A Cost/Benefit Analysis of Clinical Trial Designs for COVID-19 Vaccine Candidates

Abstract

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional randomized clinical trials and adaptive and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 504 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits---averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design---if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.

Exploring Risks of Human Challenge Trials for COVID-19

“…For example, “standard” phase 3 efficacy trials for an ongoing novel pandemic rely on high numbers of trial participants, and require this large sample for each vaccine or treatment that is trialled. Such trials are relatively expensive, and expose more trial participants to negative side effects of a given treatment, so that in many scenarios HCTs have been shown to be superior [4]. Standard trials are also difficult to pursue after an initial vaccine is available, and in the likely and hoped-for case that there will soon be at least one vaccine, finding willing participants for later and perhaps more effective vaccines, or ones with fewer side effects, is harder, and the burden of proof for benefit is far higher, or not achievable given plausible sample sizes, without an HCT.…”

“…For example, typical clinical phase 3 efficacy trials for an ongoing novel pandemic would be field trials, which rely on high numbers of trial participants, and require that a large number of people are treated with a new vaccine or drug. Such trials are relatively expensive and expose more trial participants to negative side effects of a given treatment, so that in many scenarios HCTs have been shown to be superior (Berry et al, 2020). These trials are also difficult to pursue now that an initial vaccine is available, due to ethical and logistical constraints.…”

A case for conducting business-to-business experiments with multi-arm multi-stage adaptive designs

“…Even prior to the completion of vaccine emergency use authorizations, a team of experts in the field of adaptive designs (Berry et al 2020) published a cost benefit analysis of traditional and adaptive randomized clinical trials for COVID-19 vaccine candidates. Their study compared the expected duration of the trials and the expected number of infections and deaths, and they concluded that adaptive versions of vaccine efficacy RCT designs based on group sequential methods would provide greater net benefits than traditional (fixed) RCT designs, such as accelerating licensure with the FDA by several months, and fewer infections and deaths.…”

Evidence–time dilemma in a pandemic with high mortality: Can outcome‐driven decision making on vaccines prevent deaths?

“…Further, adaptive designs with interim analyses without additional safety requirements allow for compassionate use of early access to vaccines and their potential benefits. 10 The proposed early access to vaccines for the high-risk subpopulation based on the ToE 9 contributes to a faster translation of basic science into life-saving vaccines. It demonstrates how well-known dilemmas in the classical clinical drug development and regulatory decision making framework can be addressed in the future, in the interest of public health, and, in particular, highrisk subpopulations.…”

“…However, options from the current regulatory science toolbox (e.g., early/managed access programs, simultaneous efficacy, and effectiveness trials), and quantitative methods for differentiated BRA and model‐informed regulatory decision making, carry additional potential. Further, adaptive designs with interim analyses without additional safety requirements allow for compassionate use of early access to vaccines and their potential benefits 10 . The proposed early access to vaccines for the high‐risk subpopulation based on the ToE 9 contributes to a faster translation of basic science into life‐saving vaccines.…”