New FDA Guidance on “Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry” was just finalized. Apropos as it pertains to SPI-2012. Don’t have time to read the whole thing now but the Background was an interesting read:
BACKGROUND FDA’s regulations on adequate and well-controlled studies (21 CFR 314.126) describe four kinds of concurrently controlled trials that provide evidence of effectiveness. Three of them — placebo, no treatment, and dose-response controlled trials — are superiority trials that seek to show that a test drug is superior to the control (placebo, no treatment, or a lower dose of the test drug). The fourth kind, comparison with an active treatment (active control), can also be a superiority trial, if the intent is to show that the new drug is more effective than the control. More commonly, however, the goal of such studies is to show that the difference between the new and active control treatment is small — small enough to allow the known effectiveness of the active control, based on its performance in past studies and the assumed effectiveness of the active control in the current study, to support the conclusion that the new test drug is also effective. How to design and interpret the results of such studies so that they can support a conclusion about effectiveness of the new drug is challenging.
Active controlled trials that are not intended to show superiority of the test drug but rather to show that the new treatment is not inferior to an unacceptable extent were once called clinical equivalence trials. The intent of an NI trial, however, is not to show that the new drug is equivalent, but rather that it is not materially worse than the control. Therefore, the interest is one-sided. The new drug could be better than the control, and therefore at a minimum noninferior, but it would not be equivalent.
The critical difference between superiority and NI trials is that a properly designed and conducted superiority trial, if successful in showing a difference, is entirely interpretable without further assumptions (other than lack of bias) — that is, the result speaks for itself and requires no extra-study information. In contrast, the NI study is dependent on knowing something that is not measured in the study, namely, that the active control had its expected effect in the NI study. When this occurs, the trial is said to have assay sensitivity, defined as the ability to have shown a difference from placebo of a specified size. A “successful” NI trial, one that shows what appears to be an acceptably small difference between treatments, may or may not have had assay sensitivity and therefore may or may not support a conclusion that the test drug was effective. Thus, if the active control had no effect at all in the NI trial (i.e., did not have any of its expected effect), then even ruling out a very small difference between control and test drug is meaningless and provides no evidence that the test drug is effective. (See Section III.D. for further discussion on assay sensitivity.) In the absence of a placebo arm, knowing whether the trial had assay sensitivity relies heavily on external (not within-study) information, giving NI studies some of the characteristics of a historically controlled trial.
FDA regulations have recognized since 1985 the critical need to know, for an NI trial to be interpretable, that the active control had its expected effect in the trial. Thus, 21 CFR 314.126(a)(2)(iv), unchanged since 1985, says:
If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability of the study to have detected a difference between treatments. Similarity of test drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should be considered effective in the study, for example, by reference to results in previous placebo-controlled studies of the active control drug.
This guidance consists of four parts: • A general discussion of regulatory, study design, scientific, and statistical issues associated with the use of NI studies to establish the effectiveness of a new drug • A focus on some of these issues in more detail, notably the statistical approaches used to determine the NI margin and to test for non-inferiority • Commonly asked questions about NI studies • Four examples of successful and unsuccessful efforts to define NI margins and test for non-inferiority
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