Which legislation and regulatory authorities regulate clinical trials in USA?

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This page summarizes the clinical trial registration and results information submission requirements described in Section 801 of the Food and Drug Administration Amendments Act of 2007 (PDF), known as FDAAA 801. The statutory requirements have been in effect since September 27, 2007, have been codified at section 402(j) of the Public Health Service (PHS) Act, and include conforming amendments to the Federal Food, Drug, and Cosmetic FD&C Act (FD&C Act). The regulation became effective on January 18, 2017, and responsible parties have been required to be in compliance starting April 18, 2017.

This page also provides summary information about the Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11). The Final Rule clarifies and expands the regulatory requirements and procedures for submitting registration and results information for certain trials to ClinicalTrials.gov, in accordance with FDAAA 801. The Final Rule has been in effect since January 18, 2017. For complete Final Rule requirements, please refer to 42 CFR Part 11. For additional information on the Final Rule, also see the Final Rule Information page and Frequently Asked Questions. Receive notifications when new information is added by subscribing to the ClinicalTrials.gov Hot Off the PRS! email bulletin.

For details about submitting information to ClinicalTrials.gov, see How to Register Your Study and How to Submit Your Results. For descriptions of data elements, see the documents provided in the Data Element Definitions, Templates, and Checklists section in Support Materials.

Contents

Who Is Responsible for Registering Trials and Submitting Results?

The responsible party for an applicable clinical trial (ACT) must register the trial and submit results information. The responsible party is defined as:

• The sponsor of the clinical trial, as defined in 21 CFR 50.3; or
• The principal investigator (PI) of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the PI is responsible for conducting the trial, has access to and control over the data from the clinical trial, has the right to publish the results of the trial, and has the ability to meet all of the requirements for the submission of clinical trial information

Regulations (42 CFR Part 11)

The final rule specifies that there must be one (and only one) responsible party for purposes of submitting information about an applicable clinical trial. The sponsor of an applicable clinical trial will be considered the responsible party, unless and until the sponsor designates a qualified principal investigator as the responsible party. This final rule specifies the approach for determining who will be considered the sponsor of an applicable clinical trial under various conditions, what qualifies a principal investigator to be designated a responsible party by a sponsor, and how responsibility reverts to the sponsor if a designated principal investigator is unable to fulfill the requirements for submitting information to ClinicalTrials.gov unless and until the sponsor designates another principal investigator as the responsible party (42 CFR Part 11). For more information, see 81 FR 64982.

Key regulatory provisions and related discussions in the Final Rule (81 FR 64982) include:

Which Trials Must Be Registered on ClinicalTrials.gov?

Registration is required for studies that meet the definition of an "applicable clinical trial" (ACT) and either were initiated after September 27, 2007, or initiated on or before that date and were still ongoing as of December 26, 2007. ACTs, as defined in section 402(j) of the PHS Act, include the following:

• Controlled clinical investigations (other than phase 1 investigations) of any U.S. Food and Drug Administration (FDA)-regulated drug or biological product for any disease or condition
• Certain studies of FDA-regulated medical devices, excluding small clinical trials to determine feasibility and certain clinical trials to test prototype devices, but including FDA-required pediatric postmarket surveillances of a device product

As discussed in more detail in the Final Rule, and as reflected in 42 CFR 11.10, ACTs generally include interventional studies (with one or more arms) of FDA-regulated drug, biological, or device products that meet one of the following conditions:

• The trial has one or more sites in the United States
• The trial is conducted under an FDA investigational new drug application or investigational device exemption
• The trial involves a drug, biological, or device product that is manufactured in the United States or its territories and is exported for research

For complete statutory definitions and more information on the meaning of Applicable Clinical Trial, see the Checklist and Elaboration for Evaluating Whether a Clinical Trial or Study is an Applicable Clinical Trial (ACT) ("ACT Checklist"), which follow the criteria specified in 42 CFR 11.22(b), to determine whether a study initiated on or after January 18, 2017, is an ACT subject to the expanded registration requirements under the Final Rule. Although the ACT Checklist and Elaboration document is intended for use with respect to determining the requirements for clinical trials or studies initiated on or after January 18, 2017, it may also be useful in evaluating whether a clinical trial or study that was initiated before January 18, 2017, is an ACT, even though such trials or studies are not subject to the expanded registration requirements in the Final Rule.

