Comparison: United Kingdom and United States
Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Trial Authorization
Insurance
Compensation
Quality, Data & Records Management
Site/Investigator Selection
Informed Consent
Documentation Requirements
Required Elements
Compensation Disclosure
Participant Rights
Special Circumstances/Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
Labeling & Packaging
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
For a detailed list of sources per topic, see the single country view.
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United Kingdom
United States
QUICK FACTS
English Clinical trial application language English
Yes Regulatory authority & ethics committee review may be conducted at the same time Yes
Yes Clinical trial registration required Yes
Yes In-country sponsor presence/representation required No
Under 16 Age of minors Determined at the State Level
Yes Specimens export allowed Yes
Regulatory Authority > Regulatory Authority
Last content review/update: July 23, 2020

Overview

As per the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in the United Kingdom (UK). The MHRA grants permission for clinical trials to be conducted in the UK in accordance with the MHCTR and the MHCTR2006.

According to GBR-57, the MHRA is an executive agency within the Department of Health and Social Care (DHSC), which grants the MHRA authority to regulate and license all medicines and medical devices within the UK. Per the G-MHRA-CTAuth, the agency’s Clinical Trials Unit (CTU) focuses specifically on reviewing applications to conduct clinical trials of medicinal products.

Please note: United Kingdom is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Contact Information

MHRA
10 South Colonnade
Canary Wharf
LONDON
E14 4PU
UK

Phone: +44 020-3080-6000
Fax: +44 0203-118-9803
General Email: info@mhra.gov.uk

Clinical Research Office:
Email: clintrialhelpline@mhra.gov.uk
Phone: +44 020-3080-6456

In addition, the G-MHRA-CTAuth includes other email addresses for specific purposes related to submissions.

Last content review/update: May 22, 2020

Overview

As per the FD&CAct, 21CFR50, 21CFR312, the Food & Drug Administration (FDA) is the regulatory authority that regulates clinical investigations of medical products in the United States (US). This profile is specifically focused on the FDA’s role 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 FD&CAct, 21CFR50, and 21CFR312. Regulatory requirements relating to compliance with federally funded or sponsored human subjects research protections, known as the CommonRule, which the Department of Health & Human Services (HHS) implements in subpart A of 45CFR46, are also examined. (See USA-65 for a list of federal agencies that implement the CommonRule). 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.

According to USA-32, the FDA, which is an agency within HHS, started undergoing a reorganization on March 31, 2019. One of the purposes of the reorganization is to elevate the role of the centers, offices, and field forces. An overview of the new 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, the Office of Good Clinical Practice (OGCP) plays a pivotal role in the FDA’s oversight of good clinical practice and human subject protection issues stemming from clinical research.

Implementation of the Revised Common Rule

Per 82FR7149, on January 19, 2017, HHS and 15 other federal departments and agencies released the RevisedCommonRule, which delineates basic ethical principles surrounding federally funded or sponsored human subjects research. Institutions engaged in this research and ethics committees (ECs) reviewing this research were originally required to comply with the RevisedCommonRule starting in January 2018, except for the new provisions on multicenter clinical studies, also known as cooperative research studies, which institutions were required to comply with by January 20, 2020. However, per 83FR28497, the implementation date was delayed to January 21, 2019, with the provisions on multicenter clinical studies still taking effect January 20, 2020. (Per USA-55, the RevisedCommonRule is also known as the “2018 Requirements.”) See Ethics Committee topic, Scope of Review subtopic for more information on multicenter clinical studies.

Studies Initiated Before January 21, 2019

Per the RevisedCommonRule, the CommonRule requirements apply to research that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the CommonRule.

Institutions conducting research approved prior to January 21, 2019, may choose to transition to the RevisedCommonRule 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 RevisedCommonRule beginning on that date.

Studies Initiated On or After January 21, 2019

The RevisedCommonRule applies to all research initially approved by an EC on or after January 21, 2019, or to research that had EC review waived or that was determined to be exempt on or after that date.

See USA-54 for additional information regarding compliance with the CommonRule and the RevisedCommonRule.

HHS’ Office for Human Research Protections (OHRP) guides the agency’s efforts to safeguard the rights, welfare, and well-being of human research subjects for studies conducted or supported by HHS. OHRP also provides oversight to all federal agencies engaged in human subjects research under the CommonRule and the RevisedCommonRule. For more information about the RevisedCommonRule, see USA-66.

Application of FDA and Common Rule Requirements

Although the FDA and HHS have endeavored to harmonize their respective human subjects regulations, differences still exist given the agencies’ separate authority and unique statutory mandates. Consequently, FDA, despite being a part of HHS, is not a CommonRule agency. Rather, the agency is governed by its own regulations including the earlier referenced FD&CAct and 21CFR50. If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

Contact Information: FDA
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
Telephone: (888) 463-6332
Email: druginfo@fda.hhs.gov

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

Contact Information: HHS
US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775
HHS Employee Directory: http://directory.psc.gov/employee.htm

Regulatory Authority > Scope of Assessment
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The MPHFR and the G-MHRA-CTApp specify that the scope of the MHRA’s assessment includes all clinical trials (Phases I-IV). The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the ethics committee (EC) review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal. However, pursuant to the MHCTR and the MHCTR2006, the clinical trial must be authorized by the MHRA, and an EC established and recognized by the United Kingdom Ethics Committee Authority (UKECA) must provide a favorable opinion in relation to the trial prior to the trial’s commencement. (See the Ethics Committee topic for detailed information on the EC review and approval process.)

According to the G-MHRA-CTApp and GBR-22, the sponsor or his/her designated representative must also apply for a European Clinical Trials Database (EudraCT) number by registering a clinical trial in the EudraCT database. (See Clinical Trial Lifecycle topic, Submission Process subtopic for additional details.)

Brexit

Per the Brexit, the EUCouncil-Brexit, and the WithdrlAgrmt, the UK withdrew from the European Union (EU) on January 31, 2020. As delineated in WithdrlAgrmt and explained in GBR-60, there is a transition period until December 31, 2020 while the UK and EU negotiate additional arrangements until new rules take effect on January 1, 2021. During the transition period, the UK will continue to follow the EU’s and MHRA’s current rules related to clinical research. For additional information, see GBR-60 for transition period information and resources. The ClinRegs team will continue to monitor Brexit-related activities and update the UK profile accordingly.

Expected to come into effect during 2020, the new EU Clinical Trials Regulation (GBR-21) would apply to the UK during the Brexit transition period. If GBR-21 does not come into force during the Brexit transition period, the UK’s laws will remain aligned with parts of the EU’s Clinical Trials Regulation that are within the UK’s control. Per GBR-71 and GBR-86, GBR-21 will ensure a greater level of harmonization of the rules for conducting clinical trials throughout the EU. It introduces an authorization procedure based on a single submission via a single EU portal, an assessment procedure leading to a single decision, rules on participant protection and informed consent, and transparency requirements.

Clinical Trial Review Process

Application Submission

The MHCTR, the G-MHRA-CTApp, and GBR-23 specify that the MHRA coordinates the clinical trial application process. Per GBR-23, upon receipt of a clinical trial application, the MHRA’s Clinical Trials Unit (CTU) validates it and sends the sponsor or his/her designated legal representative an acknowledgement. The G-MHRA-CTApp states that MHRA has moved from paper to automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. If the application is valid, the CTU assessment period begins from the date of receipt (Day 0). If the application is not valid, the sponsor or his/her designated representative will be informed of the deficiencies, and he/she must provide a completely new application. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered as authorized. (See the Clinical Trial Lifecycle topic, Timeline of Review subtopic for additional details.)

In addition, as stated in the G-MHRA-CTApp, certain first-in-human (Phase I) trials with specific risk factors may require the MHRA’s CTU to seek advice from an Expert Advisory Group/the Commission on Human Medicines before giving approval. See the G-MHRA-CTApp for examples of which trials require expert advice and for detailed requirements.

Notification Scheme Submission

As set forth in the G-MHRA-CTApp, GBR-23, GBR-82, and GBR-46, in lieu of a standard application, a sponsor or his/her designated representative may submit a notification of a clinical trial to the MHRA under the Notification Scheme when conducting “Type A” trials. Type A trials are those in which the potential risk associated with an IP is determined to be no higher than that of standard medical care, and involve medicinal products licensed in any EU Member State that meet the following criteria:

  • They relate to the licensed range of indications, dosage and form, or,
  • They involve off-label use established by practice and supported by published evidence and/or guidelines

See the G-MHRA-CTApp, GBR-23, GBR-82, and GBR-46, for detailed Notification Scheme requirements.

Upon receipt of a valid notification, the MHRA will send an acknowledgement to the sponsor or his/her designated representative stating that the trial may proceed if it does not raise an objection within 14 days. If the MHRA does not send a Notification Objection letter, the acknowledgement serves as the authorization. The G-MHRA-CTApp states that MHRA has moved from paper to automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address.

If the MHRA raises objections, the submission is assessed as a standard request for authorization (refer to information under the Application Submission heading above), and the CTU initial assessment is performed within 30 days of receipt of a valid application.

Governance Approval

Per GBR-78, all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-96 and GBR-67, approval from the Health Research Authority (HRA) is required for all project-based research in the National Health Service (NHS) led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national R&D coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29.

(See the Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics for detailed submission requirements.)

Last content review/update: February 05, 2020

Overview

In accordance with the FD&CAct, 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 I-IV). 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 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 completed 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 FD&CAct
  • 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 FD&CAct.

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.

IND 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 set forth in USA-5 and USA-15, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) coordinate the IND submission review process for drugs and therapeutic biological products respectively. Per the FD&CAct, 21CFR312, USA-5, and USA-15, the CDER and CBER review teams will evaluate all initial INDs and, within 30 calendar days of receipt of the original IND, contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team 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. An IND automatically goes into effect 30 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 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.

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.

(See the Clinical Trial Lifecycle topic, Submission Content and Trial Initiation subtopics for detailed submission requirements.)

Regulatory Authority > Regulatory Fees
Last content review/update: March 19, 2020

Overview

As per the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and the G-MHRAFees, the sponsor or his/her designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt, applicants do not need to attach proof of payment to applications. Applicants will receive an invoice to make a payment for the correct amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees.

As delineated in the G-MHRAFees, the MHRA levies the following processing fees, which will remain in effect through 2021:

  • 3,060 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier
  • 225 British Pounds – Applications without an IMP dossier
  • 225 British Pounds – Clinical trial variation/amendment
  • No cost – Phase IV notification

The G-MHRA-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme. However, a fee will be charged to assess an application if an objection to the notification is raised and the application is not authorized by the MHRA.

Instructions for Payment of Clinical Trial Application Fee

According to the G-MHRAPaymt, MHRA will no longer accept checks, effective December 1, 2019. Payments can be made electronically by bank transfer, credit card, or debit card. Bank transfers should be sent to:

Account Name: MHRA
Account Number: 10004386
Sort code: 60-70-80
Swift code: NWBKGB2L
IBAN: GB68NWBK60708010004386
Bank: National Westminster Bank

Bank address:
National Westminster Bank
RBS, London Corporate Service Centre, 2nd Floor
280 Bishopsgate
London
EC2M 4RB
UK

Remittance details should be sent to:

MHRA Accounts Receivable
10 South Colonnade
London
E14 4PU
Or email: sales.invoices@mhra.gov.uk

Credit or debit card payments may be made using MHRA’s online payment form (GBR-26).

Further information can be obtained by emailing sales.invoices@mhra.gov.uk or calling +44 (0)20 3080 6533 or +44 (0)30 3080 6533.

Last content review/update: February 05, 2020

Overview

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

However, per the FD&CAct, 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 (US). The data gathered during the animal studies and human clinical trials of an IND become part of the NDA.

Ethics Committee > Ethics Committee
Last content review/update: March 19, 2020

Overview

As set forth in GAfREC and GBR-9, the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), (known as research ethics committees (RECs) in the UK). Per GAfREC and GBR-9, the UK Health Departments have authorized the Research Ethics Service (RES) in England, within the Health Research Authority (HRA), to serve as the lead administrative body to coordinate the development of operational systems for ECs. See GAfREC for more detail about HRA functions related to the RES in the United Kingdom. ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA), the HRA, or the Ministers of Health Departments of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales).

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates, the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized England’s HRA to perform some functions on behalf of the other head offices. A list of recognized ECs within the RES is available through GBR-95.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, Guideline for Good Clinical Practice E6 (R2) (GBR-20), and GBR-9. However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for investigational medicinal products (CTIMPs) are authorized by the statutory body, the UKECA, and are of central importance in this topic. Please refer to the Ethics Committee topic, Authorizing Body subtopic for additional details on the RES and the UKECA.

RES EC Composition

As delineated in the MHCTR and GAfREC, a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-20 for additional recommendations for composition.

Per GBR-9, in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A), the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page, Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC, committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference and Review Procedures

In addition to complying with composition requirements, GAfREC, GBR-20, and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting. For detailed EC procedures and information on other administrative processes, see GAfREC, GBR-20, and GBR-9.

