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Human challenge study

October 21, 2023

A human challenge study, also called a challenge trial or controlled human infection model (CHIM), 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 mid 20th and 21st century, the number of human challenge studies has been increasing.[4][5] A challenge study to test promising vaccines for prevention of COVID-19 was under consideration during 2020 by several vaccine developers, including the World Health Organization (WHO),[6][7] and was approved in the UK in 2021.[8]

Over the second half of the 20th and the 21st centuries, vaccines for some 15 major pathogens have been fast-tracked in human challenge studies – involving about 30,000 participants – while contributing toward vaccine development to prevent cholera, typhoid, seasonal flu, and other infections.[9] Since the 1980s, challenge trials which reported about adverse events have had only 0.2% of patients with serious adverse events.[4] 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][9]

Design Edit

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]

Ethics Edit

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]

Vaccines for infections Edit

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]

COVID-19 Edit

See also: COVID-19 vaccine clinical research § Trial and authorization status

Human challenge studies are under consideration to hasten the development of a COVID-19 vaccine,[3][7][23] including one proposal made by bioethicist Nir Eyal,[2] and another by rubella vaccine inventor Stanley Plotkin with bioethicist Arthur Caplan.[22] 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.[22] 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.[22]

In May 2020, a guidance document was issued by the WHO on criteria for conducting challenge clinical trials and providing clinical care for the participants.[6] 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][6] 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]

References Edit

  1. ^ a b Lambkin-Williams, Rob; Noulin, Nicolas; Mann, Alex; Catchpole, Andrew; Gilbert, Anthony S. (22 June 2018). "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. ^ a b c d e f g h i j 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. ^ a b c d e f g h i j Callaway E (April 2020). "Should scientists infect healthy people with the coronavirus to test vaccines?". Nature. 580 (7801): 17. Bibcode:2020Natur.580...17C. doi:10.1038/d41586-020-00927-3. PMID 32218549. S2CID 256820005.
  4. ^ a b Adams-Phipps, Jupiter; Toomey, Danny; Więcek, Witold; Schmit, Virginia; Wilkinson, James; Scholl, Keller; Jamrozik, Joshua; Roestenberg, Meta; Manheim, David (11 October 2022). "A Systematic Review of Human Challenge Trials, Designs, and Safety". Clinical Infectious Diseases. 76 (4): 609–619. doi:10.1093/cid/ciac820. PMC 9938741. PMID 36219704.
  5. ^ Cohen, Jon (18 May 2016). "Studies that intentionally infect people with disease-causing bugs are on the rise". Science. 352 (6288): 882–885. doi:10.1126/science.aaf5726.
  6. ^ a b c d "Key criteria for the ethical acceptability of COVID-19 human challenge studies" (PDF). World Health Organization. 6 May 2020. Retrieved 18 May 2020.
  7. ^ a b c d 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. S2CID 216451224. Retrieved 19 April 2020.
  8. ^ "World's first coronavirus Human Challenge study receives ethics approval in the UK". GOV.UK. Retrieved 18 February 2021.
