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responses_to_ai:technological_inevitability:incentivized_technologies_not_pursued:vaccine_challenge_trials [2023/04/04 17:29]
jeffreyheninger |
responses_to_ai:technological_inevitability:incentivized_technologies_not_pursued:vaccine_challenge_trials [2023/06/23 18:54] (current)
jeffreyheninger Fixing a broken link |
| Human challenge trials for vaccines involve giving volunteers vaccine candidates, then deliberating exposing them to the disease, to test the efficacy of a vaccine candidate more quickly than standard vaccine trials. | Human challenge trials for vaccines involve giving volunteers vaccine candidates, then deliberating exposing them to the disease, to test the efficacy of a vaccine candidate more quickly than standard vaccine trials. |
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| Challenge trials are not a technological temptation which has been fully resisted: they have been used for dozens of diseases, including some recently. They are a technological temptation which has been significantly slowed in response to ethical concerns. | Challenge trials are not a technological temptation which has been fully resisted: they have been used for dozens of diseases, including some recently. They have been significantly slowed in response to ethical concerns. |
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| For COVID-19, if challenge trials had been done faster, we estimate that they could have allowed vaccines to be developed a few months more quickly. The value resisted by slowing this technological temptation is trillions of dollars and hundreds of thousands or millions of lives lost. | For COVID-19, if challenge trials had been done faster, we estimate that they could have allowed vaccines to be developed a few months more quickly, which could have saved trillions of dollars and hundreds of thousands or millions of lives lost. |
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| ===== Details ===== | ===== Details ===== |
| During the 1800s, challenge trials for various diseases were done with varying ethical and scientific standards. Some were done on the physician himself or on other medical practitioners, who presumably knew what they were doing to themselves. Others were done on children, prisoners, or hospital patients.((Machemer. //A Brief History of Human Challenge Trials.// Smithsonian Magazine. (2020) [[https://www.smithsonianmag.com/science-nature/brief-history-human-challenge-trials-180976556/]]. \\ Jamrozik & Selgelid. //History of Human Challenge Studies.// Human Challenge Studies in Endemic Settings. (2021) [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431914/]].)) If people died in these studies, there was often significant public and professional backlash.(("To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal." - William Osler, 1898.)) In 1900, Walter Reed developed the first written consent form which included a statement of the study’s risks for challenge trials involving yellow fever in Cuba for the US Army. This study showed that mosquitoes transmit yellow fever, but 4 participants died, including the only woman and one of the doctors conducting the studies.((Machemer. //A Brief History of Human Challenge Trials.// Smithsonian Magazine. (2020) [[https://www.smithsonianmag.com/science-nature/brief-history-human-challenge-trials-180976556/]].)) Public outcry in the US terminated the study. | During the 1800s, challenge trials for various diseases were done with varying ethical and scientific standards. Some were done on the physician himself or on other medical practitioners, who presumably knew what they were doing to themselves. Others were done on children, prisoners, or hospital patients.((Machemer. //A Brief History of Human Challenge Trials.// Smithsonian Magazine. (2020) [[https://www.smithsonianmag.com/science-nature/brief-history-human-challenge-trials-180976556/]]. \\ Jamrozik & Selgelid. //History of Human Challenge Studies.// Human Challenge Studies in Endemic Settings. (2021) [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431914/]].)) If people died in these studies, there was often significant public and professional backlash.(("To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal." - William Osler, 1898.)) In 1900, Walter Reed developed the first written consent form which included a statement of the study’s risks for challenge trials involving yellow fever in Cuba for the US Army. This study showed that mosquitoes transmit yellow fever, but 4 participants died, including the only woman and one of the doctors conducting the studies.((Machemer. //A Brief History of Human Challenge Trials.// Smithsonian Magazine. (2020) [[https://www.smithsonianmag.com/science-nature/brief-history-human-challenge-trials-180976556/]].)) Public outcry in the US terminated the study. |
