312.23)
Subpart A (56.102) and Subpart C (56.111)
46.109 and 46.111
46.104, 46.109, and 46.111

Timeline of Review

Last content review/update: January 5, 2024

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

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.

3.1.2
Subchapter V, Part A, Sec. 355
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)

Initiation, Agreements & Registration

Last content review/update: January 5, 2024

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

Safety Reporting

Last content review/update: January 5, 2024

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 – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
  • Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
  • Adverse Reaction – Any adverse event caused by a drug. Adverse reactions 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 – An adverse event/suspected adverse reaction 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
  • Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction 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 Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction 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)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define 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.

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Safety Reporting Requirements

Investigator Responsibilities

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

  • Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
  • Study endpoints that are serious adverse events 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 adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
  • Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems

Sponsor Responsibilities

As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event.

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 suspected adverse reaction 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 a serious suspected adverse reaction 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 suspected adverse reaction and must analyze the significance of the suspected adverse reaction 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 adverse event information. The tables should consist of the following summarized data:

  • All serious adverse events
  • All adverse events, other than serious adverse events, 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 adverse event reporting requirements.

Form Completion & 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 suspected adverse reaction 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. Per USA-90, fatality reports to CBER should be sent to fatalities2@fda.hhs.gov.

Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction 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)
46.109 and 46.113
46.108-46.109 and 46.113

Progress Reporting

Last content review/update: January 5, 2024

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.

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

Definition of Sponsor

Last content review/update: January 5, 2024

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 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 trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.

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

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

Site/Investigator Selection

Last content review/update: January 5, 2024

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.

As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

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 a Common Rule department/agency (as identified in USA-65), 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 Department of Health & Human Services (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

For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, 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)
46.103 and 46.111
46.101, 46.103, 46.111, and 46.114

Insurance & Compensation

Last content review/update: January 5, 2024

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 FDA’s 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 institutional 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.

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

Risk & Quality Management

Last content review/update: January 5, 2024

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.

Per the G-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

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

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-6 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.

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 the sponsor’s 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).

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA 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 and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA.

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, the sponsor 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 FDA, all ECs, 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 the sponsor’s 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.

The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.

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.

Section V.13
1.65, 5.0-5.2, 5.5, 5.18-5.19, 5.21, and 6.10
II-IV
Subpart C (312.44) and Subpart D (312.56)
Subpart B (50.25)

Data & Records Management

Last content review/update: January 5, 2024

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.

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.

5.5 and 8
Subpart D (312.57-312.58)

Personal Data Protection

Last content review/update: January 5, 2024

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 FDA’s 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.

NIH Privacy Requirements

The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct, which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.

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 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
C. Policy
Subpart A (160.103)
Subparts A and E

Documentation Requirements

Last content review/update: January 5, 2024

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. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) 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 ICF 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 the FDA’s 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 the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, 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 FDA’s G-InfrmdCnsnt, 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 that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

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-InfrmdCnsnt 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). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note.

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 or the legal representative(s)/guardian(s)
  • The participant or the legal representative(s)/guardian(s), has 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)/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)/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 will be provided with additional pertinent information after participation

In the 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 the 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.

Broad Consent in the Revised Common Rule and Informed Consent
Sections III.A and V.3-6
2.9, 4.8, 8.2, and 8.3
V (45)
III
IV
Subpart B (50.20, 50.25, and 50.27)
46.116 and 46.117
46.116 and 46.117
Subparts B-D

Required Elements

Last content review/update: January 5, 2024

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 otherwise entitled benefits
  • 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.”

In the G-InfrmdCnsnt, the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

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

See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

Compensation Disclosure

The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.

Sections III.B.6 and V.12
4.8
Subpart B (50.25)
46.116
46.116

Participant Rights

Last content review/update: January 5, 2024

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 private 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 additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.

The G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.

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 the participant’s health and welfare must take precedence over the interests of science and society.

Informed Consent
Section V.12
Introduction, 1.27, 2.2, 2.3, 3.1, and 4.8
Subpart A (312.3)
Subpart A (50.1) and Subpart B (50.20 and 50.25)
46.103, 46.109, 46.116, and 46.117
46.116
Last content review/update: January 5, 2024

21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmrgncyReqs 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-ICEmrgncyReqs 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-ICEmrgncyReqs 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-ICEmrgncyReqs 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, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.

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.

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?
4.8
III (18)
II (20), V (44), and Appendix B
1107
Subpart B (50.23 and 50.24)
Subpart A (56.102 and 56.104)
46.101(i)

Vulnerable Populations

Last content review/update: January 5, 2024

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. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

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.

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

Children/Minors

Last content review/update: January 5, 2024

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. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

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 institutional 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. Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50.

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.

The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50, and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.

