What is ClinicalTrials.gov?

ClinicalTrials.gov is a resource that provides access to information on clinical trials studying a wide range of diseases, conditions and interventions. Studies listed in the database are conducted in all 50 States and worldwide. Each ClinicalTrials.gov record includes summary information about studies.

EQUIP TIP: The clinicaltrials.gov record may be released for PRS review AFTER IRB submission.

Registration may be required if one (or more) of the following is true:

NIH funded clinical trials are required to be registered:

  • If your study is NIH funded and meets the NIH definition of a clinical trial, then clinicaltrials.gov registration is required.
  • For NIH funded research, use the following four questions to determine the difference between a clinical study and a clinical trial:
    • Does the study involve human participants?
    • Are the participants prospectively assigned to one or more interventions?
    • Is the study designed to evaluate the effect of the intervention on the participants?
    • Is the effect being evaluated a health-related biomedical or behavioral outcome?
  • If the answers to ALL 4 questions are “yes”, your study meets the NIH definition of a clinical trial.
  •  Clinical trials subject to the regulation are generally called "applicable clinical trials."
  • Applicable clinical trials are required to be registered in ClinicalTrials.gov not later than 21 calendar days after the enrollment of the first participant. 

**Resource: What NIH Researchers and Recipients Should Know about ClinicalTrials.gov Podcast

NIH Definition of an “INTERVENTION”:

An "intervention" is defined as a manipulation of the subject or subject’s environment for the purpose of modifying one or more health-related biomedical or behavioral processes and/or endpoints.

Examples include:

  • drugs/small molecules/compounds;
  • biologics; devices;
  • procedures (e.g., surgical techniques);
  • delivery systems (e.g., telemedicine, face-to-face interviews);
  • strategies to change health-related behavior (e.g., diet, cognitive therapy, exercise training, development of new habits);
  • treatment strategies; prevention strategies; and diagnostic strategies.

This Includes

- studies with healthy participants

– Phase 1 trials of FDA-regulated drugs and biological products

– Small feasibility studies of FDA regulated device products

– studies with no comparison group (placebo or control)

– studies designed to assess the pharmacokinetics / safety of an investigational drug

– Studies where only one aim or sub-aim meets the clinical trial definition.

Wide Range of NIH Interventions include: mechanic, exploratory/development, piot/feasibility, other interventional, behavioral, basic experimental
Basic experimental studies involving humans (BESH)

Basic experimental studies involving humans:

These meet both the definition of basic research and the NIH definition of a clinical trial.

  • NIH published clinical trial case studies with examples of BESH (example - cases 16, 21, 23 and 31b).
  • Example: healthy volunteers randomized to different durations of sleep deprivation where the dependent variable is stress hormone levels.

NIH Policy on Dissemination of NIH-Funded Clinical Trial Information:

  • This policy applies to all NIH-funded clinical trials regardless of study phase, type of intervention, or whether they are subject to the regulation.
  • As such, the policy encompasses all NIH-funded clinical trials, including applicable clinical trials subject to the regulation.  All NIH-funded clinical trials will be expected to register and submit results information to ClinicalTrials.gov.
    • In the regulation, results information includes participant flow, demographic and baseline characteristics, outcomes and statistical analyses, adverse events, the protocol and statistical analysis plan, and administrative information.
    • In addition, informed consent documents for clinical trials are to include a specific statement relating to posting of clinical trial information at ClinicalTrials.gov.

Clinical Trial Indicator:

  • The NIH Award Notice includes a "Clinical Trial Indicator" in Section IV which specifies whether the award supports any NIH defined clinical trials.
  • If the Clinical Trial Indicator specifies "No" then your study does NOT meet the NIH definition of a clinical trial and therefore does not need to be registered on Clincaltrials.gov.
  • If the Clinical Trial Indicator specifies "Yes" then your study meets the NIH definition of a clinical trial and must be registered on Clincaltrials.gov.

 

The Food and Drug Administration Amendments Act of 2007 (FDAAA) established legal requirements for sponsors and designated principal investigators (i.e., responsible parties) to report specified clinical trial information for certain ACT’s to ClinicalTrials.gov.

The requirements are designed to

  • provide potential participants with information about trials of interest,
  • reduce publication bias,
  • help institutional review boards (IRBs) determine the appropriateness of a research study,
  • and promote more efficient allocation of research funds.

