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

Food & Drug Administration

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

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLP) develops clinical research policies, regulation, and guidance in collaboration with the FDA’s medical product centers.

Office for Human Research Protections and Common Rule Agencies

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

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-18 and USA-65 for more information on US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

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

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

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

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

International Alignment

Per USA-16, the US is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The FDA has implemented the Guideline for Good Clinical Practice E6(R3) in US-ICH-GCP, along with other ICH guidance. See USA-19 for the implementation status of all ICH guidelines. Additionally, see USA-22 and USA-47 for links to ICH guidance documents implemented by the FDA.

Contact Information

Food & Drug Administration

As per USA-81, USA-90, and USA-91, the contact information for the FDA is as follows (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

Main FDA Telephone (general inquiries): (888) 463-6332

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@fda.hhs.gov

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Division of Drug Information
10903 New Hampshire Avenue
Building 51, Room 1109
Silver Spring, MD 20993
CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

Office for Human Research Protections

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

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

Department of Health & Human Services

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

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

Overview

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

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

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

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.

• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

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

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

• A drug is involved as defined in the FDCAct

• A clinical investigation is being conducted as defined in 21CFR312

• The clinical investigation is not otherwise exempt from 21CFR312

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

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

Clinical Trial Review Process

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

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

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

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

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

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

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

As stated in 21CFR312, the FDA will accept, as support for an IND, a well-designed and well-conducted foreign clinical study not conducted under an IND. The study must have been conducted in accordance with good clinical practice (GCP), and the FDA must be able to validate the data from the study through an onsite inspection if the agency deems it necessary. Although the FDA will not accept a study that does not meet those conditions as support for an IND, the FDA will still examine data from such a study. See 21CFR312 and the G-FrgnCT for more details on submitting data from a foreign clinical study not conducted under an IND as support for an IND.

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

Per the G-BiorsrchInspct, the FDA developed a Bioresearch Monitoring (BIMO) program to assess the quality and integrity of data submitted to the FDA in support of regulatory decision-making, as well as to provide for protection of the rights, safety, and welfare of human trial participants involved in FDA-regulated research. The BIMO program, which involves on-site inspections, investigations, and remote regulatory assessments, assesses compliance with statutory requirements and the FDA’s regulations governing the conduct of nonclinical and clinical studies, as well as applicable postmarketing activities. See the G-BiorsrchInspct and USA-20 for more information on FDA inspections and the BIMO program.

Expedited Processes

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

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

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

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

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials. Additionally, see the G-ExplrtryIND for FDA guidance regarding exploratory studies in humans.

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

Food & Drug Administration

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

However, per the FDCAct, the FDARA, and USA-45, the FDA has the authority to collect user fees from persons that submit certain human drug applications for review or that are named in approved applications as the sponsor of certain prescription drug products. See USA-45 for more information.

Overview

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

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

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

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on EC composition, functions, and operations.

Ethics Committee Composition

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

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

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

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

Additionally, 21CFR56 indicates that efforts must be made to ensure that no EC consists entirely of men or entirely of women, including the institution’s consideration of qualified persons of both sexes, so long as no selection is made to the EC on the basis of gender. No EC may consist entirely of members of one (1) profession.

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

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

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

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

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

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

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

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

Overview

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

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional EC responsibilities and requirements.

Role in Clinical Trial Approval Process

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

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the EC must ensure the following requirements are met prior to approving the study:

• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Informed consent will be sought from each prospective participant or legal representative/guardian, and will be appropriately documented (the RevComRule also requires information regarding whether informed consent was appropriately waived)
• The research plan makes adequate provision for monitoring the data collected to ensure the safety of participants, where appropriate
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate (per the RevComRule, the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data)

Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56, the Pre2018-ComRule, and the RevComRule for additional details on criteria for EC approval of research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the HHS that must also comply with FDA regulations.

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that changes in approved research may not be initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants.