Last content review/update: February 05, 2020

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 CommonRule and the RevisedCommonRule 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 CommonRule to such research. However, the RevisedCommonRule 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. A list of such technologies will be made available by the Department of Health & Human Services (HHS) on a publically accessible website. See USA-65, USA-66, and USA-54, and the Regulatory Authority topic, Regulatory Authority subtopic for more information on the RevisedCommonRule and agency-specific compliance.

EC Composition

As stated in 21CFR56, the CommonRule, and the RevisedCommonRule, 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 such issues 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 law, 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 Informed Consent topic, Vulnerable Populations subtopic for details on vulnerable populations.

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

Per the CommonRule, the RevisedCommonRule, and 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, institution, the FDA, and the 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.

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

Per 21CFR56, the CommonRule, and RevisedCommonRule, proposed research must be reviewed at 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.

Per 21CFR56 and the CommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year.

Per the RevisedCommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year, except in the following circumstances:

  • Research eligible for expedited review that involves no more than minimal risk or for minor changes in approved research (unless the reviewer explicitly justifies why continuing review would enhance protection of research participants)
  • Research for which limited EC review is a condition of exemption
  • 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

Refer to the G-RevComRule-FDA for clarification on the impact of the RevisedCommonRule on studies that must also comply with FDA regulations.

See Ethics Committee topic, Scope of Review subtopic for additional details on expedited review and limited EC review. Refer to the CommonRule, the RevisedCommonRule, 21CFR56, G-IRBProcs, and USA-18 for detailed EC procedural requirements.

Federal Assurance Requirement

Per the CommonRule and RevisedCommonRule, institutions engaging in research conducted or supported by a federal department/agency must also obtain an approved assurance that it will comply with the CommonRule or RevisedCommonRule requirements and certify to the federal 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 CommonRule or RevisedCommonRule 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 (CommonRule or RevisedCommonRule) 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 the RevisedCommonRule, 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 RevisedCommonRule. 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 IRB records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Per USA-54, institutions with an FWA do not need to change it under the RevisedCommonRule.

Ethics Committee > Scope of Review
Last content review/update: March 19, 2020

Overview

According to GAfREC, the Guideline for Good Clinical Practice E6 (R2) (GBR-20), and GBR-9, the primary scope of information assessed by ethics committees (ECs) recognized by the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK).

As per GAfREC, the MHCTR, the MHCTR2006, the MHCTR2006-No2, and GBR-20, ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See Informed Consent topic, and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired for additional information about these populations).

As indicated in GAfREC, the MHCTR, the MHCTR2006, GBR-20, and GBR-9, ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC, the MHCTR, the MHCTR2006 and GBR-9 for detailed ethics review guidelines.

Role in Clinical Trial Approval Process

As described in GBR-9, GBR-66, GBR-111, and GBR-95, the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. As discussed in the preceding subtopic, ECs recognized to conduct reviews of clinical trials for investigational medicinal products (CTIMPs) must be authorized by the United Kingdom Ethics Committee Authority (UKECA). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than CTIMPs.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, CTIMP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or his/her designated legal representative initiating the trial. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application has been electronically submitted to the Integrated Research Application System (IRAS) (GBR-78). Therefore, to prepare an EC application, an IRAS account must be created. Per GBR-78, IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies.

Prior to submitting an application, the trial must first be registered in the EU Clinical Trials Register, which provides a EudraCT number. According to GBR-9, the chief investigator (CI) must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the NHS Research Ethics Committee (REC)’s Online Booking Service (GBR-95). The EudraCT number should also be included with the application. (See the Clinical Trial Lifecycle topic, Trial Initiation subtopic for additional information.)

According to the MHCTR, GAfREC, and GBR-9, for all studies, the RES requires the CI to obtain only one (1) EC review (referred to as the “main EC”) for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the CI should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

GAfREC, the MHCTR, and GBR-9 also state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR. (See the Clinical Trial Lifecycle topic, Submission Process subtopic and Timeline of Review subtopic for detailed submission process requirements.)

While there is no stated expiration date for an EC approval in the MHCTR, GAfREC, or the Additional Resources, IRAS (GBR-78) requires identification of an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment. See GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA.

Last content review/update: February 05, 2020

Overview

21CFR56, 21CFR312, the CommonRule, the RevisedCommonRule, and US-ICH-GCPs state that the primary scope of information assessed by the ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the CommonRule, and the RevisedCommonRule, 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 Informed Consent topic and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

Role in Clinical Trial Approval Process

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

In the event of multicenter clinical studies, also known as cooperative research studies, which must comply with the RevisedCommonRule, it is required that all federally-funded or sponsored institutions located in the US and engaged in multicenter research use a single EC to review that study for the portion of the study conducted in the US, known as the IRB policy. This policy will streamline the EC review process and eliminate duplicative reviews. 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 RevisedCommonRule, 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.

Although the regulations do not specify an expiration for EC 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. Per the CommonRule, the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year.

The RevisedCommonRule provides the following exceptions:

  • Research eligible for expedited review (unless the reviewer explicitly justifies why continuing review would enhance protection of research participants)—A list of minimal-risk categories of research published by the Secretary of Department of Health & Human Services, which is evaluated and amended every eight (8) years; an EC may determine, however, that the study involves more than minimal risk
  • Minor changes in previously approved research during the period for which approval is authorized
  • Certain types of exempt research, as long as a limited EC review was conducted (per Section 104 of the RevisedCommonRule): Research that only includes educational tests, surveys, interviews, or observations of public behavior if the information obtained is recorded by the investigator in such a manner that the identity of the human subjects can readily be ascertained, directly or through identifiers linked to the subjects; Research involves benign behavioral interventions and is recorded by the investigator in such a manner that the identity of the human subjects can be readily ascertained; Storage or maintenance for secondary (future) research for which broad consent is required to use private information or identifiable biospecimens; Broad consent for storage and secondary research use of identifiable private information or identifiable biospecimens in lieu of obtaining study-specific informed consent; but note that this exemption does not apply if the investigator includes returning individual research results in the study plan
  • 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

Refer to the G-RevComRule-FDA for clarification on the impact of the RevisedCommonRule on studies that must also comply with FDA regulations.

In addition, per the RevisedCommonRule revisions, 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 104 of the RevisedCommonRule 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 RevisedCommonRule, 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. See USA-54 for more information on example research, expedited review, limited review, and continuing review.

Further, the RevisedCommonRule 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.

Due to varying institutional EC schedules, specific timeline review schedules are not available.

Ethics Committee > Ethics Committee Fees
Last content review/update: March 19, 2020

Overview

As set forth in GAfREC, ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, per GAfREC, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

Last content review/update: February 05, 2020

Overview

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.

Ethics Committee > Authorizing Body
Last content review/update: March 19, 2020

Overview

Research Ethics Service (RES)

As stated in GAfREC, the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Directorates, the Welsh Government’s Department of Health and Social Care, as well as the ethics committees (ECs) (known as research ethics committees (RECs) in the UK) collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the Health Research Authority (HRA), which is sponsored by England’s DHSC, to serve as the lead administrative body to coordinate the development of RES operational systems for ECs recognized or established by the United Kingdom Ethics Committee Authority (UKECA), the HRA, or the Ministers or Health Departments of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales), including their respective head offices.

A head office represents each of the health departments within the four (4) UK nations and serves as the appointing authority for the recognized ECs. Per GAfREC and GBR-62, within England’s DHSC, the HRA is the head office with appointing authority for the RES. The official RES head offices (i.e., appointing authorities) for the other nations are represented by the Health and Social Care Research and Development (HSC R&D) Division (GBR-90) within Northern Ireland’s HSC Public Health Agency; the Chief Scientist Office (CSO) (GBR-91) within the Scottish Government Health and Social Care Directorates; and the Ethics Service within the Health and Care Research Wales (HCRW) (GBR-93). The head offices work together to maintain a consistent approach in operating the RES ECs.

UK Ethics Committee Authority (UKECA)

As set forth in the MHCTR, the MHCTR2006, and GAfREC, the UKECA is responsible for establishing, recognizing, and monitoring ECs that review applications for clinical trials of investigational medicinal products (CTIMPs). As indicated in the MHCTR and GBR-9, the UKECA recognizes two (2) types of ECs for new CTIMPs applications:

  • Type 1: Reviews Phase I clinical trials in healthy volunteers taking place anywhere in the UK
  • Type 3: Reviews clinical trials in patients taking place anywhere in the UK

New applications are no longer allocated for review by ECs with Type 2 recognition. 

Per GAfREC and GBR-9, the HRA is responsible for providing advice, assistance, and operational support to all UK ECs recognized by the UKECA.

As indicated in GBR-97, the HRA chairs UKECA business, which is reviewed at the bimonthly Four Nations’ Meeting attended by England’s DHSC, Northern Ireland’s HSC, Scotland’s CSO, and the Health and Care Research Wales.

Registration, Auditing, and Accreditation

As delineated in GAfREC and GBR-9, the RES is responsible for ensuring the quality of the ECs, including the UKECA ECs, through regular monitoring, auditing, and accrediting their operations and performance.

Health Research Authority (HRA)

In accordance with the CareAct2014 and GBR-61, the HRA is a non-departmental public body established in 2015 and sponsored by England’s DHSC to standardize regulatory practices relating to health and social care research, and to encourage safe and ethical research conducted across the UK. According to GAfREC and GBR-9, the UK Health Departments have authorized the HRA in England to serve as the lead administrative body to coordinate the development of RES operational systems for ECs recognized or established by the UKECA, the HRA, or the Ministers or Health Departments of the four (4) UK nations (including their respective head offices). The RES is a core function of the HRA.

As indicated in GAfREC and GBR-64, the HRA, in support of the RES and UKECA, supports two (2) main types of ECs in the UK:

  • Authorized ECs – those authorized by the RES to review all applications except those relating to CTIMPs
  • Recognized ECs – those recognized by the UKECA, a statutory body established under the MHCTR, to review applications relating to CTIMPs. Recognized ECs may also review non-CTIMP research.
Last content review/update: February 05, 2020

Overview

As delineated in 21CFR56 and 45CFR46-B-E, the Food & Drug Administration (FDA) and the Department of Health & Human Services (HHS) 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 for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP) (USA-28).

In addition, per the CommonRule, the RevisedCommonRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by any federal department or agency must also submit a written assurance of compliance to HHS 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.

Per the RevisedCommonRule, which took effect January 21, 2019, 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 RevisedCommonRule. 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 IRB records.

Registration, Auditing, and Accreditation

FDA Registration

According to 21CFR56 and the G-IRB FAQ, FDA requires each EC in the US that either reviews clinical investigations regulated by the agency under the FD&CAct 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-IRB FAQ also indicates that while registration of non-US ECs is voluntary, the information FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRB FAQ, 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 IND. The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only OHRP, only FDA, or both OHRP and FDA.

FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by HHS. If an EC lacks the ability to register electronically, it must send its registration information in writing to:

Office of Good Clinical Practice
Office of Special Medical Programs
Food and Drug Administration
10903 New Hampshire Ave.
Bldg. 32, Rm. 5129
Silver Spring, MD 20993

See 21CFR56 and the G-IRB FAQ for detailed EC registration submission requirements.

HHS Registration

Per 45CFR46-B-E, USA-61, and USA-58, 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. 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.

As delineated in 45CFR46-B-E, USA-56, and USA-61, an EC must be registered in the HHS OHRP system (USA-28), before it can be designated under an OHRP FWA. 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 OHRP. The FWA is the only type of assurance of compliance accepted and approved by OHRP.

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

See the G-Info-Sheet for FDA inspection procedures of ECs.

Accreditation

In accordance with the G-IRB FAQ 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.

Clinical Trial Lifecycle > Submission Process
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and GBR-9, the United Kingdom (UK) requires the sponsor or his/her designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. The MHCTR, the G-MHRA-CTApp, and GBR-103 also state that if the sponsor is not based in the European Economic Area (EEA), he/she must appoint a legal representative located in the EEA.

The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the ethics committee (EC) review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal. Note that per GBR-9, in the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK and whether or not it has started outside the UK.

According to the G-MHRA-CTApp, the sponsor or his/her designated representative must apply for a EudraCT (GBR-87) number, which is a prerequisite to creating a clinical trial application as well as submitting an EC application to the Integrated Research Application System (IRAS) (GBR-78) – the UK’s electronic system for applying for and managing research approvals. The EudraCT number is a unique European Union (EU)-wide reference number assigned to a trial that is used by the review bodies (the MHRA and ECs) to exchange trial-related information. Only after receiving a EudraCT number can the sponsor or his/her designated representative generate a clinical trial application electronically via the EU’s EudraCT database or the UK’s IRAS database. (See GBR-87 and GBR-79 for detailed information on the EudraCT system.) Both systems provide a saved data file in the form of an XML file, which is stored on the sponsor’s or his/her designated representative’s local hard drive, can be shared across both systems, and can be generated into PDF files. However, per GBR-78, IRAS is the most efficient submission option because it enables researchers to enter the information required by the UK review bodies only once, rather than having to complete several separate application forms to obtain these permissions and approvals.

As described in GBR-78, other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the NIHR Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

(See Clinical Trial Lifecycle topic, Submission Content subtopic for detailed submission content requirements).

