Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
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Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
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Definition of Sponsor
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Required Elements
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Participant Rights
Special Circumstances/Emergencies
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Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
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United States
QUICK FACTS
Clinical trial application languageEnglish
Parallel regulatory and ethical review permittedYes
Clinical trial registration requiredYes
In-country sponsor presence/representation requiredNo
Age of minorsDetermined at the State Level
Specimens export allowedYes
Regulatory Authority > Regulatory Authority
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SUMMARY

Overview
As per the FD&CAct, 21CFR50, 21CFR312, the Food & Drug Administration (FDA) is the regulatory authority that regulates clinical investigations of medical products in the United States (US). This profile is specifically focused on the FDA’s role in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FD&CAct, 21CFR50, and 21CFR312. Regulatory requirements relating to compliance with 45CFR46 for Department of Health & Human Services (HHS)-funded or -sponsored human subjects research are also examined.

According to Additional Resource (A), the FDA is an agency within HHS comprised of the Office of the Commissioner and four (4) directorates: the Office of Foods and Veterinary Medicine, the Office of Global Regulatory Operations and Policy, the Office of Operations, and the Office of Medical Products and Tobacco (OMPT). The OMPT is responsible for the regulation of medical products. Within the OMPT directorate, 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). Also residing within the OMPT, in its Office of Special Medical Programs, is the Office of Good Clinical Practice (OGCP). The OGCP plays a pivotal role in the FDA’s oversight of good clinical practice and human subject protection issues stemming from clinical research.

In addition, as described in Additional Resource (D), in 1991, HHS published the Federal Policy for the Protection of Human Subjects, also known as the “Common Rule,” delineating basic ethical principles surrounding human subjects research. The “Common Rule” was codifed into subpart A of 45CFR46 by HHS, and incorporated into separate regulations by 15 other federal departments and agencies (see Additional Resource (D) for a complete list of participating agencies). 45CFR46 includes the “Common Rule” (subpart A) as well as additional protections for pregnant women, human fetuses, and neonates (subpart B), prisoners (subpart C), and children (subpart D). HHS’ Office for Human Research Protections (OHRP) guides the agency’s efforts to safeguard the rights, welfare, and well-being of human research subjects for studies conducted or supported by HHS. OHRP also provides oversight to all federal agencies engaged in human subjects research under the “Common Rule.”

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

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

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

Contact Information: HHS
US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Toll Free Call Center: 1-877-696-6775
HHS Employee Directory: http://directory.psc.gov/employee.htm

ADDITIONAL RESOURCES

(A) (Website) FDA Organization (Last Updated September 15, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Drugs (Last Updated September 19, 2016)
Food & Drug Administration (FDA), US Department of Health & Human Services (HHS)

(C) (Website) FDA 101: Regulating Biological Products (Last Updated November 8, 2015)
Food & Drug Administration, US Department of Health & Human Services

(D) (Website) Federal Policy for the Protection of Human Subjects ('Common Rule') (Current as of March 18, 2016)
Office for Human Research Protections (OHRP), US Department of Health & Human Services

(E) (Document) Comparison of FDA and HHS Human Subject Protection Regulations (Last Updated March 10, 2009)
Food & Drug Administration, US Department of Health & Human Services

(F) (Website) Selected FDA GCP/Clinical Trial Guidance Documents (Last Updated August 12, 2016)
Food & Drug Administration, US Department of Health & Human Services

(G) (Website) Clinical Trials Guidance Documents (Last Updated January 15, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Section: Subchapter V, Part A, Sec. 355

(2) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (50.1)

(3) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1), Subpart B (312.20), and Subpart C (312.40)

(4) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subparts A – D

Regulatory Authority > Scope of Assessment
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SUMMARY

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

As delineated in 21CFR312 and Additional Resource (A), 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 Additional Resource (A), the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

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

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

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

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

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

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

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

As set forth in Additional Resources (D) and (E), the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) coordinate the IND submission review process for drugs and therapeutic biological products respectively. Per the FD&CAct, 21CFR312 and Additional Resources (D) and (E), the CDER and CBER review teams will evaluate all initial INDs and, within 30 calendar days of receipt of the original IND, contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. An IND automatically goes into effect 30 days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold or the FDA has notified the sponsor earlier that the trial may begin.

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

ADDITIONAL RESOURCES

(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER) (Last Updated June 2, 2016)
Food and Drug Administration, US Department of Health & Human Services

(C) (Website) The Drug Development Process – Step 3: Clinical Research (Last Updated May 19, 2016)
Food & Drug Administration, US Department of Health & Human Services

(D) (Guidance) Manual of Policies and Procedures (MAPP 6030.1): IND Process and Review Procedures (Including Clinical Holds) (May 1, 1998)
Center for Drug Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Definitions and Policy

(E) (Guidance) SOPP 8201: Administrative Processing of Clinical Holds for Investigational New Drug Applications (Version #4) (Effective Date: May 19, 2014)
Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I, II, III, V, and VI

(F) (Website) Selected FDA GCP/Clinical Trial Guidance Documents (Last Updated August 12, 2016)
Food & Drug Administration, US Department of Health & Human Services

(G) (Website) Clinical Trials Guidance Documents (Current as of January 15, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Section: Subchapter V, Part A, Sec. 355

(2) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (50.1)

(3) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 – 312.3), Subpart B (312.20 – 312.23), Subpart C (312.40 and 312.42), and Subpart E (312.85)

(4) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.102)

(5) (Guidance) Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (G-PharmeCTD) (Revision 3) (May 2015)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (C)

(6) (Guidance) Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND (G-IND-Determination) (September 2013)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II - IV

Regulatory Authority > Regulatory Fees
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SUMMARY

Overview
As stated in the Prescription Drug User Fee Act (PDUFA) and Additional Resources (A) and (B), the Food & Drug Administration (FDA) does not levy a fee to review investigational new drug (IND) submissions.

However, per the FD&CAct, PDUFA, and Additional Resources (A), (B), and (C), the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). The NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States (US). The data gathered during the animal studies and human clinical trials of an IND become part of the NDA.

A company that would like the agency to approve a new drug or biologic product prior to marketing is required to submit an application along with a fee to support the review process. Under the PDUFA program, industry pays annual fees to facilitate the FDA’s ability to meet Congressionally mandated drug-review performance goals, thereby enabling companies to get their drugs to market sooner.

ADDITIONAL RESOURCES

(A) (Website) Prescription Drug User Fee Act (PDUFA) (Last Updated October 4, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Frequently Asked Questions on Prescription Drug User Fees (PDUFA) (Last Updated June 7, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) How Drugs are Developed and Approved (Last Updated August 18, 2015)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Legislation) Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Sections: Part C, Subpart 2 (379g and 379h)

(2) (Legislation) Prescription Drug User Fee Act (PDUFA) (1992)
US Congress

Relevant Sections: 502 and 504

Ethics Committee > Ethics Committee
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SUMMARY

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. Per subpart A of 45CFR46 (also known as the “Common Rule”), federally funded or sponsored human subjects research for agencies that follow the common rule also requires institutional EC approval. See Additional Resource (A) and the Regulatory Authority topic, Regulatory Authority subtopic for detailed information on the “Common Rule” and agency-specific compliance.

EC Composition
As stated in 21CFR56 and 45CFR46, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable law, and standards. Also, 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.

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule
As delineated in 21CFR56 and 45CFR46, 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 21CFR56 and 45CFR46, proposed research must be reviewed at convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members. The EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. Refer to 21CFR56 and 45CFR46 and Additional Resources (B) and (C) for detailed EC procedural requirements.