 

**NEW RESOURCE: FDA slides of ClinicalTrials.gov Policies and Enforcement

(Decorative) FDA Stamp of approval

Registration is also required if your study meets the DHHS definition of an Applicable Clinical Trial (ACT) These include:

  • 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
  • It also includes certain studies of FDA-regulated medical devices, and FDA-required pediatric post market surveillances of a device product

Researchers can use the following tools to determine if their trial meets the DHHS definition of an ACT:

Checklist for Evaluating Whether a Clinical Trial or Study is an Applicable Clinical Trial

Identifying an ACT under FDAAA (flowchart)

ACT – important definitions:

Is the study interventional (a clinical trial)?

  • Participants are prospectively assigned to an intervention(s) to evaluate the effect of the intervention(s) on biomedical or other health-related outcomes. [Source: 42 CFR 11.10(a); 81 FR 65140-41]

Does the study evaluate at least one U.S. FDA-regulated drug, biological, or device product?

FDA-regulated Device Product means:

  • A device product  subject to (1) a finding of substantial equivalence under section 510(k) of the FD&C Act, (2) under section 515 - requiring a premarket approval application (PMA) for the device product, or (3) a marketing application for a Humanitarian Use Device (HUD) - a Humanitarian Device Exemption under section 520(m) of the FD&C Act.
  • Device products that are considered to be subject to section 510(k), 515, or 520(m) of the FD&C Act include significant risk devices for which approval of an IDE is required, non-significant risk devices that subject to abbreviated IDE requirements (21 CFR 812.2(b)), or device products that are exempt from the submission requirements of 21 CFR part 812.
  • It DOES NOT include device feasibility, Phase 0 or Phase 1 trials.

 

FDA-regulated Drug Product  means:

  • A drug that is the subject of an approved NDA (new drug application) or BLA (biologic license application) or that would require an approved NDA or BLA to be legally marketed in the United States.
  • A clinical trial including an intervention with a “dietary supplement” could  be an ACT.
  • It DOES NOT include Phase 0 or Phase 1 drug / biologic trials. For determining whether a drug / biological is the variable of interest, see page 8 of the ACT checklist

Sponsor-Investigators submitting an IND, NDA, BLA, or 510k etc. application to the FDA:

  • The FDA recommends that Form FDA 3674 accompany the submission.
  • Per instructions on Form FDA 3674, Sponsors must "provide the NCT Number obtained from www.ClinicalTrials.gov for each applicable clinical trial for which the sponsor/ applicant/submitter is the “responsible party” and for which data is included, relied upon, or otherwise referred to, in the application/submission which the certification accompanies."
  • Box 10 may be left blank if the submitter has checked Box 9.C but, at the time the certification is completed, the submitter has not yet received any NCT number(s) for the applicable clinical trial(s) for which data is included, relied upon, or otherwise referred to in the IND application. There is no requirement to register the study on clinicaltirals.gov at this time! 
  •  The only expectation for registration per FDA is outlined in 42 CFR 11.24(a):
    • General. Except as provided in paragraph (b) of this section, the responsible party for an applicable clinical trial for which submission of clinical trial registration information is required must submit the clinical trial registration information specified in section 402(j)(2)(A)(ii) of the Public Health Service Act (42 U.S.C. 282(j)(2)(A)(ii)) or § 11.28(a), as applicable, not later than December 26, 2007, or 21 calendar days after the first human subject is enrolled, whichever date is later.
  • Please note that an updated Form FDA 3674 providing the applicable clinical trial’s NCT number is not required to be submitted to the IND after the trial is registered on ClinicalTrials.gov. However, the trial’s NCT number may need to be included in a Form FDA 3674 that accompanies a future application or submission to FDA (e.g., the submission of a new protocol to the IND).

Registration Requirements per International Committee of Medical Journal Editors (ICMJE):

Image of multiple medical journals
  • In 2005, the ICMJE defined trials that must be registered in order to be considered for publication in journals that adhere to ICMJE standards.
  • The ICMJE requires registration of clinical trials in a public trials registry at or before enrollment of the first participant to be considered for publication.
  • Which journals are members of the ICMJE?
  • Many journals (not limited to medical journals) have adopted the registration policy.** Editors requesting inclusion of their journal on the ICMJE website list of publications that follow ICMJE guidance listing implies enforcement by the journal of ICMJE’s trial registration policy.
Dictionary image/icon

ICMJE Definition of Clinical Trial

The ICMJE definition of clinical trial: "any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.”

