Date: August 1999
Target Audience: NDA or BLA applicants
Laws and Regulations:
- Food and Drug Administration Modernization Act (FDAMA) of 1997, Section 118 – FDA must issue guidance on when abbreviated study reports may be submitted instead of full reports
- Federal Food, Drug, and Cosmetic Act, Section 505(b)(1) – reports of studies demonstrating safety and effectiveness be submitted in an NDA
- 21 CFR 601.2(a) and (c)(1)(i) – reports demonstrating safety, purity, and potency be submitted in a BLA
- 21 CFR 314.50(d)(5) – description and analysis of each controlled clinical study be submitted in an NDA
- Guidance for Industry: Format and Content of the Clinical and Statistical Sections of an Application
- ICH E3: Structure and Content of Clinical Study Reports
This guidance provides FDA recommendations for when submitting safety and/or effectiveness data as a full clinical study report, an abbreviated study report, or a synopsis is appropriate. Recommendations for the format of abbreviated study reports and synopses are also provided.
In 1988, the FDA issued a guidance (Format and Content of the Clinical and Statistical Sections of an Application) recommending that full study reports were only required when a study provided both safety and effectiveness data. If the study was not intended to evaluate effectiveness for the proposed indication, or to support labeling information, then a less-than-full report could be submitted. Applicants, however, often continued to submit full reports because of the difficulty in interpreting the requirements.
One of the key goals of the FDA’s Modernization Act (FDAMA) in 1997 was to improve efficiency of the regulatory review process. To this end, in 1999 the FDA issued a new guidance that offers clearer instructions detailing formats for alternative reports that could be submitted in lieu of full reports. The guidance also provides explanations and examples of when such alternatives, called “abbreviated reports” and “synopses,” are appropriate.
Full study reports should be submitted for all studies that contribute data affecting a product’s labeling information, including studies that evaluate the product’s effectiveness for the proposed indication.
Examples of clinical studies requiring full reports include the following:
- Dose-finding studies
- Pivotal studies
- Controlled studies supporting effectiveness
- Controlled studies demonstrating comparativeness
- Controlled studies of different indications or dosage forms or regimens if they are intended to support approval of the proposed indication
- Controlled studies designed to evaluate effectiveness that fail to show an effect
- The format for a full report is described in ICH E3
Abbreviated reports require the same amount of safety information as would be included in a full report, but less effectiveness information. These reports should be submitted for studies that are not designed to evaluate product effectiveness or describe clinical pharmacology, but for which the reviewer needs enough information to see that the study results do not contradict effectiveness claims or clinical pharmacology profiles determined in other studies.
Examples of clinical studies requiring abbreviated reports include:
- Studies not designed as efficacy studies but that provide significant safety information
- Studies that do not provide the primary or substantiating evidence of effectiveness (results must be consistent with the substantiating studies)
- Studies of indications not intended for marketing but which are related to the proposed indication
- Studies of doses or dosage forms not intended for marketing
- Controlled safety studies
The format for an abbreviated report includes the following sections from ICH E3: 1, 2, 3, 4, 9.1, 9.8, 10.1, 12, 13, 14, 16.1.1, 16.1.2, 16.3.1, and 16.4. A summary of efficacy results (such as described in ICH E3 Section 11.4.1, if appropriate) should also be included.
Synopses should be submitted for studies that provide no relevant evaluation of effectiveness or clinical pharmacology. Safety data from such studies must still be provided for review.
Examples of clinical studies requiring synopses include:
- Studies of indications not intended for marketing and which are unrelated to the proposed indication
- Studies evaluating routes of administration not intended for marketing
- Incomplete studies (ie, enrolling fewer than one-third of intended patients), unless stopped due to safety or failure to show efficacy
- Uncontrolled studies not specifically identified as needing abbreviated or full reports
- Early general phase-1 safety-tolerance studies, but not specific, required toxicity studies
The format for an abbreviated report includes the following sections from ICH E3: 2, 12, 16.1.1.
After the guidance was implemented in 1999, FDA Commissioner Jane Henney described it as a process improvement. “This guidance not only provides clarity,” she stated, “it should also ensure that industry is not submitting more information than is required by the Agency.” Reducing the amount of information required saves applicants and reviewers time.
For more information on this issue, contact the Kulkarni Law Firm.