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Developing World Bioethics ISSN 1471-8731 (print); 1471-8847 (online)Volume 5 Number 1 2005 MODULE THREE:VULNERABLE/SPECIAL PARTICIPANT POPULATIONS This module is designed to sensitise you to the special needs of partici-pants who belong to populations that are more vulnerable than other participant populations. These populations typically include incom-petent persons women who may or may not be pregnant, children, pris-oners and refugees, impoverished people, and ethnic minorities. These andsimilar groups deserve special consideration for a number of importantethical and historical reasons, specifically those that surround the poten-tial for exploitation, problems with informed consent, and concerns about respect for participant autonomy. This module introduces modusoperandi that are based on national and international research guidelinesfor dealing with vulnerable/special participant populations, offering contextually-dependent advice and relevant ethical considerations/arguments for and against their involvement in scientific research endeavours. Clinical trials and related scientific research necessarily rely on the successful recruitment of human participants in order to yield meaningful results. In this sense, human participants are instrumental in securing data useful to the researcher, whichis often extrapolated to develop clinical techniques/drugs/methodologies applicable across a broader range of human pop-ulations. Quite simply, researchers in clinical trials are concerned Blackwell Publishing Ltd. 2005, 9600 Garsington Road, Oxford OX4 2DQ , UK and 350 Main Street, Malden, MA 02148, USA.
with generalisable results with predictive value, and particularhuman sub-populations are critically important in producingthose results.
This interplay between results-driven research and the neces- sary involvement of human participants naturally creates ten-sion between procuring scientific data and the proper ethicaltreatment of research participants. As public exposure of Nazi experimentation (conducted under the guise of ‘scientificresearch’) made painfully obvious during the Nuremberg Trials, the ethical standing of research participants is at constantrisk of sacrifice by researchers intent on deriving scientific knowl-edge. Incidents of ethical transgressions – in which humanresearch participants were exploited, unfairly treated, or in some other way harmed – on behalf of Nazi doctors and other scientists throughout the latter half of the twentieth century has prompted closer inspection of clinical research and the devel-opment of ethical guidelines for the protection of research participants.
Of concern are individuals who are already disadvantaged or vulnerable to harm independent of their involvement in clinicaltrials. Such participants, for whatever reasons, have been mar-ginalised by society and are susceptible to exploitation. They typically stand in unequal power relationships with others and/orpossess substandard mental faculties, rendering them incompe-tent. Pressing examples include the mentally disabled, abjectlyimpoverished persons, prisoners/refugees, women/pregnantwomen, children, and ethnic minorities, though this list is notexhaustive.
Vulnerable populations are attractive for research purposes precisely because of their vulnerability. Transgressions of ethicalboundaries become easier as does the consequent procure-ment of scientific data. It is of no surprise, then, that the major-ity of sensationalised research ethics cases in the past sixty yearshave involved vulnerable persons – indeed, the entire field ofresearch ethics has been built upon and refined according toexamples of ‘extreme’ clinical research that have dotted modernhistory.
In order to appreciate the ethical considerations and argu- ments guiding contemporary clinical research it is first necessaryto review a few exceptional breaches of research conduct. This isfollowed by considerations of vulnerabilities specific to the groupsmentioned above. A final discussion of the ethical arguments forand against the potential use of vulnerable human participants inclinical research concludes the module.
Modern research ethics only took form during the Nurembergtrials in 1947.1 Facing mounting wartime casualties and theFührer’s fatal intolerance of German failure (coupled with an per-sistent faith in ‘Aryan superiority’), some Nazi doctors busiedthemselves with experimentation on concentration camp prison-ers, with the intent of furthering the war effort (inflicting gunshotwounds on prisoners, deliberately infecting prisoners with typhusand other battlefield diseases, exposing prisoners to freezing temperatures for prolonged periods, etc.) or of buttressing Naziideology (eliminating homosexuality, sterilising Jews and other‘undesirables’, exposing differences in anatomical structureacross ‘races’, etc.) Other common Nazi experiments on humans included forcing prisoners to drink sea water or breathe dirty air for extendedperiods of time, developing novel techniques of castration, andperforming bone and limb transplantations.2 Though fifteen Nazi doctors were eventually tried and con- victed in Nuremberg, Dr. Joseph Mengele, the most notoriousphysician escaped. Posner offers chilling testimony regardingMengele’s research into the differences in eye colour betweenGypsy teenage twins, illustrating the extent of his cruelty: In the work room next to the dissecting room, fourteen Gypsytwins were waiting and crying bitterly. Dr. Mengele didn’t say asingle word to us, and prepared a 10 cc and a 5 cc syringe. Froma box he took Evipal and from another box he took chloro-form, which was in 20 cc glass containers, and put these on theoperating table. After that the first twin was brought in . . . afourteen year old girl. Dr. Mengele ordered me to undress the child and put her head on the dissecting table. Then heinjected the Evipal into her right arm intravenously. After the child had fallen asleep, he felt for the left ventricle of theheart and injected 10cc of chloroform . . . After one little twitch 1 P. Boleyn-Fitzgerald. 2003. Experimentation on Human Subjects. In A Companion to Applied Ethics. R.G. Frey & C. Wellman, eds. New York. BlackwellPublishers: 410–423.