Single Submission Pilot

Per GBR-72, the Health Research Authority (HRA) and MHRA are running a pilot to improve the approval and ongoing management process for clinical trials of investigational products (known as clinical trials of investigational medicinal products (CTIMPs) in the UK). The process involves a single submission, combined communications to request any further information required, and a single communication to confirm the final decision.

The pilot is currently open to applications by prior agreement only. To express interest, submit an application for the pilot to email cwow.admin@nhs.net and include “combined ways of working pilot” in the subject line. Application materials are provided in GBR-72. The pilot process requires a single application dossier for both the clinical trial authorization and the EC opinion. In England and Wales this will also incorporate HRA and Health and Care Research Wales (HCRW) approval.

Each EC has a submission period within which applications must be submitted. Participating ECs, their schedules and deadlines, and other resources are included in GBR-72.

Submitting the Clinical Trial Application

Per G-MHRA-CTApp, clinical trial applications to MHRA can be submitted electronically using the Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

Per GBR-41, applications for ethics review should be submitted on IRAS.

Assembly and Number of Copies

Based on information provided in the G-MHRA-CTApp, GBR-17, and GBR-88, once the sponsor or his/her designated representative obtains a EudraCT number by registering his/her clinical trial application in the EudraCT database, he/she must download and complete the clinical trial application form on EudraCT or IRAS. Per the G-MHRA-CTApp, XML and PDF versions must be created for the form, and all documents to be included in the application package must have copy and paste functionality. When completed, the form should be saved and signed electronically, and submitted along with the rest of the required documents.

Application files may be saved and prepared on a local computer prior to uploading to EudraCT, IRAS, or the HMA CESP for submission to the MHRA. Information included in the submission package will be used to validate the application; incomplete applications will be rejected. Per the G-MHRA-CTApp and GBR-85, the CESP is only used to submit files, not to download files to a local computer. Refer to GBR-87, GBR-79, GBR-17, and GBR-88 for detailed EudraCT application submission instructions, GBR-78 for IRAS submission information, and the G-MHRA-CTApp and GBR-85 for CESP submission information. (See Clinical Trial Lifecycle topic, Submission Content subtopic for documentation to be included in the application package.)

According to GBR-82, all EC forms and their associated supporting documentation should be submitted electronically via IRAS, thereby eliminating the need to submit any hard copies. GBR-9 and GBR-82 state that the chief investigator (CI) must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee (REC)’s Online Booking Service (GBR-95). Detailed instructions about submitting EC applications through IRAS are available at GBR-78 and GBR-94.

Clinical Trial Application Language Requirements

As delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

Last content review/update: February 05, 2020

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's (FDA) 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 FD&CAct) 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 Regulatory Authority topic, Scope of Assessment subtopic 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.

Delivery Address for Investigational New Drug Applications (INDs)

According to USA-53 and USA-41, paper submissions of INDs should be sent to the following locations:

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 Products:
U.S. 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

Assembly and Number of Copies

Currently, IND submissions may be submitted in either paper or electronic format.

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

According to the G-PharmeCTD, which implements section 745A(a) of the FD&CAct, and as described in USA-34, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this 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). For more information, and detailed requirements, see the G-PharmeCTD and G-eCTDTech. 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, USA-34, and USA-7, eCTD submissions sized 10GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (USA-44). See USA-8 for information on how to create an account.

As indicated in the G-eCTDspecs, physical media should comply with the following requirements:

  • For submissions between 10 and 45GB - use a CD-ROM (CD-R) or DVD (DVD-R, DVD+R, DVD+/-R)
  • For submissions greater than 45GB - use a USB drive (Note: email CDER (ESUB@fda.hhs.gov) or CBER (ESUBPREP@fda.hhs.gov) for specific instructions on how to send

See the G-eCTDspecs for additional physical media information.

Clinical Trial Application Language Requirements

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.

Clinical Trial Lifecycle > Submission Content
Last content review/update: March 19, 2020

Overview

As set forth in the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and GBR-9, the Medicines and Healthcare Products Regulatory Agency (MHRA) requires the sponsor or his/her designated legal representative to apply for clinical trial authorization, and the chief investigator (CI) to apply for a favorable opinion from a recognized ethics committee (EC). (See the Ethics Committee topic for detailed coverage of EC operations and responsibilities.)

MHRA Requirements

As specified in the MHCTR and the G-MHRA-CTApp, a clinical trial application submission should contain PDF and XML files for each of the following documents sent to the MHRA:

  • Cover letter (when applicable, this should include a statement that the submission is for a Phase I trial eligible for the shortened assessment time)
  • Sponsor or designated representative name and contact information
  • Investigator(s) contact information
  • Clinical Trial Application
  • Protocol and description of proposed trial
  • Copy of EC opinion, if available
  • Investigator’s Brochure (IB) or document replacing the IB
  • Investigational Medicinal Product Dossier (IMPD) or simplified IMPD
  • Non-Investigational Medicinal Product (NIMP) Dossier (if required)
  • Informed consent form (ICF)
  • Scientific advice - A summary of scientific advice from any Member State or the European Medicines Agency (EMA) regarding the trial (if available)
  • EMA Decision - A copy of the EMA’s Decision on the Pediatric Investigation Plan and the opinion of the Pediatric Committee (if applicable)
  • Investigational Medicinal Product (IMP) labeling content (or justification for its absence)
  • Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) plus Qualified Person (QP) declaration on Good Manufacturing Practice (GMP) for each manufacturing site
  • Manufacturer or importer contact information

Refer to the MHCTR and the G-MHRA-CTApp for detailed submission information.

EC Requirements

As per the MHCTR, the Guideline for Good Clinical Practice E6 (R2) (GBR-20), and GBR-77, ECs require the CI to submit the following documentation for ethics approval:

  • Application for an EC opinion (including EudraCT number)
  • A summary of the trial, including justification, relevance, and methodology to be used
  • Research hypothesis
  • Statistical analysis and justification for the numbers of participants to be recruited
  • Protocol
  • IB
  • Peer review process details
  • Sponsor name and contact information
  • Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (see Sponsorship topic, Compensation subtopic for additional information)
  • Terms of agreement between sponsor and participating institution(s)
  • Material to be used (including advertisements) to recruit potential research participants
  • ICF and copies of materials to be provided to participants (See Informed Consent topic, Required Elements subtopic for additional information)
  • Participant treatment plans
  • Benefit/risk assessment for participants
  • Investigator(s) Curriculum Vitaes (CVs)
  • Trial design and suitability of facilities

Additionally, according to GBR-95, the CI must submit the electronic application to the Integrated Research Application System (IRAS) (GBR-78) on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee’s Online Booking Service (GBR-95). EC reviews are booked through the CBS and will be booked in the first available slot for an EC that is suitable for the type of study. ECs are geographically located across the UK. Applicants are strongly encouraged to attend meetings in person. Some studies must be reviewed by an EC that is flagged for the type of research to take place. Refer to GBR-95 for detailed submission and booking instructions.

Clinical Protocol

According to GBR-20, the clinical protocol should contain the following elements:

  • Protocol Summary
  • Sponsor or designated representative name and contact information
  • Investigator(s) CV(s) and contact information
  • Investigational Product description (See Investigational Products topic for detailed coverage of this subject)
  • Form, dosage, route, method, and frequency of administration; treatment period
  • Trial objectives and purpose
  • Trial design, random selection method, and blinding level
  • Participant selection/withdrawal
  • Participant treatment
  • Summary of potential risks and known benefits to research participants
  • Safety and efficacy assessments
  • Adverse event reporting requirements (See Clinical Trial Lifecycle topic, Safety Reporting subtopic for additional information)
  • Statistics and methods to track trial data
  • Sponsor specifications for direct access to source data/documents
  • Quality control/quality assurance procedures and practices
  • Ethical considerations
  • Data management and recordkeeping
  • Financing and insurance details
  • Publication policy

For complete protocol requirements, refer to GBR-16 and GBR-20.

Last content review/update: February 05, 2020

Overview

As set forth 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's (FDA) review and authorization to obtain an agency exemption to ship investigational drugs and biological products across state lines and to administer these investigational products (IPs) in humans. See the Regulatory Authority topic, Scope of Assessment subtopic for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) approval of the proposed clinical trial is required prior the sponsor being permitted to initiate the study.

FDA IND Requirements

As specified in 21CFR312, the IND must include the following documents, in the order provided below:

  • Cover sheet (Form FDA 1571) (including, but not limited to: sponsor contact information, IP name, application date, phase(s) of clinical investigation to be conducted, and commitment that the EC will conduct initial and continuing review and approval of each study proposed in the investigation) (See USA-40)
  • 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 investigational drug
  • Additional information
  • Relevant information (e.g., foreign language materials and number of copies - see Submission Process subtopic for details)

For detailed application requirements, see 21CFR312.

Furthermore, 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.

EC Requirements

Each EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies supplied and application format 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 CommonRule, the RevisedCommonRule, 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:

  • Clinical protocol
  • Informed consent forms (ICFs) and participant information, (the RevisedCommonRule 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 to protect participant privacy and maintain confidentiality of data are made, 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 RevisedCommonRule, which took effect January 21, 2019, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants.

See 21CFR56, the CommonRule, the RevisedCommonRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

  • 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 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.

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.

Clinical Trial Lifecycle > Timeline of Review
Last content review/update: March 19, 2020

Overview

Based on the MHCTR, the MHCTR2006, GAfREC, and GBR-9, the sponsor or his/her designated representative must submit an application for clinical trial authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA)'s, and the chief investigator (CI) must submit an application to a recognized ethics committee (EC) to obtain a favorable opinion prior to the trial’s commencement. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal to the Integrated Research Application System (IRAS) (GBR-78), EudraCT, or the Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

MHRA Approval

Clinical Trial Application Submission

As per the MHCTR and the G-MHRA-CTApp, the MHRA review and approval process for a clinical trial application takes 30 days. For Phase I trials, the average is 14 days. According to the G-MHRA-CTApp, if the sponsor or his/her designated representative is required to submit an amended application, the MHRA provides a response to the amendment within 60 days of receipt of the original application. Additionally, responses for Phase I healthy volunteer studies will be reviewed within an average of 14 days, and studies using gene therapy, somatic cell therapy (including xenogenic cell therapy) products or products containing genetically modified organisms will be reviewed within 90 days or receipt of the original application.

The MHCTR and the G-MHRA-CTApp specify that the MHRA coordinates the clinical trial application process. Upon receipt, the MHRA’s Information Processing Unit conducts an application validation. If the application is validated, the sponsor or his/her designated legal representative is sent an acknowledgement. The G-MHRA-CTApp states that MHRA has moved from paper to automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. The MHRA’s Clinical Trials Unit (CTU) assessment period begins from the date of receipt (Day 0) of a valid application. According to the MHCTR, if the sponsor or his/her designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

In addition, as stated in the G-MHRA-CTApp and GBR-35, certain first-in-human (Phase I) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines before approval for the trial can be given. See the G-MHRA-CTApp and GBR-35 for detailed requirements.

Notification Scheme Submission

The G-MHRA-CTApp and GBR-82 indicate that in place of a standard application, a notification of a clinical trial may be submitted for “Type A” trials. This includes trials involving medicinal products licensed in any EU Member State that meet the following criteria:

  • they relate to the licensed range of indications, dosage and form, or,
  • they involve off-label use established by practice and supported by published evidence and/or guidelines

Type A trials include studies in which the potential risk associated with an investigational medicinal product is determined to be no higher than that of standard medical care. See the G-MHRA-CTApp and GBR-82 for detailed Notification Scheme requirements.

Upon receipt of the notification, the MHRA sends an acknowledgement to the sponsor or his/her designated representative stating that the trial may proceed if an objection is not raised within 14 days. If the MHRA does not send a Notification Objection letter, the acknowledgement serves as the authorization. If the MHRA raises objections, the submission is treated as a standard request for authorization, and the CTU initial assessment is performed within 30 days. For the purposes of this calculation, the day of receipt of the valid notification by the Clinical Trials Unit is Day 0.

Ethics Committee Approval

As specified in the MHCTR, GAfREC, GBR-9, and GBR-68, an EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion, and it is permitted to make one (1) written request for further information, clarification, or changes to documentation. The time it takes for the EC to receive a complete response to the request does not count against the 60-day timeline. Studies using gene therapy, somatic cell therapy (including xenogenic cell therapy) products or products containing genetically modified organisms will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR.

As delineated in GBR-9, the CI is responsible for submitting an application to an EC via IRAS. GBR-95 indicates that the CI must submit the electronic application to IRAS on the same day that a booking is made to schedule an EC review through the National Health Service (NHS) Research Ethics Committee’s Online Booking Service (GBR-95).

Per GBR-9, the ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK. See the Ethics Committee topic, Scope of Review subtopic for additional information on the “main EC.”

Last content review/update: February 05, 2020

Overview

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of clinical investigation may be conducted in parallel with the Food & Drug Administration’s (FDA) 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.

FDA IND Review and Authorization

Per the FD&CAct, 21CFR312, USA-5, and USA-15, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) review teams will evaluate all initial INDs for drugs and therapeutic biological products respectively. Within 30 calendar days of receipt of the original IND, the CDER/CBER team will contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team 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. An IND automatically goes into effect in 30 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.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND application, 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/sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND application should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed. Clinical studies shall not be initiated until 30 days after the date of receipt of the IND application by the FDA unless earlier notification is received from the FDA that studies may begin.