  • With or without concurrent comparison or control groups,
  • Health-related interventions are those used to modify a biomedical or health-related outcome; examples include drugs, surgical procedures, devices, behavioral treatments, educational programs, dietary interventions, quality improvement interventions, and process-of-care changes.
  • Health outcomes are any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events.

The ICMJE…

  • …encourages registration of research with non-trial designs (e.g., observational studies)
  • …journals will consider trials beginning on or after July 1, 2005 only if registration occurred before the first patient was enrolled ("prospective registration").
  • …does not define the timing of first participant enrollment, but best practice dictates registration by the time of first participant consent.
  • An acceptable registry must include the minimum 24-item trial registration data set at the time of registration.

**Those who are uncertain whether their trial meets the expanded ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal**

  • If your study will bill costs of routine standard of care to Medicare or any other insurer, the study must be registered on ClinicalTrials.gov to obtain the NCT#.
  • Claims for routine costs of Qualifying Clinical Trials (QCT) as well as services used to diagnose / treat complications arising from participation in all clinical trials covered by Medicare will require health care providers and suppliers to report a ClinicalTrials.gov Identifier (NCT Number).
  • The Centers for Medicare and Medicaid Service (CMS) issued a Clinical Trial Policy (CTP) - a National Coverage Determination (NCD) that allows payment of routine items/services, and payment of the investigational item/service if it is covered outside the trial, in clinical trials that qualify for coverage.

If you have a clinical trial that includes a drug that's available via expanded access:

Under FDA regulations (21 CFR 312.300), expanded access allows for the use of unapproved drugs and biologics outside of a clinical trial for patients with serious diseases or conditions when there is no satisfactory alternative therapy to treat the patient’s disease or condition. This is sometimes referred to as compassionate use or treatment use.

For an applicable drug clinical trial of an unapproved drug product the Public Health Service Act requires the submission of a separate expanded access record containing details about how to obtain access to the investigational product.

The final rule does not consider any expanded access use (i.e., access under treatment INDs or treatment protocols, which provide widespread access, access for intermediate-sized patient populations, or access for individual patients) to be an applicable clinical trial.

Note: Only a responsible party who is both the manufacturer of an investigational drug product or biological product and the sponsor of the trial can submit registration information for expanded access programs to ct.gov.

A responsible party who is not BOTH the manufacturer of the investigational drug product or biological product and the sponsor of the trial is not required to submit information for the Availability of Expanded Access data element (i.e., should select the response "unknown" for that data element). (81 FR 65052)

For example, a physician who submits an individual patient expanded access Investigational New Drug Application (IND), including for emergency use, as specified in 21 CFR 312.310, to the U.S. Food and Drug Administration generally would not be required to submit expanded access information to ClinicalTrials.gov.

Registration & Submission FAQ:

In 2015: 19,170 clinical trials were registered. 7,400 were applicable clinical trials, the remainder 11,770 trials, can be considered voluntary or to not fall under the rule. Of these, 526 were NIH funded. This leaves an estimated 11,244 trials that do not fall under either the rule or the NIH policy!

DHHS expects that these voluntary registrations will:

  • submit the same clinical trial registration information as applicable clinical trials.
  • expects that required elements of the record are updated as frequently as information for applicable clinical trials.
  • Estimated annual burden of 269,856 hours (almost 90,000 hours initial registration, rest from updates)

Voluntary registration places a burden on the responsible party  to comply with all registration and update requirements. Any ongoing non-compliance with these requirements on the part of the responsible party.

Source: Final Rule 42 CFR Part 11: https://www.govinfo.gov/content/pkg/FR-2016-09-21/pdf/2016-22129.pdf

Name TypeIntervention TypeRegistration Policy ScopeResults Submission Policy Scope
Final Rule for Clinical Trials Registration and Results Information Submission (42 CFR Part 11)U.S. Federal regulation implementing FDAAA 801 effective in 2017Drug, biological, and device productsClinical trials of a Food and Drug Administration (FDA)-regulated drug, biological, or device product other than Phase 1 (drug/biological products) or small feasibility studies (device products)Same scope as registration
NIH Policy on the Dissemination of NIH-funded Clinical Trial InformationNational Institutes of Health (NIH) policy effective in 2017Any (includes drug, biological, and device products, as well as surgical procedures, and behavioral interventions)Clinical trials funded in whole or in part by NIHSame scope as registration
International Committee of Medical Journal Editors (ICMJE) PolicyPublication policy initiated by the International Committee of Medical Journal Editors (ICMJE) in 2004Any (includes drugs, biological, and device products, as well as surgical procedures, and behavioral treatments)All interventional studies, including Phase 1 studies; defines criteria for "acceptable registries"The ICMJE expects authors to meet results information submission requirements "of their funding and regulatory agencies" and "encourages... results reporting even when not required."

