Consideration of Operational a Level with Different Approval Strategies
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Consideration of Operational a Level With Different Approval Strategies*
Boguong Andy Zhen, PhD Statistical Team Leader
BTSS/oB/oPaSS/ Cr)ER/Fr)A
.
-.. .-. . Silver Spring. Maryland _I
It has been the position of the Food and Drug Administration to require at least two adeqate and well-controlled studies, each convincing on its own, to establish effectiveness. Under some specific Circumstances, a sponsor may propose to conduct a single trial first and then may be willing or may be asked to start the second trial only if the positive results fiom the first trial are not striking. If using different strategies regarding how to launch clinical trials for approval in a drug development program, the operational a level (maximum
Key Words Clinical trials; “Two-trial rule”; Operational a level; Approval st ra t egies
Correspondente Address Boguang Zhen. PhD, BTSS/OB/OPaSS/ CDER/FDA. 10903 New Hampshire Avenue, Room 1210, Building 22. Silver Spring. MD 20993. ‘The views expressed in this article are those of the author and not necessarily those 0)” the US Food and Drug Administration.
INTRODUCTION Therapeutic agent sponsors often raise the questions to the Food and Drug Administration (FDA) regarding how many trials are required for supporting a licensure application. The requirement is that the results should be both demonstrable and repeatable. The Agency, in general, requires that at least two adequate and well-controlled trials should be conducted to demonstrate efficacy. The “Guidance for Industry-Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products” (1) explicitly says, “With regard to quantity, it has been FDA’s position that Congress generally intended to require at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness.” Senn (2) called it “the two-trial rule.” Nevertheless, FDA has been flexible within the limits of the congressional scheme. Under some specific circumstances, a sponsor may propose to conduct a single trial for a licensure application. Regarding the use of a single large trial instead of two similar trials for a licensure application, Senn (2) commented “They produce two trials which are so similar.. . there is no argument against simply running a larger trial and requiring that the results be signifi-
chance of approving an ineffective drug) may not be controlled at the same level. This article presents a method to calculate the operational Q level for different strategies and shows that the a level under certain strategies may be inflated compared to the one based on “the twotrial rule. ” This method also permits examination of the effect on the operational a level if different strategies oftesting are invoked. It is suggested that consideration of the operational a level should be taken into account when selecting different approval strategies.
cant at the 1/1600 level one-sided.” Fisher (3) proposed that the significance level for such a single study should be at .00125 instead of .05 based on the fac
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