Effective HIV prevention has the potential to change the landscape of HIV prevention trials. Low infection rates will make superiority studies necessarily large while non-inferiority trials will need some evidence that a counterfactual placebo group had a meaningful HIV infection rate in order to provide evidence of effective interventions. This paper explores these challenges in the context of immune related interventions of mAbs and vaccines. We discuss the issue of effect modification in the presence of PrEP, where subjects on PrEP may have less of a benefit of a mAb or (vaccine) than subjects off PrEP. We also discuss different methods of placebo infection rate imputation. We estimate infection risk as a function of mAb level (or vaccine induced immune response) in the mAb (or vaccine) arm and then extrapolate this infection risk to zero mAbs as a proxy for the placebo infection rate. Important aspects are the use of triangulation or multiple methods to impute the placebo infection rate, concern about extrapolation if few mAbs are close to zero, and the use of currently available data with placebo groups to rigorously evaluate the accuracy of imputation methods. We also discuss use of historical controls and some generalizations of the idea of (DMurray, J. 2019. “Regulatory Perspectives for Streamlining HIV Prevention Trials.” Statistical Communications in Infectious Diseases.) to use rectal gonorrhea rates to impute HIV infection rate. Generalizations include regression adjustment to calibrate for potential differences in baseline covariates for ongoing vs historical studies and the use of the gonorrhea, HIV relationship in a contemporaneous observational study. Examples of recent and ongoing trials of malaria chemoprophylaxis and HPV vaccines, where extremely effect prevention methods are available, are provided.
I would like to thank Dave Glidden for helpful discussion, Jeff Murray for allowing me to use his data, and Holly Janes for her encouragement and dedication.
Brittain, E., and J. Wittes. 1989. “Factorial Designs in Clinical Trials: The Effects of Non-Compliance and Subadditivity.” Statistics in Medicine 8 (2): 161–71.270489810.1002/sim.4780080204Search in Google Scholar
DMurray, J. 2019. “Regulatory Perspectives for Streamlining HIV Prevention Trials.” Statistical Communications in Infectious Diseases.Search in Google Scholar
Dow, G. S., W. F. McCarthy, M. Reid, B. Smith, D. Tang, and G. D. Shanks. 2014. “A Retrospective Analysis of the Protective Efficacy of Tafenoquine and Mefloquine as Prophylactic Anti-Malarials in Non-Immune Individuals During Deployment to a Malaria-Endemic Area.” Malaria Journal 13 (1): 49.2450267910.1186/1475-2875-13-49Search in Google Scholar
Fay, M. P., D. A. Follmann, F. Lynn, J. M. Schiffer, G. V. Stark, R. Kohberger, C. P. Quinn, and E. O. Nuzum. 2012. “Anthrax Vaccine–Induced Antibodies Provide Cross-Species Prediction of Survival to Aerosol Challenge.” Science Translational Medicine 4 (151): 151ra126–51ra126.Search in Google Scholar
FDA. 2016. Guidance for INDUSTRY: Non-inferiority Clinical Trials To Establish Effectiveness. .Search in Google Scholar
FDA. 2018. FDA Antimicrobial Drugs Advisory Committee Meeting July 2018.Search in Google Scholar
Fonner, V. A., S. L. Dalglish, C. E. Kennedy, R. Baggaley, K. R. O’Reilly, F. M. Koechlin, M. Rodolph, I. Hodges-Mameletzis, and R. M. Grant. 2016. “Effectiveness and Safety of Oral HIV Preexposure Prophylaxis for all Populations.” AIDS (London, England) 30 (12): 1973.Search in Google Scholar
Moon, J. E., G. A. Deye, L. Miller, S. Fracisco, R. S. Miller, D. Tosh, J. F. Cummings, C. Ohrt, and A. J. Magill. 2011. “Plasmodium Falciparum Infection During Suppressive Prophylaxis with Mefloquine does not Induce an Antibody Response to Merozoite Surface Protein-1 (42).” The American Journal of Tropical Medicine and Hygiene 84 (5): 825–29.10.4269/ajtmh.2011.10-069921540397Search in Google Scholar
Sampson, J. N., A. Hildesheim, R. Herrero, P. Gonzalez, A. R. Kreimer, and M. H. Gail. 2018. “Design and Statistical Considerations for Studies Evaluating the Efficacy of a Single dose of the Human Papillomavirus (HPV) Vaccine.” Contemporary Clinical Trials 68: 35–44.10.1016/j.cct.2018.02.01029474934Search in Google Scholar
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