ClinicalTrials.gov

ClinicalTrials.gov is a web registry and results database of publicly and privately supported clinical studies conducted around the world that involves human participants. It provides patients, family members, and healthcare professionals easy access to information about ongoing clinical studies. Information is provided and updated by the clinical study sponsor or principal investigator. The U.S. National Library of Medicine (NLM) at the National Institutes of Health (NIH) maintains the site.

It was created as a result of the Food and Drug Administration Modernization Act of 1997 (FDAMA), which required the establishment of a clinical trials information registry for both federally and privately funded trials conducted under investigatory new drug (IND) applications to test the effectiveness of experimental drugs for serious or life-threatening diseases or conditions. ClinicalTrials.gov was made available to the public in February 2000.

In September 2007 Congress enacted the Food and Drug Administration Amendments Act of 2007, commonly referred to as FDAAA. It required more types of trials to be registered and additional registration information to be submitted. FDAAA also required the submission of results for certain trials, which led to the development of the ClinicalTrials.gov results database. It contains a summary of study outcomes, including adverse events. The results database was made publicly available in September 2008. FDAAA also established penalties for failing to register or submit the results of applicable studies.

FDAAA requires registration of an “applicable clinical trial” by the “responsible party.” Additional detail is provided below; see CHA Guidance on Study Registration. The FDA created a Guidance for Sponsors, Investigators, and IRBs - Questions and Answers on Informed Consent Elements, 21 CFR 50.25(c), which may help investigators better understand the FDAAA registration requirements.

In addition, the International Committee of Medical Journal Editors (ICMJE) agreed in a 2005 policy that member journals will require registration in a public trials registry as a condition of consideration for publication in their journals. Many other journals have also ascribed to this policy. Additional detail is provided below; see CHA Guidance on Study Registration.

NOTE: Even if your investigator-initiated clinical trial does not meet the FDAAA registration requirements, CHA strongly recommends investigators read the ICMJE clinical trials registration requirements and consider registering a trial to comply with the ICMJE publication requirements.

Per FDAAA, an “applicable clinical trial” must be registered on ClinicalTrials.gov. An “applicable clinical trial” is defined as:

• Interventional studies (i.e., drug, device, biologic)
• Phase II – IV studies; not phase I drug studies and not small feasibility device studies
• Studies that are subject to US Food and Drug Administration regulation (e.g., IND/IDE, US site)
• Studies initiated on or after 09/27/07, or ongoing as of 12/26/07

Please refer to the FDA Elaboration of Definitions of Responsible Party and Applicable Clinical Trial for more information.

The “Responsible Party” (RP) is required to register and submit results. FDAAA defines the RP as:

• The IND/IDE holder
• If an IND/IDE doesn’t exist
  • The industry, cooperative group, consortium or other external sponsor that initiated the study
  • If the study is initiated by a Principal Investigator:
    • The grantee institution.
    • NOTE: Since a grantee institution is allowed to delegate the responsibilities of the RP, and given the nature of the information that must be provided as part of registration, CHA universally delegates the PI as the RP.
• If no external funding, the PI

Please refer to the FDA Elaboration of Definitions of Responsible Party and Applicable Clinical Trial for more information.

Under FDAAA, registration must be completed:

• Within 21 days of enrollment of the 1st subject, AND
• Updated at least every 12 months

FDAAA also requires reporting of aggregate results and adverse event information. Results and adverse event information must be reported for:

• Interventional studies (i.e., drug, device, biologic)
• Phase II – IV studies; not phase I drug studies and not small feasibility device studies
• Studies that are subject to US FDA regulation (e.g., IND/IDE, US site)
• Studies initiated on or after 09/27/07, or ongoing as of 12/26/07
• Study products approved (for any use) by the FDA

Results reporting must be completed as follows:

• Within 12 months of the primary endpoint completion date, which is defined as the date at which the last endpoint of the primary endpoint was collected, not the last visit of the last subject.
• Delays are possible by request to ClinicalTrials.gov if you are:
  • The manufacturer of the investigatory product and seeking initial approval
  • The manufacturer of the investigatory product and seeking approval for a new use
  • You are requesting an extension for “good cause.”