Federal Assurance Requirement
Institutions engaging in research conducted or supported by a federal department/agency must also obtain an approved assurance and certify to the federal department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance. Per Additional Resource (D), 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 45CFR46 requirements. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

ADDITIONAL RESOURCES

(A) (Website) Federal Policy for the Protection of Human Subjects ('Common Rule') (Current as of March 18, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(B) (Website) A Self-evaluation Checklist for IRBs (Current as of April 14, 2009)
Food & Drug Administration, US Department of Health & Human Services

(C) (Information Sheet) Institutional Review Boards Frequently Asked Questions - Information Sheet (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

(D) (Website) Assurance Process FAQs (Current as of September 22, 2016)
Office for Human Research Protections, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (50.3)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (56.101 - 56.103) and Subpart C (56.108)

(3) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.3), Subpart B (312.23), and Subpart C (312.40)

(4) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (46.103, 46.107 - 46.109)

(5) (Guidance) Engagement of Institutions in Human Subjects Research (G-HHS-Inst-Engagemt) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services

Ethics Committee > Scope of Review
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SUMMARY

Overview
21CFR56, 21CFR312, and 45CFR46 state that the primary scope of information assessed by the ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56 and 45CFR46, the EC must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See Informed Consent topic, and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired for additional information about these populations). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

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

In the event of multicenter clinical studies, also known as cooperative research studies, 21CFR56, 45CFR46, and the G-Cent-IRB state that with the approval of the department/agency head, an institution participating in a cooperative project may enter into a joint review arrangement, rely on the review of another qualified EC, or, establish other arrangements aimed at reducing duplicative efforts. Each institution is, however, still responsible for safeguarding the rights and welfare of human participants. The National Institutes of Health (NIH), in particular, has issued a final policy requiring all institute-funded multi-site clinical trials to be overseen by a single institutional review board (sIRB) (single EC), unless prohibited by any federal, tribal, or state law, regulation, or policy. Designed to streamline the IRB review process and eliminate duplicative reviews, this policy will take effect May 25, 2017.

Although the regulations do not specify an expiration for EC approval, 21CFR56, 45CFR46, 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 frequently than once per year.

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

ADDITIONAL RESOURCES

(A) (Website) Institutional Review Boards Frequently Asked Questions - Information Sheet (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Information Sheet Guidance for Institutional Review Boards (IRBs), Clinical Investigators, and Sponsors (Current as of March 12, 2014)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) Cooperative Research Information Sheet – Guidance for IRBs and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

(D) (Website) Non-Local IRB Review – Information Sheet (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

(E) (NIH Policy) Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research (June 21, 2016) (Effective Date: May 25, 2017)
National Institutes of Health, US Department of Health & Human Services

(F) (Website) Approval of Research with Conditions: OHRP Guidance (November 10, 2010)
Office for Human Research Protections, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (56.102 and 56.103) and Subpart C (56.108, 56.109, 56.111, and 56.114)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (312.3) and Supbart B (312.20 and 312.23)

(3) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (46.103, 46.109, and 46.111)

(4) (Guidance) Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Continuing Review after Clinical Investigation Approval (G-IRBContRev) (February 2012)
Center for Biologics Evaluation, Center for Devices and Radiological Health, Center for Drug Evaluation and Research, and Office of Good Clinical Practice, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (F)

(5) (Guidance) Guidance for Industry: Using a Centralized IRB Review Process in Multicenter Clinical Trials (G-Cent-IRB) (March 2006)
Good Clinical Practice Program, Office of the Commissioner, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Office of Regulatory Affairs; Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I and II

Ethics Committee > Ethics Committee Fees
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SUMMARY

Overview
Many institutional ethics committees (EC) (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.

ADDITIONAL RESOURCES
No additional resources
 
 
REQUIREMENTS

No applicable regulatory requirements

Ethics Committee > Authorizing Body
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SUMMARY

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

In addition, per 45CFR46 and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by the HHS must also submit a written assurance of compliance, known as a Federalwide Assurance (FWA). According to 45CFR46 and Additional Resources (B), (C), and (D), institutions that obtain an OHRP-approved FWA are obligated to comply with the HHS regulations protecting human participants as set forth in Subpart A of 45CFR46, also known as the “Common Rule.”

Registration, Auditing, and Accreditation
FDA Registration
According to 21CFR56 and the G-IRB FAQ, FDA requires each EC in the US that either reviews clinical investigations regulated by the agency under the Federal Food, Drug, and Cosmetic Act (FD&C Act) or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system. Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRB FAQ also indicates that while registration of non-US ECs is voluntary, the information FDA receives from them is very helpful.

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

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

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

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

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

As delineated in 45CFR46 and Additional Resources (B) and (E), an EC must be registered in the HHS OHRP system, before it can be designated under an OHRP FWA. Per Additional Resource (C), an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with OHRP. The FWA is the only type of assurance of compliance accepted and approved by OHRP.

See 45CFR46, and Additional Resource (E) for detailed registration requirements.

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

Accreditation
In accordance with the G-IRB FAQ and Additional Resource (E), EC registration with the HHS OHRP system 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. Neither EC competence nor expertise is assessed during the registration review process by either agency.

ADDITIONAL RESOURCES

(A) (Website) Electronic Submission System – Welcome to the Electronic Submission System for FWAs and IRB Registrations (Current as of September 22, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(B) (Website) IRBs and Assurances (Current as of March 18, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(C) (Website) Assurance Process Frequently Asked Questions (FAQs) (Current as of September 22, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(D) (Website) Federalwide Assurance (FWA) for the Protection of Human Subjects (Current as of March 17, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(E) (Website) IRB Registration Process FAQs (Current as of September 22, 2016)
Office for Human Research Protections, US Department of Health & Human Services

(F) (Website) Initial IRB Registration: Step-by-Step Instructions for Registering an Institutional Review Board (IRB) (Current as of May 2015)
Office for Human Research Protections, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart B (56.106)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (46.103) and Subpart E (46.501-505)

(3) (Guidance) Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions – IRB Registration (G-IRB FAQ) (July 2009)
Good Clinical Practice Program, Office of Science and Health Coordination, Office of the Commissioner, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I and II

(4) (Guidance) Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: FDA Institutional Review Board Inspections (G-Info-Sheet) (January 2006)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III

(5) (Guidance) Engagement of Institutions in Human Subjects Research (G-HHS-Inst-Engagemt) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services

Clinical Trial Lifecycle > Submission Process
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SUMMARY

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

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

Delivery Address for Investigational New Drug Applications (INDs)
According to Additional Resource (C), INDs should be sent to the following locations:

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

Therapeutic Biological Products:
Food and Drug Administration
Center for Drug Evaluation and Research
Therapeutic Biological Products Document Room
5901-B Ammendale Road
Beltsville, MD 20705-1266

Assembly and Number of Copies
Currently, IND submissions may be submitted either in paper or electronic format.

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

Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM. Per Additional Resource (D), sponsors may also submit the IND electronically using the FDA’s CDER/Center for Biologics Evaluation and Research (CBER) standard format, known as the Electronic Common Technical Document (eCTD). According to the G-eCTDspecs, and Additional Resources (E) and (F), the FDA’s preferred method for transmitting eCTD submissions sized 10GB and under is via the FDA Electronic Submissions Gateway. As indicated in the G-eCTDspecs, physical media should comply with the following requirements:

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

See the G-eCTDspecs for additional physical media information.