EC 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.

Clinical Trial Lifecycle > Trial Initiation
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, GAfREC, and GBR-9, a clinical trial can only commence after the sponsor or his/her designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). No waiting period is required following the applicant’s receipt of these approvals.

The MHCTR, the G-MHRA-CTApp, and GBR-103 also state that if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA. The G-MHRA-CTApp permits MHRA’s review process to be conducted in parallel with the EC review, stating that an EC opinion may be obtained before, during, or after the MHRA application submittal. Furthermore, GBR-9 states that the CI should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

In addition, per the MHCTR, the G-MHRA-CTApp, and GBR-59, a Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any investigational product (IP) (known as investigational medicinal product (IMP) in the UK) to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. (See Clinical Trial Lifecycle topic, Submission Content subtopic, and the Investigational Products topic, Manufacturing & Import subtopic for detailed submission and IMP requirements respectively).

As stated in the MHCTR and GBR-51, which comply with the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6(R2) (GBR-20), all investigators must possess appropriate qualifications, training, and experience. The trials should be conducted in compliance with GBR-20, and laboratory practices for investigational products must comply with the UK-GLPs.

GBR-42 indicates that the CI, in conjunction with the sponsor, should ensure that all trial documentation has been prepared and version controlled. For multi-site trials, the CI will ensure that each PI is provided with all relevant, version-controlled documents before commencing recruitment. See GBR-42 for a suggested guide of documents that should be in place before a trial can commence.

Governance Approval

Per GBR-78, all project-based research must also apply for governance and legal compliance approvals from the appropriate lead UK Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-96 and GBR-67, approval from the Health Research Authority (HRA) is required for all project-based research in the National Health Service (NHS) led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29.

Clinical Trial Agreement

According to GBR-81 and GBR-107, contracts and agreements should be in place prior to the initiation of a trial. GBR-81 explains that trial contracts and agreements can be formed at many levels, internal or external and both legal or non-legal. Examples (in GBR-81, GBR-107, and GBR-70) include, but are not limited to:

  • Co-sponsorship agreements (defining the legal responsibilities taken on by parties under the regulations)
  • Funding agreements
  • Clinical trial agreement/site, including between the investigators and the sponsor or his/her designated representative
  • Collaboration agreements
  • Intellectual property agreements
  • Commercialization agreements
  • Service level agreements (with external suppliers such as central laboratories, external statisticians)
  • Material transfer agreements (handling requirements for materials, such as tissue samples, transferred from one organization to another)
  • Pharmacy technical agreements
  • Agreement between the sponsor or his/her designated representative and the participating institution(s)

Additional details and templates are available in GBR-81, GBR-107, and GBR-70.

EC Confirmation of Review and Approval

The MHCTR and the MHCTR2006 mandate that the sponsor or his/her designated representative is responsible for ensuring that the CI has obtained confirmation of the EC’s approval. Per the G-MHRA-CTApp, an EC opinion may be obtained before, during, or after the MHRA application has been electronically submitted to IRAS, the EudraCT database, or the Common European Submission Portal (CESP). Per GBR-9, the EC’s final opinion will be in a letter from the Chair of the Committee (or chair of the sub-committee in the case of proportionate review). It is also acceptable for the letter to be signed by a vice-chair or a member of the staff supporting the EC acting under delegated authority from the Chair. The letter is emailed to the applicant within the relevant time limit for review of the application. The final favorable opinion letter can be obtained from IRAS. The EC must notify MHRA of the final opinion so that it can be entered in the EudraCT database. The MHRA is notified automatically through its access to the HRA Assessment Review Portal (HARP), which is a database for authorized users (e.g. EC members and regulators) who manage or review studies submitted to HRA.

As per the MHCTR and GBR-9, the sponsor or his/her designated representative should also notify the EC of any substantial amendments to the protocol, and submit all relevant documents in support of such amendments. These amendments may not be implemented without a favorable opinion from the EC. (See Ethics Committee topic, Scope of Review subtopic and Clinical Trial Lifecycle topic, Submission Content subtopic for additional details on the EC review and approval process).

Clinical Trials Registry

As per GBR-102, the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. HRA recognizes any register covered by the World Health Organization (WHO) list or the International Committee of Medical Journal Editors (ICMJE). Failure to register in this database will be treated as a breach of good research practice.

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR312, 21CFR56, and USA-42, a clinical trial can only commence following the Food & Drug Administration (FDA)’s review of the investigational new drug application (IND) within 30 calendar days of receiving the IND and ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)). No waiting period is required following the 30-day review period unless the FDA imposes a clinical hold on the IND.

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 Investigational Products topic, Manufacturing & Import subtopic for additional information).

Clinical Trial Agreement

As stated in 21CFR312 and the US-ICH-GCPs, all investigators must possess appropriate qualifications, training, and experience. Prior to the trial’s commencement, as addressed in the G-1572, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (See USA-40). This form serves as the investigator’s agreement to provide certain information to the sponsor and to assure that he/she will comply with the FDA’s clinical investigation regulations. Refer to the G-1572 and USA-40 for further information.

EC Confirmation of Review and Approval

Per 21CFR56, 21CFR312, the CommonRule, and the RevisedCommonRule, EC review of the clinical investigation must be obtained prior to the sponsor being permitted to initiate the trial.

Clinical Trials Registry

FDAMA, 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. Per FDAAA, 42CFR11, and USA-26, the sponsor/PI must register 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) has also issued a policy (USA-23) 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.

See 42CFR11, USA-26, USA-49, and USA-23 for detailed information on ClinicalTrials.gov.

Data and Safety Monitoring Board (DSMB)

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 additional DSMB/DMC establishment requirements.

The US-ICH-GCPs recommends establishing a Data and Safety Monitoring Board 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.

Additionally, as indicated in the CommonRule and the RevisedCommonRule, for all human subjects research funded and/or sponsored by the Department of Health & Human Services (HHS), the institutional EC shall ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety and privacy. Moreover, per USA-22 and USA-72, all 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 including interventions that involve potential participant risk. See USA-22 and USA-72 for detailed HHS/NIH requirements.

Clinical Trial Lifecycle > Safety Reporting
Last content review/update: March 19, 2020

Overview

According to GBR-18, GBR-1, and GBR-64, the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

  • Adverse Event (or Adverse Experience) (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
  • Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
  • Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected Serious ADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
  • Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
  • Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question.

Per the G-MHRA-CTAuth, the Medicines and Healthcare Products Regulatory Agency (MHRA) recommends full compliance with reference safety information contained in GBR-30. The guidance was developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA).

Reporting Requirements for AEs/ADRs

Investigator Responsibilities

As specified in the MHCTR and GBR-18, GBR-1, and GBR-30, the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing, and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR and GBR-18, in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

Sponsor Responsibilities

According to the MHCTR, the G-MHRA-CTAuth, GBR-18, and GBR-99, the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days, to the MHRA, to the competent authorities of any other European Economic Area (EEA) Member State other than the UK, in which the trial is being conducted, and to the ethics committee (EC). Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life-threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

As per the MHCTR, the G-MHRA-CTAuth, GBR-18, GBR-1, and GBR-30, the sponsor or his/her designated representative must also provide the MHRA and the EC with an annual list of SUSARs related to all trials, both within and outside of the UK, and within 60 days of the reporting date. The list of SUSARs is provided in an annual report, which is referred to as a Development Safety Update Report (DSUR). The DSUR also provides all new available safety information received during the reporting period. According to GBR-99, the Development International Birth Date (DIBD) is used to determine the start of the annual period for the DSUR. This date is the sponsor’s first authorization to conduct a clinical trial in any country worldwide. The start of the annual period for the DSUR is the month and date of the DIBD. See the G-MHRA-CTAuth for detailed DSUR submission instructions.

Per GBR-99, a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main EC, and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than within three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. The G-MHRA-CTAuth states that to determine whether the action being taken is a USM, GBR-19 should be consulted. Further, the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform MHRA no later than three (3) days from the date the measures are taken by email to clintrialhelpline@mhra.gov.uk. Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. When submitting a substantial amendment via the Common European Submission Portal (CESP), select ‘Regulatory Activity Type: Clinical Trial’ and not ‘Urgent Safety Restriction Procedure’.

See the MHCTR, GBR-18, GBR-1, GBR-30, and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

As per the MHCTR, the G-MHRA-CTAuth, and GBR-18, all SUSARs must be reported electronically by the sponsor or his/her designated representative and the institutions responsible for trial safety reporting by using the MHRA’s eSUSAR website (GBR-50) or the EudraVigilance System (GBR-55). See the G-MHRA-CTAuth, GBR-1, GBR-7, GBR-20, and GBR-50 for detailed reporting requirements.

Data Monitoring Committee (DMC)

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to GBR-55, researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see GBR-56.

The Guideline for Good Clinical Practice E6(R2) (GBR-20) recommends establishing a DMC 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.

Last content review/update: February 05, 2020

Overview

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

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

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

Reporting Requirements for AEs/ARs

Investigator Responsibilities

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

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

Sponsor Responsibilities

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

The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after he/she determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening SAR as soon as possible, but no later than seven (7) calendar days following his/her 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 IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
  • Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
  • Any clinically important increase in the rate of an SSAR over that listed in the protocol or IB

In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar SAR, and must analyze the significance of the SAR in light of previous, similar reports, or any other relevant information. Please 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, 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of AE/adverse drug reaction (ADR) information. The tables should consist of the following summarized data:

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

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 that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

See 42CFR11 for detailed AE/ADR reporting requirements.

Form Completion and Delivery Requirements

As per 21CFR312, the G-IND-Safety, and USA-38, the sponsor must submit each safety report in a narrative format, on FDA Form 3500A, or in an electronic format that the FDA can process, review and archive, and be accompanied by Form FDA 1571 (cover sheet) (See USA-38 and USA-48).

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 also be submitted to the appropriate review division (Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER)). Additionally, the FDA will accept foreign SARs on a CIOMS Form I (See USA-13 and USA-3) instead of FDA Form 3500A (See USA-48).

Data and Safety Monitoring Board (DSMB)

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 additional DSMB/DMC establishment requirements.

The US-ICH-GCPs recommends establishing a DSMB 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.

Additionally, as indicated in the CommonRule and the RevisedCommonRule, for HHS funded or sponsored human subjects research, the institutional EC shall ensure that, when appropriate, the research plan makes adequate provision for monitoring the data collected during the study to ensure participant safety.

Moreover, per USA-22 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 specifically required for NIH-funded multi-site clinical trials including interventions that involve potential participant risk. See USA-22 and USA-72 for detailed HHS/NIH requirements.

Clinical Trial Lifecycle > Progress Reporting
Last content review/update: March 19, 2020

Overview

As indicated in the G-MHRA-CTAuth and GBR-43, GBR-65, GBR-9, and GBR-7, the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (GBR-20).

Interim/Progress Reports

As stated in GBR-43, the investigator is required to send progress reports to interested parties, including the sponsor and the ethics committee (EC), throughout the trial. In accordance with GBR-43, GBR-65, GBR-9, and GBR-7, the chief investigator (CI) is responsible for submitting progress reports annually, or more frequently if requested by the EC, on the status of a clinical trial. The CI must complete the annual progress report form listed in GBR-27 and send it to the main EC, or, the EC reviewing the original application. See Ethics Committee topic, Scope of Assessment subtopic for additional information on the “main EC.”

Final Report

As per the MHCTR and the G-MHRA-CTAuth, the sponsor must notify MHRA and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. The G-MHRA-CTAuth further specifies that a declaration of the end of a clinical trial should be sent to MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. Per GBR-40, the sponsor should use the EudraCT End of Trial Declaration form (GBR-24). The G-MHRA-CTAuth states that end of trial declarations must be submitted via the Common European Submission Portal (CESP).

Per the G-MHRA-CTAuth, the sponsor must upload end of trial summary results to EudraCT. For pediatric clinical trials, the sponsor should post the summary within six (6) months of the end of the trial; all other trials are within one (1) year of the end of the trial. The sponsor does not need to submit the clinical trial summary report to the MHRA. However, the sponsor must send a short confirmation email to CT.Submission@mhra.gov.uk once the results have been uploaded to EudraCT with ‘End of trial: result-related information: EudraCT XXXX-XXXXXX-XX’ as the subject line.

As per GBR-9, which complies with GBR-20, the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. There is no standard format for final reports. However, the minimum information to be provided to the EC should include whether the trial achieved its objectives, the main findings, and arrangements for publication or dissemination of research.

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting final study reports upon the trial’s completion.

Interim/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.

Annual Report

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 (IND) went into effect. The report must contain the following information for each study:

  • Title, purpose, 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 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, USA-70, and USA-49, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product clinical trials to ClinicalTrials.gov 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 ClinicalTrials.gov 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.

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 42CFR11 for more detailed requirements.

Sponsorship > Definition of Sponsor
Last content review/update: March 19, 2020

Overview

As per the MHCTR, the MHCTR2006, GBR-103, GBR-9, GBR-2, and the Guideline for Good Clinical Practice E6(R2) (GBR-20), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards, and arrange for the trial to be properly conducted and reported. In addition, per GBR-101, the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-20, the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control.

