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FDAMA Section 113: Status Report on Implementation

~ EXECUTIVE SUMMARY ~

BACKGROUND

Section 113 of the Food and Drug Administration Modernization Act (FDAMA) (42 U.S.C. § 282(j)), enacted November 21, 1997, creates a public resource for information on studies of drugs, including biological drug products, to treat serious or life-threatening diseases and conditions conducted under the Food and Drug Administration's (FDA) investigational new drug (IND) regulations at Title 21, Code of Federal Regulations Part 312. (21 CFR 312). It directs the Secretary of Health and Human Services (HHS), acting through the Director of the National Institutes of Health (NIH), to establish, maintain, and operate a data bank of information on certain clinical trials.

Specifically, Section 113 of FDAMA requires that the Clinical Trials Data Bank contain:

1. information about both federally- and privately-funded clinical trials for experimental treatments (drug and biological products) for patients with serious or life-threatening diseases and conditions;
2. a description of the purpose of each experimental drug;
3. patient eligibility criteria;
4. a description of the location of clinical trial sites; and
5. a point of contact for patients wanting to enroll in the trial.

Section 113 of FDAMA requires that information be forwarded to the data bank by the sponsor of the trial not later than 21 days after the approval of the protocol.¹ It also requires information provided through the Clinical Trials Data Bank be in a form that can be readily understood by the public [42 U.S.C. 282(j)(3)(A)].

The NIH, through its National Library of Medicine (NLM) and with input from the FDA and others, developed the Clinical Trials Data Bank. The first version of the Clinical Trials Data Bank was made available to the public on February 29, 2000, via the Internet at www.clinicaltrials.gov. At that time, the data bank, referred to as ClinicalTrials.gov, contained more than 4,000 records, representing primarily trials sponsored by the NIH. Today, ClinicalTrials.gov includes more than 13,500 federally- and privately- sponsored trials.

FDA issued a final guidance to industry on March 18, 2002 to address statutory and procedural issues related to Section 113 of FDAMA. The guidance states that a trial is required to be in the data bank if it is intended to treat a serious or life-threatening disease or condition and is a phase 2, 3 or 4 trial with efficacy endpoints. On January 27, 2004, FDA issued a draft guidance revising the March 2002 guidance to include guidance for sponsors who would be submitting information required by the Best Pharmaceuticals for Children Act. The January 2004 draft guidance is available at http://www.fda.gov/cder/guidance/3901dft.pdf.

In January 2002, FDA's Office of Special Health Issues (OSHI) undertook a multi-faceted project to educate IND sponsors about Section 113 of FDAMA and to assess sponsor compliance with the law. The following section describes the various components of the project.

FINDINGS

The key components of the project are as follows:

• The Education Program, initiated in 2002, consisted of mailing letters to IND sponsors of products regulated in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) that served to inform each sponsor about the requirements of FDAMA Section 113, the availability of the final guidance to industry, and the Protocol Registration System (PRS) available through the data bank. In CDER, 1,748 letters were mailed to sponsors of commercial INDs; 612 were mailed to sponsors of commercial INDs in CBER.
• Compliance Evaluation Program I attempted to determine the extent to which sponsors' submissions to CDER were also included in ClinicalTrials.gov. It compared the number of protocols submitted to CDER and to ClinicalTrials.gov for a period of nine months. Of the 2,062 protocols submitted to CDER from January 1, 2002 to September 30, 2002, 688 protocols (33%) were trials to test effectiveness for serious and life-threatening diseases or conditions and met the criteria for inclusion in ClinicalTrials.gov. During that same time period, 239 (35%) of these 688 trials were listed by sponsors in ClinicalTrials.gov.
• In 2004, the project was expanded to include Compliance Evaluation Program II, intended to reflect any changes that may have resulted from increased public attention to making clinical trial information more publicly available. For this project, OSHI conducted a review of new cancer protocols submitted to CDER's Division of Oncology Drug Products (n = 140) for a period of three months in 2004. Overall, compliance in listing cancer trials in ClinicalTrials.gov increased from 61% in 2002 to 76% in 2004.
• FDAMA 113 provided for the voluntary inclusion of information about results of clinical trials. ClinicalTrials.gov includes data fields for sponsors to include publication citations or links to educational, research, government, and other non-profit Web pages. In 2004, we reviewed the publication citations about results and whether they were available as no-cost, full text articles. We also reviewed the links sponsors listed in ClinicalTrials.gov. Of the 358 references reviewed, 125 (35%) described human drug studies and 177 (49%) were available as full-text articles. Of the full-text articles, half were available at no cost. OSHI determined that approximately 51% of the 139 links listed by sponsors were to sponsors' websites. We did not review completed studies to identify published articles reporting the results of the clinical trial.

RECOMMENDATIONS

The Department of Health and Human Services (DHHS) developed ClinicalTrials.gov in response to legislation calling for a publicly-accessible registry of clinical trials for serious or life-threatening diseases and conditions. The response to the legislation has been mixed. Participation by the pharmaceutical industry is lower than expected despite a federal law, a final guidance document, a targeted education program, and an easy-to-use web-based data entry tool. Some pharmaceutical companies list clinical trials but provide limited information, some do not provide information on trials that fall within FDAMA 113, and others voluntarily list trials that go beyond the criteria specified in the statute.

There has been progress on implementing the legislation, however more needs to be done by FDA, pharmaceutical companies, and others to assure increased participation in ClinicalTrials.gov.

• FDA should continue to further clarify messages about which trials and what information should be listed in ClinicalTrials.gov. In November 2004, FDA updated IND acknowledgement letter templates to include a new paragraph reminding sponsors of their responsibility to comply with Section 113 of FDAMA and encouraging the listing of all trials. The draft Guidance for Industry Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions will be updated to reflect the findings from our study.
• Pharmaceutical companies and other private sector sponsors are encouraged to review their systems for identifying and submitting protocols to ClinicalTrials.gov. We expect that the number of industry-sponsored trials submitted to ClinicalTrials.gov over the next six months will continue to rise as a result of a recent PhRMA initiative. Under a new voluntary disclosure policy announced in January 2005, PhRMA member companies have agreed to provide information about ongoing hypothesis-testing trials for all diseases to ClinicalTrials.gov by September 13, 2005. The policy also encourages PhRMA member companies to establish and make public procedures for verifying compliance with the policy. In addition, the International Committee of Medical Journal Editors (ICMJE) announced their position that new trials must be registered in order to be eligible for publication.² Their policy applies to trials that start recruiting on or after July 1, 2005. Ongoing trials are required to be registered by September 13, 2005.
• Patient advocacy groups should continue to be proactive in encouraging FDA and pharmaceutical companies to make information about ongoing trials more available through ClinicalTrials.gov. Advocacy group initiatives like the Kidney Cancer Association's policy to not list a clinical trial on its website unless the trial is listed in ClinicalTrials.gov are commendable.

FDA will continue to work with sponsors to encourage their entry of required and voluntary information into ClinicalTrials.gov. We believe that a comprehensive clinical trials database can lead to more efficient and timely answers to scientific questions that will result in earlier access to effective treatments for patients.

¹ Final Guidance for Industry: Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions [PDF version: http://www.fda.gov/OHRMS/DOCKETS/98fr/00d-1033_gdl0003.pdf. Because the Agency does not approve protocols, we have interpreted this to mean within 21 days after the trial is open for enrollment.
²September 2004 ICMJE announces clinical trials must be listed in a public trials registry to be considered for publication http://www.icmje.org/clin_trial.pdf and May 2005 http://www.icmje.org/clin_trialup.htm.

FDAMA 113 Report

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