According to the G-PharmeCTD, which implements FDASIA, beginning May 5, 2018, commercial IND submissions must be submitted in eCTD format. Noncommercial INDs are exempt from this submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). For more information, and detailed requirements, see the G-PharmeCTD.

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

ADDITIONAL RESOURCES


(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER) (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) Last Updated August 31, 2015)
Food & Drug Administration, US Department of Health & Human Services

(D) (Website) Electronic Common Technical Document (eCTD) (Last Updated August 4, 2016)
Food & Drug Administration, US Department of Health & Human Services

(E) (Website) Electronic Submissions Gateway (Last Updated July 15, 2016)
Food & Drug Administration, US Department of Health & Human Services

(F) (Website) Electronic Regulatory Submission and Review (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(G) (Website) eCTD Basics and Getting Started (Last Updated July 10, 2015)
Food & Drug Administration, US Department of Health & Human Services

(H) (Website) Electronic Submissions (Last Updated July 30, 2015)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 – 312.3), Subpart B (312.20 – 312.23), and Subpart C (312.40)

(2) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Sections: Subchapter V, Part A, Sec. 355 (a and b) and Subchapter VII, Part D, Sec. 379k-1

(3) (Guidance) Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND (G-IND-Determination) (September 2013)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II - IV

(4) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.102)

(5) (Guidance) Guidance for Industry: Providing Regulatory Submissions to CBER in Electronic Format — Investigational New Drug Applications (INDs) (G-CBER-ElecINDs) (March 2002)
Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II and IV

(6) (Guidance) Transmitting Electronic Submissions Using eCTD Specifications (G-eCTDspecs) (March 4, 2016)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I and II

(7) (Legislation) Food and Drug Administration Safety and Innovation Act (Public Law 112–144) (FDASIA) (July 9, 2012)
US Congress

Relevant Section: Title XI (Subtitle C, Sec. 1136)(8)

(8) (Guidance) Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry (G-RegSubsE-Format) (December 2014)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I, II, and III

(9) (Guidance) Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (G-PharmeCTD) (Revision 3) (May 2015)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I, II, and II (A, B, C, K, L, and M)

Clinical Trial Lifecycle > Submission Content
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SUMMARY

Overview
As set forth in 21CFR312 and Additional Resources (A) and (B), the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration's (FDA) review and authorization to obtain an agency exemption to ship investigational drugs and biological products across state lines and to administer these investigational products (IPs) in humans. See the Regulatory Authority topic, Scope of Assessment subtopic for more information.

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

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

  • Cover sheet (Form FDA 1571) (See Additional Resource (C))
    (including, but not limited to: sponsor contact information, IP name, application date, phase(s) of clinical investigation to be conducted, and commitment that the EC will conduct initial and continuing review and approval of each study proposed in the investigation)
  • Table of contents
  • Introductory statement and general investigational plan
  • Investigator’s brochure (IB)
  • Protocols
  • Chemistry, manufacturing, and control data
  • Pharmacology and toxicology data
  • Previous human experience with the investigational drug
  • Additional information
  • Relevant information (e.g., foreign language materials and number of copies – see Submission Process subtopic for details)

For detailed application requirements, see 21CFR312.

EC Requirements
Each EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements. However, the requirements listed below comply with 21CFR56 as well as the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) and are basically consistent across all US ECs.

As per 21CFR56, 45CFR46, and the US-ICH-GCPs, the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study:

  • Clinical protocol
  • Informed consent forms (ICFs) and participant information
  • Participant recruitment procedures
  • IB
  • Safety information
  • Participant payments and compensation
  • Investigator(s) current Curriculum Vitaes (CVs)
  • Additional required EC documentation
  • Risks to participants are minimized and are reasonable in relation to anticipated benefits
  • Participant selection is equitable
  • Adequate provisions to protect participant privacy and maintain confidentiality of data are made, where appropriate

See 21CFR56, 45CFR46, and section 3 of the US-ICH-GCPs for additional EC submission requirements.

Clinical Protocol

  • General information
  • Background information
  • Trial objectives and purpose
  • Trial design
  • Participant selection/withdrawal
  • Participant treatment
  • Efficacy assessment
  • Safety assessment
  • Statistics
  • Direct access to source data/documents
  • Quality control/quality assurance
  • Ethics
  • Data handling/recordkeeping
  • Financing/insurance
  • Publication policy

For complete protocol requirements, see section 6 of the US-ICH GCPs.

ADDITIONAL RESOURCES

(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER) (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) IND Forms and Instructions (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(D) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 3 and 6

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 – 312.3), Subpart B (312.20 – 312.23), and Subpart C (312.40 and 312.42)

(2) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Sections: Subchapter V, Part A, Sec. 355 (a and b)

(3) (Guidance) Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND (G-IND-Determination) (September 2013)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II - IV

(4) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (56.102 and 56.103) and Subpart C (56.111)

(5) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart A (46.111)

Clinical Trial Lifecycle > Timeline of Review
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SUMMARY

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

FDA IND Review and Authorization
Per the FD&CAct, 21CFR312, and Additional Resources (A) and (B), the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) review teams will evaluate all initial INDs for drugs and therapeutic biological products respectively. Within 30 calendar days of receipt of the original IND, the CDER/CBER team will contact the sponsor when a clinical hold is being imposed. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the team determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. An IND automatically goes into effect in 30 days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or, the FDA has notified the sponsor earlier that the trial may begin.

According to Additional Resource (C), once the FDA receives the IND application, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor/sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND application should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed. Clinical studies shall not be initiated until 30 days after the date of receipt of the IND application by the FDA unless earlier notification is received from the FDA that studies may begin.

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

ADDITIONAL RESOURCES

(A) (Guidance) Manual of Policies and Procedures (MAPP 6030.1): IND Process and Review Procedures (Including Clinical Holds) (May 1, 1998)
Center for Drug Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Definitions and Policy

(B) (Guidance) SOPP 8201: Administrative Processing of Clinical Holds for Investigational New Drug Applications (Version #4) (Effective Date: May 19, 2014)
Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I, II, III, V, and VI

(C) (Website) Information for Sponsor-Investigators Submitting Investigational New Drug Applications (INDs) (Last Updated August 31, 2015)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.102)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 – 312.3), Subpart B (312.20 – 312.23), Subpart C (312.40 and 312.42), and Subpart E (312.85)

(3) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Section: Subchapter V, Part A, Sec. 355

Clinical Trial Lifecycle > Trial Initiation
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SUMMARY

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

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

As stated in 21CFR312 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), all investigators must possess appropriate qualifications, training, and experience. Prior to the trial’s commencement, as addressed in the G-1572, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572. This form serves as the investigator’s agreement to provide certain information to the sponsor and to assure that he/she will comply with the FDA’s clinical investigation regulations. Refer to the G-1572 and Additional Resource (D) for further information.

Clinical Trials Registry
FDAMA, FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank. Per FDAAA, 42CFR11, and Additional Resource (E), the sponsor/PI must register 21 calendar days after the first human participant is enrolled in a trial.

42CFR11, which takes effect January 18, 2017, expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the Food & Drug Administration (FDA).

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

See 42CFR11 and Additional Resources (E), (F), and (G) for detailed information on ClinicalTrials.gov.

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

Additionally, as indicated in 45CFR46, for all human subjects research funded and/or sponsored by the Department of Health & Human Services (HHS), the institutional EC shall ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per Additional Resources (H) and (I), 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 including interventions that involve potential participant risk. See Additional Resources (H) and (I) for detailed HHS/NIH requirements.