  9. ^ a b Wade Hemsworth (13 May 2020). "McMaster researcher contributes to WHO guidelines for COVID-19 vaccine testing". McMaster University Medical School, Hamilton, Canada. Retrieved 25 May 2020.
  10. ^ Eric Boodman (13 March 2020). "Coronavirus vaccine clinical trial starting without usual animal data". STAT. Retrieved 19 April 2020.
  11. ^ Metzger, W. G.; Ehni, H.-J.; Kremsner, P. G.; Mordmüller, B. G. (2019). "Experimental infections in humans—historical and ethical reflections". Tropical Medicine & International Health. 24 (12): 1384–1390. doi:10.1111/tmi.13320. ISSN 1365-3156. PMID 31654450.
  12. ^ Gordon, SB; Rylance, J; Luck, A; Jambo, K; Ferreira, DM; Manda-Taylor, L; Bejon, P; Ngwira, B; Littler, K; Seager, Z; Gibani, M; Gmeiner, M; Roestenberg, M; Mlombe, Y; Wellcome Trust CHIM workshop, participants. (2017). "A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi". Wellcome Open Research. 2: 70. doi:10.12688/wellcomeopenres.12256.1. PMC 5627502. PMID 29018841.
  13. ^ a b Binik, Ariella (May 2020). "What risks should be permissible in controlled human infection model studies?". Bioethics. 34 (4): 420–430. doi:10.1111/bioe.12736. PMID 32115747. S2CID 211727412.
  14. ^ D, Sinclair; K, Abba; K, Zaman; F, Qadri; PM, Graves (16 March 2011). "Oral vaccines for preventing cholera". The Cochrane Database of Systematic Reviews. 2011 (3): CD008603. doi:10.1002/14651858.CD008603.pub2. PMC 6532691. PMID 21412922.
  15. ^ Waddington, Claire S.; Darton, Thomas C.; Woodward, William E.; Angus, Brian; Levine, Myron M.; Pollard, Andrew J. (1 May 2014). "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.
  16. ^ a b c d e J, Tuju; G, Kamuyu; Lm, Murungi; Fha, Osier (1 October 2017). "Vaccine candidate discovery for the next generation of malaria vaccines". Immunology. 152 (2): 195–206. doi:10.1111/imm.12780. PMC 5588761. PMID 28646586.
  17. ^ Osowicki, Joshua; Azzopardi, Kristy I.; McIntyre, Liam; Rivera-Hernandez, Tania; Ong, Cheryl-lynn Y.; Baker, Ciara; Gillen, Christine M.; Walker, Mark J.; Smeesters, Pierre R.; Davies, Mark R.; Steer, Andrew C. (13 February 2019). "A Controlled Human Infection Model of Group A Streptococcus Pharyngitis: Which Strain and Why?". mSphere. 4 (1): e00647–18, /msphere/4/1/mSphere647–18.atom. doi:10.1128/mSphere.00647-18. PMC 6374595. PMID 30760615.
  18. ^ McShane, Helen (15 May 2020). "Controlled Human Infection Models: Is it Really Feasible to Give People Tuberculosis?". American Journal of Respiratory and Critical Care Medicine. 201 (10): 1180–1181. doi:10.1164/rccm.201912-2408ED. PMC 7233336. PMID 31904993. S2CID 210041310.
  19. ^ MacLennan, Calman A; Aguilar, Anastazia Older; Steele, A Duncan (9 December 2019). "Consensus Report on Shigella Controlled Human Infection Model: Introduction and Overview". Clinical Infectious Diseases. 69 (Supplement_8): S577–S579. doi:10.1093/cid/ciz886. PMC 6901124. PMID 31816066.
  20. ^ Merkel, Tod J (11 July 2020). "Toward a Controlled Human Infection Model of Pertussis". Clinical Infectious Diseases. 71 (2): 412–414. doi:10.1093/cid/ciz842. PMC 7353834. PMID 31552410.
  21. ^ Rose, Anuradha; Sekhar, Amrita (July 2019). "Bioethics of establishing a CHIM model for dengue vaccine development". International Journal of Infectious Diseases. 84: S74–S79. doi:10.1016/j.ijid.2019.01.013. PMID 30641207.
  22. ^ a b c d Plotkin, Stanley A.; Caplan, Arthur (20 April 2020). "Extraordinary diseases require extraordinary solutions". Vaccine. 38 (24): 3987–8. doi:10.1016/j.vaccine.2020.04.039. PMC 7167540. PMID 32331807.
  23. ^ "UK plan to be first to run human challenge Covid trials". BBC News. 20 October 2020.