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| During the 1900s, the scale of medical research often increased more quickly than the ethics of medical research. The worst abuses of challenge trials were done during WWII by Germany and Japan. In response, the Nuremberg Code of 1947 established the first international rules for medical research involving human subjects.((//Nuremberg Code.// United States Holocaust Memorial Museum. (Accessed March 21, 2023) [[https://www.ushmm.org/information/exhibitions/online-exhibitions/special-focus/doctors-trial/nuremberg-code]].)) There was also some unethical research done in the West during and after WWII. For example, hepatitis challenge trials at the Willowbrook School from 1954-1971 were done on mentally disabled children.((Berkich. //Case: Willowbrook Experiment.// CUNY (2002) [[https://www.qcc.cuny.edu/socialsciences/ppecorino/medical_ethics_text/chapter_7_human_experimentation/case_study_willowbrook_experiments.htm]].)) In the early 1970s, concern about unethical medical research, including the Willowbrook study, Tuskegee Syphilis Study, Fernald State School trials, and Jewish Chronic Disease Hospital case,((Moon. //The History and Role of Institutional Review Boards: A Useful Tension.// AMA Journal of Ethics (2009) [[https://journalofethics.ama-assn.org/article/history-and-role-institutional-review-boards-useful-tension/]].)) led Congress to pass the National Research Act of 1974 which created IRBs.((A more detailed history of IRBs is more complicated, with some institutions adopting similar review practices decades earlier and some institutions resisting IRBs for decades afterwards.)) IRBs review all potential medical research and determine if it is ethical to proceed. | During the 1900s, the scale of medical research often increased more quickly than the ethics of medical research. The worst abuses of challenge trials were done during WWII by Germany and Japan. In response, the Nuremberg Code of 1947 established the first international rules for medical research involving human subjects.((//Nuremberg Code.// United States Holocaust Memorial Museum. (Accessed March 21, 2023) [[https://www.ushmm.org/information/exhibitions/online-exhibitions/special-focus/doctors-trial/nuremberg-code]].)) There was also some unethical research done in the West during and after WWII. For example, hepatitis challenge trials at the Willowbrook School from 1954-1971 were done on mentally disabled children.((Berkich. //Case: Willowbrook Experiment.// CUNY (2002) [[https://www.qcc.cuny.edu/socialsciences/ppecorino/medical_ethics_text/chapter_7_human_experimentation/case_study_willowbrook_experiments.htm]].)) In the early 1970s, concern about unethical medical research, including the Willowbrook study, Tuskegee Syphilis Study, Fernald State School trials, and Jewish Chronic Disease Hospital case,((Moon. //The History and Role of Institutional Review Boards: A Useful Tension.// AMA Journal of Ethics (2009) [[https://journalofethics.ama-assn.org/article/history-and-role-institutional-review-boards-useful-tension/2009-04]].)) led Congress to pass the National Research Act of 1974 which created IRBs.((A more detailed history of IRBs is more complicated, with some institutions adopting similar review practices decades earlier and some institutions resisting IRBs for decades afterwards.)) IRBs review all potential medical research and determine if it is ethical to proceed. |