EC Confirmation of Review and Approval
Per 21CFR56, 21CFR312, and 45CFR46, EC review of the clinical investigation must be obtained prior to the sponsor being permitted to initiate the trial.

ADDITIONAL RESOURCES

(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER) (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 4 and 5

(D) (Website) IND Forms and Instructions (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(E) (Website) ClinicalTrials.gov - Frequently Asked Questions (Last Updated February 2015)
National Institutes of Health, US Department of Health & Human Services

(F) (Website) FDA's Role: ClinicalTrials.gov Information (Last Updated September 23, 2016)
Food & Drug Administration, US Department of Health & Human Services

(G) (NIH Policy) NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (September 21, 2016) (Effective Date: January 18, 2017)
Office of Science Policy, National Institutes of Health, US Department of Health & Human Services

Relevant Sections: NIH Policy, Purpose, and Scope

(H) (NIH Policy) NIH Policy for Data and Safety Monitoring (June 10, 1998)
National Institutes of Health, US Department of Health & Human Services

(I) (Website) Frequently Asked Questions From Applicants – Data and Safety Monitoring (Last Updated May 5, 2016)
National Institutes of Health, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 – 312.3), Subpart B (312.20 – 312.23), Subpart C (312.40), Subpart D (312.53), and Subpart F (312.110)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.102)

(3) (Guidance) Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND (G-IND-Determination) (September 2013)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Food Safety and Applied Nutrition, Food and Drug Administration, US Department of Health & Human Services

Relevant Sections: II - IV

(4) (Legislation) 21 US Code Chapter 9: Federal Food, Drug, and Cosmetic Act (FD&CAct) (June 25, 1938)
US Congress

Relevant Sections: Subchapter V, Part A, Sec. 355 (a and b)

(5) (Guidance) Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement of Investigator (Form FDA 1572) (G-1572) (May 2010)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: I (1)

(6) (Guidance) Guidance for Clinical Trail Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees (G-DMCs) (March 2006)
Center for Biologics Evaluation and Research, Center for Drug Evaluation Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 1

(7) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food and Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart B (50.24)

(8) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart A (46.111)

(9) (Legislation) Food and Drug Administration Modernization Act of 1997 (FDAMA) (November 21, 1997)
US Congress

Relevant Section: 113

(10) (Legislation) Food and Drug Administration Amendments Act of 2007 (FDAAA) (September 27, 2007) (Effective Date: October 1, 2007)
US Congress

Relevant Section: Title VIII (Section 801)

(11) (Regulation) Code of Federal Regulations – Title 42, Part 11 – Clinical Trials Registration and Results Information Submission (42CFR11) (September 21, 2016) (Effective Date: January 18, 2017)
US Department of Health & Human Services

Relevant Sections: Subparts A, B, and C

Clinical Trial Lifecycle > Safety Reporting
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SUMMARY

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

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

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS) does not define or use the terms “adverse event” or “unanticipated problems.” However, 45CFR46 does contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs and 45CFR46 for further information.

Reporting Requirements for AEs/ARs
Investigator Responsibilities
As delineated in 21CFR312, the G-IND-Safety, and the G-IRB-AERepts, 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
  • Nonserious AEs must be recorded and reported to the sponsor according to the protocol specified timetable
  • Report promptly to the institutional ethics committee (EC) (institutional review boards (IRBs) in the US) all unanticipated problems involving risk to human participants or others where AEs should be considered unanticipated problems

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

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

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

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

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

As part of the clinical trial results information submitted to ClinicalTrials.gov, 42CFR11, which takes effect on January 18, 2017, requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of AE/adverse drug reaction (ADR) information. The tables should consist of the following summarized data:

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

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

See 42CFR11 for detailed AE/ADR reporting requirements.

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

The submission must be identified as follows:

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

The report must also be submitted to the appropriate review division (Center for Drug Evaluation and Research (CDER)/Center for Biologics Evaluation and Research (CBER)). Additionally, FDA will accept foreign SARs on a CIOMS I Form instead of FDA Form 3500A (see Additional Resources (D) and (E)).

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

Additionally, as indicated in 45CFR46, for HHS funded or sponsored human subjects research, the institutional EC shall ensure that, when appropriate, the research plan makes adequate provision for monitoring the data collected during the study to ensure participant safety. Moreover, per Additional Resources (F) and (G), all National Institutes of Health (NIH) funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are specifically required for NIH-funded multi-site clinical trials including interventions that involve potential participant risk. See Additional Resources (F) and (G) for detailed HHS/NIH requirements.

ADDITIONAL RESOURCES

(A) (Website) IND Application Reporting: Safety Reports (Last Updated October 9, 2015)
Food & Drug Administration, US Department of Health & Human Services

(B) (Document) Instructions for Completing Form FDA 3500A (February 2014)
Food & Drug Administration, US Department of Health & Human Services

(C) (Form) Form 3500A - Mandatory Reporting (February 2013)
Food & Drug Administration, US Department of Health & Human Services

(D) (Form) Suspect Adverse Reaction Report Form (CIOMS Form I) (Date Unavailable)
Council for International Organizations of Medical Sciences, Geneva, Switzerland

(E) (Document) Reporting Adverse Drug Reactions: Definitions of Terms and Criteria for Their Use (1999)
Council for International Organizations of Medical Sciences, Geneva, Switzerland

(F) (NIH Policy) NIH Policy for Data and Safety Monitoring (June 10, 1998)
National Institutes of Health, US Department of Health & Human Services

(G) (Website) Frequently Asked Questions From Applicants – Data and Safety Monitoring (Last Updated May 5, 2016)
National Institutes of Health, US Department of Health & Human Services

(H) (Website) Summary of HHS/NIH Initiatives to Enhance Availability of Clinical Trial Information (September 16, 2016)
National Institutes of Health, US Department of Health & Human Services

Relevant Section: Results Information

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (312.32) and Subpart D (312.64 and 312.66)

(2) (Guidance) Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (G-IND-Safety) (December 2012)
Center for Drug Evaluation Research and Center for Biologics Evaluation and Research, Food and Drug Administration, US Department of Health & Human Services

Relevant Sections: III-VIII and Appendix B

(3) (Guidance) Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs — Improving Human Subject Protection (G-IRB-AERepts) (January 2009)
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health, and Office of Good Clinical Practice, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: II

(4) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart B (50.24)

(5) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.103, 46.109, 46.111, and 46.113)

(6) (Guidance) Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees (G-DMCs) (March 2006)
Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 1

(7) (Guidance) Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (G-HHS-AEReqs) (January 15, 2007)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Regulatory Background and Guidance (I and II)

(8) (Regulation) Code of Federal Regulations – Title 42, Part 11 – Clinical Trials Registration and Results Information Submission (42CFR11) (September 21, 2016) (Effective Date: January 18, 2017)
US Department of Health & Human Services

Relevant Sections: Subparts A (11.10) and Subpart C (11.44 and 11.48)


Clinical Trial Lifecycle > Progress Reporting
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SUMMARY

Overview
In accordance with 21CFR312 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the investigator and the sponsor share responsibility for submitting progress reports on the status of a clinical trial and for submitting final study reports upon the trial’s completion.

Interim/Progress Reports
As 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, 45CFR46, and the US-ICH-GCPs, the investigator should submit written summaries of the trial status to the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) annually, or more frequently, if requested by the institutional EC.