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA), and to specify who is responsible for carrying out the following functions:

  • Communications relating to substantial amendments, modified amendments, and the conclusion of the trial
  • Communications relating to urgent safety measures
  • Pharmacovigilance reporting

As stated in the MHCTR, the sponsor must either be established in the European Economic Area (EEA), or designate a legal representative who is established in the EEA. The MHCTR, GBR-103, and GBR-2 also specify that the sponsor may delegate any or all of his/her trial-related duties and functions to a CRO. However, the sponsor must ensure that this arrangement is formally agreed upon and documented.

For purposes of data protection requirements, the GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database.

Last content review/update: February 05, 2020

Overview

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. The term does not include any person other than an individual.

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

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

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

Sponsorship > Trial Authorization
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, the G-MHRA-CTApp, GBR-2, and GBR-9, the sponsor or his/her designated representative is responsible for submitting a clinical trial application to the Medicines and Healthcare Products Regulatory Agency (MHRA) to obtain authorization to conduct a clinical trial. The MHCTR, the G-MHRA-CTApp, and GBR-9 also state that if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA.

As delineated in the G-MHRA-CTApp, GBR-87, and GBR-79, to complete the clinical trial application package, the sponsor or his/her designated representative must apply for a EudraCT number, which is a prerequisite to creating a clinical trial application. The EudraCT number is a unique European Union (EU)-wide reference number assigned to a trial that is used by the review bodies (the MHRA and the ethics committees (ECs)) to exchange trial-related information. Only after receiving a EudraCT number can the sponsor or his/her designated representative generate a clinical trial application via the EU’s EudraCT database or the UK’s Integrated Research Application System (IRAS)'s database (GBR-78). Both systems provide a saved data file in the form of an XML file, which is stored on the sponsor’s or his/her designated representative’s local hard drive, can be shared across both systems, and can be generated into PDF files. However, per GBR-78, IRAS is the most efficient submission option because it enables researchers to enter the information required by all UK review bodies only once, rather than having to complete several separate application forms to obtain these permissions and approvals.

The submission package may then be uploaded to EudraCT, IRAS, or the Heads of Medicines Agencies (HMA)'s Common European Submission Portal (CESP) for submission to the MHRA. Per the G-MHRA-CTApp and GBR-85, the CESP is only used to submit files, not to download files to a local computer. Refer to GBR-87, GBR-79, GBR-17, and GBR-88 for detailed EudraCT application submission instructions, and GBR-85 for CESP submission information. (See the Clinical Trial Lifecycle topic, Submission Content subtopic for documentation to be included in the application package.)

In addition to the completed application, per the MHCTR and the G-MHRA-CTApp, the sponsor or his/her designated representative must provide the MHRA with a copy of the EC opinion (if available), the clinical protocol, the investigator’s brochure, a signed declaration by the investigators, a certificate of good manufacturing practice for the manufacture of the trial medicine, and other documentation covered in the Clinical Trial Lifecycle topic, Submission Content subtopic.

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR312, USA-42, and USA-52, the sponsor is responsible for submitting an investigational new drug application (IND) for the Food & Drug Administration's (FDA) review to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans.

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

Per 21CFR312, to complete the IND application package, the sponsor must provide the following information in paper format or electronically:

  • Cover sheet (Form FDA 1571) (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 EC will conduct an initial and continuing review and approval of each study proposed in the investigation) (See USA-40)
  • Protocols
  • Chemistry, manufacturing, and control data
  • Pharmacology and toxicology data
  • Previous human experience with the investigational drug

Additional documentation and paper/electronic submission instructions are covered in the Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics.

Furthermore, 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.

Sponsorship > Insurance
Last content review/update: March 19, 2020

Overview

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial related injuries. The MHCTR does not ascribe responsibility to the sponsor or his/her designated representative to obtain insurance and indemnity. However, GBR-2, GBR-103, and GBR-101, state that the sponsor or his/her designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2, the sponsor or his/her designated representative must ensure that the research covered by the National Health Service (NHS)'s indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33, specifically addresses the sponsor’s or his/her designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase I clinical trials.

See the Sponsorship topic, Compensation subtopic and Informed Consent topic, Compensation Disclosure subtopic for specific details related to sponsorship compensation obligations.

Last content review/update: February 05, 2020
No relevant provisions
Sponsorship > Compensation
Last content review/update: March 19, 2020

Overview

As specified in the MHCTR, the sponsor or his/her designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase I trial-related injuries or death.

According to GBR-33, the sponsor or his/her designated representative may be required to follow the principles set forth in the Association of the British Pharmaceutical Industry (ABPI)’s guidelines to comply with the United Kingdom (UK)’s participant compensation and treatment requirements due to Phase I trial-related injuries.

The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or his/her legal heirs in the event of trial-related injuries or death whenever a causal relationship with participation is demonstrated. The investigator, in turn, communicates this information to the relevant ethics committees (ECs).

See the Informed Consent topic, Compensation Disclosure subtopic for additional information.

Last content review/update: February 05, 2020

Overview

The United States (US) regulations do not require compensation for trial participants either for participation in a trial or in the event of trial-related injuries or death.

However, as specified in 21CFR50, the CommonRule, the RevisedCommonRule, and US-ICH-GCPs, for research involving more than minimal risk, the sponsor is responsible for providing information as to whether there is compensation to research participants and/or their legal heirs in the event of trial-related injuries. The sponsor must also inform participants who suffer any trial-related injuries of any available medical treatments, what they consist of, and where further information can be obtained.

As per USA-20, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence, and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the Food & Drug Administration (FDA). Further, 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.

Sponsorship > Quality, Data & Records Management
Last content review/update: March 19, 2020

Overview

As stated in the MHCTR, the MHCTR2006, and GBR-92, the sponsor is responsible for maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6(R2) (GBR-20). The sponsor is required to obtain 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.

The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

  • Conduct the trial in compliance with GBR-20 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
  • Comply with data recording and reporting procedures
  • Permit monitoring, auditing, and inspection
  • Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to effect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches, the sponsor, or delegated party, should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: GCP.SeriousBreaches@mhra.gov.uk.

Per GBR-110, MHRA accepts a risk-adapted approach to trial management. Early in the protocol design stage, researchers should ask what are the critical processes and critical data for this trial and how best can any risks and/or vulnerabilities identified in these areas be mitigated. For more information on risk-adapted trial management, see GBR-110.

Data Protection

Per the GDPR, the UK-DPAct, and the G-GDPR, the sponsor (known as the “controller” in data protection legislation) must comply with the principles of the data protection legislation:

  • Lawfulness, fairness, and transparency
  • Purpose limitation
  • Data minimization
  • Accuracy
  • Storage limitation
  • Integrity and confidentiality (security)
  • Accountability

The sponsor must show that each activity of processing data has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the type of organization that is the data controller for the processing:

  • For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
  • For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data starting from May 25, 2018. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100 and GBR-89. For additional information about consent and individual rights, see the Informed Consent topic, Documentation Requirements and Required Elements subtopics.

Per the GDPR, the UK-DPAct, and GBR-110, the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments, and is a point of contact for participants and the supervisory authority.

Electronic Data Processing System

GBR-44 states that source data and other essential documents may be kept in electronic format. See GBR-44 for more information and resources on electronic health records and systems, GCP inspections, and European Commission Guidance Documents.

According to GBR-20, 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 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.

Record Management

As set forth in GBR-20, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request, and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

Per GBR-45, a trial master file (TMF) should be set up at the beginning of a trial. The essential documents that make up the file should be kept in a secure but accessible manner. A well-kept TMF can help with efficient trial management and can facilitate the audit/inspection process. The TMF should be held at the coordinating site (usually the Chief Investigator’s office or Coordinating Center) and for multi-site trials, copies of relevant documents should be kept at each participating site in an investigator site file (ISF). Most sponsors will provide guidance on the content and setup of the TMF/ISF based on their local policies/procedures. The TMF/ISF should be maintained throughout the course of the trial. See GBR-45 for additional details and guidance.

In addition, GBR-20 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.

Audit Requirements

Per GBR-39, the sponsor is responsible for developing an audit plan for the trials they manage. The audit should assess and assure the reliability and integrity of a sponsor’s trial systems against all relevant written standards. Activities and system checks that may be undertaken during an audit include staff interviews, facility tours, and document reviews. Auditors should be independent of the trial team/process and trained for their role. Findings and observations from any audit conducted should be documented in a formal audit report. Any deficiencies identified during an audit should be rectified with appropriate corrective and preventive actions wherever possible.

As part of its QA system, GBR-20 notes that the sponsor should ensure the trial is monitored. If or when the sponsor performs an audit, the purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, GBR-20, 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 auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Premature Study Termination/Suspension

The G-MHRA-CTAuth states that if a trial is prematurely terminated or suspended, the sponsor should inform the MHRA and the EC no later than 15 days after the termination or suspension. The notification should be made as a substantial amendment using the notification of amendment form (GBR-25), and explain what has been stopped and the reasons for the suspension. To terminate a trial, the sponsor should complete the end-of-trial declaration form (GBR-24) and include a brief explanation of the reasons for ending the trial. Both types of forms should be submitted using Heads of Medicines Agencies (HMA) Common European Submission Portal (CESP).

According to GBR-20, 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.

Multicenter Studies

As delineated in GBR-20, 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
  • 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 between investigators is facilitated

Data Monitoring Committee (DMC)

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to GBR-43, researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see GBR-10.

GBR-20 recommends establishing a DMC 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.

Last content review/update: February 05, 2020

Overview

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.

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 SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the US-ICH-GCPs for additional information.

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

Record 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 marketing application (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.

Audit 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 auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Premature Study Termination/Suspension

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

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

Multicenter Studies

In the event of multicenter clinical studies, also known as cooperative research studies, which are required to comply with the RevisedCommonRule, all federally-funded or sponsored institutions that are located in the US and engaged in multicenter research must use a single EC to review that study, known as the IRB policy. This policy will streamline the EC review process and eliminate duplicative reviews. The exceptions to this requirement include: when multiple-EC 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 RevisedCommonRule, which took effect January 21, 2019, 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 United States be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

In addition, the US-ICH-GCPs specifies that the sponsor must ensure all investigators conduct the trial in strict compliance with the FDA and EC approved protocol.

Per USA-22 and USA-72, Data Safety and Monitoring Boards are also specifically required for NIH-funded multi-site clinical trials including interventions that involve potential participant risk.

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

Sponsorship > Site/Investigator Selection
Last content review/update: March 19, 2020

Overview

As set forth in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (GBR-20) and GBR-83, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 and GBR-83 indicate that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study.

As delineated in the MHCTR, the MHCTR2006, GBR-20, and GBR-35, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-20, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators.

Although there is no statutory requirement under the MHCTR for a Data Monitoring Committee (DMC), according to GBR-43, researchers should prepare and present interim reports to DMCs, as applicable. For more information on assessing the need for, establishing, and responsibilities and procedures of DMCs, see GBR-10. GBR-20 recommends establishing a DMC 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.

Per GBR-38, adding a new trial site or change of principal investigator constitutes a substantial amendment, which requires notification to the ethics committee (EC). Sites that were listed as potential sites on the original ethics application do not need to be submitted as a substantial amendment.

Per GBR-63, on June 5, 2019, the UK launched the UK Local Information Pack. Researchers working with National Health Service (NHS)/ Health and Social Care in Northern Ireland (HSC) organizations will use one (1) consistent package to support study setup and delivery across the UK. The Statement of Activities (used in England and Wales) and the Site Specific Information form (used in Northern Ireland and Scotland) are being replaced with a UK-wide Organizational Information document. The Organizational Information document will be a component of the IRAS form submission and will be required as part of the UK Local Information Pack for both commercial and non-commercial research. GBR-106 provides guidance, background information, and templates of the commercial and non-commercial versions of the Organizational Information document.

Foreign Sponsor Responsibilities

As per the MHCTR and GBR-103, if the sponsor is not based in the European Economic Area (EEA), it is a statutory requirement for the sponsor to appoint a legal representative located in the EEA. Additional foreign sponsor requirements are listed in Section 5.2 of GBR-20.

Last content review/update: February 05, 2020

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 FD A 1572) (See USA-40)
  • Curriculum vitae
  • Clinical protocol
  • Financial disclosure information

As addressed in the G-1572, Form FDA 1572 (See USA-40) serves as the investigator’s agreement to provide certain information to the sponsor and to assure that he/she will comply with the Food & Drug Administration’s (FDA) clinical investigation regulations. Refer to the G-1572 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.

Data Safety and Monitoring Board

Although not specified as a sponsor requirement, the US-ICH-GCPs states that a Data and Safety Monitoring Board 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.

Foreign Sponsor Responsibilities

No applicable regulatory requirements.

Informed Consent > Documentation Requirements
Last content review/update: March 19, 2020

Overview

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the Guideline for Good Clinical Practice E6 (R2) (GBR-20). As per the MHCTR, the MHCTR2006, and GBR-9, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (GBR-9) issued by England’s Health Research Authority (HRA). The ICF must be provided to the EC with the clinical trial application. (See the Informed Consent topic, Required Elements subtopic for details on what should be included in the form.)