2 R.N. Procter. 1992. Nazi Doctors, Racial Medicine, and Human Experi- mentation. In The Nazi Doctors and the Nuremberg Code. G.J Annas & M.A. Grodin,eds. New York. Oxford University Press: 17–31.
the child was dead . . . in this manner all fourteen twins werekilled.
Mengele then removed the eyes from the dead twins and shippedthem off to Berlin for further study.3 Revelations of Nazi experiments at Nuremberg sparked the beginning of ethical analyses and oversight of research protocolsinvolving human participants, leading to the development of theNuremberg Code, ‘the first international normative frameworkregulating the standards of research clinical trials.’4 This andother research guidelines are discussed more fully below.
Jewish chronic disease hospital cancer experiments (1963–1966) Questionable clinical trials conducted by Dr. Chester Southam inBrooklyn, New York, were first reported in a landmark ethicsarticle published in the New England Journal of Medicine by Dr.
Henry Beecher.5 Interested in the immunoreactivity response to cancer, Southam began routinely injecting twenty-two elderlyJewish patients with live cancerous liver cells and monitoring theirresponse – entirely in the absence of informed consent by thepatients (who were told they would be ‘receiving some cells’).6No therapeutic value ever accrued to the patients (many wereharmed and subsequently died from the injections), nor were theexperiments conceived of to that end.7 Willowbrook state school hepatitis experiments (1955–1970) Experiments conducted by Saul Krugman investigated the effectsof hepatitis infection among mentally disabled children at theWillowbrook State School, located in Staten Island. To do so,Krugman did not treat the children already infected with hepati-tis and deliberately infected others with the virus.8 Again, the 3 U. Schüklenk. Protecting the Vulnerable: Testing Times for Clinical Research Ethics. Social Science and Medicine 2000; 51: 969–977. Available at:, 2003).
4 Ibid.
5 H. Beecher. Ethics and Clinical Research. New England Journal of Medicine 6 Ibid. Boleyn-Fitzgerald, op. cit. note 1.
7 R. Finn. 1999. Cancer Clinical Trials: Experimental Treatments & how they can Help You. New York. O’Reily and Associates. Apatientcenters.com/trials/news/ethics_of.html (accessed 19 September, 2003).
8 Boleyn-Fitzgerald, op. cit. note 1.
ethical foundation of this experiment was first questioned byBeecher, who noted that none of the students had been ade-quately informed of this experiment, nor could they have beengiven their mental status.9 The experiment was intended to trackthe development of the viral infection, and carried no direct therapeutic benefit to the children involved.10 Tuskegee syphilis study (1932–1972) Following the Nazi concentration camp experiments, theTuskegee syphilis study is perhaps the most well known exampleof unethical human experimentation. Sponsored by the USCentral for Disease Control (CDC) and headed (initially) by Tal-iaferro Clark of the National Public Health Service, the ‘TuskegeeStudy of Untreated Syphilis in the Negro Male’ examined theuntreated effects of the disease in 600 blacks (399 who had thedisease, 201 who did not) in rural Alabama.11 Though the participants in the study had voluntarily agreed to receive treatment for their ‘bad blood’ (the local term for syphilis,as well as anaemia and fatigue), none had been informed aboutthe true purpose of the study. Each had been mislead into believ-ing that he was receiving proper treatment. Worse, even when aneffective syphilis treatment (penicillin) had been discovered mid-way through the study, none of the participants were informed of the treatment, were offered the treatment, or were given thechance to quit the study.12 The Tuskegee syphilis experiment ended following the publication of a front-page New York Times article by Jean Heller describing the study and its effects.13 It has been estimatedthat at least 28–100 participants died because of the experi-ment (for a comprehensive account of the Tuskegee study, seeJones14).