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

See the G-IRBResp for FDA guidance for ECs on reviewing the adequacy of investigators and research sites, and determining if an IND or investigational device exemption is required. The FDA’s G-SubRecruit also provides guidance for ECs on reviewing participant recruitment methods.

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

As stated in the G-IRBWaiver, sponsors and sponsor-investigators may request a waiver of EC requirements for drug and biological product studies regulated by the FDA. The most common circumstance for which the FDA receives a waiver request is when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically sponsors utilize an independent ethics committee (IEC) that operates in accordance with good clinical practice (GCP). See the G-IRBWaiver for more information.

Additionally, see the G-IRBTransfer for FDA guidance on the regulatory responsibilities of ECs, clinical investigators, and sponsors when oversight of a previously approved, ongoing clinical investigation under the FDA’s jurisdiction is transferred from one (1) EC to another EC.

Expedited Review

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

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

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

Continuing Review and Re-approval

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

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

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

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

Exemptions under the Revised Common Rule

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

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

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

USA-32 notes that the regulations do not specify who at an institution may determine that research is exempt, and that institutions should implement exemption policies that most effectively address the local setting and programs of research. The HHS retains final authority as to whether a particular human subjects research study conducted or supported by HHS is exempt.

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-32 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, continuing review, and exempt research.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-18 and USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

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

For more information on multicenter research, see the FDA’s G-CentralIRB and G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS’ Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.

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

Overview

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

Registration, Auditing, and Accreditation

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

Food & Drug Administration

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

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

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

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-18 and USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

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

See USA-57 for more information on FWAs.

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

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

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

Overview

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

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

Regulatory Submission

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

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

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

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

As stated in USA-34, the electronic submission of eCTD v4.0 to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) is supported for new INDs, as well as certain other submission types, beginning September 16, 2024. Only new applications may be submitted in v4.0, and forward compatibility functionality is not yet available. Electronic submissions made in eCTD format must utilize either v3.2.2 or v4.0, which are both currently supported by the FDA.

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

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, USA-34, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs, eCTD submissions sized 10 GB and under for most applications must be submitted via the Electronic Submissions Gateway (ESG), and the FDA also recommends the use of the ESG for submissions greater than 10 GB when possible. However, USA-44 specifies that the Electronic Submissions Gateway Next Generation (ESG NextGen) should be utilized for all electronic submissions to the FDA. See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login and USA-37 for ESG NextGen submission user guides.

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

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

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 USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

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

Therapeutic Biological Product (submitted by Sponsor-Investigators):

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

Center for Biologics Evaluation and Research-Regulated Products:

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

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

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

Ethics Review Submission

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

Regulatory Authority Requirements

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

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

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions. Also see USA-100 for Phase 1 IND resources, and USA-39 for information on first in human Phase 1 INDs.

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

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

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

See 21CFR312 and the G-IPCharge for additional submission requirements if a sponsor is seeking FDA authorization to charge for the use of its own IP in a clinical trial.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ regarding application content requirements.

Clinical Protocol

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

Additionally, the G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. According to the G-DecentralCT, the protocol should include specific instructions for limiting variability in the data collected. The protocol should specify which visits will be conducted at traditional clinical trial sites, which visits will be conducted remotely, and which visits can be left to participants’ choice. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical protocol contents.

Overview

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

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.

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

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial.

Overview

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

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

See the G-CTPrtcptn for FDA guidance on enrollment practices to enhance participation in clinical trials.

Clinical Trial Agreement

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

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical trial agreements.

Clinical Trial Registration

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

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA. See the G-3674Cert for additional FDA guidance on certifying compliance with applicable requirements, including the requirement to register applicable clinical trials.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78). See USA-98 for the NIH’s definition of a clinical trial.

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

Safety Reporting Definitions

In accordance with 21CFR312, the G-SpnsrRpt, the G-InvstRpt, the US-ICH-E2A, 42CFR11, and USA-99, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US) (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

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

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the Pre2018-ComRule, and the RevComRule for further information.