For more information, see the following frequently asked questions (FAQs):

Regulations (42 CFR Part 11)

Overall, the final rule clarifies which clinical trials of FDA-regulated drug products (including biological products) and device products and which pediatric postmarket surveillances of a device product, are applicable clinical trials for which information must be submitted to ClinicalTrials.gov. The final rule considers all clinical trials with one or more arms and with one or more pre-specified outcome measures to be controlled clinical trials. The final rule explains that we have determined that no expanded access use would be considered an applicable clinical trial under section 402(j) of the PHS Act. The final rule also describes an approach for evaluating, prior to registration, whether a particular clinical trial or study is an applicable clinical trial. [81 FR 64982] For more information on regulatory requirements, see 42 CFR Part 11. For additional information on evaluating whether a study is an applicable clinical trial, see the Checklist and Elaboration for Evaluating Whether a Clinical Trial or Study is an Applicable Clinical Trial (ACT) (PDF).

Key regulatory provisions and related discussions in the Final Rule (81 FR 64981) include:

• 42 CFR 11.22 Which applicable clinical trials must be registered? (See Sec. IV.B.2 of the Final Rule for discussion)
  • § 11.22(a)(3) Determining the date of initiation for an applicable clinical trial.
  • § 11.22(b) Determination of applicable clinical trial for a clinical trial or study initiated on or after January 18, 2017.

• 42 CFR 11.10 What definitions apply to this part? (see Sec. IV.A.5)
• 42 CFR 11.35 By when will the NIH Director post clinical trial registration information submitted under §11.28?
  • 42 CFR 11.35(b)(2) For an applicable device clinical trial of a device product that has not been previously approved or cleared (see Sec. IV.B.5)

Pediatric Postmarket Surveillances of Device Products

Pediatric postmarket surveillances of device products ordered under Section 522 of the FD&C Act (PDF) as amended by Section 307 of FDAAA are considered ACTs and must be registered on ClinicalTrials.gov and have results information submitted.

Note: The remaining sections of this FDAAA 801 and the Final Rule page do not discuss requirements or exceptions for pediatric postmarket surveillances of device products.

See the relevant regulatory sections listed in the blue box below for more information.

Regulations (42 CFR Part 11)

Key regulatory provisions and related discussions in the Final Rule (81 FR 64981) include:

• 42 CFR 11.10 What definitions apply to this part? (see Sec. IV.A.5 of the Final Rule for discussion)
• 42 CFR 11.22 Which applicable clinical trials must be registered?
  • § 11.22(b)(1)(i) Determination of applicable clinical trial for a clinical trial or study initiated on or after January 18, 2017.
• 42 CFR 11.28 What constitutes clinical trial registration information?
• 42 CFR 11.44 When must clinical trial results information be submitted for applicable clinical trials subject to §11.42?
  • § 11.44(f) Pediatric postmarket surveillance of a device product that is not a clinical trial
• 42 CFR 11.48 What constitutes clinical trial results information?

Exclusions and Voluntary Submissions

The following types of studies are not subject to the registration and results submission requirements of section 402(j) of the PHS Act, including its implementing regulations (see the note below the bulleted list). Note that this is not a complete list.