  • The “Responsible Party” refers to the entity or individual who is responsible for registering a trial on ClinicalTrials.gov.
  • The Responsible Party is responsible for the initial release of the record, all future updates and ensuring the trial registration stays accurate and up-to-date.
  • For studies registered by UCI, the PI serves as the responsible party if they meet all the following criteria:
    1. They are responsible for conducting the clinical trial.
    2. They have access to and control over the data
    3. They have the right to publish the results of the trial
    4. They can meet all the requirements for the submission of clinical trial information.

  1. A ClinicalTrials.gov staff member will review the study record after it is submitted and before it is published on ClinicalTrials.gov.
  2. The review process may take up to a few days. Ensuring that the record is consistent with the ClinicalTrials.gov Protocol Review Criteria (PDF) before releasing it will expedite publication on the site.
  3. After it is accepted by review staff for publication, the record, including its NCT Number, will be available on ClinicalTrials.gov within 2–5 business days.

The date of registration is the date The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. A trial is registered in ClinicalTrials.gov after a new “protocol record” is created and passes QA review in the Protocol Registration and Results System (PRS) for ClinicalTrials.gov. Once a record passes review with the PRS reviewers, it is assigned a clinical trial identifier (NCT#) and registered.  

Required Registration Updates

See related FAQ on the ClinicalTrials.gov related webpage

Responsible Parties should update their records within 30 days of a change to any of the following:

Other changes or updates to the record, such as protocol amendments, must be made at least every 12 months.

**It is recommended that the Record Verification Date be updated at least every 6 months for studies that are not yet completed, even if there were no changes to the record.

Results Reporting:

  • The Food and Drug Administration Amendments Act (FDAAA), National Institutes of Health (NIH) require the publication of results for certain studies on ClinicalTrials.gov (Ct.gov).
  • The ICMJE Policy recommends results publication but it is not required.
  • After a clinical trial has been registered on ClinicalTrials.gov and the study is completed, the Responsible Party must publish the results on ClinicalTrials.gov.
  • Submission of results information is required no later than 12 months after the Primary Completion Date (the last subject last visit) of the clinical trial, which is defined as the date of final data collection for the primary outcome measure.

1 - If Overall Recruitment Status is changed to "suspended," "terminated," or "withdrawn," the Why Study Stopped data element must be submitted at the time the update is made.

If needed submit an Amendment for the following

  • For studies that meet the criteria for clinical trials per NIH Definition and Applicable Clinical Trials, ensure the ClinicalTrials.gov statement is included in the Consent Form / Study Information Sheet
  • Under “Type of Research” – “yes” to Does this research meet the definition of a clinical trial that requires adherence to Clinicaltrials.gov?
  • Once obtained, NCT# is added to this section
  • Recruitment section reflects ClinicalTrials.gov as a recruitment method.

Please see the Clinicaltrials.gov related FAQ

  • For ACTs that are required by 42 CFR 11.22(a) to be registered and with a primary completion date on or after January 18, 2017:
    • The responsible party's obligation to submit updates under 42 CFR 11.64(a) ends when all required clinical trial results information has been submitted as specified in 42 CFR 11.48 and the responsible party has made all corrections and/or addressed all concerns in response to any electronic notice received under 42 CFR 11.64(b)(1).
  • For ACTs that are required by 42 CFR 11.22(a) to be registered and with a primary completion date before January 18, 2017:
    • If the ACT studies a drug, biological, or device product that is approved, licensed, or cleared as of the primary completion date, then the responsible party's obligation to submit updates under section 402(j)(4)(C) of the Public Health Service Act (PHS Act) ends when all required clinical trial results information has been submitted as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act.
    • If the ACT studies a drug, biological, or device product that is not approved, licensed, or cleared for any use as of the primary completion date, then clinical trial results information must be submitted not later than 30 days after approval, licensure, or clearance of the drug, biological, or device product for any use, in accordance with section 402(j)(3)(E)(iv) of the PHS Act and pursuant to the Federal Court decision in Seife et al. v. HHS et al., 18-cv-11462 (NRB) (S.D.N.Y. Feb. 24, 2020). A responsible party's obligation to submit updates for such ACT under section 402(j)(4)(C) of the PHS Act ends when all required clinical trial results information has been submitted as specified in sections 402(j)(3)(C) and 402(j)(3)(I) of the PHS Act.
  • For clinical trials initiated on or after January 18, 2017, for which clinical trial information is submitted voluntarily pursuant to 42 CFR 11.60(c):
    • The responsible party's obligation to submit updates under 42 CFR 11.60(c)(2)(v), 11.64(a)(1)(ii), and 11.64 (a)(2) ends when all required clinical trial results information has been submitted as specified in 42 CFR 11.48(a) and the responsible party has made all corrections and/or addressed all concerns in response to any electronic notice received under 42 CFR 11.64(b)(1).

