TABLE 36.

Types of controlled human challenge studies and their regulatory requirements^a

Study type and description	Examples of study objectives	Regulatory requirements in the United States	Regulatory requirements in the United Kingdom
Challenge study: a challenge strain of a pathogen is administered to healthy adult volunteers.	Establish dose-response curve for infection, time to onset of disease, range of disease symptoms, time to resolution of symptoms if no specific treatment is available, effect of prior natural exposure to the pathogen. Evaluate immune response to infection. Establish or optimize model.	Study must be conducted under an IND application that has been approved by the U.S. Food and Drug Administration. Challenge strains are ideally manufactured in compliance with GMP at a level similar to that required for a product to be studied in a phase 1 clinical trial. Once allowed to proceed, IND applications (or drug master files) for challenge strains may be cross-referenced in subsequent studies. In addition, the study must undergo review and approval by an IRB, or multiple IRBs if the study is to be conducted at multiple sites. Other review agencies may also have jurisdiction under certain circumstances (see Table 37).	Study does not require review by the MHRA if it does not involve a vaccine. The challenge strains do not necessarily need to meet GMP requirements. Review and approval by an IRB is a requirement, and by other agencies in select circumstances (see Table 37).
Rechallenge study: a challenge strain of a pathogen is administered to healthy adult volunteers previously challenged with the same strain or a heterologous strain.	Determine whether prior infection protects against reinfection with a homologous or heterologous strain of the pathogen. Identify breadth and/or correlates of protective immunity.	Same as for challenge study.	Same as for challenge study.
Vaccine trial using a challenge model: a candidate vaccine is administered to healthy adult volunteers that are later (or in some cases, previously) challenged with one or more strains of the pathogen against which the vaccine (or drugb) is directed.	Evaluate the capacity of a candidate vaccine to prevent infection, colonization/carriage, or transmission of the pathogen; or limit severity of or prevent disease symptoms. Compare different vaccine formulations and/or regimens for the immune responses elicited and level of protection. A candidate vaccine may be directly compared to a licensed vaccine that is suboptimal in some important respect.	Candidate vaccine must be administered under an approved IND application and must undergo ethical review and approval by the relevant IRB(s), in addition to the approvals for the challenge strain and study procedures as described above.	Candidate vaccine must be administered under an MHRA-approved application. The protocol must also undergo ethical review and approval by the relevant IRB(s).

^aIND, Investigational New Drug; GMP, Good Manufacturing Practice; IRB, institutional review board; MHRA, Medicines and Healthcare products Regulatory Agency.

^bThe fourth type of challenge study that might be conducted is one in which the challenge agent is used to infect trial subjects that are then treated with investigational drugs for the purposes of drug development. This type of study is not described here, as the focus is on vaccine development.