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?
Section V.1-2
4.8.12
Subpart A (50.3) and Subpart D
46.111
46.104 and 46.111
Subpart D

Pregnant Women, Fetuses & Neonates

Last content review/update: January 5, 2024

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. Furthermore, according to 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. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

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.

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 institutional 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.

4.8.10
Subpart B (50.25)
46.111
46.104
Subparts B and D
Last content review/update: January 5, 2024

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. As delineated in 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-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

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 institutional 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

See USA-62 for more HHS 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.

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

Mentally Impaired

Last content review/update: January 5, 2024

In accordance with 21CFR56, the Pre2018-ComRule, and the US-ICH-GCPs, an institutional 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. According to the G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.

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. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) 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.

As stated in the FDA’s G-InfrmdCnsnt, ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:

Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional

Establishing a waiting period in the decision-making process to allow additional time for decision-making

Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible

Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire

Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline

Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes

Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented

Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time

Determining whether the EC or a third party should observe the consent process

See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50.

What should be considered in seeking informed consent from individuals with diminished decision-making capacity?
Section V.8
1.61
Subpart B (50.20)
Subpart C (56.111)
46.111
46.111

Definition of Investigational Product

Last content review/update: January 5, 2024

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.

1.33
Subpart A (312.3)

Manufacturing & Import

Last content review/update: January 5, 2024

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)

Quality Requirements

Last content review/update: January 5, 2024

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 Management

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.

2.12, 5.12, 7, and 8.2
312.23 and 312.120
Last content review/update: January 5, 2024

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.

5.13
Subpart A (312.6)

Product Management

Last content review/update: January 5, 2024

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.

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

Definition of Specimen

Last content review/update: January 5, 2024

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. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)

Subpart F (73.1)
46.102
Subpart D (173.134)

Specimen Import & Export

Last content review/update: January 5, 2024

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.

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
Category 1
Subpart F (71.54)
Subpart F (73.1)
Subpart D (173.134)

Requirements

(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: 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: 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 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 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: 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, 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) 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) Transmitting Electronic Submissions Using eCTD Specifications (G-eCTDspecs) (Version 1.9) (June 14, 2021)
Food & Drug Administration, 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
(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
(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
(Regulation) Code of Federal Regulations - Title 15, Part 774 - The Commerce Control List (15CFR774) (Up to Date as of January 1, 2024)
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 1, 2024)
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 1, 2024)
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 1, 2024)
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 1, 2024)
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 1, 2024)
US Department of Health & Human Services
(Regulation) Code of Federal Regulations - Title 42, Part 71 - Foreign Quarantine (42CFR71) (Up to Date as of January 1, 2024)
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 1, 2024)
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 1, 2024)
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 1, 2024)
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 1, 2024)
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 (Pre-2018 Requirements) (Pre2018-ComRule) (Spanish-Pre2018-ComRule – Unofficial translation) (Effective July 14, 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 1, 2024)
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 1, 2024)
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) 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 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: 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 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) 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) Informed Consent Requirements in Emergency Research (OPRR Letter, 1996) (G-HHS-Emrgncy) (Last Reviewed March 21, 2016)
US Department of Health & Human Services
(Guidance) Guidance for Industry: E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials (G-ICH-E19) (December 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Clinical Investigator Administrative Actions - Disqualification (G-InvstgtrAdmin) (December 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry, Investigators, and Institutional Review Boards: Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies (G-CTEmrgncy) (September 2023)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products (G-CovariatesCT) (May 2023)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers (G-RiskMntrngQA) (April 2023)
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-Doc) (September 2022)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for Industry: Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products (G-RWDRWE-Reg) (August 2023)
Food & Drug Administration, US Department of Health & Human Services
(Guidance) Guidance for IRBs, Clinical Investigators, and Sponsors: Informed Consent (G-InfrmdCnsnt) (August 2023)
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-ICEmrgncyReqs) (Updated April 2013)
Food & Drug Administration, US Department of Health & Human Services
(Legislation) Food and Drug Omnibus Reform Act of 2022 (FDORA) (December 29, 2022)
US Congress
(Legislation) Privacy Act of 1974 – 5 U.S.C. 552a: Records Maintained on Individuals (PrvcyAct) (Text in effect as of January 3, 2024)
US Congress
(Policy) NIH Policy Manual - 3014-107 - Privacy and Confidentiality (NIHPrvcy) (Partial Revision Date: June 7, 2021)
National Institutes of Health, US Department of Health & Human Services
(Policy) Final NIH Policy for Data Management and Sharing (NIHDataMngmnt) (Effective January 25, 2023)
National Institutes of Health, US Department of Health & Human Services