External links Edit

  • 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)

October 21, 2023
human, challenge, study, human, challenge, study, also, called, challenge, trial, controlled, human, infection, model, chim, type, clinical, trial, vaccine, other, pharmaceutical, involving, intentional, exposure, test, subject, condition, tested, human, chall. A human challenge study also called a challenge trial or controlled human infection model CHIM 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 mid 20th and 21st century the number of human challenge studies has been increasing 4 5 A challenge study to test promising vaccines for prevention of COVID 19 was under consideration during 2020 by several vaccine developers including the World Health Organization WHO 6 7 and was approved in the UK in 2021 8 Over the second half of the 20th and the 21st centuries vaccines for some 15 major pathogens have been fast tracked in human challenge studies involving about 30 000 participants while contributing toward vaccine development to prevent cholera typhoid seasonal flu and other infections 9 Since the 1980s challenge trials which reported about adverse events have had only 0 2 of patients with serious adverse events 4 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 9 Contents 1 Design 2 Ethics 3 Vaccines for infections 3 1 COVID 19 4 References 5 External linksDesign EditThe 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 Ethics EditAwareness 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 Vaccines for infections EditChallenge 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 COVID 19 Edit See also COVID 19 vaccine clinical research Trial and authorization status Human challenge studies are under consideration to hasten the development of a COVID 19 vaccine 3 7 23 including one proposal made by bioethicist Nir Eyal 2 and another by rubella vaccine inventor Stanley Plotkin with bioethicist Arthur Caplan 22 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 22 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 22 In May 2020 a guidance document was issued by the WHO on criteria for conducting challenge clinical trials and providing clinical care for the participants 6 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 6 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 References Edit a b Lambkin Williams Rob Noulin Nicolas Mann Alex Catchpole Andrew Gilbert Anthony S 22 June 2018 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 a b c d e f g h i j 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 a b c d e f g h i j Callaway E April 2020 Should scientists infect healthy people with the coronavirus to test vaccines Nature 580 7801 17 Bibcode 2020Natur 580 17C doi 10 1038 d41586 020 00927 3 PMID 32218549 S2CID 256820005 a b Adams Phipps Jupiter Toomey Danny Wiecek Witold Schmit Virginia Wilkinson James Scholl Keller Jamrozik Joshua Roestenberg Meta Manheim David 11 October 2022 A Systematic Review of Human Challenge Trials Designs and Safety Clinical Infectious Diseases 76 4 609 619 doi 10 1093 cid ciac820 PMC 9938741 PMID 36219704 Cohen Jon 18 May 2016 Studies that intentionally infect people with disease causing bugs are on the rise Science 352 6288 882 885 doi 10 1126 science aaf5726 a b c d Key criteria for the ethical acceptability of COVID 19 human challenge studies PDF World Health Organization 6 May 2020 Retrieved 18 May 2020 a b c d 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 S2CID 216451224 Retrieved 19 April 2020 World s first coronavirus Human Challenge study receives ethics approval in the UK GOV UK Retrieved 18 February 2021 a b Wade Hemsworth 13 May 2020 McMaster researcher contributes to WHO guidelines for COVID 19 vaccine testing McMaster University Medical School Hamilton Canada Retrieved 25 May 2020 Eric Boodman 13 March 2020 Coronavirus vaccine clinical trial starting without usual animal data STAT Retrieved 19 April 2020 Metzger W G Ehni H J Kremsner P G Mordmuller B G 2019 Experimental infections in humans historical and ethical reflections Tropical Medicine amp International Health 24 12 1384 1390 doi 10 1111 tmi 13320 ISSN 1365 3156 PMID 31654450 Gordon SB Rylance J Luck A Jambo K Ferreira DM Manda Taylor L Bejon P Ngwira B Littler K Seager Z Gibani M Gmeiner M Roestenberg M Mlombe Y Wellcome Trust CHIM workshop participants 2017 A framework for Controlled Human Infection Model CHIM studies in Malawi Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre Malawi Wellcome Open Research 2 70 doi 10 12688 wellcomeopenres 12256 1 PMC 5627502 PMID 29018841 a b Binik Ariella May 2020 What risks should be permissible in controlled human infection model studies Bioethics 34 4 420 430 doi 10 1111 bioe 12736 PMID 32115747 S2CID 211727412 D Sinclair K Abba K Zaman F Qadri PM Graves 16 March 2011 Oral vaccines for preventing cholera The Cochrane Database of Systematic Reviews 2011 3 CD008603 doi 10 1002 14651858 CD008603 pub2 PMC 6532691 PMID 21412922 Waddington Claire S Darton Thomas C Woodward William E Angus Brian Levine Myron M Pollard Andrew J 1 May 2014 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 a b c d e J Tuju G Kamuyu Lm Murungi Fha Osier 1 October 2017 Vaccine candidate discovery for the next generation of malaria vaccines Immunology 152 2 195 206 doi 10 1111 imm 12780 PMC 5588761 PMID 28646586 Osowicki Joshua Azzopardi Kristy I McIntyre Liam Rivera Hernandez Tania Ong Cheryl lynn Y Baker Ciara Gillen Christine M Walker Mark J Smeesters Pierre R Davies Mark R Steer Andrew C 13 February 2019 A Controlled Human Infection Model of Group A Streptococcus Pharyngitis Which Strain and Why mSphere 4 1 e00647 18 msphere 4 1 mSphere647 18 atom doi 10 1128 mSphere 00647 18 PMC 6374595 PMID 30760615 McShane Helen 15 May 2020 Controlled Human Infection Models Is it Really Feasible to Give People Tuberculosis American Journal of Respiratory and Critical Care Medicine 201 10 1180 1181 doi 10 1164 rccm 201912 2408ED PMC 7233336 PMID 31904993 S2CID 210041310 MacLennan Calman A Aguilar Anastazia Older Steele A Duncan 9 December 2019 Consensus Report on Shigella Controlled Human Infection Model Introduction and Overview Clinical Infectious Diseases 69 Supplement 8 S577 S579 doi 10 1093 cid ciz886 PMC 6901124 PMID 31816066 Merkel Tod J 11 July 2020 Toward a Controlled Human Infection Model of Pertussis Clinical Infectious Diseases 71 2 412 414 doi 10 1093 cid ciz842 PMC 7353834 PMID 31552410 Rose Anuradha Sekhar Amrita July 2019 Bioethics of establishing a CHIM model for dengue vaccine development International Journal of Infectious Diseases 84 S74 S79 doi 10 1016 j ijid 2019 01 013 PMID 30641207 a b c d Plotkin Stanley A Caplan Arthur 20 April 2020 Extraordinary diseases require extraordinary solutions Vaccine 38 24 3987 8 doi 10 1016 j vaccine 2020 04 039 PMC 7167540 PMID 32331807 UK plan to be first to run human challenge Covid trials BBC News 20 October 2020 External links EditCallaway 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 Retrieved from https en wikipedia org w index php title Human challenge study amp oldid 1175661292, wikipedia, wiki, book, books, library,

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