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for guidance on safety reporting.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-InvstRpt, 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-SAEs must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others

The G-InvstRpt adds that although the investigator must immediately report any SAE to the sponsor, more data may be collected and submitted after submitting the initial report. For the purposes of the G-InvstRpt, the FDA interprets “immediately” to be as soon as feasible after the investigator recognizes an event is an SAE and obtains relevant information for the sponsor. The FDA recommends that this timeframe for submitting initial information also be specified in the protocol and anticipates that the timeframe for submission of initial information will generally not exceed one (1) calendar day.

Sponsor Responsibilities

As delineated in 21CFR312, the G-SpnsrRpt, and USA-99, the sponsor must report in an investigational new drug application (IND) safety report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event. The sponsor is required to notify the FDA and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. Any relevant information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a follow-up IND 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, the G-SpnsrRpt, and USA-99,the sponsor must also report the following to the FDA in an IND safety report:

• Any findings from animal or in vitro testing, epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report) that suggest a significant risk in humans exposed to the drug, regardless of whether they are conducted under the IND or by the sponsor
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each IND safety report, the sponsor must identify all IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312, the G-SpnsrRpt, and USA-99 for more details on these safety reporting requirements.

The G-SpnsrRpt notes that the sponsor is ultimately responsible for evaluating the available information and deciding whether there is a reasonable possibility that the drug caused the adverse event, and therefore that the event meets the definition of a suspected adverse reaction. Aggregate analyses are needed for (1) anticipated SAEs for which it is difficult or impossible to make a causal determination based on a single case or a small number of cases; or (2) expected serious suspected adverse reactions that must be reported if there is a clinically important increase in the rate over that described in the protocol or IB. See the G-SpnsrRpt for additional FDA guidance on aggregate analyses.

The FDA’s G-DecentralCT indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. As in any clinical trial, the safety monitoring plan should describe how participants are expected to respond to and report adverse events, including where to seek medical assistance locally when necessary, and where to receive follow-up care. See the G-DecentralCT for more information.

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

• All SAEs
• All adverse events, other than SAEs, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11, 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 a responsible party submits a certification that: 1) the FDA has not approved, licensed, or cleared the investigational product (IP) being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

The G-SpnsrRpt indicates that as of April 1, 2026, IND safety reports of serious and unexpected suspected adverse reactions (which contain individual data from one (1) or more participants) should be submitted as individual case safety reports (ICSRs) to the FDA’s Adverse Event Monitoring System (AEMS) (formerly FDA Adverse Event Reporting System (FAERS)) (USA-50). As per the G-SpnsrRpt, the G-INDElecSubs, and USA-46, sponsors must submit such IND safety reports to USA-50 using either the Electronic Submissions Gateway Next Generation (ESG NextGen) or the Safety Reporting Portal (SRP) (USA-51). See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login, as well as USA-37 and USA-44 for more information on ESG NextGen. Also see USA-46 for more information on making submissions to USA-50.

The G-SpnsrRpt notes that other types of required IND safety reports (overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies and reports of increased rates of occurrences of expected serious suspected adverse reactions) should be submitted by the sponsor in a narrative format in electronic common technical document (eCTD) format, and should not be submitted to USA-50.

See USA-99 for additional information on submitting IND safety reports.

According to the G-SpnsrRpt and the G-INDElecSubs, submissions regarding non-commercial INDs are exempt from the above electronic submission requirements. The G-SpnsrRpt states that sponsors with INDs that are exempted from the electronic submission requirement, and who are not submitting IND safety reports of serious and unexpected suspected adverse reactions to USA-50 or the other types of IND safety reports with eCTD format submission requirements, should submit IND safety reports in an alternate electronic format or using other means of rapid communication. When utilizing an alternate electronic format (see the G-AltrntElecSubs) or other means of rapid communication, Form FDA 3500A (USA-75) may be used. For additional information on other reporting using Form FDA 3500A (USA-75), see the G-SpnsrRpt and USA-48.