• Phase 1 trials of investigational drug products or biological products, including studies in which investigational drug products are used as research tools to explore biological phenomena or disease processes (see the note below)
• Small clinical trials to determine the feasibility of a device product or a clinical trial to test prototype devices, where the primary outcome measure relates to feasibility and not to health outcomes (see the note below)
• Trials that do not include drug, biological, or device products, such as behavioral interventions
• Noninterventional (observational) clinical research, such as cohort studies

Note: If a responsible party voluntarily submits clinical trial information for a clinical trial that is not otherwise subject to the registration and results submission requirements, the responsible party may have to comply with certain requirements under section 402(j) of the PHS Act and its implementing regulations.

Regulations (42 CFR Part 11)

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

• 42 CFR 11.60 What requirements apply to the voluntary submission of clinical trial information for clinical trials of FDA-regulated drug products (including biological products) and device products? (see Sec. IV.D.1 of the Final Rule for discussion)

When Do I Need to Register?

The responsible party (that is, the sponsor or designated PI) for an ACT must submit the required clinical trial information no later than 21 days after enrollment of the first participant.

Exceptions

For ACTs that were 1) initiated on or before September 27, 2007, and 2) ongoing as of December 26, 2007, the following applies:

• Trials involving a "serious or life-threatening disease or condition" were required to have registration information submitted by December 26, 2007.
• Trials not involving a "serious or life-threatening disease or condition" were required to have registration information submitted by September 27, 2008.

See the statutory provision on data submission (PDF) and the following FAQs for more information.

Regulations (42 CFR Part 11)

Overall, the final rule specifies requirements for registering applicable clinical trials at ClinicalTrials.gov. It requires that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human subject (also referred to as participant or subject) (81 FR 64982).

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

• 42 CFR 11.24 When must clinical trial registration information be submitted? (see Sec. IV.B.3 of the Final Rule for discussion)

Which Trials Must Have Results Information Submitted to ClinicalTrials.gov?

Product Approved, Licensed, or Cleared as of the Primary Completion Date

Results information submission is required for all ACTs of approved, licensed, or cleared products that reach their primary completion date after December 26, 2007. If the primary completion date was between December 27, 2007, and January 17, 2017, results information submission is required as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act. If the primary completion date was on or after January 18, 2017, results information submission is required as specified in 42 CFR Part 11.

Product Not Approved, Licensed, or Cleared as of the Primary Completion Date

For ACTs of unapproved, unlicensed, or uncleared products that reached their primary completion date on or after January 18, 2017, results information submission is required as specified in 42 CFR Part 11. For ACTs with a primary completion date before January 18, 2017, which studied products that were unapproved, unlicensed, or uncleared when the ACTs reached their primary completion date but are subsequently approved, licensed, or cleared, the responsible party must submit the results information specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act not later than 30 days after product is approved, licensed, or cleared by FDA. See the following FAQ for more information:

Regulations (42 CFR Part 11)

The final rule addresses the statutory requirement for the submission of summary results information for applicable clinical trials of drug products (including biological products) and device products that are approved, licensed, or cleared by FDA. It also extends the requirement for results information submission to applicable clinical trials of drug products (including biological products) and device products that are not approved, licensed, or cleared by FDA. The rule requires the submission of data in a tabular format summarizing participant flow; demographic and baseline characteristics; primary and secondary outcomes, as well as results of any scientifically appropriate statistical tests; and adverse event information. In addition, the rule requires the submission of the full protocol and statistical analysis plan (if a separate document) (81 FR 64983).

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

• 42 CFR 11.42 For which applicable clinical trials must clinical trial results information be submitted? (see Sec. IV.C.2 of the Final Rule for discussion)
• For a discussion of "Submission of Results Information for Applicable Clinical Trials of Unapproved, Unlicensed, or Uncleared Products for Any Use," see Sec. III.B.
• 42 CFR 11.48 What constitutes clinical trial results information?

When Do I Need to Submit Results Information?

In general, results information for an ACT subject to the results information submission requirements must be submitted by the responsible party no later than 1 year after the primary completion date.

