1.3. Statistical support to clinical testing

Clinical testing is typically conducted in a staged fashion to explore the effect of pharmaceutical products on humans. The investigation starts with pharmacokinetic and pharmacodynamic studies, followed by proof-of-concept and dose-ranging studies. Some specialty studies such as drug effect on QT/QTc prolongation and drug-drug interactions studies are conducted at this early stage. The identification of Common adverse reactions and early signs of efficacy are the objectives of such trials. The early testings, if satisfactory, lead to the confirmatory phase where the efficacy and safety of the product candidate are more thoroughly investigated in a more heterogeneous population.

Despite common statistical principles, different stages of clinical testing focus on different statistical skill sets. For early proof-of-concept and dose-ranging efforts, study designs could be more flexible and the goal is to learn as efficiently and effectively as possible. Adaptations, in terms of dose allocation, early termination, and study population give great flexibility to such trials. Extensive modeling that incorporates accumulated learning on a real-time basis can lead a sponsor to decision points in a more expedited fashion. Because the purpose of this phase of development is primarily to generate information to aid internal decisions, the developers are freer to use innovative approaches as long as they can successfully defend the decisions that become the basis for later development.

By comparison, statistical approaches for the confirmatory phase need to be carefully pre-planned, pre-specified, and followed in order to give credibility to the results. A pharmaceutical sponsor needs to decide a priori study designs, primary endpoints, primary analysis population, success criterion, handling of missing data, multiple comparisons, plus many others. ICH E9 (1998) gives a very detailed description of all aspects of trial design and analysis that a statistician should consider at this stage. When adaptation is planned, the rule needs to be clearly specified in advance. When interim analysis is anticipated, a sponsor's access to the interim results needs to be tightly controlled.

The confirmatory phase is the place where knowledge about a new molecular or biologic entity is solidified to support a target label. The knowledge, along with the approved label, becomes the basis for recommendations to prescribing physicians and the medical community. The confirmatory trials are also the place where the risk-benefit and cost-effectiveness of a new pharmaceutical product are first delineated. The greater number of subjects studied at this stage gives a sponsor a decent chance to study adverse actions that have a rate between 0.1% and 1%. This phase overlaps somewhat with the life cycle management phase where new indications are being explored and drug differentiation is being sought. If there is a post-marketing study commitment, additional studies will be initiated to fulfill the conditions for approval.

Increasingly, statisticians are participating in promotion review and educational communications to the general public. In addition, many statisticians contribute to activities related to pharmacovigilance and epidemiology.