Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products

Target Audience: Industry sponsors planning to apply for a New Drug Application, Biologic License Application, or applications for supplemental indications

Laws and Regulations:

  1. The Federal Food, Drug, and Cosmetic Act of 1962 amended that in addition to demonstrating safety, manufacturers must also demonstrate their product’s effectiveness through “adequate and well-controlled studies” to gain marketing approval.
  2. The Food and Drug Administration Modernization Act of 1997 for human drug and biological products (P.L. 105-115) subsection 403(b)(1), which requires the FDA to provide guidance on conditions in published material may partially or completely support approval of a supplemental application, and subsection 403(b)(2), which requires the FDA to provide guidance on conditions in which relating existing data from the original application or other sources can be used to support approval of a supplemental application.
  3. The Food and Drug Administration Modernization Act of 1997 section 115(a) allows the FDA to consider “data from one adequate and well-controlled clinical investigation and confirmatory evidence” to establish effectiveness.
  4. The Public Health Service Act section 351 authorizes the FDA to grant marketing approval to biological products with established “continued safety, purity, and potency” (in which potency is interpreted to include effectiveness).
  5. 21 Code of Federal Regulations 314.126 defines proof of effectiveness and describes the essential characteristics of “adequate and well-controlled studies.”


This document provides guidance for filing applications on evidence of effectiveness, as well as fulfilling the requirements of subsections 403(b)(1-2) of the Modernization Act.


At least two adequate and well-controlled studies with confirmatory results are needed for a sponsor to demonstrate effectiveness. However, sometimes the FDA grants marketing approval based on a single study if:

  1. It is multicenter, excellently designed, and provides highly reliable and statistically strong evidence of an important clinical benefit, e.g., prolongation of survival, and there are ethical grounds against conducting a second study
  2. Other adequate and well-controlled studies of the drug in other dosages, dosage forms, disease stages, patient populations, or endpoints demonstrate effectiveness of the new use
  3. When an alternative method adequately substantiates effectiveness, e.g., serologic response data known to be correlated with clinical effectiveness (for biologics only)


Existing data may provide “independent substantiation of related claims” if:

  1. Extrapolation from existing studies (e.g., pediatric uses; bioequivalence; modified-release dosage forms; different doses, regimens, or dosage forms)
  2. Demonstration of effectiveness by a single study of a new use, with independent substantiation from related study data (e.g., different doses, regimens, or dosage forms; studies in other disease phases; studies in other populations; studies as monotherapy or combination therapy; studies in a closely related disease; studies in less closely related diseases but with a similar general purpose of therapy; studies of different clinical endpoints; pharmacologic/pathophysiologic endpoints)
  3. Evidence of effectiveness from a single study (e.g., large multicenter study; consistency across study subsets; multiple studies in a single study; multiple endpoints involving different events; statistically very persuasive findings)

However, there is always a possibility of relying on an incorrect outcome from a single multicenter study, especially when the benefit is unrepeatable or inconsistency is seen with other data.

Documentation of the quality of evidence supporting an effectiveness claim

Supportive clinical studies are typically conducted in accordance with good clinical practices, with sponsors routinely monitoring all clinical sites, and the FDA having routine access to the original clinical protocols, primary data, clinical site source documents for audits, and complete study reports. However, when some of these are lacking, sponsors may still rely on such studies to support an effectiveness claim.

Less than usual access to clinical data or detailed study reports may be supplemented by:

  1. Submission of published literature or other reports with important information enhancing the data reliability (e.g., study protocol and protocol amendments in relation to study accrual/randomization; record of each patient’s data for critical variables and baseline characteristics)
  2. Submission of published literature reports alone (e.g., consistent findings across multiple adequately designed studies by different investigators; clearly appropriate, objective endpoints; robust results from pre-specified analyses that yield a consistent conclusion of efficacy)

Studies with alternative, less intensive quality control/on-site monitoring may be supplemented by:

  1. Prospective plan to assure data quality
  2. Studies designed to prevent bias, e.g., relatively simple procedures, noncritical entry criteria, readily assessed outcomes
  3. Ability to sample critical data and compare with supporting records, e.g., hospital records
  4. Study conduct by a group with established operating procedures and a history of effectiveness implementation of such procedures


This guidance allows sponsors to plan drug development programs sufficient to demonstrate effectiveness without excessive scope. The FDA’s assessment of clinical study data required to support drug effectiveness will be more consistent and predictable with this guidance as reference. The guidance clarifies the requirements and may encourage more sponsors to file supplemental applications.

For more information on this issue, contact the Kulkarni Law Firm.