NOTE: Clinical investigations of a FDA approved product that are not intended to be submitted to the FDA in support of a change in labeling are not eligible for a delay in results reporting. This includes investigations that are conducted under an IND/IDE.

CHA has created a flow chart to help researchers determine if their study requires registration on clinicaltrials.gov according to FDAAA requirements.

The ICMJE is a group of medical journal editors; the member journals require registration in a public trials registry as a condition of consideration for publication in their journals.

The ICMJE defines a clinical trial as 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. Health-related interventions include any intervention used to modify a biomedical or health-related outcome (e.g., drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes). Health outcomes include any bio-medical or health-related measures obtained in patients or participants, including pharmacokinetic measures and adverse events. Purely observational studies (those in which the assignment of the medical intervention is not at the discretion of the investigator) will not require registration. Per the ICMJE, those who are uncertain whether their trial meets the ICMJE definition should err on the side of registration if they wish to seek publication in an ICMJE journal.

The PI should make the decision whether to register or not fully aware of the consequences of not registering a study, which include restrictions on where a study manuscript may be published.

Additional information about the ICMJE clinical trial registration requirements and Obligation to Register Clinical Trials can be found online.

Registration must be completed:

• Prior to enrollment of the 1st subject, AND
• Updated at least every 6 months

FDAAA

Who is responsible for registering trials and submitting results?

The Responsible Party (RP) for a clinical trial must register the trial and submit results information. The RP is defined as:

1. • The sponsor of the clinical trial; or
   • The 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 FDAAA's requirements for the submission of clinical trial information.

NOTE: CHA designates the PI as the responsible party.

For complete statutory definitions and more information on the meaning of "responsible party" and "sponsor," see Elaboration of Definitions of Responsible Party and Applicable Clinical Trial. See also the Responsible Party data element on ClinicalTrials.gov.

Which trials must be registered and have results submitted to ClinicalTrials.gov?

Registration is required for trials that meet the FDAAA definition of an "applicable clinical trial" and were either initiated after 09/27/07 or initiated on or before that date and were still ongoing as of 12/26/07.  Trials that were ongoing as of 9/27/07 and reached the completion date (see Primary Completion Date data element) before 12/26/07 are excluded. "Applicable Clinical Trials" include the following:

1. • Trials of drugs and biologics. Controlled clinical investigations, other than phase I clinical investigations, of drugs or biological products subject to FDA regulation
   • Trials of devices.
     1. Controlled trials with health outcomes of devices subject to FDA regulation, other than small feasibility studies, and
     2. pediatric postmarket surveillance required by FDA

"Applicable clinical trials" generally include interventional studies (with 1 or more arms) of FDA-regulated drugs, biological products, or devices that meet one of the following conditions:

1. • The trial has 1 or more sites in the United States
   • The trial is conducted under a FDA IND application or IDE
   • The trial involves a drug, biologic, or device 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 Elaboration of Definitions of Responsible Party and Applicable Clinical Trial.

• When do I need to register and submit results?

The Responsible Party (that is, the sponsor or designated PI) for an “Applicable Clinical Trial” must submit required information not later than 21 days after enrollment of the 1st participant.

Exceptions:
For Applicable Clinical Trials that were (1) initiated on or before September 27, 2007, and (2) "ongoing" as of December 26, 2007:

1. • Trials involving a "serious or life threatening disease or condition" should have been submitted by December 26, 2007.
   • Trials not involving a "serious or life threatening disease or condition" should have been submitted by September 27, 2008.

See the statutory provision on Data Submission for more information.

In general, results of an Applicable Clinical Trial of a drug, biologic, or device that is approved, licensed, or cleared by FDA must be submitted by the Responsible Party no later than 12 months after the Completion Date (see Primary Completion Date data element). See the statutory definition of Completion Date.