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

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

As indicated in 42CFR11, which takes effect on January 18, 2017, trial updates must be submitted to ClinicalTrials.gov according to the following guidelines:

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

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

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

Additionally, per 42CFR11 (effective January 18, 2017) and Additional Resources (B) and (C), the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product clinical trials to ClinicalTrials.gov no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.

The results information must include data on the following:

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

See 42CFR11 for more detailed requirements.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Section: 4

(B) (NIH Policy) NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (September 21, 2016) (Effective Date: January 18, 2017)
Office of Science Policy, National Institutes of Health, US Department of Health & Human Services

Relevant Sections: NIH Policy and Purpose

(C) (Website) Summary of HHS/NIH Initiatives to Enhance Availability of Clinical Trial Information (September 16, 2016)
National Institutes of Health, US Department of Health & Human Services

Relevant Sections: Results Information and Updates and Other Required Information

(D) (Website) FDA's Role: ClinicalTrials.gov Information (Last Updated September 23, 2016)
Food & Drug Administration, US Department of Health & Human Services

(E) (Website) ClinicalTrials.gov - Frequently Asked Questions (Last Updated February 2015)
National Institutes of Health, US Department of Health & Human Services


REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (312.33) and Subpart D (312.64 and 312.66)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.108)

(5) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart A (46.103 and 46.115)

(6) (Regulation) Code of Federal Regulations – Title 42, Part 11 – Clinical Trials Registration and Results Information Submission (42CFR11) (September 21, 2016) (Effective Date: January 18, 2017)
US Department of Health & Human Services

Relevant Sections: Subpart C

Sponsorship > Definition of Sponsor
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SUMMARY

Overview
As per 21CFR312, 21CFR50, and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312, 21CFR50, and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed. The term does not include any person other than an individual.

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

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

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Sections: 1 and 5.2

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.3), Subpart D (312.52), and Subpart F (312.110)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (50.3)

Sponsorship > Trial Authorization
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SUMMARY

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

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

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

  • Cover sheet (Form FDA 1571) (See Additional Resource (C)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the EC will conduct an initial and continuing review and approval of each study proposed in the investigation)
  • Protocols
  • Chemistry, manufacturing, and control data
  • Pharmacology and toxicology data
  • Previous human experience with the investigational drug

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

ADDITIONAL RESOURCES

(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

(B) (Website) Investigational New Drug (IND) or Device Exemption (IDE) Process (CBER) (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) IND Forms and Instructions (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (312.1 and 312.3), Subpart B (312.20 and 312.23), and Subpart C (312.40)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (56.102 and 56.103)

Sponsorship > Insurance
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SUMMARY

No relevant provisions

ADDITIONAL RESOURCES

No additional resources

REQUIREMENTS

No applicable regulatory requirements

Sponsorship > Compensation
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SUMMARY

Overview
As specified in 21CFR50 and 45CFR46, the sponsor is responsible for providing information related to compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. The sponsor must also inform participants who suffer any trial-related injuries of any available medical treatments, what they consist of, and where further information can be obtained.

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

ADDITIONAL RESOURCES

(A) (Document) Payment to Research Subjects – Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (50.20 and 50.25)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (46.116)

Sponsorship > Quality, Data & Records Management
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SUMMARY

Overview
As stated in the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Electronic Data Processing System
When using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that SOPs are maintained for using these systems. Refer to the US-ICH-GCPs for additional information.

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

Audit Requirements
As part of its QA system, the US-ICH-GCPs notes that the sponsor should perform a clinical trial audit. The sponsor should appoint auditors to review the clinical trial, ensure that the auditors are qualified by training and experience, and document their qualifications. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs, the auditor observations are documented, and data are available as needed for the FDA. No specific timeframe is provided for the audit process.

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

Multicenter Studies
The G-Cent-IRB states that in the event of a multicenter clinical trial, the sponsor is responsible for obtaining commitment from each investigator that he/she will ensure EC review and approval requirements are met. Sponsors may also initiate plans for use of a centralized EC review process and facilitate agreements and other necessary communications among the parties involved. In addition, the US-ICH-GCPs specifies that the sponsor must ensure all investigators conduct the trial in strict compliance with the FDA and EC approved protocol.

Per Additional Resources (C) and (D), Data Safety and Monitoring Boards are also specifically required for National Institutes of Health (NIH)-funded multi-site clinical trials including interventions that involve potential participant risk. Also, per Additional Resource (E), the NIH has issued a final policy, effective May 25, 2017, requiring all institute-funded multi-site clinical trials to be overseen by a single institutional review board (single EC), unless prohibited by any federal, tribal, or state law regulation or policy.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 5.1, 5.5, 5.19, 5.21, and 5.23

(B) (Website) Types of Applications (Last Updated October 23, 2014)
Food & Drug Administration, US Department of Health & Human Services

(C) (NIH Policy) NIH Policy for Data and Safety Monitoring (June 10, 1998)
National Institutes of Health, US Department of Health & Human Services

(D) (Website) Frequently Asked Questions From Applicants – Data and Safety Monitoring (Last Updated May 5, 2016)
National Institutes of Health, US Department of Health & Human Services

(E) (NIH Policy) Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research (June 21, 2016)
National Institutes of Health, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart D (312.56 – 312.58)

(2) (Guidance) Guidance for Industry: Using a Centralized IRB Review Process in Multicenter Clinical Trials (G-Cent-IRB) (March 2006)
Good Clinical Practice Program, Office of the Commissioner, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Office of Regulatory Affairs; Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (C)

Sponsorship > Site/Investigator Selection
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SUMMARY

Overview
As set forth in 21CFR312 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

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

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

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

Foreign Sponsor Responsibilities
No applicable regulatory requirements.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Section: 5.6

(B) (Website) IND Forms and Instructions (Last Updated June 2, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart D (312.50 and 312.53)

(2) (Guidance) Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions – Statement of Investigator (Form FDA 1572) (G-1572) (May 2010)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: I (3)

Informed Consent > Documentation Requirements
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SUMMARY

Overview
In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50, for Food & Drug Administration (FDA) regulated clinical trials, and 45CFR46, for Department of Health & Human Services (HHS) funded or sponsored clinical trials. The International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) has also been adopted by the FDA as guidance.

As per 21CFR50, 45CFR46, and the US-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND). (See the Informed Consent topic, Required Elements subtopic for ICF content details.)

21CFR50, 45CFR46, and the US-ICH-GCPs state that the investigator must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or his/her legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.

In addition, per 21CFR50 and 45CFR46, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or his/her legal representative(s) or guardian(s) to read before it is signed.

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

Additional Resource (B) 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, 45CFR46, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or his/her legal representative(s) or guardian(s). The US-ICH-GCPs also indicates that an impartial witness should be present, where applicable, when the ICF is being presented.

As delineated in the G-ICInfoSheet and the G-ICInfoSheet2, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language and at a level they can comprehend. The EC must review and approve all English and non-English language versions of consent documents. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available.

Additional Resource (C) also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-ICInfoSheet, the G-ICInfoSheet2, and Additional Resource (C) for detailed information.

Documentation Copies
As set forth in 21CFR50, 45CFR46, and the US-ICH-GCPs, the participant and/or his/her legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A copy of the form must be given to the participant and/or his legal representative(s) or guardian(s).

Per 21CFR50, 45CFR46, and the US-ICH-GCPs, if the consent information is only presented orally using the short form, the participant and/or his/her legal representative(s) or guardian(s) must sign the form (if capable), the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form should be given to the participant and/or his/her legal representative(s) or guardian(s).