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| Dozens of human challenge trials have been approved by IRBs, including for malaria,((Sauerwein et al. //Experimental human challenge infections can accelerate clinical malaria vaccine development.// Nature Reviews Immunology **11**. (2011) p. 54-56. [[https://www.nature.com/articles/nri2902]].)) influenza,((Pleguezuelos et al. //Efficacy of FLU-v, a broad-spectrum influenza vaccine, in a randomized phase IIb human influenza challenge study.// npj Vaccines **5.22**. (2020) [[https://www.nature.com/articles/s41541-020-0174-9]].)) cholera,((Haney et al. //Antibody-Based Correlates of Protection against Cholera: Analysis of a Challenge Study of a Cholera-Naive Population.// Clinical and Vaccine Immunology **24**. (2017) [[https://journals.asm.org/doi/pdf/10.1128/cvi.00098-17]].)) typhoid,((Darton et al. //Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a.// PLOS Neglected Tropical Diseases. (2016) [[https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004926]].)) dengue,((Kirkpatrick et al. //The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.// Science Translational Medicine **8.330**. (2016) [[https://centerforimmunizationresearch.org/wp-content/uploads/2018/08/The-live-attenuated-dengue-vaccine-TV003-elicits-complete-protection-against-dengue-in-a-human-challenge-model.pdf]].)) and others.((Roestenberg et al. //Experimental Infection of Human Volunteers.// The Lancet Infectious Diseases **18.10**. (2018) [[https://scholarlypublications.universiteitleiden.nl/access/item%3A3005330/view]].)) | Dozens of human challenge trials have been approved by IRBs, including for malaria,((Sauerwein et al. //Experimental human challenge infections can accelerate clinical malaria vaccine development.// Nature Reviews Immunology **11**. (2011) p. 54-56. [[https://www.nature.com/articles/nri2902]].)) influenza,((Pleguezuelos et al. //Efficacy of FLU-v, a broad-spectrum influenza vaccine, in a randomized phase IIb human influenza challenge study.// npj Vaccines **5.22**. (2020) [[https://www.nature.com/articles/s41541-020-0174-9]].)) cholera,((Haney et al. //Antibody-Based Correlates of Protection against Cholera: Analysis of a Challenge Study of a Cholera-Naive Population.// Clinical and Vaccine Immunology **24**. (2017) [[https://journals.asm.org/doi/pdf/10.1128/cvi.00098-17]].)) typhoid,((Darton et al. //Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a.// PLOS Neglected Tropical Diseases. (2016) [[https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004926]].)) dengue,((Kirkpatrick et al. //The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.// Science Translational Medicine **8.330**. (2016) [[https://centerforimmunizationresearch.org/wp-content/uploads/2018/08/The-live-attenuated-dengue-vaccine-TV003-elicits-complete-protection-against-dengue-in-a-human-challenge-model.pdf]].)) and others.((Roestenberg et al. //Experimental Infection of Human Volunteers.// The Lancet Infectious Diseases **18.10**. (2018) [[https://scholarlypublications.universiteitleiden.nl/access/item%3A3005330/view]].)) |
| Trials can be slowed or stopped by IRBs, which have very different incentives. This is a description of the situation in the US; similar ethics committees exist in other countries as well. | Trials can be slowed or stopped by IRBs, which have very different incentives. This is a description of the situation in the US; similar ethics committees exist in other countries as well. |
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| There are two types of IRBs: 'Central' or 'independent' IRBs are for profit enterprises which charge investigators for reviewing their proposed research. 'Local' IRBs are associated with the institution where the research is done and seem to be significantly more common.((Moon. //The History and Role of Institutional Review Boards: A Useful Tension.// AMA Journal of Ethics (2009) [[https://journalofethics.ama-assn.org/article/history-and-role-institutional-review-boards-useful-tension/]].)) Oversight of IRBs is done by the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP). Their audits encourage detailed documentation of all parts of the investigation.((Gunsalus et al. //Mission Creep in the IRB World.// Science **312.5779**. (2006) p. 1441. [[https://www.science.org/doi/full/10.1126/science.1121479]].)) Other than these audits, there are few incentives acting on IRBs, especially local IRBs. They do not have to justify their decisions and their decisions cannot be appealed.((Bagley. //Should IRBs be dismantled? The Incidental Economist.// (2015) [[http://theincidentaleconomist.com/wordpress/should-irbs-be-dismantled/]].)) If research results in an important discovery, the research institution and investigators gain prestige, but this is rarely shared with the IRB which approved it. The IRB is much more likely to gain infamy if it approves research which is considered unethical. The result is a form of asymmetric justice: IRBs face more criticism for their mistakes than praise for their successes.