The Case for Deliberately Exposing Healthy People to COVID-19
Last week, 35 members of the U.S. House of Representatives sent a letter to the heads of the Food and Drug Administration and the Department of Health & Human Services urging the agencies to consider the use of “challenge studies” in COVID-19 vaccine development. Nearly 5,000 people have already indicated their interested in volunteering for such studies by signing up with the grass-roots organization 1 Day Sooner. This post answers some basic questions about challenge studies and explains how deliberately exposing healthy people to COVID-19 can be both scientifically useful and ethically sound.
What are challenge studies?
The term “challenge study” refers to research in which healthy people are intentionally exposed to a pathogen or other microorganism. They may be used to identify factors that contribute to or protect individuals from becoming infected, as well as to evaluate the safety and efficacy of candidate vaccines or drugs. One recent review found more than 120 scientific publications on challenge studies in the past decade, primarily for influenza, rhinovirus and malaria, and noted that challenge studies have “provided landmark data for several registered drugs and vaccines and have generated unprecedented scientific insights.”
Why are challenge studies so important?
Challenge studies are often conducted as small pilot studies to generate preliminary efficacy data on candidate vaccines or drugs. Those that appear promising may then be tested in larger field trials in areas where the disease is endemic. Because challenge studies are typically short and involve a small number of participants, they are both quicker and cheaper than later-phase field trials, which require researchers to enroll large groups of people and wait for some of them to become infected. Because challenge studies enable researchers to quickly test a large number of vaccine or drug candidates, they increase the likelihood of identifying one that will work.
How might challenge studies be used to respond to the COVID-19 pandemic?
While the primary role of challenge studies in COVID-19 response efforts would be to speed the development of an effective vaccine, challenge studies could also be used to answer other important scientific questions important to pandemic response efforts. For example, our knowledge about the duration of immunity conferred by infections with other strains of coronavirus stems largely from data obtained in studies in which volunteers were deliberately infected with those strains. Similar studies could help determine whether, and if so for how long, individuals infected with COVID-19 remain immune to the virus. Challenge studies could also be used to help researchers better understand the relationship between the initial dose of the virus and the severity of disease.
Isn’t it unethical to deliberately infect people with a disease?
It certainly can be. As a World Health Organization (WHO) expert committee noted, many “well documented historical examples of human exposure studies would be considered unethical by current standards.” Examples include studies conducted by the U.S. government in the 1940s in which over 5,000 Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases, and a study conducted in the 1950s at the Willowbrook State School in New York in which mentally disabled children were intentionally infected with hepatitis.
However, most bioethicists agree that the idea of deliberately provoking infections is “not a wrong in itself.” Research with human participants often involves knowingly exposing healthy people to some level of risk. For example, in Phase 1 safety trials for new drugs, healthy volunteers are given unproven drugs to determine whether they are safe enough to proceed with additional testing. Provided the participants have voluntarily provided informed consent, appropriately designed Phase I trials are not considered unethical, even though it is foreseeable that some of the participants may suffer harm.
Whether a particular challenge study is ethical depends on factors like the level of risks involved, the precautions taken to mitigate those risks, and how individuals are recruited to participate in the study. Like other types of clinical research, challenge studies can be ethically acceptable if the risks are reasonable in relation to the anticipated benefits to society, precautions have been taken to protect participants from excessive harms, and participation is limited to individuals who are in a position to provide voluntary, informed consent.
Even if challenge studies can be appropriate for some diseases, isn’t COVID-19 different because it is a life-threatening disease for which no proven treatments exist?
One objection to challenge trials for COVID-19 is that, in contrast to infectious diseases like influenza or malaria, COVID-19 is a potentially fatal disease for which no proven treatments currently exist. According to the fifth principle of the Nuremberg Code, “No experiment should be conducted, where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.” Deliberating infecting individuals with an untreatable, life-threatening disease would arguably violate this principle. Indeed, in 2016, a WHO expert committee opined that, “if an organism causes a disease with a high case fatality rate (or there is a long and uncertain latency period) and there are no existing therapies to prevent or ameliorate disease and preclude death, then it would not be appropriate to consider human challenge trials with such an organism.”
