Section 113: Status Report on Implementation
BIOLAW & BUSINESS
V 0 L U M E 7, NUMBER 2
Food and Drug Modernization Act (FDAMA)
Section 113: Status Report on Implementation
Office of Special Health Issues, Food and Drug Administration
Copyright 2004 By The Journal of Biolaw & Business
Theresa Toigo, RPh, MBA, is Director, Office of Special Health Issues, at the Food and Drug Administration (FDA).
The views expressed in this paper are those of the author and do not necessarily represent those of the Food and Drug Administration.
Cite as: Theresa Toigo, Food and Drug Modernization Act (FDAMA) Section 113: Status Report on implementation. J. BIOLAW & BUS., Vol. 7. No. 2, 2004.
The Food and Drug Administration Modernization Act (FDAMA; herein referred to as the "Modernization Act"), enacted November 21, 1997, amended the Federal Food, Drug, and Cosmetic Act. Section 113 of FDAMA directed the Secretary of the Department of Health and Human Services (DHSS), acting through the Director of the National Institutes of Health (NIH), to establish a publicly accessible data bank of information about clinical trials for serious or life threatening diseases and conditions. The National Library of Medicine made the first version of the Clinical Trials Data Bank available to the public on February 29, 2000, on the Internet at http://clinicaltrials.gov. The data bank included mainly NIH-sponsored trials. On March 18, 2002, the Food and Drug Administration (FDA) issued a final guidance entitled Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions. One and one-half years after publication of the final guidance, FDA issued a press release acknowledging the listing of the 1,000th industry-sponsored study in ClinicalTrials.gov. Although this milestone is gratifying, more needs to be done by FDA, pharmaceutical companies, and other sponsors. The challenge for FDA is to assess the need for further efforts to facilitate or perhaps to compel the pharmaceutical industry's participation in ClinicalTrials.gov.
Congress has demonstrated a longstanding interest in improving public access to information about opportunities to participate in clinical trials of promising new treatments. In November 1988, Congress passed the Health Omnibus Programs Extension (HOPE) Act. Section 2317 of the HOPE Act directed the Secretary of the Department of Health and Human Services (DHHS), to establish services to disseminate information on HIV research, treatment, and prevention.  These services included providing information about clinical trials of investigational drugs, including biologic products, for HIV-related diseases. Almost 10 years later, Congress passed the 1997 Food and Drug Administration Modernization Act (Modernization Act). Section 113 of the Modernization Act directed the DHHS Secretary, acting through the Director of the National Institutes of Health (NIH), to establish a publicly accessible data bank of information about clinical trials for serious or life threatening diseases and conditions. 
The intent and language of Section 113 of the Modernization Act and Section 2317 of the 1988 HOPE Act are similar. Both directed DHHS to make information about clinical trials publicly available. In 1989, the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and NIH established the AIDS Clinical Trials Information Service (ACTIS) to provide information on clinical trials for HIV-related diseases. In 2000, NIH, through its National Library of Medicine (NLM), and FDA developed the ClinicalTrials.gov site, to provide information on clinical trials for serious or life-threatening diseases as required by the Modernization Act.  Although the provisions of the 1988 HOPE Act, which established ACTIS, are similar to those of Section 113 of the Modernization Act, the focus has shifted from technical data for health professionals to information accessible to the public.
AIDS CLINICAL TRIALS INFORMATION SERVICE
In 2002, ACTIS was reviewed after more than a decade of providing HIV/AIDS clinical trial information to the public.  As ACTIS moved into its second decade, the service merged with its sister service, the HIV/AIDS Treatment Information Service (ATIS), to form AIDSinfo.  AIDSinfo includes the services that were available from both ACTIS and ATIS. More recently, the AIDSinfo clinical trials search screen was designed to help users find HIV/AIDS-related clinical trials in ClinicalTrials.gov. Using the AIDSinfo search screen, each search is automatically limited to trials studying HIV/AIDS.