((Zvi Mowshowitz. //Asymmetric Justice.// Don’t Worry About the Vase. (2019) [[https://thezvi.wordpress.com/2019/04/25/asymmetric-justice/]].)) In these circumstances, it is not surprising that IRBs are often cautious and insist on justifying and documenting everything. | There are two types of IRBs: 'Central' or 'independent' IRBs are for profit enterprises which charge investigators for reviewing their proposed research. 'Local' IRBs are associated with the institution where the research is done and seem to be significantly more common.((Moon. //The History and Role of Institutional Review Boards: A Useful Tension.// AMA Journal of Ethics (2009) [[https://journalofethics.ama-assn.org/article/history-and-role-institutional-review-boards-useful-tension/2009-04]].)) Oversight of IRBs is done by the Food and Drug Administration (FDA) and the Office for Human Research Protections (OHRP). Their audits encourage detailed documentation of all parts of the investigation.((Gunsalus et al. //Mission Creep in the IRB World.// Science **312.5779**. (2006) p. 1441. [[https://www.science.org/doi/full/10.1126/science.1121479]].)) Other than these audits, there are few incentives acting on IRBs, especially local IRBs. They do not have to justify their decisions and their decisions cannot be appealed.((Bagley. //Should IRBs be dismantled? The Incidental Economist.// (2015) [[http://theincidentaleconomist.com/wordpress/should-irbs-be-dismantled/]].)) If research results in an important discovery, the research institution and investigators gain prestige, but this is rarely shared with the IRB which approved it. The IRB is much more likely to gain infamy if it approves research which is considered unethical. The result is a form of asymmetric justice: IRBs face more criticism for their mistakes than praise for their successes.((Zvi Mowshowitz. //Asymmetric Justice.// Don’t Worry About the Vase. (2019) [[https://thezvi.wordpress.com/2019/04/25/asymmetric-justice/]].)) In these circumstances, it is not surprising that IRBs are often cautious and insist on justifying and documenting everything. |
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| During the pandemic, there was also significant political pressure to make vaccines available faster. Operation Warp Speed provided funding for vaccine research and preordered hundreds of millions of doses of promising vaccine candidates so vaccine manufacturing could scale up before the vaccines were approved.((//Explaining Operation Warp Speed.// US Department of Health and Human Services. (2020) [[https://health.mo.gov/living/healthcondiseases/communicable/novel-coronavirus-lpha/pdf/fact-sheet-operation-warp-speed.pdf]].)) These efforts probably shortened the time until vaccines were widely available by months. However, the FDA and Pfizer proved to be effective at resisting political pressure to get the vaccines approved before Election Day.((Regalado. //One doctor’s campaign to stop a covid-19 vaccine being rushed through before Election Day.// MIT Technology Review. (2020) [[https://www.technologyreview.com/2020/10/19/1010646/campaign-stop-covid-19-vaccine-trump-election-day/]].)) | During the pandemic, there was also significant political pressure to make vaccines available faster. Operation Warp Speed provided funding for vaccine research and preordered hundreds of millions of doses of promising vaccine candidates so vaccine manufacturing could scale up before the vaccines were approved.((//Explaining Operation Warp Speed.// US Department of Health and Human Services. (2020) [[https://health.mo.gov/living/healthcondiseases/communicable/novel-coronavirus-lpha/pdf/fact-sheet-operation-warp-speed.pdf]].)) These efforts probably shortened the time until vaccines were widely available by months. However, the FDA and Pfizer proved to be effective at resisting political pressure to get the vaccines approved before Election Day.((Regalado. //One doctor’s campaign to stop a covid-19 vaccine being rushed through before Election Day.// MIT Technology Review. (2020) [[https://www.technologyreview.com/2020/10/19/1010646/campaign-stop-covid-19-vaccine-trump-election-day/]].)) |