Per USA-90, fatality reports to the Center for Biologics Evaluation and Research (CBER) should be sent to fatalities2@fda.hhs.gov.

Interim and Annual Progress Reports

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, the Pre2018-ComRule, and the RevComRule, the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must have written procedures for determining which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review.

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

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

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

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

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on clinical trial reports.

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.

Additionally, per 42CFR11, the responsible party must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the responsible party submits a certification that indicates: 1) the FDA has not approved, licensed, or cleared the IP being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval. The clinical trial results information must include data on the following:

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

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data. See the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E3 Structure and Content of Clinical Study Reports (US-ICH-E3 and the US-ICH-E3-QA) for additional guidance on report structure.

As per 21CFR312 and 21CFR50, 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 and 21CFR50 define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 states that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO). Any trial-related responsibilities transferred to and assumed by a CRO must be described in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations.

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

Overview

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

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

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

In addition, 21CFR312 indicates that prior to the start of the study, the sponsor must provide the investigator(s) with the investigator’s brochure. The sponsor is also responsible for providing the investigator(s) with the information needed to conduct an investigation properly.

See G-InvstgtrResp for more information on investigator responsibilities.

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

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT notes that because decentralized clinical trials may involve many contracted services, sponsors should ensure proper coordination of decentralized elements (e.g., use of remote trial personnel for at-home visits, use of local health care providers (HCPs), direct shipping of the investigational product to participants, etc.). Such contracted services may be performed by networks of local HCPs (e.g., local clinic networks, pharmacy chains). Sponsors should ensure these networks of local HCPs are qualified to perform the contracted activities. Sponsors should also keep a record of these networks and other contracted service providers, including their roles and assigned activities. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on investigator selection, qualifications, and training.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50, Data and Safety Monitoring Boards (DSMBs), (also known as 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, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-18 and USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.

Multicenter Studies

The RevComRule delineates that for all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, the G-CentralIRB, and G-CoopRes for additional information.

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

Insurance

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

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s). Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, which guides sponsors on providing compensation.

Injury or Death

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

Trial Participation

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

Quality Assurance/Quality Control

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

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

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT states that to account for multiple sources of data collection in a decentralized clinical trial, the sponsor should include at least the following in a data management plan or other trial-related documents: data origin and data flow from all sources to the sponsor (e.g., a diagram that depicts the flow of data from creation to final storage); methods and technologies used for remote data acquisition from trial participants, trial personnel, and contracted service providers (e.g., local clinical laboratory facilities and local health care providers who perform trial-related activities); and a list identifying service providers for data collection, handling, and management.

The G-DecentralCT further indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. When applicable, the safety monitoring plan should describe the type of information that will be collected by a digital health technology, how that information will be used and monitored, and what action trial participants or personnel should take in response to abnormal findings or electronic alerts. See the G-DecentralCT for additional information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research, and see the G-RemoteData for recommendations on the use of digital health technologies for remote data acquisition from participants in clinical investigations that evaluate medical products. Furthermore, see the G-ESourceData for FDA guidance regarding the capture, review, and retention of electronic source data, particularly for use in filling the predefined fields in an electronic case report form.

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

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

See the FDA’s G-EnrchStrat for enrichment strategies that can be used in clinical investigations intended to demonstrate the effectiveness of drug and biological products, and the G-DataCollect for recommendations on the use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials.

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

See USA-97 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data. Additionally, see USA-6 for other scientific data sharing policies, including genomic data.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving quality management, assurance, and control. Additionally, see USA-69 for 10 guiding principles that industry and product developers can consider when using artificial intelligence (AI) to advance drug and biological product development.

Monitoring Requirements

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

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

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA. Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving monitoring and auditing.

