1. Adaptive trial designs in HIV vaccine clinical trials Morenike Ukpong Obafemi Awolowo University Ile-Ife, Nigeria

2. The need for ACTD Adaptive clinical trial design (ACTD) are meant to be used to accelerate the pace of discovery in products in clinical trial including HIV vaccine trials. The trial involves the use of multi-arm trials that compares multiple concepts. The design increases the likelihood of identifying those concepts with potentially higher efficacy more quickly.

3. What is ACTD? A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned time points within the study, can be performed in a fully blinded manner or in an un-blinded manner, and can occur with or without formal statistical hypothesis testing.

4. ACTD and HIV Vaccine Research Participants recognised that ACTD allows investigators to learn from accumulating trial data and make changes as necessary to increase the chances of a successful outcome. It can accelerate discovery through the concurrent testing of multiple concepts in multi-arm comparative trials with the goal of removing inferior concepts early in the development process so that resources can be shifted to more promising candidates. It could also advance understanding of the immune correlates of protection as well as provide safer trial experiences for participants.

5. How does it differ from standard CT practices? Researchers do routinely modify clinical studies during the course of the studies via “Protocol Amendment” or “Protocol Modification.” Modification in clinical trials may include administrative changes, early trial termination, addition/removal of treatment arms, changes in trial sample population size, and treatment arm allocation regimen.

6. How do they differ - 2 Conventional clinical trial designs often use fixed or pre-determined sample sizes that do not use adaptive elements. Amendments of sample size are allowed to be made after the commencement of a study for safety reasons if they do not impact the integrity of the data collected or statistically alter the initial statistical design or hypothesis of the study. With ACTD, changes are anticipated and planned before the study commences and adjusted accordingly.

7. How do they differ - 3 This means that unlike with conventional designs in which data is analysed at the end of the study, with ACTD, data is analysed at pre-defined periods while the study is in progress. This allows for modification of ongoing trials if necessary based on the result of the data analysis. The study design amendment however should not undermine the validity and integrity of the study.

8. Advantages Allow studies to be operated more efficiently and provides the same information. Increases the likelihood of success on the study objective. Yields improved understanding of the treatment’s effect (e.g., better estimates of the dose-response relationship or subgroup effects, which may also lead to more efficient subsequent studies).

9. Advantages - 2 In terms of cost, the initially invested cost is much more than what is invested in conventional designs. However, the overall cost of getting a trial to produce conclusive evidence may be cheaper as the adaptive design allows for real time study modification so as to prevent outright loss of invested resources in failed trials.

10. Why the need for ACTD? The primary reason for this phenomenon is due to the increasing cost of operating clinical trials. For biomedical HIV prevention research, the design is apt due to the high failure rates of these clinical trials. It has many advantages to facilitate the effectiveness of clinical trial operations. However, as a relatively new methodology, it does have its challenges as well.

11. Features Adaptive features are incorporated into one or more phases of the existing conventional trial framework and as such do not represent a novel phase or stand- alone alternative to conventional trials. They however, in certain cases, could facilitate the merging of two phases (e.g. seamless phase II/III studies).

12. Features - 2 Adaptive trial design requires extensive pre- planning as well as early and frequent consultation with regulatory agencies. Early regulatory agents engagement ensure that regulatory issues that may lead to product licensure are taken into account in the design of the trial Communication to participants and others is expected to provide a challenge.

13. Caution The advantages, however, need to be cautiously weighed with the increase likelihood of introducing study bias with a poorly designed or poorly implemented adaptive methodology. This is a major disadvantage and concern that is shared by regulatory authorities, drug developers, and the end users.

14. Conclusion As we make progress with planning for the implementation of HIV vaccine clinical trials, we should expect to see more of these adaptive trial designs. They are complex studies and for communities who plan to actively engage with trials, you need to get to start to understand the science now. HIV vaccine studies in Africa needs to continue as this is main future of HIV infection prevention.

15. References Jason Montez. WHO/UNAIDS/IAVI/the Enterprise expert group consultation on ‘Adaptive Trial Design for HIV Vaccine Clinical Trials: Opportunities and Challenges’ Meeting report. 2011 Adaptive Clinical Trial Design parts I, II, III. NHVMAS listserv postings - 2011