 

EntityRegistrationResults ReportingPenalties
Health and Human Services
(HHS)		Within 21 days of enrollmentWithin 365 days of primary completion date for ACTs
  • $13,237/study/day
  • Criminal proceedings
  • Loss of grant funding
National Istitutes of Health
(NIH)		Within 21 days of enrollmentWithin 365 days of primary completion date
for clinical trials receiving NIH funding
  • Loss of grant funding (to include the institution)
National Cancer Institute
(NCI)		Within 21 days of enrollmentWithin 365 days of primary completion date of NCI-supported clinical trials (in a peer-reviewed journal and/or ClinicalTrials.gov)
  • Loss of grant funding
Veterans Health Administration
(VHA)		Prior to release of funding. Prior to enrollmentWithin 365 days of primary completion date
  • Loss of grant funding
Centers for Medicare & Medicaid Services
(CMS)		All qualifying clinical trialsStudy-specific
  • Coverage denial
  • Costs and fraud investigations
Patient-Centered Outcomes Research Institute
(PCORI)		All Clinical studies (including observational)Expected of all PCORI
Clinical studies – 500 word abstract published on PCORI website
  • Loss of grant funding
International Committee of Medical Journal Editors
(ICMJE)		Prior to enrollment
  • Ineligibility to publish
Department of Defense
(DoD)		Prior to enrollment.
Prior to release of funding. 		Study-specific
  • $13,237/study/day
  • Withholding or recovery of award funds

Adapted from: Clinicaltrials.gov enforcement: an update. Anthony Keyes, John Hopkins University. January 18, 2022

Why Do I Need to Register My Trial and Submit Results to ClinicalTrials.gov? Here are just some of the reasons…

What is the penalty for non-compliance?

(Decortative) Envelope with a letter that says "FDA Warning"

Under NIH Policy: Noncompliance with the terms and conditions of the NIH award may provide a basis for enforcement actions, such as withholding current and future funding [45 CFR 75.371, 42 CFR 11.66]

Under Final Rule, responsible parties could be held accountable for noncompliance, with the potential for substantial civil monetary penalties, the withholding of grant funding from HHS agencies, and criminal proceedings.[2016 NEJM article]

  • Case in point:
    On 28 April 2021, the FDA issued its first Notice of Noncompliance to Georgia-based Accuitis who failed to submit required summary results information. The company could be “subject to a civil monetary penalty of $10,000 for each day of the violation” until the noncompliance is corrected.
  • FDA has issued already issued multiple Notices of Non-Compliance 
  • In addition, as of 12/04/2023 the FDA began publicly posting Pre-Notices for Potential Noncompliance
    • This means that even if the responsible party resolves it so a Notice of Noncompliance is never sent or posted, the Pre-Notice for Potential Noncompliance and the responsible party will be publicly posted!

ICMJE: authors failing to prospectively register a trial risk its inadmissibility to journals following the ICMJE’s trial registration policy.

Resources

OFFICE HOURS - TUESDAY 2-3pm with Kendrick Canizales (EQUIP Sr. Analyst)

Zoom Link

OFFICE HOURS - FRIDAY 11am-12pm with Anu Mathur (EQUIP Manager)

Zoom Link

Protocol Registration and Results System (PRS) FAQ and User Guide

FAQ
User Guide

Important Definitions of Required Elements and Glossary Terms

Important Definitions
Glossary Terms

OHRP Guidance - Posting the Consent Form

Download

Clinicaltrials.gov Educational Webinars / Tutorials:

** NOTE: At UCI, the Principal Investigator / Lead Researcher is ALWAYS listed as the Responsible Party on their Clinicaltrials.gov record **