10 D. Berkich. 2003. Medical Ethics Online: Human Experimentation Cases. Avail- human_experimentation_cases.html (accessed 19 September, 2003).
11 United States Center for Disease Control. 2003. Tuskegee Timeline Website.
12 Ibid. Boleyn-Fitzgerald, op. cit. note 1.
13 J. Heller. Syphilis Victims in U.S. Study Went Untreated for 40 Years. New York Times 26 July, 1972: A1.
14 J. Jones. 1992. Bad Blood: The Tuskegee Syphilis Experiment. New York. Free ZDV (AZT) drug trials in developing world countries (1997) An HIV-related clinical trial that took place in South Africa andother developing countries came under heavy criticism by SouthAfrican expatriate doctor Peter Lurie and his colleague SydneyWolfe in a landmark New England Journal of Medicine article in1997.15 The trial was designed to determine the efficacy of severalnew drug regimens in the prevention of vertical HIV transmissionfrom mother-to-child, in hopes of finding a cheaper (yet equallyeffective) drug protocol. The standard zidovudine (ZDV, formerlyAZT) treatment used regularly in developed world countries (in particular, the United States and Europe) cost at the timeapproximately US$1000 and was far too costly for use in thepoorer developing world. Researchers were searching for cheaperdrug regimens that could be feasibly introduced in developingworld countries.
While the intent of the research was admirable, the method- ology raised significant ethical problems. Instead of comparingthe new drug regimens against the best proven diagnostic andtherapeutic method of care, as required at the time by the Dec-laration of Helsinki, these studies were comparing the new drugregimen against a placebo. The unfortunate consequence wasthat only half of the pregnant mothers in the study were benefit-ting from participation. No clinical equipoise existed between thetrial arms, because zidovudine was already accepted as the goldstandard of care at the time. Worse, it was unclear whether thesemothers would receive any potential benefit in the future, either,since results from the study were being exported back to theUnited States, with little indication what (if any) benefits wouldaccrue back to the placebo-treated study participants. Indeed, theSouth African government refused to implement the treatmentregimen underpinning the trial.
As Lurie and Wolfe forcefully pointed out, such placebo- controlled studies could never have been conducted in developedworld countries – all participants would have been guaranteed toreceive at least the standard ZDV treatment protocol. Accordingly,the placebo-controlled studies were accused of being exploitative,capitalising on the poor of the developing world who had no alternative treatment to prevent HIV transmission under ‘localstandards of care.’ (See the module on ‘Standards of Care’ for a 15 P. Lurie & S.M. Wolfe. Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in DevelopingCountries. New England Journal of Medicine 1997; 337: 853–856.
more detailed discussion of this matter.) The developed worldresearchers, they argued, knew that their work could only be‘acceptably’ carried out among the poor of the developing world,who had little choice about treatment and who would be ‘grateful’ to receive any treatment at all – their vulnerability thusmade them prime research targets. Indeed, the ZDV studies werejustified by its proponents along these lines, who noted ‘it is anunfortunate fact that the current standard of perinatal care forthe HIV-infected pregnant women in the sites of the studies doesnot include any HIV-prophylactic intervention at all.’16 These five paradigmatic cases in research ethics share a commontheme of exploitation.
Nazi concentration camp prisoners were powerless against their captors, who had no other options (aside from immediatedeath) but to undergo horrific medical research. Dr. Southam’scancer research was only feasible insofar as his elderly Jewishpatients lacked information about his true motives and were significantly disadvantaged because of their advanced age (i.e.
they were likely to be more trusting of medical professionals, less willing or able to question their ‘treatment’, etc.), while Dr. Krugman capitalised on his participants’ young age andmental incompetence to pursue his hepatitis studies. TheTuskegee syphilis study, on the other hand, exploited the socio-economically disadvantaged status of adult black males livingwithin the racist, segregated society recently characteristic of the southern United States. Similarly, the ZDV (AZT) studiesexploited poor, pregnant African women who could not afford‘standard’ Western drugs to prevent vertical transmission of HIVand who were more likely to agree to participate in such studiesbecause they sought care for their unborn children.