Additional Resources

(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) (65th Edition) (Effective January 1, 2024)
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) 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) (September 7, 2023)
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) Technical Instructions for the Safe Transport of Dangerous Goods by Air (USA-10) (Addendum No. 1) (2023/2024 Edition) (March 31, 2023)
International Civil Aviation Organization, United Nations (Note: This document is available for purchase only.)
(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
(Webpage) Assurance Process FAQs (USA-59) (Current as of January 4, 2024)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Cellular & Gene Therapy Guidances (USA-80) (FDA reviewed December 28, 2023)
Food & Drug Administration, 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 4, 2024)
US Department of Health & Human Services
(Webpage) Clinical Trials Guidance Documents (USA-47) (FDA reviewed December 20, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Clinical Research (USA-29) (Last Updated April 2023)
National Institutes of Health, US Department of Health & Human Services
(Webpage) ClinicalTrials.gov (USA-78) (Current as of January 4, 2024)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Commerce Control List (CCL) (USA-30) (Current as of January 4, 2024)
US Department of Commerce
(Webpage) Contact FDA (USA-81) (FDA reviewed August 17, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Contact OHRP (USA-82) (Last Reviewed August 28, 2023)
Office for Human Research Protections, 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 March 22, 2023)
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 4, 2024)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Electronic Submissions Gateway (USA-44) (FDA reviewed November 29, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review (USA-84) (FDA reviewed June 12, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA Overview Organization Chart (USA-33) (FDA reviewed October 13, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) FDA's Role: ClinicalTrials.gov Information (USA-49) (FDA reviewed December 4, 2023)
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 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) HHS – Contact Us (USA-83) (Last Reviewed September 21, 2022)
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 December 13, 2023)
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 4, 2024)
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 4, 2024)
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) Division of Occupational Health and Safety - Biological Materials Shipping - QPSO (USA-71) (Current as of January 4, 2024)
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) National Institutes of Health (NIH) Clinical e-Protocol Writing Tool (USA-27) (Current as of January 4, 2024)
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) Prescription Drug User Fee Amendments (USA-45) (FDA reviewed December 14, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Prisoner Research FAQs (USA-62) (Current as of January 4, 2024)
Office for Human Research Protections, 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) Revision of the Common Rule (USA-66) (Last Reviewed March 8, 2021)
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 September 29, 2023)
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 4, 2024)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) About OHRP (USA-93) (Last Reviewed February 12, 2016)
Office for Human Research Protections, US Department of Health & Human Services
(Webpage) Biologics Procedures (SOPPs) (USA-95) (FDA reviewed February 28, 2023)
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 December 21, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Contacts in the Center for Biologics Evaluation & Research (CBER) (USA-90) (FDA reviewed April 4, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Regulatory Submissions in Electronic and Paper Format for CBER-Regulated Products (USA-94) (FDA reviewed May 23, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) What We Do (USA-92) (FDA reviewed November 21, 2023)
Food & Drug Administration, US Department of Health & Human Services
(Webpage) Research Covered Under the Data Management & Sharing Policy (USA-6) (Current as January 4, 2024)
National Institutes of Health, US Department of Health & Human Services
(Webpage) Members and Observers (USA-16) (Current as of January 4, 2024)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(Webpage) Advancing Real-World Evidence Program (USA-17) (FDA reviewed July 25, 2023)
Food & Drug Administration, US Department of Health & Human Services

Form

(Form) CIOMS Form I (USA-13) (Date Unavailable)
Council for International Organizations of Medical Sciences
(Form) Form FDA 1571 (3/23): Investigational New Drug Application (IND) (USA-76) (Expires March 31, 2025)
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
Sign up to get United States updates Sign up to get United States updates
Menu
|
Announcement

Country Announcement

See the United States updates page for details on recent revisions to the profile.

COUNTRY NEWS (Information Not Yet Incorporated Into Country Profile):

New FDA Final Rule Issued for Informed Consent Exceptions for Minimal Risk Clinical Investigations
The Food and Drug Administration (FDA) issued a final rule, which went into effect on January 22, 2024. The final rule allows an institutional review board (IRB) to waive or alter certain informed consent elements, or waive the informed consent requirement for certain FDA-regulated minimal risk clinical investigations.

COVID-19 Guidance:

As of May 12, 2023, the federal Public Health Emergency (PHR) for COVID-19, declared under Section 319 of the Public Health Service Act, has expired. See the Fact Sheet: COVID-19 Public Health Emergency Transition Roadmap released by the Department of Health & Human Services (HHS) for more details. The ClinRegs team will monitor any changes made to the COVID-19 guidance documents listed below and will update them accordingly.

Office for Human Research Protections:

National Institutes of Health:

Effective May 12, 2023, NIH will no longer issue Emergency Notices of Funding Opportunities related to COVID-19. Ongoing emergency awards will not be impacted and will retain all existing emergency flexibilities for the remained of the current competition segment. See NIH notice NOT-OD-23-095 for more details.

This message was reviewed on February 23, 2024