Although experience gained from developing and maintaining the ACTIS database was helpful, the broad scope of the Modernization Act required a general clinical trials data bank rather than separate data banks for each disease category. Design and development for ClinicalTrials.gov, therefore, was more technically and organizationally challenging. Issues pertaining to design and implementation, including lessons learned in developing the database, have been well described.  One study concluded that because data in the system are constantly changing, no phase of this project is ever completed.
Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Establishment of a Data Bank
NLM made the first version of the Clinical Trials Data Bank available to the public on February 29, 2000, on the Internet at http://clinicaltrials.gov. The data bank included mainly NIH-sponsored trials. At about the same time, FDA published the first of three guidance documents.
On March 29, 2000, FDA published in the Federal Register a notice of availability (NOA) for a draft guidance entitled Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Establishment of a Data Bank.  The draft guidance provided recommendations for industry on filing protocol information to the Clinical Trials Data Bank. It included discussion about the types of clinical trials for which submissions will be needed under Section 113 of the Modernization Act and the types of information to be filed.
Section 113 of the Modernization Act requires that sponsors of investigational new drug applications (IND's) submit to the Clinical Trials Data Bank a description of the purpose of each experimental drug, eligibility criteria for participation in the trial, the location of clinical trial sites, and a point of contact for those wanting to enroll in the trial. The statute requires the information to be provided in a form that can be readily understood by the public. The guidance addressed questions to be considered when submitting protocol information under the Modernization Act. For example, What is a serious or life-threatening disease? What is a trial to test effectiveness? and What does submission to the data bank "not later than 21 days after approval" mean?
A life threatening disease is a disease or condition where the likelihood of death is high unless the course of the disease is interrupted and includes diseases with potentially fatal outcomes where the endpoint of the clinical trial analysis is survival. The seriousness of a disease is a matter of judgment but is based on such factors as survival, day-to-day functioning, and the likelihood the untreated disease will progress to a more serious condition. To respond to the effectiveness requirement in the statute, a trial to test effectiveness is defined as a phase 2, phase 3, or phase 4 trial with efficacy endpoints. Section 113 of the Modernization Act requires that sponsors forward information to the Clinical Trials Data Bank no later than 21 days after approval. Because FDA does not specifically approve an IND protocol, we recognized the need to clarify the date of submission to the data bank. For purposes of responding to Section 113 of the Modernization Act, the guidance recommends that sponsors submit protocol information to the Clinical Trials Data Bank no later than 21 days after the trial is first opened for enrollment; on amending the protocol with respect to one of the required data elements; or when recruitment for the study is interrupted, resumed, or completed.
Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Implementation Plan
On July 9, 2001, FDA published in the Federal Register an NOA for the second draft guidance entitled Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Implementation Plan.  This guidance addressed procedural issues, including how to file mandatory and voluntary protocol information in the Clinical Trials Data Bank. Information is submitted to the data bank through a Web-based protocol registration system (PRS) available at http://prsinfo.clinicaltrials.gov/. The guidance set up a time frame for filing the information. It also discussed exemption from the reporting requirements of Section 113, which are based on submitting certification to the DHHS Secretary that disclosure of information for a particular protocol would substantially interfere with the timely enrollment of subjects in the clinical investigation.
On March 18, 2002, FDA published in the Federal Register an NOA for the final guidance entitled Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions.  The final guidance combined the two draft guidances into a single guidance, incorporated comments received on the draft guidances, and provided more details on the use of the PRS. For example, the guidance clarified that intermediaries acting for a sponsor can submit data to the PRS and the PRS includes a mechanism for uploading and downloading XML-formatted records. The guidance also clarified how to submit requests for exemption when disclosure of information would substantially interfere with enrollment of subjects in a clinical investigation.
The FDA initiated a program during 2002 to inform pharmaceutical companies and other IND sponsors of the statutory requirement that they list their studies in ClinicalTrials.gov. FDA sent letters directing sponsors to the guidance document and describing mandatory and voluntary data submission through the PRS.
Pharmaceutical companies have made important progress in making summary trial information available through the ClinicalTrials.gov site. As of November 18, 2003, 254 pharmaceutical companies and 29 educational or organizational sponsors had registered. Of the sponsors who have registered, 215 pharmaceutical companies and 22 educational or organizational sponsors have listed 1093 protocols.