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 2.9 and 4

(B) (Document) Institutional Review Boards Frequently Asked Questions - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: V (45)

(C) (Website) Informed Consent of Subjects Who Do Not Speak English (November 9, 1995)
Office for Human Research Protections, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (50.20, 50.25, and 50.27)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.116 and 46.117)

(3) (Guidance) Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors (G-ICInfoSheet) (January 15, 2016)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: IV (B) and V (B)

(4) (Guidance) A Guide to Informed Consent - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (G-ICInfoSheet2) (January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Non-English Speaking Subjects


Informed Consent > Required Elements
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SUMMARY

Overview
As delineated in 21CFR50 and 45CFR46, and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) (institutional review board (IRB) in the United States (US)) approval for the written informed consent form (ICF) and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s). 21CFR50, 45CFR46, and the US-ICH-GCPs state that information about the study should be presented in easily understandable language and in a format that facilitates understanding. The participant and/or his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

No Coercion
As indicated in 21CFR50, 45CFR46, and the US-ICH-GCPs, none of the oral and written information concerning the research study should contain any language that causes the participant and/or his/her legal representative(s) or guardian(s) to waive or appear to waive his/her legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.

ICF Required Elements
Based on 21CFR50, 45CFR46, and the US-ICH-GCPs, the ICF must include the following statements or descriptions, as applicable:

  • The study purpose, procedures, and expected duration of the trial
  • Identification of any experimental procedures
  • Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
  • Any expected benefits to the participant
  • Disclosure of appropriate alternative procedures that might be advantageous to the participant
  • Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
  • Compensation and/or treatment available for the participant in the case of trial-related injury
  • Contact information for relevant individuals to contact in the event of a trial-related injury
  • That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of benefits to which he/she is otherwise entitled
  • Foreseeable circumstances under which the investigator may remove the participant without his/her consent
  • Any expenses the participant needs to pay to participate in the trial
  • The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
  • Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
  • Approximate number of participants in the study
  • As per 21CFR50, participants must be notified about the ClinicaTrials.gov registry. Please see 21CFR50 for the specific Ianguage to be included
ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 4.8

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21 – Food and Drugs – Chapter I – Food and Drug Administration Department of Health and Human Services (FDA HHS) – Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (50.20, 50.25, and 50.27)

(2) (Regulation) Code of Federal Regulations – Title 45 - Public Welfare Department of Health and Human Services (PW HHS) –Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.116 and 46.117)

Informed Consent > Compensation Disclosure
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SUMMARY

Overview
In accordance with 21CFR50, 45CFR46 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

Additional Resource (A) further states that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).

Compensation for Participation in Research
According to the G-ICInfoSheet, the FDA considers payment to participants for participation in clinical studies to be compensation for expenses and inconveniences, rather than a benefit of participation in research. Additionally, per Additional Resource (B), compensation for participation is considered to be a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the ethics committee (EC) (institutional review board (IRB) in the United States (US)) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are 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.

21CFR50, 45CFR46, and the US-ICH-GCPs also state that the ICF should inform the participants if they will need to pay for any expenses in order to participate in the trial.

Compensation for Injury
As per 21CFR50, 45CFR46, the US-ICH-GCPs, the G-ICInfoSheet, the G-ICInfoSheet2, and Additional Resource (A), the participant should be told whether compensation and any medical treatment(s) are available for research involving more than minimal risk. Because available compensation and treatments may vary depending on the medical circumstances of the participant, or, the institutional policies, the consent process should include an explanation of where participants may obtain further information. This information must be explained in the ICF and cannot waive or appear to waive the participant’s rights or release or appear to release those conducting the study from liability for negligence.

According to the G-ICInfoSheet2, when no system has been established to provide funds, the preferred wording is: “no funds have been set aside for,” “[the cost] will be billed to you or your insurance,” or similar wording that explains the provisions or the process.

ADDITIONAL RESOURCES

(A) (Document) Institutional Review Boards Frequently Asked Questions - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: I

(B) (Document) Payment to Research Subjects – Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Section: 4.8

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart B (50.25)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart A (46.116)

(3) (Guidance) Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors (G-ICInfoSheet) (January 15, 2016)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (B)

(4) (Guidance) A Guide to Informed Consent - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (G-ICInfoSheet2) (January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Assent of Children Elements of Informed Consent, 21 CFR 50.25 and Compensation v. Waiver of Subject's Rights

Informed Consent > Participant Rights
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SUMMARY

Overview
In accordance with 21CFR50, 21CFR312, 45CFR46, the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), and the G-ICInfoSheet, the United States’ ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw
As set forth in 21CFR50, 45CFR46, and the US-ICH-GCPs, a potential participant and/or his/her legal representative(s) or guardian(s) must be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information
As delineated in 21CFR50, 45CFR46, and the US-ICH-GCPs, a potential research participant, and/or his/her legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality
As per 21CFR50, 45CFR46, and the US-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF shall provide a statement that recognizes this right. It is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal
21CFR50, 45CFR46, and the US-ICH-GCPs state that the research participant, and/or his/her legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of his/her rights.

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Introduction, 1.27, 2.2, 2.3, 3.1, and 4.8

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (50.1) and Subpart B (50.25)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (312.3)

(3) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.103, 46.109, 46.116, and 46.117)
 
(4) (Guidance) Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors (G-ICInfoSheet) (January 15, 2016)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II, III (E), and (IV) (A)

Informed Consent > Special Circumstances/Emergencies
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SUMMARY

Overview
21CFR50, 21CFR56, the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the G-ICEmergencyReqs, and the G-ICInfoSheet make provisions to protect the rights of a research participant during the informed consent (IC) process when the procedure is complicated by special circumstances. Special circumstances may include life-threatening medical emergencies, public health emergencies, military operations, or when a participant is mentally incapacitated.

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

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

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

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

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

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

See 21CFR50, the G-ICEmergencyReqs, and Additional Resource (B) for additional information.

Military Operations Emergencies
21CFR50 and 10USC55 require the Secretary of Defense to request that the President waive the IC requirement prior to a member of the armed forces being administered an IP in connection with his/her participation in a particular military operation. The President must determine in writing that: obtaining consent is not feasible; is contrary to the best interests of the military personnel; or, is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 4.8

(B) (Document) Emergency Use of an Investigational Drug or Biologic - Information Sheet (Last Updated January 19, 2016)
Food & Drug Administration, US Department of Health & Human Services

(C) (Document) Institutional Review Boards Frequently Asked Questions - Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators (Last Updated January 25, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (18)

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (50.23 and 50.24)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (56.102 and 56.104)

(3) (Guidance) Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors; Exception from Informed Consent Requirements for Emergency Research (G-ICEmergencyReqs) (March 2011) (Updated April 2013)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: II (20) and V (44)

(4) (Guidance) Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors (G-ICInfoSheet) (January 15, 2016)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: III (A)

(5) (Regulation) US Code – Title 10, Chapter 55 (10USC55) (2013)
US Congress

Relevant Section: 1107

Informed Consent > Vulnerable Populations
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SUMMARY

Overview
As per 21CFR50, 45CFR46 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

21CFR50, 45CFR46, and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

21CFR50, 45CFR46, and the US-ICH-GCPs also specify that ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting participants who are from vulnerable populations.

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Sections: 1 and 3.1

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart C (56.111)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart A (46.111)
 

Informed Consent > Children/Minors
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SUMMARY

Overview
As set forth in 21CFR50 and 45CFR46, 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. Additional Resource (A) 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 Additional Resource (A) for a table delineating the legal age of majority by state in the United States (US).