However, while COVID-19 can be life threatening for some patients, the case fatality rate for persons not in high-risk groups is relatively low, roughly comparable to the worldwide mortality rate for living kidney donation (another context in which individuals are knowingly exposed to risk for the benefit of other persons). It is true that the risk of death is higher than for diseases like malaria (which is generally curable if treated promptly), but in research involving competent adults, even high levels of risk can be justifiable if the potential benefits are sufficiently great. Here, the potential benefits of challenge studies would be considerable, as they could potentially lead to the faster development of a vaccine for a disease that is currently threatening the lives of millions of people.
Moreover, as recently argued by bioethicist Nir Eyal and colleagues, during a pandemic in which most people are already exposed to the virus, individuals who participate in a challenge study “may be just hastening an event that is likely to occur in later months anyhow.” And, if they are infected during a challenge study, they may have a better chance of surviving, as they would be “guaranteed access to state-of-the-art facilities of the health system, notwithstanding the possibility of severe shortages of medical care during the evolving pandemic.” In other words, some people might actually be safer participating in a well-controlled challenge study than if they took their chances of becoming infected out in the world.
What safeguards need to be in place for COVID-19 challenge studies to be ethically acceptable?
In order to minimize the risks of COVID-19 challenge studies, participation should be limited to individuals least likely to experience poor outcomes should they become infected, i.e., young adults without any relevant comorbidities such as chronic lung disease or severe obesity. The additional risk of study participation can also be minimized by limiting enrollment to persons who are already “at high risk of exposure to the virus in the ordinary course of their work or living arrangement.” In addition, study participants should be regularly monitored to detect any early signs of infection, and they should have access to the best care available should infection occur. To avoid the risk of transmission to third parties, participants should be isolated during the study in special facilities.
In addition to minimizing risks, it is essential to ensure that individuals who enroll in these studies are fully aware of the risks, including the potential for death or severe disability, and that they are participating voluntarily and understand their right to withdraw. Careful attention should be given to the manner in which individuals are recruited for these studies, in order to ensure that the burdens of participation do not fall disproportionately on particular segments of society. For example, this is not the type of study where it would be acceptable to focus recruitment efforts on undergraduate students at the institutions where the research is being conducted, as is common for many low-risk medical and psychological experiments.
Should people who enroll in COVID-19 challenge studies be paid?
At a minimum, participants in challenge studies should be reimbursed for any out-of-pocket expenses and paid a fair daily rate for their time spent in the study. Making these payments is a basic matter of respect and fair treatment. Individuals who make important contributions to scientific research should not be expected to suffer financially as a result.
Whether to provide incentive payments beyond this basic minimum is a more difficult question. Some people believe that incentive payments are problematic because they could lead people to take risks they would not otherwise be willing to accept; this concern is referred to in the ethics literature as the problem of “undue inducement.” Like others, I am not persuaded that undue inducement is a serious concern in the vast majority of cases. However, it may not be necessary to resolve this debate in the context of COVID-19 challenge studies because, as noted above, it appears that thousands of people are prepared to enroll in these studies without any expectation of payment. If incentive payments are not necessary to enroll a sufficient number of participants, there is no reason to offer them, as long as individuals are fairly compensated for their actual time spent.
Carl H. Coleman is a Professor of Law at Seton Hall University School of Law and specializes in the legal, ethical, and public policy implications of medical treatment, research, and public health. He also currently serves as Academic Director of the Law School's Division of Online Learning. Professor Coleman's biography and publications are available online.
