What is FDAAA (U.S. Public Law 110-85 or the Food and Drug Administration Amendments Act of 2007)?
On September 27, 2007, the President signed U.S. Public Law 110-85. The law includes a section on clinical trial databases (Title VIII) that expands the types of clinical trials that must be registered in ClinicalTrials.gov, increases the number of data elements that must be submitted, and also requires submission of certain results data.
What trials are affected by this law?
Trials considered to be "applicable clinical trials" under the statute are subject to FDAAA. Applicable clinical trials generally include:
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase 1 investigations, of a product subject to FDA regulation; and
Trials of Devices: Controlled trials with health outcomes, other than small feasibility studies, and pediatric postmarket surveillance.
Thus applicable clinical trials generally include interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the U.S, involves a drug, biologic, or device that is manufactured in the US (or its territories), or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE).
Who is responsible for meeting FDAAA’s requirements to register and report results for applicable clinical trials?
The "responsible party" is the term used in FDAAA to refer to the entity or individual responsible for meeting FDAAA's requirements. FDAAA defines the responsible party as:
the sponsor of the clinical trial (as defined in section 50.3 of title 21, Code of Federal Regulations (or any successor regulation)); or
the Principal Investigator (PI) of an applicable clinical trial if 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.
When must an applicable clinical trial be registered?
Trials initiated after 9/27/2007 must be registered in full not later than 21 days after the first patient is enrolled, or by 12/26/2007, whichever is later.
Trials that were initiated on or before 9/27/2007 and “ongoing” (see Definitions) as of 12/26/2007 and that do involve a “serious or life threatening disease or condition” (see Definitions) must be registered in full by 12/26/2007.
Trials that were initiated on or before 9/27/2007 and ongoing as of 12/26/2007 and that do not involve a serious or life threatening disease or condition must be registered in full by 9/27/2008.
Trials that were ongoing as of 9/27/2007, did involve a serious or life threatening disease or condition and were completed (meaning, not ongoing) by 12/26/2007 are not subject to these requirements, though they may be subject to pre-existing registration requirements under the Food and Drug Administration Modernization Act (FDAMA) of 1997.
Trials that were ongoing as of 9/27/2007, did not involve a serious or life threatening disease or condition, and were completed (meaning, not ongoing) by 12/26/2007 are not subject to these requirements, nor were they subject to pre-existing registration requirements under FDAMA.
What data elements are required for registration and results reporting to be in compliance with FDAAA?
Information on the data elements required by FDAAA for registration and results reporting may be found on the ClinicalTrials.gov PRS (Protocol Registration System) Information Web site.
Does FDAAA apply to NIH extramural grants (including cooperative agreements)?
Yes. Compliance with FDAAA is a legal requirement and a term and condition of NIH awards. If an applicable clinical trial is funded in whole or in part by a grant from any agency of the Department of Health and Human Services (such as NIH), any grant or progress report forms required under such grant shall include a certification that the responsible party has made all required submissions for the applicable clinical trial to ClinicalTrials.gov.
Who determines if a clinical trial supported by an NIH grant (or proposed in an application) is considered an applicable clinical trial, and subject to the registration requirement under FDAAA?
The grantee institution is required to assure compliance with FDAAA. Investigators and institutional officials (e.g. sponsored research office, general counsel, and/or other similar office) are encouraged to work together to determine whether or not an NIH grant is supporting an applicable clinical trial, and whether or not that trial must be registered under FDAAA. This determination is communicated to the NIH in the grantee's certification of compliance with FDAAA. For further information on identifying applicable clinical trials, see step 1 of OER’s “Steps to Compliance for NIH Grantees”.
What entity or individual is the responsible party for an applicable clinical trial supported by an NIH grant (including cooperative agreements)?
For applicable clinical trials where there is an IND or IDE, the IND/IDE holder is geneerally considered to be the sponsor and therefore the responsible party, unless this obligation is delegated to a principal investigator.
For applicable clinical trials where there is no IND or IDE holder, the funding recipient (the grantee organization) is generally considered to be the sponsor and therefore the responsible party. According to the Elaboration of Definitions of Responsible Party and Applicable Clinical Trial: "Where the clinical trial is being conducted by an entity under a research assistance funding agreement such as a grant or sponsored research agreement the funding recipient generally will be considered to be the initiator of the trial, and therefore, the sponsor. This is because, as a general rule, when a trial is funded in this manner, the funding recipient 'initiates' the clinical trial process by, for example, submitting a funding proposal and designing the clinical trial. In this scenario, the funding recipient will be the 'responsible party' unless responsibility is delegated to the principal investigator, consistent with the conditions described in the statutory definition."