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant, and his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. Per the GDPR and UK-DPAct, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. For more information about the sponsor’s and investigator’s responsibilities to comply with the data protection requirements (e.g., transparency, safeguards, and data rights), see the Sponsorship topic.

As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Re-Consent

According to GBR-16, changes to the protocol might lead to a modification of the PIS and any new participant information should be appended. If there is a need to obtain new consent from the participants, the procedure should be described and approved by the EC before such changes are implemented. The participant and/or his/her legal representative(s) or guardian(s) will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per the G-GDPR, because consent is not a legal basis for processing data under data protection legislation, in most cases researchers will not need to obtain re-consent from existing participants or legal representatives to comply with new data protection requirements.

Language Requirements

As stated in the MHCTR, applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documentation Copies

The MHCTR states that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. Where the participant is illiterate, and/or his/her legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Last content review/update: February 05, 2020

Overview

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, or the CommonRule or the RevisedCommonRule for federally funded or sponsored clinical trials. Department of Health & Human Services (HHS) funded or sponsored clinical trials must also comply with 45CFR46-B-E. The FDA has also adopted the US-ICH-GCPs as guidance.

As per 21CFR50, the CommonRule, the RevisedCommonRule, 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). (See the Informed Consent topic, Required Elements subtopic for ICF content details.)

Per the RevisedCommonRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved informed consent form used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov and a docket folder on Regulations.gov (Docket ID: HHS-OPHS-2018-0021). According to the RevisedCommonRule, 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or his/her 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 his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

Additionally, per the RevisedCommonRule, 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 RevisedCommonRule 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 for additional information regarding informed consent and broad consent requirements.

In addition, per 21CFR50, the CommonRule, and the RevisedCommonRule, 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 his/her legal representative(s) or guardian(s) to read before it is signed.

See G-ElectronicIC for further guidance related to electronic informed consent.

Re-Consent

According to 21CFR50, the US-ICH-GCPs, and USA-63, 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.

USA-63 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or his/her legal representative(s) or guardian(s). As delineated in the G-ICInfoSheet, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language and at a level they can comprehend. The EC must review and approve all English and non-English language versions of consent documents. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available.

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

Documentation Copies

As set forth in 21CFR50, the CommonRule, and the US-ICH-GCPs, the participant and/or his/her legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. The RevisedCommonRule explicitly allows electronic signatures for consent documentation. See G-ElectronicIC for further guidance related to electronic informed consent. A written copy of the form must be given to the participant and/or his legal representative(s) or guardian(s). Per the CommonRule and the RevisedCommonRule, 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 RevisedCommonRule 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.

Per 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, if the consent information is only presented orally using the short form, the participant and/or his/her legal representative(s) or guardian(s) must sign the form (if capable), 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 should be given to the participant and/or his/her legal representative(s) or guardian(s).

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

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

Before participating in the study, the participant or his/her legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

Per the G-RevComRule-FDA, the informed consent requirements of the RevisedCommonRule are consistent 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 RevisedCommonRule and FDA regulations.

Informed Consent > Required Elements
Last content review/update: March 19, 2020

Overview

As delineated in the MHCTR, the MHCTR2006, and the Guideline for Good Clinical Practice E6(R2) (GBR-20), prior to beginning a clinical trial, the chief investigator (CI) is required to obtain a favorable opinion from a recognized ethics committee (EC) for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s).

No Coercion

As per the G-ConsentPIS, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or to appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Participant Information Sheet

Per the G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. As indicated in the G-GDPR and GBR-100, the Health Research Authority (HRA) has developed a series of templates to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study (i.e., before or after May 25, 2018).

Per the GDPR and UK-DPAct, consent to participate in research is not the same as consent as the legal basis for processing under the data protection legislation. For more information about the sponsor’s and investigator’s responsibilities to comply with the data protection requirements (e.g., the lawful basis to hold and use personal data, transparency, safeguards, and data rights), see Sponsorship topic.

Per GBR-31, the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

  • The nature and the complexity of the research
  • The risks, burdens, and potential benefits (to the participants and/or society
  • The ethical issues at stake

ICF Required Elements

Based on the MHCTR, the G-ConsentPIS, and GBR-20, the ICF should 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 duration
  • Study title and the study IRAS ID are clearly displayed
  • Approximate number of participants involved in the trial
  • The participant’s responsibilities in participating in the trial
  • Trial treatment schedule and the probability for random assignment to each treatment
  • Experimental aspects of the study
  • Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
  • Any benefits or prorated payment to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
  • A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
  • Compensation and/or medical treatment available to the participant in the event of a trial-related injury
  • Any additional costs to the participant that may result from participation in the research
  • That participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
  • The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA), the ECs, the auditor(s), and the monitor(s)
  • That the participant and/or his/her legal representative(s) or guardian(s) will be notified if significant new findings developed during the study may affect the participant's willingness to continue
  • Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
  • Foreseeable circumstances under which the investigator(s) may remove the participant without his/her consent

ICF examples and templates are provided in the G-ConsentPIS.

(See the Informed Consent topic, Compensation Disclosure and Vulnerable Populations subtopics and the Specimens topic, Consent for Specimen subtopic for further information.)

For more information about informed consent required elements, see GBR-20, GBR-100, GBR-31, and GBR-69.

Last content review/update: February 05, 2020

Overview

As delineated in 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) (institutional review board (IRB) in the United States (US)) approval for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s). 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that information about the study should be presented in easily understandable language and in a format that facilitates understanding. The participant and/or his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

Per the RevisedCommonRule, 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 and a docket folder on Regulations.gov (Docket ID: HHS-OPHS-2018-0021). According to the RevisedCommonRule, 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.

No Coercion

As indicated in 21CFR50, the CommonRule, the RevisedCommonRule, 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 his/her legal representative(s) or guardian(s) to waive or appear to waive his/her legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

ICF Required Elements

Based on 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, the ICF must include the following statements or descriptions, as applicable:

  • The study purpose, procedures, and expected duration of the trial
  • Identification of any experimental procedures
  • Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
  • Any expected benefits to the participant
  • Disclosure of appropriate alternative procedures that might be advantageous to the participant
  • Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
  • Compensation and/or treatment available for the participant in the case of trial-related injury
  • Contact information for relevant individuals to contact in the event of a trial-related injury
  • That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of benefits to which he/she is otherwise entitled
  • Foreseeable circumstances under which the investigator may remove the participant without his/her 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 http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

The RevisedCommonRule, which took effect January 21, 2019, 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

Per the G-RevComRule-FDA, the informed consent requirements of the RevisedCommonRule are not consistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two separate ICFs for research that must comply with both the RevisedCommonRule and FDA regulations.

Informed Consent > Compensation Disclosure
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the G-ConsentPIS, and GBR-35, the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

Compensation for Participation in Research

As stated in the MHCTR and the Guideline for Good Clinical Practice E6 (R2) (GBR-20), ethics committees should consider, in particular, the provision of indemnity or compensation in the event of injury or death attributable to the trial.

Compensation for Injury

As per the MHCTR and GBR-20, the ICF should contain a statement advising the participant of available compensation and medical treatment in the event of any trial-related injury in a clinical trial.

(See the Informed Consent topic, Required Elements subtopic for additional details on what should be included in the ICF, and the Sponsorship topic, Compensation subtopic for information on sponsor requirements.)

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

USA-18 further states 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).

Compensation for Participation in Research

Per USA-20, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the ethics committee (EC) (institutional review board (IRB) in the United States (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 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.

21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs also state that the ICF should inform the participants if they will need to pay for any expenses in order to participate in the trial.

Compensation for Injury

As per 21CFR50, the CommonRule, the RevisedCommonRule, the US-ICH-GCPs, the G-ICInfoSheet, and USA-18, the participant should be told whether compensation and any medical treatment(s) are available for research involving more than minimal risk. Because available compensation and treatments may vary depending on the medical circumstances of the participant, or, the institutional policies, the consent process should include an explanation of where participants may obtain further information. This information must be explained in the ICF and cannot waive or appear to waive the participant’s rights or release or appear to release those conducting the study from liability for negligence.

According to the G-ICInfoSheet, when no system has been established to provide funds, the preferred wording is: “no funds have been set aside for,” “[the cost] will be billed to you or your insurance,” or similar wording that explains the provisions or the process.

Informed Consent > Participant Rights
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, and the G-ConsentPIS, the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR and the G-ConsentPIS, the participant or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she 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 the MHCTR, and the G-ConsentPIS, a potential research participant and/or his/her legal representative(s) or guardian(s) has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per the MHCTR, the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

Per the GDPR, the UK-DPAct, the G-GDPR, and GBR-89, participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR, exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under GDPR, then the PIS may need to be revised as a non-substantial amendment. For more information about the sponsor’s (called the “controller” in the GDPR) data protection requirements, see the Sponsorship topic, Quality, Data & Records Management subtopic.

The Right of Inquiry/Appeal

The MHCTR states that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR and the MHCTR2006, state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR50, 21CFR312, the CommonRule, the RevisedCommonRule, 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, a potential participant and/or his/her legal representative(s) or guardian(s) must be informed that participation is voluntary, that he/she 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 CommonRule, the RevisedCommonRule, and the US-ICH-GCPs, a potential research participant, and/or his/her legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per 21CFR50, the CommonRule, and the RevisedCommonRule, 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 shall 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 RevisedCommonRule does allow the use of identifiable information or biospecimens in instances where the ethics committee (EC) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information.

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

The Right of Inquiry/Appeal

21CFR50, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs state that the research participant, and/or his/her 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 his/her rights.

The Right to Safety and Welfare

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

Informed Consent > Special Circumstances/Emergencies
Last content review/update: March 19, 2020

Overview

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, and GBR-3 make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product is complicated by special circumstances. Special circumstances include medical emergencies and when a participant is mentally incapacitated.

Medical Emergencies

As delineated in the G-ConsentPIS, GBR-3, and GBR-4, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of his/her legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or his/her legal representative(s) or guardian(s) cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or his/her legal representative(s) or guardian(s) should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

Mentally Incapacitated Persons

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the inclusion of adults lacking capacity in research is governed by the provisions of Section 51 of the AIA2000.

The G-ConsentPIS states that the UK allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

  • Treatment needs to be given urgently
  • It is also necessary to take urgent action to administer the drug (IMP) for the purposes of the trial
  • It is not reasonably practicable to obtain consent from a legal representative
  • The procedure is approved by an EC
  • Consent is sought from a legal representative as soon as possible
Last content review/update: February 05, 2020

Overview

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

Medical Emergencies

Unplanned Emergency Research

As stated in 21CFR50, 21CFR56, and USA-17, in an unplanned emergency situation, obtaining participant consent is required before using the investigational product (IP) unless the investigator and a physician not participating in the trial certify in writing the following:

  • Participant is confronted by a life-threatening situation
  • IC 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 is available

The investigator(s) must obtain ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) review and approval for any subsequent use of the IP.

Further, per 21CFR50, 21CFR56, USA-17, and USA-18, 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 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 and submitted to an EC within five (5) working days.

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 his/her legal representative(s) or guardian(s), or, if an effective treatment is lacking but the 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 EC must approve the protocol in advance. The participant and/or his/her 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.

Planned Emergency Research

As delineated in 21CFR50, the G-ICEmergencyReqs, and USA-17, in a planned emergency research study, if a ICF cannot be obtained from the participant and/or his/her legal representative(s) or guardian(s), the EC may approve the investigation without requiring the consent of all the participants, if a licensed physician who is an EC member, or, an EC consultant, and not otherwise participating in the trial, certifies in writing the following:

  • Participant is confronted by a life-threatening situation and available treatments are unproven or unsatisfactory
  • IC cannot be obtained due to an inability to communicate with the participant
  • It is unfeasible to obtain consent from the participant’s legal representative and/or guardian(s) due to his/her life-threatening condition
  • No alternative methods of approved or generally recognized therapy is available
  • The research must have the prospect of direct benefit to the participant
  • The collection of scientific evidence is necessary to determine the safety and effectiveness of the intervention

See 21CFR50, the G-ICEmergencyReqs, and USA-17 for additional information.

Military Operations Emergencies

21CFR50 and 10USC55 require the Secretary of Defense to request that the President waive the IC requirement prior to a member of the armed forces being administered an IP in connection with his/her participation in a particular military operation. The President must determine 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.

Waiver or Alteration of Consent

The CommonRule, the RevisedCommonRule, and G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration. In addition, the CommonRule states that the EC may approve a waiver or alteration of consent if the study satisfies all of the following conditions:

  • The research involves no more than minimal risk
  • The research could not practicably be carried out without the requested waiver or alteration
  • The waiver or alteration will not adversely affect the rights and welfare of the participants
  • Whenever appropriate, the participants will be provided with additional pertinent information after participation

The RevisedCommonRule, which took effect January 21, 2019, adds the following conditions:

  • 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
  • Whenever appropriate, the legally authorized representatives will be provided with additional pertinent information after participation

Per G-MinRiskWaiver, the Food & Drug Administration (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.

