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FDA has issued two new draft guidance documents regarding clinical trial designs: Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics, and Guidance for Industry: Non-inferiority Clinical Trials.

Adaptive Design Guidance: This draft guidance is designed to provide sponsors and the review staff in both the drugs and biologics divisions with information regarding adaptive design clinical trials when used in drug development programmes, including aspects of adaptive design clinical trials that deserve special consideration and how a sponsor should interact with FDA while planning and conducting such a study.

An "adaptive" design has been described as a clinical study design that allows users to adapt or modify a trial during its progress based on examination of the accumulated data at an interim point without affecting the validity and integrity of the trial.

The FDA defines an adaptive clinical trial design 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 modifications, the FDA states, there is the possibility that one can make the study more efficient (eg, shorter duration, fewer patients), or have the study be more likely to demonstrate an effect of the drug if one exists, or be more informative (eg, by providing broader dose-response information). The regulator adds, "FDA shares the interest of drug developers in these advantages, but is also concerned with several aspects of such approaches, notably the possible introduction of bias and the increased possibility of an incorrect conclusion."

The guidance notes that such prospectively planned modifications can be submitted with the written study protocol, or in a statistical analytic plan, if used.

The FDA has invited comments on some recommended reporting requirements. It has stated that, in the drug development process, it is important to protect study blinding of an adaptive design study. To this end, it recommends that, where the design is modified after examination of unblinded interim data, and to avoid the introduction of bias (and to maintain confidence in the validity of the study's result), sponsors include in the adaptive design protocol written standard operating procedures (SOPs) that define who will implement the interim analyses and adaptation plan, and all monitoring and related procedures to accomplish the plan, providing for strict control of access to unblinded data. Other information to be included in the SOPs: who would perform the interim analyses and would have access to unblinded data; how compliance with SOPs would be documented; and what information, and under what circumstances, would be permitted to be passed from the Data Monitoring Committee to the sponsor or investigators.

In one part of the guidance document, it is stated: "Adaptive design studies may work best, and with least risk, when there truly are just a few issues (eg, dose, population subsets, endpoints) that need to be examined and are built into an adaptive design."

The document also states: "The greatest interest in adaptive design clinical trials has been in the adequate and well-controlled setting intended to support marketing a drug. Because these studies have the greatest regulatory impact, this guidance is generally oriented toward the use of adaptive design methods in adequate and well-controlled studies, where avoiding rates of false positive study results (increased Type 1 error rate) is critical, and introducing bias should be minimised. Many adaptive methods, however, are also applicable to exploratory studies. This guidance encourages sponsors to gain experience with the less well-understood methods in the exploratory study setting."

According to the guidance, the range of possible study design modifications is described as "broad". The guidance includes both familiar and less familiar approaches in the use of such adaptive designs – as the regulators state that "the less familiar design methods incorporate methodological features with which there is little experience in drug development at this time." Early interaction with the FDA is encouraged on any adaptive design.

Non-Inferiority Clinical Trials Guidance: This guidance provides the FDA's view of how a sponsor can use non-inferiority study design to provide evidence of a drug's effectiveness. This includes the agency's advice on how a sponsor can choose an appropriate non-inferiority margin and how to analyse the results. As stated by the agency in the guidance, a non-inferiority trial compares two treatments and seeks to demonstrate that "any difference [between the 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." (These trials contrast with the more common superiority trials, specifically a placebo-controlled trial, where the intent is to show that the new drug is more effective than the control.)

The guidance states: "The usual reason for using a non-inferiority active control design instead of a study design having more readily interpretable results (ie, a superiority trial), is an ethical one. Specifically, this design is chosen when it would not be ethical to use a placebo, or a no-treatment control, or a very low dose of an active drug, because there is an effective treatment that provides an important benefit (eg, life-saving or preventing irreversible injury) available to patients for the condition to be studied in the trial."

Part of the guidance includes five examples of successful and unsuccessful efforts to define non-inferiority margins and conduct non-inferiority studies.