The grantee Institution is the funding recipient, and is required to assure compliance with FDAAA in applications and progress reports. Investigators and institutional officials (e.g. sponsored research office, general counsel, and/or other similar official) should work together to determine the responsible party for an applicable clinical trial funded by the NIH. This determination is communicated to the NIH during the certification assuring compliance with FDAAA (see below).
For a graphic representation to help determine the responsible party for an applicable clinical trial under FDAAA, please access the OER flowchart Identifying the "Responsible Party", also available in PDF (177 KB).
There is more than one award supporting a non-IND/IDE applicable clinical trial. Who determines which grantee is the responsible party, and how do the other grantees learn that this determination has been made?
All grantees are required to assure compliance with FDAAA as a term and condition of award. Investigators and institutional officials associated with the trial are encouraged to work together to determine the responsible party, and to coordinate and communicate the determination with other grantees.
Is the information submitted to ClinicalTrials.gov for an applicable clinical trial subject to review?
Yes; ClinicalTrials.gov reviews protocol and results information for apparent validity, meaningful entries, logic and internal consistency, and formatting. The review focuses on assessing whether the entered data could be understood by a reader of the medical literature who is not already familiar with the study. For further information, please see: ClinicalTrials.gov Review of Results Submissions.
If a clinical trial is not an "applicable clinical trial", can it be registered in ClinicalTrials.gov?
Yes; the NIH encourages registration of all clinical trials whether required under the law or not. The NIH defines a clinical trial as a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective.
In order to clarify in ClinicalTrials.gov that your trial is not subject to FDAAA, please go to the trial’s registration record and answer “No” to the data element (field) “Section 801 Clinical Trial?”. Answering “no” documents that the trial is not subject to FDAAA (US Public Law 110-85, Title VIII, Section 801). For further information on this and other data elements, please review the NLM “ClinicalTrials.gov Protocol Data Element Definitions”.
Investigators should be aware that since July 2005, the International Committee of Medical Journal Editors (ICMJE) have required, as a condition of consideration for publication in its member journals, clinical trial registration in a public registry like ClinicalTrials.gov (http://www.icmje.org/clin_trial.pdf). For further information on the ICMJE policy, please access: http://www.icmje.org/faq_clinical.html
Are the costs (including staff time) of registration and results reporting (including summary adverse event information) in ClinicalTrials.gov allowable charges on an NIH grant?
Given the nature of this requirement and that the project staff will generally be in the best position to submit and maintain these data, the costs of FDAAA compliance will be generally be allowable as direct charges to NIH supported grants. While it is expected that these costs will be covered by the funds provided with the grant, administrative supplements could also be considered.
How can trial records be transferred from one Protocol Registration System (PRS) account to another?
The owner of a protocol record (usually the account administrator or the Responsible Party), or an employee from the owner's organization, can request the transfer by emailing the following information to email@example.com:
the NCT number of the record (or the Unique Protocol ID if no NCT number has been issued yet),
the name of the organization (or the PRS organizational account) to receive the trial,
the account owner’s name (user name; note: this user name must already exist in the recipient PRS organization account),
and any NIH grant numbers applicable to this protocol.
The account administrator should review the FAQ “Can a protocol record be transferred between organizations?” which is available once they have logged in to the PRS (click on “FAQ”).
If the trial is currently registered in an NIH IC PRS organizational account, please contact that IC to make the transfer. The IC will use its administrative access to transfer the trial to the new account. Provide the same information described above.
How should NIH support be indicated in the ClinicalTrials.gov record?
Use the “Secondary ID” and “Collaborators” fields in the PRS record. Enter the complete award number (e.g. R01DA013131) in the Secondary ID field and select “US NIH Grant/Contract Number” as the ID Type. PRS is linked to other NIH databases that attempt to validate your award number. At a minimum, the activity code, institute code and 6-digit serial number must be provided (e.g., R01HL123451). Other components of the number (type code, support year and suffix, if applicable) are optional (e.g., 5R01HL123451-01A2). In the Collaborators field, enter the name of the NIH Institute or Center funding the award.
C. Certifying Compliance with FDAAA in NIH Grant Applications and Progress Reports
What needs to be included in NIH competing (new and renewal) applications and progress reports to provide certification of compliance with FDAAA?
OER’s Web site What NIH Grantees Need to Know About ClinicalTrials.gov and FDAAA provides a full description of what needs to be included in NIH competing renewal applications and non-competing continuation progress reports.
