Statistical communications in infectious diseases最新文献

Four randomized placebo-controlled efficacy trials of a candidate vaccine or passively infused monoclonal antibody for prevention of HIV-1 infection are underway (HVTN 702 in South African men and women; HVTN 705 in sub-Saharan African women; HVTN 703/HPTN 081 in sub-Saharan African women; HVTN 704/HPTN 085 in U.S., Peruvian, Brazilian, and Swiss men or transgender persons who have sex with men). Several challenges are posed to the optimal design of the sequel efficacy trials, including: (1) how to account for the evolving mosaic of effective prevention interventions that may be part of the trial design or standard of prevention; (2) how to define viable and optimal sequel trial designs depending on the primary efficacy results and secondary "correlates of protection" results of each of the ongoing trials; and (3) how to define the primary objective of sequel efficacy trials if HIV-1 incidence is expected to be very low in all study arms such that a standard trial design has a steep opportunity cost. After summarizing the ongoing trials, I discuss statistical science considerations for sequel efficacy trial designs, both generally and specifically to each trial listed above. One conclusion is that the results of "correlates of protection" analyses, which ascertain how different host immunological markers and HIV-1 viral features impact HIV-1 risk and prevention efficacy, have an important influence on sequel trial design. This influence is especially relevant for the monoclonal antibody trials because of the focused pre-trial hypothesis that potency and coverage of serum neutralization constitutes a surrogate endpoint for HIV-1 infection. Another conclusion is that while assessing prevention efficacy against a counterfactual placebo group is fraught with risks for bias, such analysis is nonetheless important and study designs coupled with analysis methods should be developed to optimize such inferences. I draw a parallel with non-inferiority designs, which are fraught with risks given the necessity of making unverifiable assumptions for interpreting results, but nevertheless have been accepted when a superiority design is not possible and a rigorous/conservative non-inferiority margin is used. In a similar way, counterfactual placebo group efficacy analysis should use rigorous/conservative inference techniques that formally build in a rigorous/conservative margin to potential biases that could occur due to departures from unverifiable assumptions. Because reliability of this approach would require new techniques for verifying that the study cohort experienced substantial exposure to HIV-1, currently it may be appropriate as a secondary objective but not as a primary objective.

While much has been achieved, much remains to be accomplished in the science of preventing the spread of HIV infection. Clinical trials that are properly designed, conducted and analyzed are of integral importance in the pursuit of reliable insights about HIV prevention. As we build on previous scientific breakthroughs, there will be an increasing need for clinical trials to be designed to efficiently achieve insights without compromising their reliability and generalizability. Key design features should continue to include: 1) the use of randomization and evidence-based controls, 2) specifying the use of intention-to-treat analyses to preserve the integrity of randomization and to increase interpretability of results, 3) obtaining direct assessments of effects on clinical endpoints such as the risk of HIV infection, 4) using either superiority designs or non-inferiority designs with rigorous non-inferiority margins, and 5) enhancing generalizability through the choice of a relative risk rather than risk difference metric. When interventions have complementary and potentially synergistic effects, factorial designs should be considered to increase efficiency as well as to obtain clinically important insights about interaction and the contribution of component interventions to the efficacy and safety of combination regimens. Key trial conduct issues include timely enrollment of participants at high HIV risk recruited from populations with high viral burden, obtaining 'best real-world achievable' levels of adherence to the interventions being assessed and ensuring high levels of retention. High quality of trial conduct occurs through active rather than passive monitoring, using pre-specified targeted levels of performance with defined methods to achieve those targets. During trial conduct, active monitoring of the performance standards not only holds the trial leaders accountable but also can assist in the development and implementation of creative alternative approaches to increase the quality of trial conduct. Designing, conducting and analyzing HIV prevention trials with the quality needed to obtain reliable insights is an ethical as well as scientific imperative.