Premature Study Termination/Suspension

As delineated in 21CFR312, if the sponsor determines the investigational product (IP) presents an unreasonable and significant risk to the participants, the sponsor must discontinue the associated study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining stock of the IP and provide the FDA with a full report on the sponsor’s actions.

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

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

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving premature termination or suspension of a trial.

Electronic Data Processing System

As per the Food & Drug Administration (FDA)’s G-DecentralCT, electronic systems can be used to perform multiple functions to manage decentralized clinical trial (DCT) operations. Training should be provided to all parties (e.g., trial personnel, local health care providers, and trial participants) who are using electronic systems to support the conduct of DCTs. Electronic systems that are used to produce and process trial records required by the FDCAct and FDA regulations are subject to 21CFR11. These systems must ensure data reliability, security, privacy, and confidentiality.

See 21CFR11 and the G-Part11 for general FDA regulations and guidance on electronic records and systems. Additionally, see the G-ElecSyst for guidance specific to clinical investigations.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on data handling and processing, including the use of computerized systems.

Records Management

According to 21CFR312, the sponsor must maintain complete and accurate records showing financial interest paid to clinical investigators by the sponsor, as well as records concerning all other financial interests of investigators.

As set forth in 21CFR312, the sponsor must retain the above records and reports for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued and the FDA has been notified. Additionally, upon request from the FDA, the sponsor must 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.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on record keeping and management.

Responsible Parties

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

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

Data Protection

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

28CFR202 prohibits certain data transactions that involve giving a country of concern or covered person access to: 1) bulk US sensitive personal data that involves bulk human ‘omic data; or 2) to human biospecimens from which bulk human ‘omic data could be derived. Human ‘omic data includes human genomic data, human epigenomic data, human proteomic data, and human transcriptomic data. However, 28CFR202 notes that there is an exemption for data transactions involving regulatory approval data, which refers to sensitive personal data that is de-identified or pseudonymized and that is required to be submitted to a regulatory entity, or is required by a regulatory entity to be submitted to a covered person, to obtain or maintain authorization or approval to research or market a drug, biological product, device, or combination product. Data transactions that are necessary to obtain or maintain regulatory authorization or approval to research or market a drug, biological product, device, or combination product may also be exempt. See 28CFR202 for more information on countries of concern, exempt transactions, and reporting requirements.

NIH Privacy Requirements

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

Consent for Processing Personal Data

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

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

See USA-86 for more information on these circumstances.

Obtaining Consent

In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on agency-specific compliance.) Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E.

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, 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).

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

According to 21CFR50, the Pre2018-ComRule, and the RevComRule, no investigator may involve a human being as a participant in research unless the investigator has obtained the legally effective informed consent of the participant or the legal representative/guardian. The participant or the legal representative/guardian should also be given adequate time to consider whether to participate to minimize the possibility of coercion or undue influence.

As indicated in 21CFR50, the Pre2018-ComRule, and the RevComRule, no informed consent, whether oral or written, may contain any language that causes the participant or the legal representative/guardian to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

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

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

As per the FDA’s G-DecentralCT, obtaining informed consent remotely may be considered as part of a decentralized clinical trial. EC oversight is required to ensure the process is adequate and appropriate. See the G-DecentralCT for more information.

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

See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, see USA-60 for additional information regarding informed consent.

Additionally, see the FDA’s G-SEInfrmdCnsnt for guidance intended to help small businesses better understand the informed consent requirements set forth in 21CFR50.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on obtaining consent.

Re-Consent

According to 21CFR50 and the G-IRBFAQs, participants who are enrolled and actively participating in a study must be informed of significant new findings which may relate to their willingness to continue participation in the study.

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

Language Requirements

21CFR50, the Pre2018-ComRule, and the RevComRule state that any information provided must be in a language understandable to the participant or the legal representative/guardian.

As delineated in the FDA’s G-InfrmdCnsnt, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants or their legal representative/guardian is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.