That exploitation has persisted, even under a growing body of national and international legislation/regulation addressingthe structure and conduct of ethically acceptable clinical trials,shows that research involving the use of vulnerable populationsremains a serious issue that cannot be ignored by the clinicalresearcher.
16 United States Department of Health. 1997. The Conduct of Clinical Trials of Maternal-Infant Transmission of HIV. Washington, DC. Government PrintingOffice.
As mentioned previously, all vulnerable populations stand in unequal power relationships with others that typically do not char-acterise ‘normal’ (or most) members of society. Such relation-ships may instantiate themselves in numerous ways to creatediffering vulnerabilities across groups. The clinical researchermust be aware of the concerns specific to each vulnerable popu-lation and adjust his research protocols to compensate. What maybe considered ethically acceptable research involving prisoners,may be entirely unacceptable when applied to mentally incom-petent adults, pregnant women, or children.
Each vulnerable population deserves individual treatment according to their specific circumstances.
Prisoners have been deprived of freedoms normally enjoyed byother members of society. Their actions are directly controlled by others (locally, prison guards and more generally, the state),whom they rely upon for food, shelter, clothing, and other basicnecessities of life. In other words, they find themselves in a strictlyhierarchically ordered form of life with detrimental consequencesfor their capacity to live autonomously. For whatever punitive orrehabilitative reasons supporting their confinement, imprisonedpersons are intentionally made vulnerable.
Coercive conditions necessarily impose constraints on the degree of free decision-making exercised by prisoners. Specifi-cally, prisoners may be unable to make informed judgementsregarding their participation in clinical trials, for a number ofreasons.17 First, prisoners may fear retribution from prison guards or otherauthority figures if they do not appear co-operative. Constantlyseeking to please those in charge of them, if only to make dailyprison life easier, prisoners may readily agree to engage in clinical research if they think it will send a positive signal toauthorities and possibly confer future benefits, or at least pre-vent the harm that comes with not acting like a ‘good’ prisonershould.
17 L.D. De Castro. Human Organs from Prisoners: Kidneys for Life. Journal of Medical Ethics 2003; 29: 171–175. Acgi/content/full/29/3/171 (accessed 19 September, 2003).
Annas et al. have reported a series of studies in which prison- ers ‘voluntarily’ agreed to be subjected to cholera, typhoid, andother diseases.18 During the 1940s in the United States, forexample, prisoners consented to participate in clinical trials (ledby Dr. Andrew Ivy under the supervision of the US military) inwhich they were directly exposed to malaria. Dr. Ivy’s defence ofhis work consisted in appealing to earlier studies conducted byUS Colonel R. P. Strong, ‘who injected attenuated plague organ-isms into 900 condemned prisoners in Manila in the 1900s.’19 Clearly these experiments (and others like them) call into ques- tion the voluntariness of the prisoners’ actions. Few, if any,normal, non-incarcerated adults would have given informedconsent to participate in this research, casting doubt upon theethical acceptability of using prisoners in these trials, who werelikely only trying to curry favour from those who had power overthem.
Prisoners may be unduly influenced by potential gains offered byresearch participation, such as reduced prison time or ‘extra’perks (more/better food, increased access to entertainment orexercise facilities, increased ‘free’ time, etc.) These rewards maycloud prisoners’ judgements and prevent them from adequatelyassessing the potential risks involved in the proposed research.
This same concern applies to research involving non-vulnerablehuman populations – the prospect of immense gains can arguablyoutweigh any risks, no matter how devastating or probable.
With prisoners, however, the prospects of rewards through research participation should be taken even more seriously, if onlybecause of their coercive environment. The possibility of rewardsbecomes all the sweeter – and coercive – when punishment is thestandard offering.
Prisoners may consent to participate in clinical trials simplybecause they have very few other options to pursue. Prison life ishighly regimented with little variability in day-to-day activities. The 18 G. Annas, L. Glantz & B. Katz. 1997. Informed Consent to Human Experimen- tation: The Subject’s Dilemma: 1–36. Asph/lw/pvl/book/Ch4.pdf (accessed 19 September, 2003) sheer novelty of research participation, along with the opportu-nity to distinguish oneself from other inmates, may unduly influ-ence the prisoner’s decision. Kahn has noted that clinicalresearch conducted in prisons has always been successful and‘very popular’ among the prison population, to an extent that does not typically characterise research in non-prison settings.20 The mere option of participation may be an over-riding influence barring informed consent in the same way theprospects of rewards or pleasing authorities distorts prisoners’judgements.
