Substantial Evidence

In order to obtain marketing approval, a drug manufacturer must provide the FDA with substantial evidence of safety and efficacy. Substantial evidence is defined as consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. The FDA and the sponsor will agree upon beforehand, the specific substantial evidence that must be provided for marketing approval.

The quality of evidence used by the FDA in making a determination to approve a new drug, or to approve an old drug for a new use, is significantly greater than that found in a peer reviewed medical journal study. The agency bases its determination of efficacy on its own examination of the data, including statistical analyses done by highly skilled, Ph.D.- level statisticians. Additionally, the FDA has the authority and the responsibility to audit clinical research sites to ensure that the data the agency uses in making its decisions are valid. Good laboratory practices (GLP), as well as good clinical (GCP) and good manufacturing practices (GMP) should be followed to ensure the validity of the substantial evidence.

The excerpt below, taken from 21CFR314.126, “Adequate and Well-Controlled Studies”, (http://edocket.access.gpo.gov/cfr_2001/aprqtr/21cfr314.126.htm revised April 2008), describes the characteristics of studies that can provide substantial evidence:

1. There is a clear statement of the objectives of the investigation and a summary of the proposed or actual methods of analysis in the protocol for the study and in the report of its results.
2. The study uses a design that permits a valid comparison with a control to provide a quantitative assessment of drug effect.
3. The method of selection of subjects provides adequate assurance that they have the disease or condition being studied, or evidence of susceptibility and exposure to the condition against which prophylaxis is directed.
4. The method of assigning patients to treatment and control groups minimizes bias and is intended to assure comparability of the groups with respect to pertinent variables such as age, sex, severity of disease, duration of disease, and use of drugs or therapy other than the test drug.
5. Adequate measures are taken to minimize bias on the part of the subjects, observers, and analysts of the data.
6. The methods of assessment of subjects' response are well-defined and reliable.
7. There is an analysis of the results of the study adequate to assess the effects of the drug.

The FDA Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) released the document, Guidance for Industry Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072008.pdf). The source discusses studies used in support of providing substantial evidence, noting that there may exist studies of a drug in different populations, studies of a drug alone or in combination, and studies of different doses and dosage forms, all of which may support a particular new use of a drug. The following bullets reflect key elements of the guidance document:

• Quantity of Evidence Necessary to Support Effectiveness
  • Legal Standards for Drug and Biological Products
  • Scientific Basis for the Legal Standard
  • The Quantity of Evidence to Support Effectiveness
• Documentation of the Quality of Evidence Supporting An effectiveness Claim
  • Reliance on Less Than Usual Access to Clinical Data or Detailed Study Reports
  • Reliance on Studies with Alternative, Less Intensive
  • Quality Control/On-Site Monitoring

Research by Theresa Pipher