As delineated in the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), when the research participant is a minor, informed consent should be obtained from his/her legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.

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

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

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

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

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

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

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

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

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

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

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

When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or, if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented.
21CFR50 and 45CFR46 do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:

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

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

ADDITIONAL RESOURCES

(A) (Publication) Ethical Conduct of Clinical Research Involving Children (2004)
Committee on Clinical Research Involving Children, Institute of Medicine, Washington, DC

Relevant Sections: 5, Appendix B, and Table B2

(B) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Section: 4.8

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart A (50.3) and Subpart D

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart D

(3) (Guidance) Informed Consent Information Sheet: Guidance for IRBs, Clinical Investigators, and Sponsors (G-ICInfoSheet) (January 15, 2016)
Office of Good Clinical Practice, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, and Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: V (F)

Informed Consent > Pregnant Women, Fetuses & Neonates
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SUMMARY

Overview
As per 21CFR50, 45CFR46, and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), 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.

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.

Pregnant Women and Fetuses
As per 45CFR46, 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 states that neonates may not be involved in research unless all of the following criteria are met:

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

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

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

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

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

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Section: 4.8


REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 50 – Protection of Human Subjects (21CFR50) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart B (50.25)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: Subpart B

Informed Consent > Prisoners
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SUMMARY

Overview
21CFR50, 45CFR46, and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), include prisoners in their description of vulnerable populations. As set forth in 45CFR46, 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.

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

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

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

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

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Sections: 1 and 3.1

(B) (Website) Prisoner Research FAQs (Current as of September 14, 2016)
Office for Human Research Protections, US Department of Health & Human Services


REQUIREMENTS


(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart C (56.111)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.111 and Subpart C)

Informed Consent > Mentally Impaired
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SUMMARY

Overview
In accordance with 21CFR50, 45CFR46, and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), an ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. Per 45CFR46, this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. Additional Resource (B) further indicates that while the regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US  Department of Health & Human Services

Relevant Sections: 1.61 and 3.1

(B) (Website) Informed Consent FAQs (Current as of September 14, 2016)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Section: What should be considered in seeking informed consent from individuals with diminished decision-making capacity?

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 56 – Institutional Review Boards (21CFR56) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart C (56.111)

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subject (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.111 and Subpart C)

Investigational Products > Definition of Investigational Product
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SUMMARY

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

Additionally, the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 1.33

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (312.3)

Investigational Products > Manufacturing & Import
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SUMMARY

Overview
According to 21CFR312 and Additional Resource (A), 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 days after the FDA receives the IND, unless FDA notifies the sponsor that the investigation(s) described in the IND are subject to a clinical hold, or,
  • On earlier FDA authorization to ship the IP

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

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

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

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

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

ADDITIONAL RESOURCES

(A) (Website) Investigational New Drug (IND) Application (Last Updated August 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application  (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (312.22 and 312.23), Subpart C (312.40) and Subpart F (312.110)

Investigational Products > IMP/IND Quality Requirements
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SUMMARY

Overview
In accordance with 21CFR312 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The IB must contain all of the relevant information on the investigational new drug(s) /investigational product(s) (IPs) obtained through the earlier research phases, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

IB Content Requirements

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

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

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

For Investigational New Drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.12 of 21CFR312 for detailed requirements.

Certificate of Analysis
According to Additional Resources (B) and (C), submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA).

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 5 and 7

(B) (Website) IND Applications for Clinical Investigations: Chemistry, Manufacturing, and Control (CMC) Information (Last Updated October 9, 2015)
Food & Drug Administration, US Department of Health & Human Services

(C) (Website) Certificate of Analysis for Investigational Drug (April 28, 2009)
First Clinical Research

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (312.23), Subpart D (312.55, 312.57, 312.59 and 312.62) and Subpart F (312.120)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General; (21CFR210) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 210.2

(3) (Guidance) Guidance for Industry: CGMP for Phase 1 Investigational Drugs (G-CGMP-Phase1) (July 2008)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I – V

(4) (Guidance) Guideline on the Preparation of Investigational New Drug Products (Human and Animal) (G-INDPrep) (March 1991)
Center for Drug Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I – IX

Investigational Products > Labeling & Packaging
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SUMMARY

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

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

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

ADDITIONAL RESOURCES

No additional resources

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: Subpart A (312.6)

Investigational Products > Product Management
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SUMMARY

Overview
In accordance with 21CFR312 and the International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs), the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), and for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The IB must contain all of the relevant information on the investigational new drug(s) (INDs)/investigational product(s) (IPs) obtained through the earlier research phases, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

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

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

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

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

ADDITIONAL RESOURCES

(A) (US ICH Guidance) International Conference on Harmonization (ICH) Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance (US-ICH-GCPs) (April 1996)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 5 and 7

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 21, Part 312 – Investigational New Drug Application (21CFR312) (April 1, 2016)
Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: Subpart B (312.23) and Subpart D (312.55, 312.57, 312.59 and 312.62)

(2) (Regulation) Code of Federal Regulations – Title 21, Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General (21CFR210) (April 1, 2015)
Food & Drug Administration, US Department of Health & Human Services

Relevant Section: 210.2

(3) (Guidance) Guidance for Industry: CGMP for Phase 1 Investigational Drugs (G-CGMP-Phase1) (July 2008)
Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I – V

(4) (Guidance) Guideline on the Preparation of Investigational New Drug Products (Human and Animal) (G-INDPrep) (March 1991)
Center for Drug Evaluation and Research, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: I – IX

Specimens > Definition of Specimen
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SUMMARY

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

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

According to Additional Resource (B), the National Bioethics Advisory Commission (NBAC), also defines specimens or human biological materials as the full range of specimens, from subcellular structures such as DNA, to cells, tissues (e.g., blood, bone, muscle, connective tissue, and skin), organs (e.g., liver, bladder, heart, kidney, and placenta), gametes (i.e., sperm and ova), embryos, fetal tissues, and waste (e.g., hair, nail clippings, urine, feces, and sweat, which often contains shed skin cells).

ADDITIONAL RESOURCES

(A) (Manual) NIH Policy Manual 1340-1 - Permits for the Import, Transfer, or Export of Biological Materials (June 7, 2016)
National Institutes of Health, US Department of Health & Human Services

Relevant Section: E

(B) (Report) Research Involving Human Biological Materials: Ethical Issues and Policy Guidance – Volume I: Report and Recommendations of the National Bioethics Advisory Commission (August 1999)
National Bioethics Advisory Commission, Rockville, MD

Relevant Section: Chapter 1

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 49, Part 173 – Shippers – General Requirements for Shipments and Packagings (49CFR173) (September 23, 2016)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation

Relevant Section: Subpart D (173.134)

(2) (Regulation) Code of Federal Regulations – Title 42, Part 72 – Interstate Shipment of Etiologic Agents (42CFR72) (October 1, 2007)
Public Health Service, US Department of Health & Human Services

Relevant Section: Subpart F (72.1)

(3) (Regulation) Code of Federal Regulations – Title 42, Part 73 – Select Agents of Toxins (42CFR73) (October 1, 2007)
Public Health Service, US Department of Health & Human Services

Relevant Section: Subpart F (73.1)

Specimens > Import & Export
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SUMMARY

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

Per Additional Resource (A), the Food & Drug Administration (FDA) is not responsible for licensing the import of specimens intended only for testing in a clinical laboratory or for basic scientific research, and, that are not articles intended to prevent, treat, diagnose, or cure diseases, injuries, or conditions in human beings.