• What are my responsibilities once I register a trial?

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

1. • Recruitment Status and Overall Recruitment Status
   • Completion Date (See Primary Completion Date data element in ClinicalTrials.gov)

Other changes to the protocol or updates to the record must be made at least every 12 months. It is recommended that the Record Verification Date be updated at least every 6 months, even if there were no changes to the record, for studies that are not yet completed. See How to Edit Your Study Record for more information.

How do I register a study on ClinicalTrials.gov?

Please refer to the very detailed and helpful instructions on ClinicalTrials.gov.

NOTE: When registering, please list the institution as Cambridge Health Alliance, not Cambridge Hospital, etc.

How do the requirements affect NIH funded studies?

NIH and FDA have two separate certification requirements. NIH grantees must certify compliance with FDAAA in their competing applications and noncompeting continuation progress reports for any NIH grant that supports an Applicable Clinical Trial, even if the grantee (i.e., CHA) is not the Responsible Party. An application/submission to FDA for a drug, biological product, or device must be accompanied by a certification indicating that the requirements of FDAAA have been met. In addition, informed consent for Applicable Clinical Trials subject to FDA's Protection of Human Subjects regulation must include a specific statement about trial registration.

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: What NIH Grantees Need to Know About FDAAA

See the statutory provisions for Clinical Trials Supported by Grants From Federal Agencies.

Are there penalties if I fail to register or submit results?

FDAAA establishes penalties for Responsible Parties who fail to comply with registration or results submission requirements. Penalties include civil monetary penalties and, for federally funded studies, the withholding of grant funds. See the statutory provisions amending Civil Money Penalties and Clinical Trials Supported by Grants From Federal Agencies.

ICMJE

What are the ICMJE requirements for registering a study?

The ICMJE defines a clinical trial as any research project that prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. The ICMJE member journals will require, as a condition of consideration for publication in their journals, registration in a public trials registry. The details of this policy are contained in a series of editorials. The ICMJE encourages editors of other bio-medical journals to adopt a similar policy.

See the ICMJE Obligation to Register Clinical Trials for additional information.

What journals follow the ICMJE Uniform Requirements for Manuscripts?

The ICMJE has posted a list of the journals that follow the ICMJE's Uniform Requirements for Manuscripts.

What are the ICMJE Uniform Requirements for Manuscripts?

The ICMJE Uniform Requirements for Manuscriptsare posted online.

What are the NIH requirements for ClinicalTrials.gov registration in applications and progress reports?

The NIH requirements for ClinicalTrials.gov registration for competing applications and non-competing progress reports have been outlined on the NIH website.

Where can I find more information about the NIH requirements to register clinical trials?

The NIH fact sheet about ClinicalTrials.gov may be helpful to researchers. The NIH also outlines what NIH grantees need to know about FDAAA.

Other

What information do study participants have to be given about trial registration?

On January 4, 2011, the FDA published a regulation that changed the required elements of informed consent to include a statement regarding ClinicalTrials.gov registration. Studies approved after 03/07/12 that are required to be listed on ClinicalTrials.gov must have the following statement in the informed consent form (ICF); it cannot be altered:

‘‘A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.’’

ICFs approved before 03/07/12 are not required to be amended to include that language and re-consent of subjects is not required. Sponsors, however, may decide to add the new language to an existing ICF. If an ICF is amended to include the new language it must be the exact language above.

Who should I contact if I have questions about trial registration?

Please email the CHA Office of Sponsored Research with questions about this process.

Where can I find more information about trial registration?

Please see the Helpful Links below for additional information and resources.

ClinicalTrials.gov

• ClinicalTrials.gov website.
• ClinicalTrials.gov Protocol Registration System login
• ClinicalTrials.gov Training Materials and Presentations

NIH:

• Office of Extramural Research (OER)
• Frequently Asked Questions for NIH Grantees
• NIH National Library of Medicine FAQs

ICMJE