"Jumla ya tatu ya washiriki wa Baraza la Wawakilishi la Marekani waliwatumia barua viongozi wa Idara ya Chakula na Dawa na Idara ya Afya na Huduma za Binadamu, wakiwahimiza mashirika kuzingatia matumizi ya ""mafunzo ya changamoto"" katika maendeleo ya chanjo ya COVID-19." Watu zaidi ya elfu tano wamejiandikisha katika shirika la 1 Day Sooner. "Kichapo hiki kinatoa majibu ya maswali ya msingi kuhusu masomo ya changamoto na kuelezea jinsi ya kuwafunua watu wenye afya kwa COVID-19 inaweza kuwa muhimu kisayansi na ya maadili. """ Uchunguzi wa changamoto ni nini? Neno "mafunzo ya changamoto" linarejelea utafiti ambao watu wenye afya hufunuliwa kimakusudi kwa vimelea au viumbe vingine vidogo. Vifaa hivyo vinaweza kutumiwa kutambua mambo yanayochangia au kulinda watu dhidi ya kuambukizwa virusi, na pia kutathmini usalama na ufanisi wa chanjo au dawa zinazotazamiwa. "Utafiti wa hivi karibuni uligundua zaidi ya machapisho ya kisayansi 120 juu ya masomo ya changamoto katika muongo uliopita, haswa kwa virusi vya mafua, rhinovirus na malaria, na ilibainisha kuwa masomo ya changamoto yametoa data muhimu kwa dawa kadhaa zilizosajiliwa na chanjo na yamezalisha ufahamu wa kisayansi usio na kifani. """ Mafunzo ya changamoto mara nyingi hufanywa kama masomo madogo ya majaribio ili kutengeneza data ya awali ya ufanisi juu ya chanjo au dawa za mgombea. Hizi zinazoonekana kuwa zenye kuahidi zinaweza kisha kupimwa katika majaribio makubwa zaidi ya shambani katika maeneo ambako ugonjwa huo ni wa kawaida. Kwa sababu masomo ya changamoto ni fupi na yanahusisha idadi ndogo ya washiriki, ni ya haraka na ya bei nafuu kuliko majaribio ya uwanja wa hatua ya baadaye, ambayo yanahitaji watafiti kuandikisha vikundi vikubwa vya watu na kusubiri baadhi yao kuambukizwa. Kwa sababu utafiti wa changamoto huwezesha watafiti kupima haraka idadi kubwa ya chanjo au madawa ya kulevya, huongeza uwezekano wa kutambua moja ambayo itafanya kazi. Utafiti wa changamoto unaweza kutumikaje kukabiliana na janga la COVID-19? Ingawa jukumu la msingi la masomo ya changamoto katika juhudi za kukabiliana na COVID-19 itakuwa kuharakisha maendeleo ya chanjo yenye ufanisi, masomo ya changamoto yanaweza pia kutumika kujibu maswali mengine muhimu ya kisayansi muhimu kwa juhudi za kukabiliana na janga. Kwa mfano, maarifa yetu kuhusu muda wa kinga inayotolewa na maambukizi ya aina nyingine za virusi vya corona inatokana na data zilizopatikana katika masomo ambayo wajitoleaji waliambukizwa kwa makusudi na aina hizo. Uchunguzi kama huo unaweza kusaidia kuamua ikiwa, na ikiwa ndivyo, kwa muda gani, watu walioambukizwa COVID-19 wanabaki kuwa na kinga dhidi ya virusi. Uchunguzi wa changamoto pia unaweza kutumika kusaidia watafiti kuelewa vizuri uhusiano kati ya kipimo cha kwanza cha virusi na ukali wa ugonjwa. Je, si jambo lisilo la adili kuambukiza watu ugonjwa kimakusudi? Bila shaka, inaweza kuwa hivyo. "Kama ilivyoelezwa na kamati ya wataalamu wa Shirika la Afya Ulimwenguni (WHO), ""mfano mwingi wa kihistoria ulioandikwa vizuri wa masomo ya mfiduo wa binadamu ungechukuliwa kuwa usio wa maadili kwa viwango vya sasa.""Mifano ni pamoja na masomo yaliyofanywa na serikali ya Marekani katika miaka ya 1940 ambapo watu zaidi ya 5,000 wa Guatemala waliambukizwa