FDA's Office of Special Health Issues (OSHI) is completing a review of participation by IND sponsors during 2002. OSHI identified 2060 new commercial protocols filed between January 1, 2002 and September 30, 2002; extracted protocol information and identified protocols that met the criteria for inclusion (phase 2, 3 or 4 protocols testing effectiveness for a serious disease); and compared protocol listings in ClinicalTrials.gov with protocol listings in the OSHI database.
Information Program on Clinical Trials for Serious or Life-Threatening Diseases: Beyond Implementation
FDA is analyzing data from the review of sponsor participation in ClinicalTrials.gov. At present, some pharmaceutical companies are not providing adequate information about the trials. Some companies list their clinical trials but provide limited information about the trial, making it difficult for patients to find the trial and make informed decisions. Some companies do not provide the sponsor name or the name of the drug; 10% of the protocols do not include specific drug names. For these trials, sponsors generally list "investigational drug" as the drug name. Because patients often search ClinicalTrials.gov using a specific drug name, they will not find a trial for the drug if it is listed in the database as "investigational drug." Academic institutions and organizations not affiliated with pharmaceutical companies include both drug and sponsor names.
Some companies list no trials in ClinicalTrials.gov. Some list only a few trials that meet the criteria specified in the guidance. Other companies voluntarily list trials that go beyond the criteria specified in the guidance, which FDA and NLM welcome them to do. Data compiled by the FDA's Office of Special Health Issues and presented at a recent FDA Science Forum show that 48% of the mandated industry-sponsored and 91% of the mandated NIH cancer-related trials were in ClinicalTrials.gov.  A preliminary review of non-cancer protocols in the sponsor participation study suggests a single-digit participation rate in some serious disease categories. FDA is working to further quantify the extent of participation in ClinicalTrials.gov required under the Modernization Act.
FDA recently acknowledged the listing of the 1,000th industry-sponsored trial in ClinicalTrials.gov.  Although this milestone is gratifying, more needs to be done by FDA, pharmaceutical companies, and other sponsors. FDA should further clarify guidance on which trials and what information needs to be listed in ClinicalTrials.gov. FDA should identify opportunities to remind sponsors of the Modernization Act's 113 requirements. Companies should review their systems for identifying and submitting protocols to ClinicalTrials.gov and reconsider why mandated protocols are not being submitted in accordance with federal law. 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.
DHHS developed ClinicalTrials.gov in response to legislation calling for a publicly accessible registry of clinical trials for patients with serious or life threatening diseases and conditions. The project is an evolving long-term program involving collaboration among federal agencies, patient advocates, and pharmaceutical companies. As Congress recognized in enacting Section 113 of the Modernization Act, programs that enhance patient access to clinical trials may benefit public health. At the same time, expanding the pool of research participants may benefit pharmaceutical company sponsors by speeding enrollment in their clinical trials. Aside from the obvious benefits to various parties from participating in ClinicalTrials.gov, Federal law requires that pharmaceutical companies make clinical trials information more publicly available. Many pharmaceutical companies are not participating in ClinicalTrials.gov, or are not fully participating. The challenge for the Food and Drug Administration is to assess the need for further efforts to facilitate or perhaps to compel participation in ClinicalTrials.gov.
 The Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 113 (1997).
 National Institutes of Health. http://ClinicalTrials.gov
 Katz, Deborah G., Dutcher, Gale A., Toigo, Theresa A., Bates, Ruthann, Temple, Freda, Cadden, Cynthia G. The AIDS Clinical Trials Information Service (ACTIS): A Decade of Providing Clinical Trials Information Public Health Reports. 117(2):123-130, March/April 2002.
 U.S. Department of Health and Human Services. AIDs info. www.aidsinfo.nih.gov
 Derbis, J. Toigo, T. Woods, J. Evelyn,B. Banks, D FDAMA Section 113: Information Program on Clinical Trials for Serious or Life Threatening Diseases: Update on Implementation
 U.S. Food and Drug Administration. A Milestone for ClinicalTrials.gov Web Site.