Human challenge study

A human challenge study or human challenge trial is a type of clinical trial for a vaccine or other pharmaceutical involving the intentional exposure of the test subject to the condition tested.[1][2][3] Human challenge studies may be ethically controversial because they involve exposing test subjects to dangers beyond those posed by potential side effects of the substance being tested.[2][3]

During the 21st century, the number of human challenge studies was increasing.[4] A challenge study to test promising vaccines for prevention of COVID-19 disease is under consideration during 2020 by several vaccine developers, including the World Health Organization (WHO).[5][6]

Over the 20th and 21st centuries, vaccines for some 15 major pathogens have been fast-tracked in human challenge studies – involving about 30,000 participants who had no serious adverse effects – while contributing toward vaccine development to prevent cholera, typhoid, seasonal flu, and other infections.[7] According to medical ethicists, methods of conducting clinical trials by human challenge testing have improved over the 21st century to satisfy ethical, safety, and regulatory requirements, becoming scientifically acceptable and ethically valid as long as participants are well-informed and volunteer freely, and the trials adhere to established rigor for conducting clinical research.[2][3][7]

Design

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][8] 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][6]

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 COVID‑19 for comparison with a placebo control group.[2][3][6] 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][5]

Vaccines for viral infections

Challenge studies have been used to expedite evaluation of vaccines for several pandemic viral diseases,[3] such as cholera,[9] typhoid fever,[10] malaria,[11] and influenza.[1]

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.[11] 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.[11] 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.[11][12] 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.[11]

COVID-19
See also: COVID-19 vaccine § Controversy of proposed "challenge" studies

Human challenge studies are under consideration to hasten the development of a COVID-19 vaccine,[3][6] with a guidance document being issued by the WHO on criteria for conducting challenge clinical trials and providing clinical care for the participants.[5] Following the challenge infection with or without the candidate vaccine, volunteers would be monitored closely in hospitals or clinics managed by physicians treating people with COVID-19 disease and with life-saving resources, if needed.[2][3][5] Volunteering for a vaccine challenge study during the COVID‑19 pandemic is likened to the emergency service of healthcare personnel for COVID‑19-infected people, firefighters, or organ donors.[2][3]

One proposal for a human challenge study of COVID-19 vaccine candidates was made by bioethicist Nir Eyal,[2] and another by rubella vaccine inventor, Stanley Plotkin, with bioethicist Arthur Caplan.[12] These authors propose that the multi-year duration and multinational location of a typical Phase III efficacy clinical trial will continue as usual, while people infected with COVID-19 will continue to suffer or die.[12] As an alternative based on emerging results from COVID-19 vaccine challenge studies, regulatory agencies could allow early emergency use of the vaccine, while the challenge study continues collecting data for eventual licensure.[12]

References
  1. Lambkin-Williams, Rob; Noulin, Nicolas; Mann, Alex; Catchpole, Andrew; Gilbert, Anthony S. (2018-06-22). "The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics". Respiratory Research. 19 (1): 123. doi:10.1186/s12931-018-0784-1. ISSN 1465-993X. PMC 6013893. PMID 29929556.
  2. Eyal N, Lipsitch M, Smith PG (31 March 2020). "Human challenge studies to accelerate coronavirus vaccine licensure". The Journal of Infectious Diseases. 221 (11): 1752–1756. doi:10.1093/infdis/jiaa152. PMC 7184325. PMID 32232474.
  3. Callaway E (April 2020). "Should scientists infect healthy people with the coronavirus to test vaccines?". Nature. 580 (7801): 17. doi:10.1038/d41586-020-00927-3. PMID 32218549.
  4. Cohen, Jon (2016-05-18). "Studies that intentionally infect people with disease-causing bugs are on the rise". Science. doi:10.1126/science.aaf5726.
  5. "Key criteria for the ethical acceptability of COVID-19 human challenge studies" (PDF). World Health Organization. 2020-05-06. Retrieved 2020-05-18.
  6. Cohen, Jon (31 March 2020). "Speed coronavirus vaccine testing by deliberately infecting volunteers? Not so fast, some scientists warn". Science. doi:10.1126/science.abc0006. Retrieved 19 April 2020.
  7. Wade Hemsworth (2020-05-13). "McMaster researcher contributes to WHO guidelines for COVID-19 vaccine testing". McMaster University Medical School, Hamilton, Canada. Retrieved 2020-05-25.
  8. Eric Boodman (13 March 2020). "Coronavirus vaccine clinical trial starting without usual animal data". STAT. Retrieved 19 April 2020.
  9. D, Sinclair; K, Abba; K, Zaman; F, Qadri; PM, Graves (2011-03-16). "Oral vaccines for preventing cholera". The Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD008603.pub2. PMC 6532691. PMID 21412922.
  10. Waddington, Claire S.; Darton, Thomas C.; Woodward, William E.; Angus, Brian; Levine, Myron M.; Pollard, Andrew J. (2014-05-01). "Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies". Journal of Infection. 68 (5): 405–418. doi:10.1016/j.jinf.2014.01.006. ISSN 0163-4453. PMID 24491597.
  11. J, Tuju; G, Kamuyu; Lm, Murungi; Fha, Osier (2017-10-01). "Vaccine candidate discovery for the next generation of malaria vaccines". Immunology. doi:10.1111/imm.12780. PMC 5588761. PMID 28646586.
  12. Plotkin, Stanley A.; Caplan, Arthur (April 20, 2020). "Extraordinary diseases require extraordinary solutions". Vaccine. 38 (24): 3987–8. doi:10.1016/j.vaccine.2020.04.039. PMC 7167540. PMID 32331807.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.