19.4  Adaptive Trial Design

The Office of Biostatistics and the Office of New Drugs in CDER in conjunction with CBER released a Draft Guidance document on “Adaptive Design Clinical Trials for Drugs and Biologics” in February 2010 that clearly underscores the growing interest and push towards adaptive design clinical trials to make the studies more efficient and more informative. The Draft Guidance defines an adaptive design clinical study as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on the analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating data are performed at prospectively planned timepoints within the study, can be performed in a fully blinded manner or unblinded manner, and can occur with or without formal statistical hypotheses testing. In other words, adaptive clinical trials will empower the sponsors and investigators to change the design or analyses of clinical trials based on insights obtained by examination of the accumulated data at an interim point in the trial. Since this is a relatively new concept, the greatest interest in this approach has been in the adequate and well-controlled studies intended to support marketing a drug. It is always in the best interest of the sponsor to plan the adaptation in advance (being prospective) and discuss the details of this adaptation with the FDA in order to avoid any potential complications that may affect the validity of the interim analysis, the changes implemented the following interim analysis or the integrity of the entire clinical study itself. It would be devastating if the entire study is deemed invalid due to issues such as introduction of bias based on an unplanned action by the sponsor.

Adaptive Design clinical trials offer some key advantages over the conventional design clinical trials. Planning a well-designed study to support market registration of a drug requires adequate knowledge on a variety of parameters such as event rates, variance, discontinuation rates, etc., and these are generally incorporated in a conventional design clinical trial as assumptions or “best estimates.” If these assumptions are incorrect, the study may fail to achieve its goal. Therefore to increase the likelihood of success, the study may be designed with higher number of patients or duration resulting in increased cost and time. Additionally, it may also lead to instances where the patients in the suboptimal dose group continue to get dosed for the entire duration of the study providing no meaningful data and therefore increasing the cost of the study and reducing the overall efficiency. An adaptive design clinical trial takes this into account and eliminates some of these issues by including an interim analysis at predetermined timepoints. Following interim analysis of the dose response or other parameters, a decision can be made on whether the suboptimal dose group should continue to be dosed or discontinued (will dosing this group provide any additional value). Discontinuation may lead to a decrease in cost and time of the study without reducing the informativeness. This can lead to efficient allocation of resources and potentially the collection of more data on more parameters than would be possible with the conventional design.

Even though interactions by the sponsor with the FDA are commonplace during the course of a drug development program, these become even more crucial when

the sponsor decides to use an adaptive design for conducting a clinical trial. Due to the increased complexity of the adaptive design, it is important that the sponsor has earlier and more extensive interactions with the FDA. If the study is an exploratory study, the FDA will focus upon the safety of the study participants and will consider the relevance of the parameters being examined (dose response, endpoints, biomarkers, etc.) to guide the design of later studies. The efficacy measurements are outside the realm of this review and will be focused on during the late stages of drug development. The assessment of the adaptive design features by the FDA gets more extensive during the late stages of drug development. This review still focuses on the safety of study participants and now includes evaluation of the assessment of safety and efficacy to ensure that the study data will be of sufficient quality and quantity to inform a regulatory decision. It is important to note that the FDA will generally not be involved in examining the interim data used for the adaptive decision making and will not provide comments on the adaptive decision while the study is ongoing. In addition, the acceptance of adaptive design at the protocol design stage does not imply its advance concurrence that the adaptively selected choices will be optimal choices. An overview of the regulatory mechanisms for obtaining formal approval, substantive, feedback from FDA on design of the later stage trials and their place in drug development program are described in the Sect. 19.3 of this chapter.

19.5  Drug-Device Combinations

Since local delivery of the drug to the posterior segment of the eye typically requires intraocular injections, devices such as needles and syringes play a prominent role in facilitating such delivery. As a result, the new therapeutic products may not be classified exclusively as a drug or device but rather a “combination” product. OZURDEX™, a dexamethasone biodegradable Intravitreal implant marketed by Allergan Inc, is one such example of a combination product. The drug product is a rod-shaped intravitreal implant that comes preloaded into a standard 22-G thin wall hypodermic needle of a single-use applicator that delivers the implant directly to the posterior segment of the eye. CDER, CBER, and the Center for Devices and Radiological Health (CDRH) have entered into agreements clarifying the product jurisdictional issues per Part 3 of Title 21 of the Code of Federal Regulations (Product Jurisdiction). The sponsor of the drug application (IND, NDA, or any other premarket or investigational application) needs to contact the appropriate center in the agency to confirm coverage and discuss the application process. Even though the application is made to a single center in the agency, it does not preclude the center from requesting assistance from the other centers to evaluate the appropriate parts of the application, as needed.

According to 21 CFR Part 3, the primary mode of action of the product needs to be clarified in order to determine which center will take the lead role in reviewing the premarket application. Here are some examples:

1. If the primary mode of action of the product is that of a drug (other than biological products), then CDER will have primary jurisdiction for the application