See the statutory provision for completion date (PDF) and the following FAQ for more information:

Regulations (42 CFR Part 11)

In general, the final rule requires the submission of results information not later than 1 year after the completion date (referred to as the "primary completion date") of the clinical trial, which is defined as the date of final data collection for the primary outcome measure (81 FR 64983). For more information, see the following FAQs:

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

• 42 CFR 11.44 When must clinical trial results information be submitted for applicable clinical trials subject to § 11.42? (see Sec. IV.C.3 of the Final Rule for discussion)
  • § 11.44(a) Standard submission deadline (see Sec. IV.C.3 - §11.44(a))
  • § 11.44(d) Submitting partial results information (see Sec. IV.C.3 - §11.44(d))

Delayed Submission of Results Information

CERTIFICATION

A responsible party may delay the submission of results information (see the note below the bulleted list) by submitting a certification that one of the two following conditions has been met prior to the date of (i.e., the day before) the standard submission deadline for results information (or no later than 1 year after the ACT's primary completion date):

• Certify Initial Approval - The ACT reached its primary completion date on or after January 18, 2017, and before the drug, biological, or device product is initially approved, licensed, or cleared by FDA for any use (referred to on ClinicalTrials.gov as "certify initial approval").
  • Results deadline:
    (1) The earlier of the date that is 30 days after the date that:
    • The drug, biological, or device product is approved, licensed, or cleared by FDA for any use that was studied in the ACT
    • The application or premarket notification is withdrawn without resubmission for not less than 210 days

    or (2) 2 years after the date that a certification is submitted, if neither of the events listed above has occurred by that time.

• Certify New Use - The ACT studies a new use of an FDA-approved drug, biological, or device product (that is, a use not included in the labeling), and the manufacturer of the drug, biological, or device product is the sponsor of the trial and has filed or will file within 1 year an application to FDA for approval or clearance of that use (referred to on ClinicalTrials.gov as "certify new use").
  • Results deadline:
    (1) The earlier of the date that is 30 days after the date that:
    • The new use of the drug, biological or device product is approved, licensed, or cleared by FDA;
    • FDA issues a letter ending the regulatory review cycle for the application or submission for the new use of the drug, biological, or device product, such as a complete response letter, or
    • The application or premarket notification for the new use is withdrawn without resubmission for no less than 210 days

    or (2) 2 years after the date that a certification is submitted, if none of the events listed above has occurred by that time.

Note: If a responsible party that is both the sponsor and the manufacturer submits a new use certification, this certification must be made with respect to each ACT that is required to be submitted in an application or premarket notification for licensure, approval, or clearance of the use studied in the clinical trial.

See the statutory provision for Delayed Submission of Results With Certification (PDF).

PARTIAL RESULTS

If the required clinical trial results information has not been collected for one or more secondary outcome measures or additional adverse event information by the primary completion date, the responsible party must submit the remaining required clinical trial results information by the deadlines specified in 42 CFR 11.44(d).

Regulations (42 CFR Part 11)

Under the final rule, results information submission could be delayed for up to 2 additional years from the date of submission of a certification that either (1) an unapproved, unlicensed, or uncleared product studied in the trial is still under development by the manufacturer or (2) that approval will be sought within 1 year after the primary completion date of the trial for a new use of an approved, licensed, or cleared product that is being studied in the trial (81 FR 64983).

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

• 42 CFR 11.44 When must clinical trial results information be submitted for applicable clinical trials subject to § 11.42? (see Sec. IV.C.3 of the Final Rule for discussion)
  • § 11.44(b) Delayed submission of results information with certification if seeking approval, licensure, or clearance of a new use (see Sec. IV.C.3 - §11.44(b) and (c))
  • § 11.44(c) Delayed submission of results with certification if seeking initial approval, licensure, or clearance (see Sec. IV.C.3 - § 11.44(b) & (c))
  • § 11.44(d) Submitting partial results information (see Sec. IV.C.4 - § 11.44(d))

EXTENSIONS FOR GOOD CAUSE

The Director of the NIH may extend the deadline for submission of results information for an ACT if the responsible party submits a written request that demonstrates good cause for the extension. An extension request must be submitted via the Protocol Registration and Results System (PRS) prior to the date (i.e., the day before) that results information would otherwise be due and must include a description of the reasons that the responsible party believes constitute good cause to justify an extension and an estimated date on which the results information will be submitted. The Director will review the extension request and notify the responsible party as to whether the request demonstrates good cause and has been granted.

