Unblinding design

It is typical before conducting a post-marketing surveillance study to obtain the view of the regulatory authorities on its design. The study may have been a condition of product approval, and it is both reasonable and wise to ensure that the study design can be expected to provide the information that is needed both by the sponsor and the regulators. Unblinded designs that imitate the ordinary clinical situation are the norm. 

The phase-three results were unblinded in March 2003 and overall, for all types of metastatic brain cancer, were reported as nonpositive, showing the drug to have efficacy but not at the statistical level set at the beginning of the trial by Alios Therapeutics Inc. for a successful phase-three trial. The subset analysis for the different types of metastatic cancer to brain, however, showed that breast cancer patients had a 100% increase in survival. The 500 plus patient trial also demonstrated RSR 13 to be extremely safe, confirming our early design feature of using a known antilipidemic drug, clofibrate, as a substructure. An NDA for RSR 13 with trade name efaproxaril was reviewed by the PDA on a fast track review for use in treatment of metastases of breast cancer to brain. 

What can be allowed in relation to adapting the trial design based on unblinded data ... 

Phase III studies include the same type of blinded, randomized, controlled studies performed in Phase II, but in larger patient populations to provide statistical power to reject the null hypothesis of no treatment effect. The results of these pivotal trials are the primary factor determining the regulatory fate of the drug candidate. During Phase III, unblinded safety studies may also be conducted. These studies ensure that a sufficient number of patients are tested so that rare adverse events can be detected. Specific aspects of study design will depend on the drug, proposed patient population, and indication. 

More recently, there has been interest in adaptive designs where the sample size and number of events are increased based on an unblinded look at interim analysis results. For example, a trial might be initially sized based on the number of MACE outcomes needed to demonstrate noninferiority however, if superiority appears likely based on the conditional power available at the time of an interim analysis, the number of needed MACE outcomes and the sample size could be increased. Such adaptive designs require special statistical analyses to protect the alpha level and special provisions to minimize operational bias (FDA 2010). This approach reduces the risks to participants (and to the sponsor) associated with initiating a large superiority trial up-front, when there is limited information about the compound. 

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