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

Documenting Consent

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

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

The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note. See 21CFR11 and the G-Part11 for general FDA regulations and guidance on electronic signatures. Additionally, see the G-ElecSyst for guidance specific to clinical investigations.

Waiver of Consent

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

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

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

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

In addition, 21CFR50, the RevComRule, and the Pre2018-ComRule state that for an EC to approve a general waiver or alteration of consent, the EC must find that:

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

21CFR50 and the RevComRule also state that for an EC to approve the general waiver or alteration of consent, the EC must find that 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.

Furthermore, the Pre2018-ComRule and the RevComRule 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.

Based on 21CFR50, the Pre2018-ComRule, and the RevComRule, the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• 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
• The extent, if any, to which confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
• Compensation and/or treatment available for the participant in the case of trial-related injury
• Contact information for relevant individuals to contact in the event of a trial-related injury
• That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
• Foreseeable circumstances under which the investigator may remove the participant without consent
• Any additional costs to the participant that may result from participation in the research
• 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

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

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

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

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

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

Additionally, the G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT indicates that, as applicable, the informed consent process in a decentralized clinical trial should inform trial participants: whether local healthcare providers will be used in the conduct of the trial; which trial activities will take place at their homes; and who will have access to their protected health information.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on the informed consent discussion and materials that should be provided to participants.

Compensation Disclosure

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

Overview

In accordance with 21CFR50, 21CFR312, the Pre2018-ComRule, and the RevComRule, 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.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional guidance on participant rights.

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

The Right to Privacy and Confidentiality

As per 21CFR50, the Pre2018-ComRule, and the RevComRule, participants must be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained.

The RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-18 and USA-65 for more information on Common Rule departments/agencies, and see the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

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

The Right of Inquiry/Appeal

21CFR50, the Pre2018-ComRule, and the RevComRule state that the research participant or legal representative/guardian must be given an explanation of whom to contact for answers to pertinent questions about the research and the participants’ rights, and whom to contact in the event of a research-related injury.

The Right to Safety and Welfare

21CFR50 indicates that compliance with FDA regulations, including 21CFR50, is intended to protect the rights and safety of participants involved in investigations filed with the FDA. As per the Pre2018-ComRule and the RevComRule, an EC may require that additional information be given to participants if the EC determines the information would meaningfully add to the protection of the rights and welfare of participants.

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

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional guidance on obtaining consent in emergency situations.

Medical Emergencies

Emergency Use Situation

21CFR56 describes emergency use as the use of a test article, such as an investigational product (IP), on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) approval.

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

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

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

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

Emergency Research

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

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

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

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

USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative/guardian, no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the RevComRule applies to research.

Military Operations

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

Overview

As per 21CFR56, the Pre2018-ComRule, and the RevComRule, in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

Per 21CFR56, vulnerable populations may include children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons. The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.

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

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

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

Per the Pre2018-ComRule and the RevComRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

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 parent/legal guardian.

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 parent/legal guardian

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

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

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

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

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

For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11, the G-ChldrnSfgrd, and USA-60. Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50.

Assent Requirements

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

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

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

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

When parent/legal guardian permission is necessary, the EC must determine whether the permission of one (1) parent/legal 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 parents/legal guardians 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 consent requirement involving both parents/legal guardians include when one (1) parent/legal guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) parent/legal guardian has legal responsibility for the care and custody of the child.

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

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.

Per the Pre2018-ComRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule, all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

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

Pregnant Women and Fetuses

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

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

Neonates

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

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

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

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

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

• Vital functions will not be maintained artificially
• Research will not terminate the heartbeat or respiration
• The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
• Consent is obtained from both parents. If neither parent is able to provide consent, then 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 Pre2018-ComRule and the RevComRule, as applicable, and subpart D of 45CFR46-B-E.

As set forth in 45CFR46-B-E, a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.