Regulations (42 CFR Part 11)

The final rule permits responsible parties to request extensions to the results information submission deadlines for "good cause" (81 FR 64983).

For information on regulatory requirements, see 42 CFR Part 11. In particular, see:

Submitting a Certification for the Delayed Submission of Results Information or a Good Cause Extension Request

A certification for the delayed submission of results information or good cause extension request must be submitted via the Protocol Registration and Results System (PRS). Submission of the certification or request through the PRS in this manner facilitates the automated identification of trials that may not yet be required to submit results information.

Regarding good cause extension requests, the Final Rule describes the process by which the Director of the NIH reviews such requests and notifies responsible parties whether their request demonstrates good cause and has been granted. More information about extension requests will be made available in the future on the Final Rule Information page.

Are There Potential Legal Consequences If I Fail to Register or Submit Results?

Section 801 of FDAAA amended the FD&C Act to authorize civil monetary penalties against responsible parties who fail to comply with registration and/or results submission requirements. In addition, in relation to federally funded studies, section 402(j)(5)(A) of the PHS Act provides for the withholding of remaining or future grant funds from a grantee for failure to submit clinical trial registration and results information.

See the statutory provisions regarding Civil Money Penalties (PDF) and Clinical Trials Supported by Grants From Federal Agencies (PDF).

For more information, see:

Regulations (42 CFR Part 11)

The final rule outlines the potential civil or criminal actions, including civil monetary penalty actions, and grant funding actions that may be taken if responsible parties fail to comply with the rule's requirements. It does not outline all potential legal consequences, e.g., laws governing the veracity of information submitted to the federal government, however, and should not be understood as describing the only types of enforcement that the government might undertake with respect to compliance with the provisions of section 402(j) of the PHS Act, including its implementing regulations. [81 FR 64983]

For more information on the potential legal consequences of non-compliance, see:

• 42 CFR 11.66 What are potential legal consequences of not complying with the requirements of this part?
• Sec. IV.E.1 of the Final Rule for a discussion

Other FDAAA 801 Requirements: NIH and FDA

NIH Certification Requirements

HHS agency grantees must certify that the responsible party has made all required registration and results submissions in their competing applications and noncompeting continuation progress reports for any NIH grant that supports an ACT, even if the grantee is not the responsible party. See section 402(j)(5)(A) of the PHS Act and 42 CFR 11.66(c).

Please refer to the following grants policy information from NIH's Office of Extramural Research to learn more about ensuring compliance with NIH's implementation of FDAAA 801:

See the statutory provision for Clinical Trials Supported by Grants From Federal Agencies (PDF) for more information.

Certification Requirements

Certain drug, biological, and device product applications or submissions made to FDA must be accompanied by a certification of compliance indicating that the requirements of section 402(j) of the PHS Act, including any applicable provisions of the Final Rule, have been met.

Please refer to the following information from FDA to learn more about this requirement:

See the statutory provisions for Certification to Accompany Drug, Biological Product, and Device Submissions (PDF) for more information.

Informed Consent Regulations

FDA regulations at 21 CFR 50.25(c) require that the informed consent document for an ACT must include a specific statement regarding trial registration.

See the following for more information:

See the statutory provision requiring FDA to amend the informed consent regulations (PDF) for more information.

Which government agency in the US reviews and approves clinical trials?

What is an FDA regulated clinical trial?

Which regulation governs the conduct of clinical studies?

Who has the regulatory responsibility for monitoring the clinical trial?