Informed Consent > Vulnerable Populations
Last content review/update: March 19, 2020

Overview

As per the MHCTR, GBR-3, and GBR-4, in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. GBR-3, GBR-4, and GBR-35 characterize vulnerable populations as those who are dependent on others and are unable to express their opinion freely or make their own decisions. These participants may include children, persons with mental or physical incapacities, persons with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, prisoners, detainees, refugees, members of a group with a hierarchical structure, such as students, subordinate hospital and laboratory personnel, pharmaceutical industry employees, members of the armed forces, and persons kept in detention.

See the Informed Consent topic, and the subtopics of Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired for additional information about these vulnerable populations.

Last content review/update: February 05, 2020

Overview

As per 21CFR56, the CommonRule, the RevisedCommonRule, 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.

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 CommonRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations.

The RevisedCommonRule, which took effect January 21, 2019, describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

21CFR56, the CommonRule, the RevisedCommonRule, and the US-ICH-GCPs also specify that ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting participants who are from vulnerable populations.

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

Informed Consent > Children/Minors
Last content review/update: March 19, 2020

Overview

According to the MHCTR, a minor is an individual under 16 years of age. However, per GBR-4, in situations where the MHCTR does not apply, a minor is an individual under 18 years of age.

As set forth in the MHCTR, the MHCTR2006, the G-ConsentPIS, GBR-4, and GBR-9, when the research participant is a minor, informed consent should be obtained from his/her legal representative(s) and/or guardian(s). As per GBR-4, legally, the researcher needs only to obtain consent from one (1) person with parental responsibility; however, consent from all legal representative(s) and/or guardians is encouraged.

Additionally, precautions against possible physical and mental harms should be exercised. All pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand. The rights of the minors should also be respected for their voluntary decision to participate in a clinical study.

The MHCTR, the MHCTR2006, GBR-4, GBR-9, and GBR-35 state that a study may only be conducted on minors if several conditions are fulfilled including:

  • An ethics committee (EC), following consultation with pediatric experts, has endorsed the protocol
  • The legal representative(s) and/or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the minor from the trial at any time
  • No incentives or financial inducements are given to the minor or his/her legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
  • The trial relates directly to a condition from which the minor suffers, or, is of such a nature that it can only be carried out on minors
  • The participant(s) will derive some direct benefit from their participation in the trial
  • The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or, by other research methods
  • The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the minor’s stage of development

See the MHCTR, the MHCTR2006, GBR-4, and GBR-9 for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet.

Assent and Minor Privacy Requirements

As delineated in GBR-4, if a minor is deemed competent to give assent to decisions about participation in research, the investigator(s) must obtain that assent in addition to the consent of his/her legal representative(s) and/or guardian(s). If the child does not assent, this should be respected.

Furthermore, GBR-4 states that a minor’s ability to assent or consent is based on his/her ability to understand and assess options, rather than on his/her age. For a minor to be able to have the capacity to make a particular decision, he/she must be able to:

  • Comprehend and retain information material to the decision, especially the consequences of having or not having any intervention
  • Use and weigh this information in a decision-making process
  • Reach and communicate a decision

In addition, GBR-4 specifies that if the competent minor specifically asks for the family not to be involved, and they cannot be persuaded otherwise, his/her privacy should be respected.

Last content review/update: February 05, 2020

Overview

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 CommonRule and the RevisedCommonRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare.

As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from his/her 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 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 risk
  • The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social or educational situation
  • Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)

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

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

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

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

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.

Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: March 19, 2020

Overview

The G-ConsentPIS states that in studies where there could be harm to an unborn child and/or risk to an infant when breastfeeding the Participant Information Sheet (PIS) should provide specific advice to potential participants about the risks of becoming pregnant, of fathering a child or of breastfeeding while taking part in the research.

For women, researchers must give a clear warning to potential participants when there is a risk of harm to an unborn child or risk when breastfeeding. The information should include the need for pregnancy testing, contraceptive requirements, and how to report a pregnancy during the study. The PIS should also provide information about what will happen if a participant becomes pregnant, including whether and how the researcher will monitor the pregnancy. This would include access to mother's and/or child's notes, and any possible follow up of the child including post-natal examinations.

For men, researchers must provide clear warnings and advice if the research treatment could damage sperm and consequently pose a risk to possible pregnancies. Information concerning the importance of careful contraception and what to do if their partner becomes pregnant is essential. Specific advice for pregnant partners may be needed, including information on any compensation arrangements.

Further, the G-ConsentPIS finds that the risk of harm caused during pregnancy is most likely when recruiting young people to a clinical trial for an investigational medicinal product (CTIMP). In this case, there should be consent from someone over the age of 16, and the following should be done:

  • Discuss the risk of pregnancy, pregnancy testing and the use of appropriate contraception with their parents (or his/her legal representative(s) and/or guardian(s)) during the consent process and with young potential participants as part of the assent process
  • Consider local social beliefs
  • Involve pediatricians and the ethics committee in preliminary discussions if this is a concern
  • Consult young people when designing consent and writing information
  • Respect the young person's autonomy but encourage involvement of the parents
  • Be aware that in CTIMPs, it is the parents of children under 16 who legally provide consent, and this will include consent to pregnancy testing and discussion of contraception
  • Information needs to go beyond "We will do a pregnancy test…" to include, what in broad terms, will happen

As set forth in GBR-35, any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. According to GBR-35, the following conditions are required for research to be conducted with this population:

  • Reproductive toxicology studies have been completed and the results support conducting a trial, or, there is a good reason not to conduct the reproductive toxicology studies and/or the risk of pregnancy is minimized (e.g., because she agrees to adhere to a highly effective method of contraception); Women using a hormonal contraceptive, such as “the pill,” should use an alternative method of contraception until the possibility of an interaction with the investigational product has been excluded
  • The female participant is not pregnant according to her menstrual history and a pregnancy test, and is not at risk of becoming pregnant during, and for a specified interval, after the trial
  • The female participant is warned about the potential risks to the developing child should she become pregnant, and she is tested for pregnancy during the trial, as appropriate
  • The female is tested for pregnancy before dosing starts and possibly during the trial, as appropriate
Last content review/update: February 05, 2020

Overview

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 CommonRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare.

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

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

Pregnant Women and Fetuses

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

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

Neonates

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

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

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

  • Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
  • 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
  • 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 RevisedCommonRule and subparts B and D of 45CFR46-B-E.

Informed Consent > Prisoners
Last content review/update: March 19, 2020
No relevant provisions
Last content review/update: February 05, 2020

Overview

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 CommonRule and the RevisedCommonRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare.

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

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

Per the RevisedCommonRule, 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.

Ethics Committee Responsibilities

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 his/her 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 his/her 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.

Informed Consent > Mentally Impaired
Last content review/update: March 19, 2020

Overview

As per the MHCTR and GBR-9, a recognized ethics committee (EC) within the Health Research Authority (HRA), must approve the participation of adult research participants who are incapable by reason of physical and mental capacity to give consent, and must obtain advice from professionals with expertise in handling this patient population.

The MHCTR and the G-ConsentPIS, specify that when a study involves adult participants with mental incapacities, informed consent should be obtained from his/her legal representative (s) and/or guardian(s). This consent should only be provided once the legal representative(s) or guardian(s) has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the participant from the trial at any time. The G-ConsentPIS provides additional country-specific information on legal representative requirements.

As delineated in the MHCTR, a clinical trial of an investigational product may involve participants with mental incapacities under the following conditions:

  • The participant has received information according to his/her capacity of understanding regarding the trial, its risks, and its benefits
  • No incentives or financial inducements are given to the participant or his/her legal representative(s) and/or guardian(s) except in the event of trial-related injury or loss
  • The trial relates directly to a condition from which the participant suffers, or, is of such a nature that it can only be carried out on participants with mental incapacities
  • The participant(s) will derive some direct benefit from their participation in the trial, or produce no risk at all
  • The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or, by other research methods
  • The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the participant’s stage of development

See the MHCTR, G-ConsentPIS, and GBR-9 for detailed requirements.

Last content review/update: February 05, 2020

Overview

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

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

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

Investigational Products > Definition of Investigational Product
Last content review/update: March 19, 2020

Overview

As delineated in the MHCTR, the Guideline for Good Clinical Practice E6(R2) (GBR-20), GBR-9, and GBR-35, an investigational product (IP), referred to as an investigational medicinal product (IMP) in the United Kingdom (UK), is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

Last content review/update: February 05, 2020

Overview

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 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.

Investigational Products > Manufacturing & Import
Last content review/update: July 23, 2020

Overview

According to the MHCTR, the MHCTR2006, the G-MHRA-CTApp, and the G-MHRA-GMP/GDP, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture and import of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture or importation of any IP to be used in the trial. The sponsor or his/her designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in GBR-28 to obtain an MIA(IMP) from the MHRA. The MHCTR defines “manufacturing authorization” to include importing and assembly authorizations, as applicable. The G-MHRA-CTApp states that if an IP is manufactured outside the European Union (EU), the MIA(IMP) should include the importer’s authorization for each manufacturing site. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

As per the MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, GBR-46, and GBR-15, and the EU Good Manufacturing Practice Directive (GBR-12), the MIA(IMP) holder must also comply with the Good Manufacturing Practice (GMP) guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, GBR-46, the EU Good Manufacturing Practice Directive (GBR-12), and the EU Good Clinical Practice Directive (GBR-13), specify that the holder of an MIA(IMP) must always have the services of at least one Qualified Person (QP) at his/her disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to using in a clinical trial, or prior to releasing for sale and placing on the market. The G-MHRA-CTApp states that if an IP is manufactured outside the EU, the clinical trial application should include a MIA(IMP), importer authorization, and QP declaration on GMP for each manufacturing site. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

Please note: United Kingdom is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Last content review/update: February 05, 2020

Overview

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, unless FDA notifies the sponsor that the investigation(s) described in the IND are subject to a clinical hold, or,
  • On earlier FDA authorization to ship the IP

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 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

Per 21CFR312, the FDA will permit the export of an IP from the US for use in a clinical investigation under any of the following conditions:

  • An IND is in effect for the IP, the drug complies with the laws of the country to which it is being exported, and, each person who received the IP is an investigator in a study submitted to the FDA and allowed to proceed under the IND, or,
  • The IP has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, or in any country in the European Union or the European Economic Area, and complies with the laws of the country to which it is being exported, or,
  • The IP is being exported to any one of the aforementioned countries (see previous bullet), or,
  • The person exporting the drug sends a written certification to the FDA’s Office of International Programs when the IP is first exported and maintains records documenting compliance with the FDA requirements

See Section 312.110 of 21CFR312 for additional detailed IP export requirements.

Investigational Products > IMP/IND Quality Requirements
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, and the EU Good Clinical Practice Directive (GBR-13), the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (GBR-20), and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or his/her designated representative should also update the IB as significant new information becomes available.

IB Content Requirements

As specified in GBR-20, the IB must provide coverage of the following areas:

  • Physical, chemical, and pharmaceutical properties and formulation parameters
  • Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
  • Effects of IMPs in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
  • Summary of data and guidance for the investigator(s)
  • Bibliography

See Section 7 of GBR-20 for detailed content guidelines.

As defined in GBR-20, the sponsor is also accountable for supplying the IMP, including the comparator(s) and placebo, if applicable. The MHCTR, the MHCTR2006, the G-MHRA-GMP/GDP, GBR-12, GBR-15, and GBR-35 also specify that the sponsor or his/her designated representative must ensure that the products are manufactured in accordance with current Good Manufacturing Practice (GMP) guidelines. (See Investigational Products topic, Product Management subtopic for additional information on IP supply, storage, and handling requirements).

Certificate of Analysis and Drug Manufacturing Certificate Requirements

As stated in GBR-46, the Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) holder must provide the Medicines and Healthcare Products Regulatory Agency (MHRA) with documentation including the following:

  • MIA(IMP) license of final Qualified Person (QP) releasing site
  • MIA(IMP) license of placebo manufacturing site (if different from final QP releasing site)
  • Certified QP release statement
  • Import QP release certificate (if applicable)
  • QP declaration
  • IP certificate of analysis
Last content review/update: February 05, 2020

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. 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, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

IB Content Requirements

As specified in 21CFR312 and the US-ICH-GCPs, the IB must provide coverage of the following areas:

  • Physical, chemical, and pharmaceutical properties and formulation parameters
  • Pharmaceutical aspects
  • Pharmacokinetics and metabolism
  • Toxicological effects in any animal species tested under a single dose study, a repeated dose study, or a special study
  • Results of clinical pharmacokinetic studies
  • Information regarding safety, pharmacodynamics, efficacy, and dose responses obtained from prior clinical trials in humans

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.

As specified in the US-ICH-GCPs, the sponsor must ensure that the products are manufactured in accordance with GMPs.