kwa makusudi na bakteria zinazosababisha magonjwa ya kuambukizwa kwa njia ya ngono, na utafiti uliofanywa katika miaka ya 1950 katika Shule ya Jimbo la Willowbrook huko New York ambapo watoto wenye ulemavu wa akili waliambukizwa kwa makusudi." Hata hivyo, wataalamu wengi wa maadili ya kibiolojia wanakubali kwamba wazo la kuchochea maambukizo kimakusudi "si kosa lenyewe". Utafiti uliofanywa kwa washiriki wa kibinadamu mara nyingi huhusisha kuwaweka watu wenye afya katika hatari fulani kwa kujua. Katika majaribio ya usalama wa dawa mpya, watu wenye afya wanapewa dawa ambazo hazijathibitishwa ili kujua ikiwa ni salama na kuendelea na majaribio ya ziada. Kwa hivyo, ikiwa washiriki wametoa idhini ya kujitolea, majaribio ya awamu ya kwanza hayawezi kuchukuliwa kuwa ya maadili, hata ingawa inaweza kutazamwa kuwa baadhi ya washiriki wanaweza kuathiriwa. Kama utafiti wa changamoto ni maadili inategemea mambo kama vile kiwango cha hatari zinazohusika, tahadhari zilizochukuliwa ili kupunguza hatari hizo, na jinsi watu ni kuajiriwa kushiriki katika utafiti. Kama aina nyingine za utafiti wa kliniki, utafiti wa changamoto unaweza kukubaliwa kiadili ikiwa hatari ni ya busara kuhusiana na faida zinazotarajiwa kwa jamii, tahadhari zimechukuliwa kulinda washiriki kutoka kwa madhara ya kupita kiasi, na ushiriki ni mdogo kwa watu ambao wako katika nafasi ya kutoa idhini ya hiari. Hata kama utafiti wa changamoto unaweza kuwa sahihi kwa magonjwa fulani, je, COVID-19 si tofauti kwa sababu ni ugonjwa unaohatarisha maisha ambao hakuna matibabu yaliyothibitishwa? "Kila mtu anaweza kupinga majaribio ya COVID-19 kwa sababu, tofauti na magonjwa ya kuambukiza kama vile mafua au malaria, COVID-19 ni ugonjwa unaoweza kuua ambao hakuna matibabu yaliyothibitishwa kwa sasa.""" "Kulingana na kanuni ya tano ya kanuni ya Nuremberg, ""hakuna majaribio yanapaswa kufanywa ambapo kuna sababu ya a priori ya kuamini kwamba kifo au majeraha ya kulemaza yatatokea, isipokuwa, labda, katika majaribio ambayo madaktari wa majaribio pia hutumika kama masomo."" - Nuremberg Code, 2001" "Kwa kweli, katika 2016, kamati ya wataalamu wa WHO ilisema kwamba, ""Ikiwa kiumbe husababisha ugonjwa na kiwango cha juu cha vifo (au kuna kipindi kirefu na kisicho na uhakika) na hakuna matibabu ya sasa ya kuzuia au kuboresha ugonjwa na kuzuia kifo, basi haingekuwa sahihi kuzingatia majaribio ya binadamu na kiumbe kama hicho.""" Ni kweli kwamba hatari ya kifo ni kubwa kuliko kwa magonjwa kama malaria (ambayo kwa ujumla inaweza kutibiwa ikiwa inatibiwa haraka), lakini katika utafiti unaohusisha watu wazima wenye uwezo, hata viwango vya juu vya hatari vinaweza kustahili ikiwa faida zinazowezekana ni kubwa vya kutosha. """Hapa, faida za utafiti wa changamoto zitakuwa kubwa, kwani zinaweza kuongoza kwa maendeleo ya haraka ya chanjo ya ugonjwa ambao kwa sasa unahatarisha maisha ya mamilioni ya watu." "Bado, kama ilivyosemwa hivi karibuni na mtaalamu wa bioethics Nir Eyal na wenzake, wakati wa janga ambalo watu wengi tayari wamewekwa wazi kwa virusi, watu wanaoshiriki katika utafiti wa changamoto ""wanaweza kuwa wakiharakisha tukio ambalo linawezekana kutokea katika miezi ya baadaye.""" Ni nini kinachohitajika ili kuhakikisha kwamba utafiti wa changamoto ya COVID-19 