Human challenge study

The intent of a challenge study is to fast-track the timeline for providing evidence of safety and efficacy of a therapeutic drug or vaccine, especially by compressing (to a few months) the usually lengthy duration of Phase II–III trials (typically, many years).[2][3][10] Following preliminary proof of safety and efficacy of a candidate drug or vaccine in laboratory animals and healthy humans, controlled "challenge" studies may be implemented to bypass typical Phase III research, providing an accelerated path to regulatory approval of the test compound for widespread prevention against an infectious disease, such as COVID‑19.[2][7]

The design of a challenge study involves first, simultaneously testing a vaccine candidate for immunogenicity and safety in laboratory animals and healthy adult volunteers (100 or fewer) – which is usually a sequential process using animals first – and second, rapidly advancing its effective dose into a large-scale Phase II–III trial in low-risk, healthy volunteers (such as young adults), who would then be deliberately infected with the disease being tested against for comparison with a placebo control group.[2][3][7] In a challenge study for a vaccine to prevent an infectious disease, participants would be closely monitored for signs of toxicity and adequate immune response, such as by producing substantial levels of antibodies against the virus causing the disease.[2][3][6]

Awareness of the history of challenge trials is indispensable, including trials that were problematic or even connected to abuse.[11] Special ethical issues can arise when a wealthy country finances and organizes these clinical trials in a less wealthy country.[12]

Two commonly discussed general thresholds for risk to research participant are minimizing all risk after the infection and avoiding serious injury.[13] Researchers typically customize other thresholds for each clinical trial.[13]

Challenge studies have been used to expedite evaluation of vaccines for several diseases,[3] such as cholera,[14] typhoid fever,[15] malaria,[16] influenza,[1] streptococcal pharyngitis,[17] tuberculosis,[18] shigella,[19] pertussis,[20] and dengue fever.[21]

Other than expediting clinical evaluation of vaccine properties, advantages of using challenge studies for vaccine candidates include minimizing bias which is inherently part of traditional cohort studies, as both the exposure (timing of infection, virus challenge dose) and outcome (assessment of blood biomarkers) are standardized.[16] Disadvantages include high cost of conducting the trial at multiple locations and the complex management of infrastructure for a challenge trial, especially for obtaining national regulatory approval, organizing participants and trial personnel, and implementing laboratories with Good Clinical Laboratory Practice qualifications.[16] Before beginning a challenge study, a vaccine sponsor must have demonstrated Good Manufacturing Practice standards for approval to use the candidate vaccine in humans, including expensive toxicology and immunogenicity testing.[16][22] The vaccine sponsor may have required proof of safety and efficacy of adjuvants for delivering the vaccine, demonstrated what the effective vaccination schedule may be, and coordinated with international regulatory agencies and bioethicists for approval and eventual distribution, all requiring coordinated financing and planning.[16]

• Callaway, Ewen (22 April 2020). "Hundreds of people volunteer to be infected with coronavirus". Nature. doi:10.1038/d41586-020-01179-x. PMID 32322034. S2CID 216082569.
• Let volunteers take the COVID challenge: Young, healthy, informed people should be allowed to participate in vaccine trials. Conor Friedersdorf, The Atlantic, 21 April 2020
• 1 Day Sooner, US-UK advocacy organization for human challenge studies of candidate COVID-19 vaccines (25,104 volunteers from 102 countries, as of late May 2020)