Certificate of Analysis

According to USA-39 and USA-67, 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 Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Investigational Products > Labeling & Packaging
Last content review/update: March 19, 2020

Overview

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR, the MHCTR2006, GBR-15, the EU Good Manufacturing Practice Directive (GBR-12), and the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (GBR-20). Per GBR-12, labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in GBR-15 and GBR-46, for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in GBR-15 and GBR-46, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

  • Name, address and telephone number of the sponsor, contract research organization (CRO), or investigator
  • Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/concentration
  • Batch and/or code number to identify the contents and packaging operation
  • Trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
  • Trial participant identification number/treatment number and where relevant, the visit number
  • Investigator name (if not already included above)
  • Instructions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
  • “For clinical trial use only” or similar wording indicating the IP is clinical trial material
  • Storage conditions
  • Expiration date (use by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
  • “Keep Out of Reach of Children” except when the product is not going to be taken home by participants

As per the MHCTR and GBR-46, a sample of the labeling is required as part of the clinical trial application submission. (See Clinical Trial Lifecycle topic, Submission Content subtopic for detailed clinical trial application submission requirements). In addition, GBR-46 states that the IP should be coded and labeled in a manner that protects the blinding, if applicable. Furthermore, according to GBR-15, the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Last content review/update: February 05, 2020

Overview

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. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Investigational Products > Product Management
Last content review/update: March 19, 2020

Overview

In accordance with the MHCTR, the MHCTR2006, and the EU Good Clinical Practice Directive (GBR-13), the sponsor or his/her designated representative is responsible for complying with the principles of good clinical practice (GCP) as specified in the European Medicines Agency’s implementation of the Guideline for Good Clinical Practice E6 (R2) (GBR-20) and for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. The sponsor should also update the IB as significant new information becomes available.

Investigational Product Supply, Storage, and Handling Requirements

As defined in the MHCTR, GBR-20, and GBR-35, the sponsor must supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

The sponsor must ensure the following:

  • IP product quality and stability over the period of use
  • IP manufactured according to EU Good Manufacturing Practice Directive (GBR-12)
  • Proper coding, packaging and labeling of the IMP(s)
  • IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation and destruction of the unused IP
  • Acceptable storage temperatures, conditions, and times for the IP
  • Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
  • Timely delivery of the IP(s)
  • Establishment of management and filing systems for the IPs
  • Sufficient quantities of the IP for the trial

As delineated in GBR-15, IPs should remain under the control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person (QP) and release by the sponsor for use in a clinical trial. Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. De-coding arrangements should be available to the appropriate responsible personnel before IPs are shipped to the investigator site. A detailed inventory of the shipments made by the manufacturer or importer should be maintained and include the addressees’ identification.

Refer to the MHCTR, GBR-20, and GBR-35 for detailed, sponsor-related IP requirements.

Record Requirements

As per GBR-35 and GBR-20, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related pharmacy records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics.

As set forth in GBR-20 and the EU Good Clinical Practice Directive (GBR-13), sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request, and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

Last content review/update: February 05, 2020

Overview

In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The IB must contain all of the relevant information on the investigational new drug(s) (INDs)/investigational product(s) (IPs) obtained through the earlier research phases, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

IND/IP Supply, Storage, and Handling Requirements

As defined in 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must also supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor must ensure the following:

  • IP product quality and stability over the period of use
  • IP manufactured according to any applicable GMPs
  • Proper coding, packaging, and labeling of the IP(s)
  • Records maintained for document shipment, receipt, disposition, return, and destruction 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

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 a marketing application (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.

Specimens > Definition of Specimen
Last content review/update: March 19, 2020

Overview

The term “specimen” is not referenced within the United Kingdom (UK). However, the following terms are used relating to specimens:

  • Relevant material: As per the UK-HTA, CODE E, GBR-73, GBR-76, and GBR-54, “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
  • Substance/active substance: GBR-11 defines “substance” as any matter regardless of origin which may be human (e.g., blood and blood products), animal, vegetable, or chemical.
Last content review/update: February 05, 2020

Overview

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, 42CFR72 and 42CFR73, define specimen or diagnostic specimen, as any human or animal material including, but not limited to, excreta, secreta, blood and its components, tissue and tissue fluids, or environmental samples to be used for diagnosis, verification or proficiency testing.

The RevisedCommonRule, which took effect January 21, 2019, defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. Federal agencies will reexamine what is an identifiable biospecimen within one (1) year of the effective date of the RevisedCommonRule revisions and at least every four (4) years thereafter.

Specimens > Specimen Import & Export
Last content review/update: March 19, 2020

Overview

As set forth in the UK-HTA, the HTRegs, and GBR-9, the Human Tissue Authority (HTA) regulates the storage and use of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Per GBR-9, HTA and the Health Research Authority (HRA) have agreed to collaborative arrangements in a Memorandum of Understanding.

Note that per GBR-9 and GBR-105, an HTA license is not needed for storage of specimens for certain research projects that have been approved by an ethics committee (EC). HTA and the UK Health Departments’ Research Ethics Service (RES) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

Per the UK-HTA, the G-HTA-QAHumanTissue, and CODE E, the scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research. Per GBR-52, the Scotland-HTA does not regulate the use of tissue from the living for research.

Relevant Materials/Human Tissue

As specified in the UK-HTA, the HTA has jurisdiction regarding the import and export of relevant materials/human tissue, and complies with the Code of Practice on import and export set forth in CODE E. According to the UK-HTA, CODE E, and GBR-52, the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA. However, once the material is imported, storage of this material may be licensable if it is deemed to be for a specified or scheduled purpose.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third party agreement with an establishment licensed by the HTA to store material for human application.

CODE E requires imported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in CODE E. Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales or Northern Ireland must comply with the guidelines set forth in CODE E.

Exported material should also be procured, used, handled, stored, transported and disposed of, in accordance with the donor’s consent, with due regard for safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as stated in CODE E. This includes providing donors with adequate information upon taking consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

In addition, the G-QualityBlood lists the quality and safety standards when importing or exporting blood into or from the European Union (EU)/European Economic Area (EEA). In addition, after the Brexit transition period from January 1, 2021, this guidance states that there will be no change to blood quality and safety practices. The UK will maintain the existing quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components. The Medicines and Healthcare Products Regulatory Agency (MHRA) should be consulted before importing or exporting blood or blood components. See the G-QualityBlood for relevant EU quality and safety directives.

Last content review/update: February 05, 2020

Overview

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 NationsInternational Civil Aviation Organization (ICAO).

According to USA-14 and USA-68, the first step in preparing a specimen for import or export is to classify the specimen as either infectious or non-infectious. Packaging and shipping of these specimens must then comply with all applicable federal and international ground and air transport standards.

Import/Export Requirements

Non-Infectious Specimens

A non-infectious specimen/substance is referred to as a Category B Biological Substance by DOT‘s PHMSA in 49CFR173, and an exempt human specimen or exempt animal specimen by IATA and USPS in USA-21 and USA-4 respectively. These specimens are not considered to be hazardous materials for import, transfer, or export by these agencies because they do not contain infectious substances, or, they are not substances likely to cause disease in humans or animals. However, they are subject to specific packaging and labeling 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.

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 Category A Biological Substance, 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.

NIH Import/Export 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 as well as receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens. 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.

Specimens > Consent for Specimen
Last content review/update: March 19, 2020

Overview

In accordance with the UK-HTA, Code A, GBR-35, GBR-34, and GBR-9, prior to collecting, storing, or using a research participant’s specimens (known as relevant material/human tissue in the United Kingdom (UK)), consent from the participant and/or his/her legal representative(s) and ethics committee (EC) approval must be obtained. The scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research.

Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. As delineated in the GDPR and UK-DPAct, personal data includes genetic data and biological samples. G-GDPR indicates that for the purposes of the GDPR, the legal basis for processing data for health and social care research should not be consent. This means that requirements in GDPR relating to consent do not apply to health and care research, and therefore, do not change the consent requirements to participate in a clinical trial and remove human tissue samples. For more information about the sponsor and investigator’s responsibilities to comply with the data protection requirements (e.g., transparency, safeguards, and data rights), see the Sponsorship topic.

Human Genetic Research Consent Requirements

As set forth in the UK-HTA, GBR-9, GBR-104, and GBR-37, the UK-HTA considers it a UK-wide offense to have relevant material/human tissue with the intention of conducting a DNA analysis or using the results of this analysis without “qualifying consent” from a participant and/or his/her legal representative(s), unless the information is being used for an “excepted purpose.” The UK-HTA states that “qualifying consent” is consent required in relation to the analysis of DNA manufactured by the human body. An “excepted purpose” is defined as the following:

  • Medical diagnosis/treatment
  • Coroner purposes
  • Crime prevention/detection
  • Prosecution
  • National security
  • Court/tribunal order
  • An existing holding to be used for research

In addition to participant consent, EC approval is required for the analysis of DNA in material from the living, where the research is not within the terms of consent for research from the person whose body manufactured the DNA. Please refer to the UK-HTA, GBR-9, GBR-104, GBR-37, and GBR-75 for detailed DNA analysis consent requirements.

Human Tissue/Relevant Material Consent Requirements

In accordance with the UK-HTA, Code A, GBR-35, GBR-34, and GBR-9, prior to removing, storing, or using any living or deceased person’s organs, tissues, or cells for the purpose of research in connection with disorders in, or the functioning of the human body, investigators must obtain “appropriate consent” from the trial participants and/or their legal representative(s) as well as EC approval. The UK-HTA and Code A define “appropriate consent” in terms of the person who may give consent. This person may be either the trial participant, his/her legal representative (referred to as “nominated representative” in the UK-HTA), or, in the absence of either of these, the consent of a person in a “qualifying relationship” with the participant immediately before he/she dies.

As indicated in the UK-HTA and Code A, in the case of a living child donor, “appropriate consent” must be obtained from the child’s legal representative(s). If the child has died, the written consent must be obtained prior to the child’s death in the presence of at least one (1) witness, or, it must be signed at the direction of the child concerned, in his/her presence, and in the presence of at least one (1) witness.

As indicated in the UK-HTA and Code A, in the case of an adult donor, 18 years or older, his/her consent must be obtained prior to removing any materials from his/her body. If the adult has died, his/her written consent is only valid when it is signed by the person prior to his/her death in the presence of at least one (1) witness at his/her direction, or it is contained in the person’s will. An adult donor may also appoint one (1) or more people (“nominated representative(s)”) to consent on his/her behalf in the event of his/her death. This consent may be obtained orally or in writing. If the deceased donor has neither provided consent nor an appointed or nominated representative, appropriate consent may be given by someone in a “qualifying relationship” with the donor immediately prior to his/her death. Refer to the UK-HTA and Code A to obtain a complete list of relatives in hierarchical order who may qualify to provide this consent.

In the case of obtaining materials from an adult donor who lacks the capacity to consent, and neither a decision to consent or not consent is in force, the UK-HTA, the MCA2005, GBR-9, and GBR-37 state that approval by an EC is required. In addition, a living person’s organs, tissues, or cells may be stored and used without consent if the investigator is unable to identify the individual and it is being used for an EC-approved research project. Please refer to the UK-HTA and Code A for detailed consent requirements.

See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent.

Last content review/update: February 05, 2020

Overview

As delineated in the G-IC-IVDs, the Food & Drug Administration (FDA) only provides informed consent (IC) guidance with respect to its regulations governing the IC requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.

IC requirements guiding Department of Health & Human Services (HHS)-conducted or -supported research on human research participants is regulated by the CommonRule and 45CFR46-B-E.

Per the CommonRule, and the G-SpecimensResrch, HHS views human subject specimens as research involving human participants, and subject to IC requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevisedCommonRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the CommonRule, RevisedCommonRule, the G-SpecimensResrch, USA-2, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, according to USA-72, research with specimens, cells, cell lines, or data involves human subjects when:

  • The specimens, cells, or data must be or must have been obtained from individuals who are alive, and, must be or must have been obtained by an investigator conducting research, and
  • The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or, must be obtaining or have obtained individually identifiable private information.

See USA-72 for detailed frequently asked questions (FAQs) on this topic.

Per the CommonRule, the RevisedCommonRule, and USA-2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or his/her legal representative(s).

The RevisedCommonRule requires the informed consent form to provide one of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

  • A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility; or
  • A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.
  • A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit;
  • Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen).

Furthermore, the RevisedCommonRule delineates the requirements of broad consent-an alternative consent process-for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or his/her legal representative(s) or guardian(s):

  • Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
  • Types of research that may be conducted
  • A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
  • A description of the length of time that the information or biospecimens may be stored, maintained, and used
  • A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
  • A statement that research results either will or will not be disclosed to participants
  • An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

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

The G-StoredData/Tissues and USA-2 recommend that the following be included in IC documents for biospecimen collection:

  • A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
  • Conditions under which samples and data will be released to recipient investigators
  • Procedures for protecting the privacy of human research participants and confidentiality of data
  • Specific descriptions of the nature and purpose of the research
  • Information about the consequences of DNA typing if human genetic research is anticipated

As stated in USA-2, the National Institutes of Health (NIH)’s National Cancer Institute (NCI) has also developed the following list of recommended elements to include in an informed consent form (ICF):

  • Participants have the right to refuse biospecimen donation, and this will in no way influence their treatment or eligibility to participate in research studies/clinical trials
  • Why particular specimens/data are being sought and why participants are being asked to participate
  • The biospecimens source that will be collected for research (e.g., ascertaining what procedure will the specimen come from)
  • Who will be the custodian of the biospecimens and what will be the custodian’s role
  • How the biospecimens will be used and whether they will be used in secondary research
  • How data collected or generated will be shared
  • Whether biospecimens will continue to be stored in an identifiable or non-identifiable manner
  • Who may access biospecimens/associated data

See USA-2 for detailed NCI biospecimen recommendations and best practices.

(See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent).

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