unakubaliwa kiadili? Ili kupunguza hatari za masomo ya changamoto ya COVID-19, ushiriki unapaswa kuwa mdogo kwa watu ambao wana uwezekano mdogo wa kupata matokeo mabaya ikiwa wataambukizwa, yaani, watu wazima vijana bila magonjwa yoyote ya kawaida kama ugonjwa wa mapafu sugu au unene mkubwa. "Hata hivyo, hatari ya ziada ya kushiriki katika utafiti inaweza kupunguzwa kwa kupunguza uandikishaji kwa watu ambao tayari wako katika ""hatari kubwa ya kuambukizwa virusi katika mwendo wa kawaida wa kazi yao au mpangilio wa kuishi.""Kwa kuongezea, washiriki wa utafiti wanapaswa kufuatiliwa mara kwa mara ili kugundua dalili zozote za mapema za maambukizi, na wanapaswa kuwa na huduma bora inayopatikana ikiwa maambukizi yatatokea." Ili kuepuka hatari ya maambukizi kwa watu wa tatu, washiriki wanapaswa kutengwa wakati wa utafiti katika vifaa maalum. "Kwa kuongezea kupunguza hatari, ni muhimu kuhakikisha kwamba watu wanaojisajili katika masomo haya wanafahamu kabisa hatari, ikiwa ni pamoja na uwezekano wa kifo au ulemavu mkubwa, na kwamba wanashiriki kwa hiari na wanaelewa haki yao ya kujiondoa. """ """Ni lazima tahadhari ya makini ipewe kwa njia ambayo watu wanaajiriwa kwa ajili ya masomo haya, ili kuhakikisha kwamba mzigo wa ushiriki haupatikani kwa kiasi kikubwa kwa makundi fulani ya jamii." Kwa mfano, hii si aina ya utafiti ambapo ingekuwa kukubalika kuzingatia juhudi za kuajiri wanafunzi wa shahada ya kwanza katika taasisi ambapo utafiti unafanywa, kama ilivyo kawaida kwa majaribio mengi ya matibabu na kisaikolojia ya hatari ya chini. Je, watu wanaojisajili katika masomo ya changamoto ya COVID-19 wanapaswa kulipwa? Kwa kiwango cha chini, washiriki katika masomo ya changamoto wanapaswa kulipwa kwa gharama yoyote ya nje ya mfuko na kulipwa kiwango cha haki cha kila siku kwa wakati wao uliotumika katika utafiti. Kufanya malipo hayo ni jambo la msingi la kuheshimiwa na kutendewa kwa haki. Watu ambao hufanya michango muhimu kwa utafiti wa kisayansi hawapaswi kutarajiwa kuteseka kifedha kama matokeo. Kama kutoa malipo ya motisha zaidi ya kiwango hiki cha chini ya msingi ni swali ngumu zaidi. "Watu wengine wanaamini kwamba malipo ya motisha ni tatizo kwa sababu yanaweza kuwaongoza watu kuchukua hatari ambayo vinginevyo hawatakuwa tayari kukubali; wasiwasi huu unatajwa katika fasihi ya maadili kama tatizo la ""kuchochea isiyofaa"" kama wengine, mimi si kushawishiwa kwamba kuchochea isiyofaa ni wasiwasi mkubwa katika idadi kubwa ya kesi." Hata hivyo, huenda isiwe muhimu kutatua mjadala huu katika muktadha wa masomo ya changamoto ya COVID-19 kwa sababu, kama ilivyoelezwa hapo juu, inaonekana kwamba maelfu ya watu wako tayari kujiandikisha katika masomo haya bila matarajio yoyote ya malipo. Ikiwa malipo ya motisha hayahitajiki kuandikisha idadi ya kutosha ya washiriki, hakuna sababu ya kuwapa, mradi tu watu binafsi wanalipwa kwa haki kwa wakati wao halisi uliotumika. Carl H. Coleman ni Profesa wa Sheria katika Chuo Kikuu cha Seton Hall School of Law na mtaalamu wa athari za kisheria, maadili, na sera za umma za matibabu, utafiti, na afya ya umma. Yeye pia kwa sasa hutumika kama Mkurugenzi wa Chuo cha Sheria ya Idara ya Mafunzo ya Mtandao. Biografia ya Profesa Coleman na machapisho yake yanapatikana mtandaoni.