Per the Pre2018-ComRule and the RevComRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule, none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

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

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

See USA-62 for more HHS information on prisoner research.

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

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

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

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

Per the Pre2018-ComRule and the RevComRule, mentally disabled persons/individuals with impaired decision-making capacity require additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

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

• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional
• Establishing a waiting period in the decision-making process to allow additional time for decision-making
• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible
• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire
• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline
• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes
• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented
• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time
• Determining whether the EC or a third party should observe the consent process

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

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

Manufacturing

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

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

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

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

The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, the G-CMC-Phase2-3, and the G-INDPrep.

Import

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

• The IP consignee is the IND sponsor, or
• The consignee is a qualified investigator named in the IND, or
• The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP

See USA-23 for general FDA information on importing human drugs.

Investigator's Brochure

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

As specified in 21CFR312, the IB must provide coverage of the following areas:

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

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 practice (GCP). See Section 312.120 of 21CFR312 for detailed requirements.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional guidance on IB development and contents.

Quality Management

According to USA-39, submitting a copy of the Certificate of Analysis of the clinical batch is suggested, but not required by the FDA.

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.

Supply, Storage, and Handling Requirements

Per 21CFR312, the G-CGMP-Phase1, and the G-CMC-Phase2-3, and the G-INDPrep, the sponsor/manufacturer must ensure the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Investigational new drug/investigational product (IP) product quality and stability
• IP manufactured according to any applicable good manufacturing practice (GMP)
• Proper coding, packaging, and labeling of the IP(s)
• The return and disposition of all unused supply of the IP

Refer to the G-CGMP-Phase1, the G-CMC-Phase2-3, and the G-INDPrep for detailed IP management requirements.

The FDA’s G-DecentralCT states that in some cases, decentralized clinical trials may involve the direct distribution of IPs to trial participants or local health care providers (HCPs). In these cases, investigators must remain responsible for supervising the supply of IP to trial participants or local HCPs. When applicable, trial personnel should be trained on procedures and appropriate documentation for handling, packaging, shipping, and tracking IPs. See the G-DecentralCT for detailed information.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional guidance on IP management.

Record Requirements

According to 21CFR312, the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. Additionally, the investigator(s) is required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by participants. The investigator(s) is also required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual to which the IP was administered, or who was employed as a control in the investigation. See 21CFR312 for more details.

As per 21CFR312, the sponsor/the investigator(s) must retain the above records and reports for two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the FDA has been so notified.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on IP record keeping.

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

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

The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the RevComRule applies to research.)

Per the National Cancer Institute (NCI)’s USA-2, a Material Transfer Agreement (MTA) or contract should be used for the transfer of biospecimens and data among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.

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

Informed consent requirements guiding Department of Health & Human Services (HHS)-conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E.

Per the Pre2018-ComRule and the G-SpecimensResrch, the HHS views research involving human subject specimens as research involving human participants and subject to informed consent 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 RevComRule 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 Pre2018-ComRule, RevComRule, the G-SpecimensResrch, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-24, 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-24 for detailed frequently asked questions (FAQs) on this topic.

Per the Pre2018-ComRule and the RevComRule, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant or legal representative/guardian. See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

The RevComRule requires the informed consent form to provide one (1) 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
• 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 RevComRule 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 or legal representative/guardian:

• 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 participant's rights and about storage and use of the participant's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.

The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) 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.

The HHS’ G-StoredData-Tissues states that among the basic informed consent elements, clear descriptions of the following should be included for specimen collection and storage:

• The operation of the cell repository and the specific types of research to be conducted
• Conditions under which specimens and data will be released to recipient investigators
• Procedures for protecting the privacy of human research participants and maintaining the confidentiality of data
• The nature and purpose of the research, as specific as possible
• The consequences of DNA typing if human genetic research is anticipated

(See the Required Elements and Participant Rights sections for additional information on informed consent).