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

Import/Export Requirements
Non-Infectious Specimens
A non-infectious specimen/substance is referred to as a Category B Biological Substance by DOT‘s PHMSA in 49CFR173, and an exempt human specimen or exempt animal specimen by IATA and USPS in Additional Resources (D) and (E) respectively. These specimens are not considered to be hazardous materials for import, transfer, or export by these agencies because they do not contain infectious substances, or, they are not substances likely to cause disease in humans or animals. However, they are subject to specific packaging and labeling procedures which must be followed when shipped. Please refer to 49CFR173 and Additional Resources (D), (E), and (F) for detailed DOT, IATA, and USPS shipping instructions.

Infectious Specimens
Per 49CFR173, 42CFR73, 42CFR71, and Additional Resources (D), (E), (F), and (G), DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Category A Biological Substance, or, a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use and transfer of select agents and toxins per 42CFR73. See 42CFR71, 42CFR73, and Additional Resources (G) and (H) for further information and permit applications for these import/transfer programs.

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

NIH Import/Export Specimen Requirements
HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations as well as receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens. Detailed instructions about how to proceed are outlined in the NIH Policy Manual (Additional Resource (A)).

Per Additional Resource (J), the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations.

See Additional (J) for detailed MTA requirements and Appendix 4 for a sample MTA.

ADDITIONAL RESOURCES

(A) (Manual) NIH Policy Manual 1340-1 - Permits for the Import, Transfer, or Export of Biological Materials (June 7, 2016)
National Institutes of Health, US Department of Health & Human Services

Relevant Sections: A-G

(B) (Guidance) Best Practices for Repositories: Collection, Storage, Retrieval and Distribution of Biological Materials for Research (Third Edition) (2011)
International Society for Biological and Environmental Repositories, Vancouver, CA

Relevant Section: Section J

(C) (Website) Permits for Import or Export of Biological Materials (Current as of September 27, 2016)
National Eye Institute, National Institutes of Health, US Department of Health & Human Services

(D) (Manual) Dangerous Goods Regulations: (IATA—Resolution 618 Attachment “A”)* (54th Edition) (Effective January 1 – December 31, 2013)
International Air Transport Association, Montreal, CA and Geneva, Switzerland
*Note: The most recent edition of the IATA DGR Manual is only available for purchase on the IATA website.

(E) (Document) Publication 52: Hazardous, Restricted, and Perishable Mail – 346 Toxic Substances and Infectious Substances (Hazard Class 6) (March 2016)
United States Postal Service, Washington, DC

Relevant Sections: 346.1 – 346.3

(F) (Document) Transporting Infectious Substances Safely – Federal Register: Hazardous Materials: Infectious Substances; Harmonization with the United Nations Recommendations (Effective October 1, 2006)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation

(G) (Website) Import Permit Program (Last Updated October 26, 2015)
Centers for Disease Control and Prevention, US Department of Health & Human Services

(H) (Website) Request to Import Biological Agents or Vectors of Human Disease (Last Updated March 14, 2014)
Import Permit Program, Centers for Disease Control and Prevention, US Department of Health & Human Services
 
(I) (Website) Commerce Control List (CCL) (Current as of September 27, 2016)
Export Administration, Bureau of Industry and Security, US Department of Commerce

(J) (Guidance) NCI Best Practices for Biospecimens Resources (March 2016)
Biorepositories and Biospecimen Research Branch, National Cancer Institute, National Institutes of Health, US Department of Health & Human Services

Relevant Sections: C.5 and Appendix 4

REQUIREMENTS

(1) (Regulation) Code of Federal Regulations – Title 49, Part 173 – Shippers – General Requirements for Shipments and Packagings (49CFR173) (September 23, 2016)
Pipeline and Hazardous Materials Safety Administration, US Department of Transportation

Relevant Section: Subpart D (173.134)

(2) (Regulation) Code of Federal Regulations – Title 42, Part 73 – Select Agents and Toxins (42CFR73) (October 1, 2007)
Public Health Service, US Department of Health & Human Services

Relevant Section: Subpart F (73.1)

(3) (Regulation) Code of Federal Regulations – Title 42, Part 71 – Foreign Quarantine (42CFR71) (September 23, 2016)
Public Health Service, US Department of Health & Human Services

Relevant Section: Subpart F (71.54)

(4) (Regulation) Code of Federal Regulations – Title 15, Part 774 – The Commerce Control List (15CFR774) (January 1, 2012)
Export Administration Regulations, Bureau of Industry and Security, US Department of Commerce

Relevant Section: Category 1

Specimens > Consent for Specimens
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Last content review/update: October 06, 2016. Submit updates or comments.
SUMMARY

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

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

Per 45CFR46 and the G-SpecimensResrch, HHS views human subject specimens as research involving human participants, and subject to IC requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. See 45CFR46, the G-SpecimensResrch, and Additional Resources (A), (B), and (C) for additional information. See also the G-SpecimensResrch for exemptions to this definition.

Additionally, according to Additional Resource (D), 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 Additional Resource (D) for detailed FAQs on this topic.

Per 45CFR46 and Additional Resource (A), prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or his/her legal representative(s).

The G-StoredData/Tissues and Additional Resource (A) recommend that the following be included in informed consent (IC) documents for biospecimen collection:

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

As stated in Additional Resource (A), the NIH’s National Cancer Institute (NCI) has also developed the following list of recommended elements to include in an informed consent form (ICF):

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

See Additional (A) for detailed NCI biospecimen recommendations and best practices.

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

ADDITIONAL RESOURCES

(A) (Guidance) NCI Best Practices for Biospecimens Resources (March 2016)
Biorepositories and Biospecimen Research Branch, National Cancer Institute, National Institutes of Health, US Department of Health & Human Services

Relevant Sections: B3.3, B5.2, and C

(B) (Document) Attachment D: FAQ's Terms and Recommendations on Informed Consent and Research Use of Biospecimens (July 20, 2011)
The Secretary’s Advisory Committee on Human Research Protections, Office for Human Research Protections, US Department of Health & Human Services

(C) (Chart) Research Involving Private Information or Biological Specimens (June 6, 2005)
National Institutes of Health, US Department of Health & Human Services

(D) (Website) Human Specimens, Cell Lines, or Data Frequently Asked Questions (May 5, 2016)
National Institutes of Health, US Department of Health & Human Services

REQUIREMENTS
(1) (Guidance) Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff: Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable (G-IC-IVDs) (April 25, 2006)
Office of In Vitro Diagnostic Device Evaluation and Safety, Center for Devices and Radiological Health, Food & Drug Administration, US Department of Health & Human Services

Relevant Sections: 1 and 2

(2) (Regulation) Code of Federal Regulations – Title 45, Part 46 – Protection of Human Subjects (45CFR46) (January 15, 2009) (Effective Date: July 14, 2009)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Subpart A (46.102, 46.116, and 46.117)

(3) (Guidance) Guidance on Research Using Coded Private Information or Specimens (G-SpecimensResrch) (October 16, 2008)
Office for Human Research Protections, US Department of Health & Human Services

Relevant Sections: Background and Guidance

(4) (Guidance) Issues to Consider in the Research Use of Stored Data or Tissues (G-StoredData/Tissues) (1996, 1997)
Office for Protection from Research Risks, US Department of Health & Human Services

Relevant Sections: 2 and 3
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Expiration Date: 2/28/2019