When does the requirement to certify compliance with FDAAA go into effect?
Competing (new and renewal) applications: Competing applications submitted to the NIH on January 25, 2008 or after later, which incorporate an applicable clinical trial in their proposed project are required to provide certification of compliance.
Non-competing continuation progress reports: All progress reports for grants which include an applicable clinical trial with budget start dates of April 1, 2008 or later are required to provide certification of compliance.
Is a certification of compliance with FDAAA required for NIH grants providing statistical, laboratory, administrative or other support functions for applicable clinical trials?
Yes; any grantee receiving NIH funds to provide support for an applicable clinical trial is required to certify compliance with FDAAA. Even if the grantee is not the responsible party, the grantee must certify compliance with FDAAA.
I am the PD/PI on an NIH grant, but I am not the responsible party for the applicable clinical trial that the grant supports. The trial is not in compliance with FDAAA; may I register or submit results of the trial in ClinicalTrials.gov?
No. Only the responsible party may register a trial or report results in ClinicalTrials.gov. If you are not the responsible party, you should work with your Authorized Organizational Representative (Signing Official) to identify the responsible party and work with that entity to promote compliance with FDAAA.
Is a certification of compliance with FDAAA required for grants supporting an applicable clinical trial when the grantee institution is not the sponsor and therefore not the responsible party (e.g. an IND/IDE is held by another entity or individual)?
Yes, a certification of compliance with FDAAA is required. FDAAA includes a requirement that if an applicable clinical trial is funded in whole or in part by an award from any agency of the U.S. Department of Health and Human Services (e.g. NIH), any application or progress report forms required under such award shall include a certification that the responsible party has made all required submissions for the applicable clinical trial to ClinicalTrials.gov. Even if the grantee is not the responsible party, the grantee needs to certify compliance with FDAAA.
Which applicable clinical trials are subject to the results reporting requirement under FDAAA?
At this time, FDAAA requires the reporting of summary results information (including adverse events) no later than 1 year after the completion date for registered applicable clinical trials involving drugs that are approved under section 505 of the Food, Drug and Cosmetic Act (FDCA) or licensed under section 351 of the PHS Act, biologics, or of devices that are cleared under section 510k of FDCA. However, NIH encourages results reporting for all NIH supported clinical trials registered in ClinicalTrials.gov, regardless of whether or not they are required to do so under FDAAA.
How does the "primary completion date" in the ClinicalTrials.gov record relate to results reporting requirement under FDAAA?
In general, results of applicable clinical trials are due not later than 12 months after the primary completion date (see Definitions). For this reason, it is imperative that the primary completion date is correct. If the estimated primary completion date changes, update it in the Protocol Registration System.
Under what circumstances can the responsible party delay or request an extension for submission of results for an applicable clinical trial?
Under certain circumstances, a responsible party may delay submission of results or receive an extension to the deadline for submitting results information.
Under the law, a responsible party may submit a certification for delayed submission of results information for an applicable clinical trial that is:
completed before the drug or device is initially approved, licensed, or cleared by the FDA ("seeking initial approval") or
studying a new use of an FDA-approved drug or device (i.e., a use not included in the labeling) for which the manufacturer of a drug or device is the sponsor of the trial and has filed or will file within a year an application to the FDA for approval or clearance of that use ("seeking approval for a new use").
The Director of NIH may provide an extension of the deadline for submission of results information if the responsible party submits a written request that demonstrates good cause for the extension and provides an estimate of the date on which the results information will be submitted. Pending publication is not considered a good cause for an extension.
Are there resources on how to report results in ClinicalTrials.gov?
Yes; ClinicalTrials.gov provides a wide range of resources to help investigators successfully enter results into the database. First and foremost, however, successful results reporting depends on having a complete understanding of the study design and study data. Typically, the people who would write up the results for a journal article are the ones who would be involved in preparing and entering data for ClinicalTrials.gov. Second, the results records must be logical, internally consistent, and meaningful. This means, among other things, providing data that make sense, using technical terms precisely, providing all necessary data, and ensuring there are no invalid entries. The responsible party should review the record in accordance with ClinicalTrials.gov review criteria prior to submitting it for posting.
Are non-applicable clinical trials registered in ClinicalTrials.gov required to report results?
No; trials not subject to FDAAA are not required to report results. In order to clarify in the database that the trial is not subject to FDAAA, please go to the trial’s registration record and answer “No” to the data element (field) “Section 801 Clinical Trial?”. Answering “no” documents that the trial is not subject to FDAAA and not out of compliance.