FDA Issues Two New Clinical Trial Design Guidances

By David B. Clissold & Carrie S. Martin –

Last Friday, FDA issued two new draft guidance documents regarding clinical trial designs: Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics (February 2010) and Guidance for Industry: Non-Inferiority Clinical Trials (March 2010).

These draft guidance documents are products of FDA’s Critical Path Initiative (“CPI”), FDA’s effort to modernize the scientific process through which a potential drug or device goes from “proof of concept” to a marketed medical product.  The CPI is an effort to optimize the scientific tests and tools used to determine whether a product is safe and effective.  One of the goals of the CPI is to streamline clinical trials, and the Adaptive Design and Non-Inferiority guidances are solid examples of FDA’s progress towards that objective.

Adaptive Design Guidance

The Adaptive Design draft guidance provides sponsors with information on those features of  adaptive designs that are valid, and discusses elements that may be problematic.  FDA defines an adaptive design clinical trial as one that “includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study.”  By allowing these modifications, a study may more efficiently provide information, increase the likelihood of successfully meeting a study objective, or improve the understanding of the drug’s treatment effect.  The guidance notes that such prospectively planned modifications can be submitted with the study protocol or in a statistical analysis plan (“SAP”).

Among the possible study design modifications, the guidance discusses study eligibility criteria, randomization procedure, total sample size, primary endpoints and secondary endpoints, and the methods used to analyze those endpoints.  The Agency explains that the adaptive design concept is best used in adequate and well-controlled studies and that study revisions should be based on blinded data.  A chief concern with adaptive design studies is the possibility of bias and false-positives.  To address these concerns, FDA recommends – among other things – that sponsors submit a written standard operating procedure (“SOP”), which defines who will conduct the interim analysis and implement the adaptation plan.  The Agency recommends using an independent entity for this purpose, such as a Data Monitoring Committee ("DMC"), to control access to unblinded data.

Because adaptive study designs may require more advanced planning by sponsors, the guidance document encourages sponsors to interact with the Agency during the planning stages of the clinical trials.  The timing and frequency of such meetings will vary based on the complexity of the study designs.

Non-Inferiority Clinical Trials Guidance 

The Non-Inferiority draft guidance explores FDA’s thinking on the use of non-inferiority study designs to provide evidence of a drug’s effectiveness.  This includes FDA’s thoughts on how best to choose an appropriate non-inferiority margin and how to analyze the results.  FDA explains that a non-inferiority trial seeks to demonstrate that “any difference between [ ] two treatments is small enough to allow a conclusion that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control.”  This is in contrast to the more common superiority trials, such as a placebo-controlled trial, which seek to prove a new drug is more effective than the control.  Non-inferiority trials are most often used when it would be unethical to use a placebo control. 

In addition to providing recommendations regarding study design and interpretation, the guidance provides answers to nine “commonly asked questions” regarding the estimation of margins, appropriate active control drugs, endpoints, and reliance on a single non-inferiority study to support effectiveness.  The guidance also discusses five examples derived from publicly available information that describe how to choose a non-inferiority margin, how to analyze the results, and other considerations relevant to the design and interpretation of non-inferiority studies.

Comments on both guidance documents are due June 1, 2010, and can be submitted to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, rm. 1060, Rockville, MD 20852 or electronically at http://www.regulations.gov.