Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions

Draft guidance released January 2004, available at:

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126838.pdf

Target Audience

This guidance assists individuals including clinical trials professionals, quality assurance staff, regulatory affairs personnel, and others who submit data (collectively: sponsors) to the Clinical Trials Data Bank (http://www.clinicaltrials.gov/). The guidance also is germane to those who are responsible for implementation of the FDA Modernization Act (FDAMA) of 1997.

Laws, Regulations, and Related Guidances

Section 113 of the FDAMA, 1997

Public Law 107-109 Best Pharmaceuticals for Children Act (BPCA), 2002

Federal Food, Drug, and Cosmetic Act Section 505(i)

21 CFR [Investigational New Drugs (INDs)]

21 CFR 312 (regarding clinical trials)

21 CFR 312.81(a) (defines life-threatening diseases)

21 USC 356 (defines fast-track designation)

42 USC 282 especially Section 282(j)(3)(A)

Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions, March 2000

Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases: Implementation Plan, June 2001

Guidance for Industry: Information Program on Clinical Trials for Serious or Life-threatening Diseases and Conditions, March 2002 [NOTE: This 2002 guidance incorporated the 2 guidances just cited. The 2004 guidance updates the 2002 version.]

Guidance for Industry: Fast Track Drug Development Programs— Designation, Development, and Application Review (revision 2, January 2006)

Summary

Section 113 of FDAMA directs the Secretary of the Department of Health and Human Services, via the Director of the National Institutes of Health (NIH), to “establish, maintain, and operate a data bank of information on clinical trials for drugs to treat serious or life-threatening diseases and conditions.” The Clinical Trials Data Bank at http://www.clinicaltrials.gov is a central resource that provides information about clinical trials for individuals who have serious or life-threatening diseases or conditions. Because this is a public site, researchers, health care providers, and the public at large have access to the information. The site includes:

• information about federally and privately funded clinical trials for experimental drug and biological treatments for patients with serious or life-threatening diseases or conditions
• a description of the purpose of each experimental drug
• patient eligibility criteria
• the location of clinical trial sites
• a point of contact for patients wanting to enroll in the trial.

Sponsors must submit required information no later than 21 days after trial opens for enrollment. Every 30 days thereafter sponsors can provide supplemental information (amendments, interruptions, continuations, or completion, as well as changes in eligibility). The guidance recommends posting closings (eg, clinical holds) within 10 days or fewer from the closing. Finally, the guidance suggests that sponsors should conduct overall reviews of the posting at least semiannually to ensure all data remain current.

As the guidance notes, the term life-threatening diseases is defined as diseases or conditions where the likelihood of death is high unless the course of the disease is interrupted and, when the endpoint of the clinical trial is survival, diseases or conditions with potentially fatal outcomes. Overall, FDA’s view is that untreated patients who have life-threatening diseases will move from less-severe conditions to more-serious ones in terms of survival and day-to-day functioning. Life-threatening diseases include Human Immunodeficiency Virus, Alzheimer disease, angina pectoris, heart failure, cancer, all conditions treated by fast-track drugs, and others).

The Clinical Trials Data Bank supercedes the former AIDS Clinical Trials Information System (ACTIS) and the Physician’s Data Query (PDQ) databases and incorporates information from the Rare Diseases and National Institute of Aging Databases. Posting clinical trial information to the Data Bank does not require the approval of the trial’s institutional review board(s).

Sponsors who conduct an ex–US study under an IND must comply with this guideline.

Rationale

As the guidance notes, FDAMA section 113 “creates a public resource for information on studies of drugs, including biological drug products, to treat serious or life-threatening diseases and conditions.” Although the guidance does not address historical context, since the first (2000) version was published, Internet use in the United States expanded rapidly, and the public increasingly asked for information about drugs in development to treat serious diseases. In some cases, patients and their relatives were seeking access to advanced therapies that might offer hope to friends and family members. To others, the fact that the federal government regulated clinical trials suggested that results from these trials should be more public.¹ Revocation of marketing privileges for several drugs, notably those in the COX-2 inhibitor class, involved public outcry about underreported and possibly distorted reports from clinical trials (eg, the RECORD Trials).^2,3

Resulting Recommendations

The Clinical Trials Data Bank established 4 fundamental data elements for posting on http://www.clinicaltrials.gov:

• Descriptive information about the clinical trial
• Brief title (in lay language)
• Brief summary (in lay language)
• Study design/phase/type
• Condition or disease
• Intervention
• Single-patient/expanded access information (if any)
• Recruitment Information
• Status: Recruiting/Not recruiting/Completed
• Individual site status
• Location and Contact Information
• Administrative data
• Protocol ID number
• Sponsor
• Verification date.

To enable clinical trial sponsors to provide this information, FDA established the Protocol Registration System (http://prsinfo.clinicaltrials.gov/). This tool allows sponsors to submit necessary information. Importantly, the Protocol Registration System sends FDA a receipt after the sponsor submits the information package.

Impact

The first version of the Clinical Trials Data Bank was posted publicly on 29 Feb 2000. The site reports that it now contains 87,850 trials sponsored by the National Institutes of Health, other federal agencies, and private industry. It includes trials in all 50 states and in 172 countries and receives more than 50 million page views per month and 65,000 visitors daily. Public posting of clinical trials can be seen as a step toward the disclosure of the results of all clinical studies.

Note that sponsors are required to post information to the Clinical Trials Data Bank unless the sponsor provides a detailed certification to FDA that disclosure would “substantially interfere with the timely enrollment of subjects” in the trial. But at line 341 (p 9) the guidance notes that FDA has received no comments that attempted to justify not posting to the Clinical Trials Data Bank.

Note

The Food and Drug Administration Amendment Act (FDAAA) of September 2007 requires sponsors of all clinical trials registered at www.clinicaltrials.gov (excepting Phase I trials) to report key outcomes no later than 12 months after they receive data for the last patient. As noted, this requirement results from public and Congressional pressure to ensure that outcomes of all trials are available in the public record.

References

1. Although the movement toward public access of NIH-funded research and open access in general are peripheral to this blog, the guidance discussed here is part of the context in which several medical journals refused to publish results from trials that were not registered at, eg, clinicaltrials.gov. See: DeAngelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medicl Journal Editors. JAMA. 2004;292:1363–1364.

2. Nissen SE. Setting the RECORD straight. JAMA. 2010;303(12):1194–1195. This study obviously follows FDAMA, but it helpfully frames some of the issues that were under debate when FDAMA was enacted. Note references herein.

3. DeAngelis CD, Fontanarosa PB. Ensuring integrity in industry-sponsored research. JAMA. 2010;202(12):1196–1198. This editorial by JAMA editors shows some results of the apparent lack of transparency in the conduct and reporting of clinical trials. Note references herein.