The prison population is attractive to clinical researchers because of the controlled conditions characteristic of prisonsthemselves. Researchers have less trouble keeping track of theirresearch participants, environmental conditions remain relativelyconstant, and follow-up studies are easy to pursue – the prisoners,after all, are not going anywhere and the prisons themselves areunlikely to change significantly over time. Moreover, researchersmay be more willing to conduct risky or ‘sloppy’ research in prisoners precisely because they are perceived (consciously or un-consciously) to be less valuable than other (non-incarcerated)members of society.
Because potential harm to prisoners ‘doesn’t mean as much’ as harm to non-prisoners, researchers may also be more lax inadherence to research protocols, thereby exposing prisonerresearch participants to riskier experimentation than that whichthe prisoners and researcher initially agreed upon. These reasons,combined with the aforementioned motivations of prisoners to participate, merits prison populations special considerationduring the development and implementation of clinical trials.
The plight of refugees is very similar to that of prisoners. Refugeesare persons that have been displaced from their permanenthomes or residences and who now live elsewhere – within foreignboundaries – as non-citizens. As Leaning has noted, refugees arevulnerable for several reasons.21 20 J. Kahn. 6 September, 1999. Prison Research: Does Locked up Mean Locked Out? CNN Health: Ethics Matters Website. Acnn.com/HEALTH/bioethics/9909/prison.research/ (accessed 19 September,2003).
21 J. Leaning. Ethics of Research in Refugee Populations. Lancet 2001; 357: Indefinite Legal Status/Lack of Rights/Dependency on HostCountry Governments Because of their non-citizen status, refugees inherently possessfewer legal rights than the citizens of the host country in whichthey are residing and ‘stand outside the regulatory protection ofdomestic legislation and are vulnerable to arbitrary action on partof the host country.’ The United Nations and other internationalregulatory bodies have only issued provisional recommendationsregarding the status of refugees, leaving almost total discretion tothe host country for their treatment under domestic law. Lackingimpetus from the international community, host countries torefugees have consequently pursued few reforms or legislationaimed specifically at refugee populations, placing refugee groupsin an ill-defined relationship with the host country’s governmentand citizens.
Refugees are typically created in the midst of severe societalupheaval and destruction, ‘where human rights abuses arerampant and where refugees are considered hostile targets bythose who force them to flee.’ Additionally, citizens of the hostcountries to which refugees eventually migrate are also frequentlyunwelcoming. A direct consequence of this hostility is that theremay be little oversight or protection afforded to refugee groupswho are considered for clinical research projects. Possibly caringlittle about the lives of refugees to begin with, authorities fromboth the countries from which they were expelled as well as thecountries where they temporarily reside may do little to ensureproper ethical standards are satisfied during clinical researchtrials involving refugees.
Lack of Guidance from International Regulations and Ethics Recommendations The international regulations that provide guidance on clinicalresearch have not addressed research involving refugee popula-tions. Neither the Declaration of Helsinki nor the Council forInternational Organizations of Medical Sciences (CIOMS) re-search guidelines specifically mention refugee populations, forexample. The Belmont report and the Nuremberg Code are alsosilent on this issue. Lacking credible ethical guidance to structureresearch involving refugees, they are exposed to breaches of ethically acceptable research protocols.
Barriers to Informed Consent Arising from Social, Cultural,Economic, Linguistic and Other Factors Refugees are usually economically destitute and can be easilyinfluenced to participate in research at the prospect of minimalfinancial gain. Procuring genuine voluntary informed consentamidst such poverty may prove an insurmountable challenge tothe researcher. Additionally, language barriers, unspoken culturalnorms, the desire to appear compliant within a foreign country,and other refugee-centric factors may cause additional problems.
The World Health Organization has noted that clinical researchinvolving refugees must consider their ‘recent drastic physical andpsychological losses’ contributing to extreme psychological andemotional stress.22 Obtaining informed consent from refugeesexperiencing disarrayed mental states can be difficult. Participa-tion in clinical trials may further contribute to and exaggerate thispsychological stress.
Like prisoners, refugees are attractive to researchers because of external constraints on movement and location as well as the com-position of refugee populations. Follow-up studies are also easierto implement within well-defined, geographically isolated refugeecamps. The camps are also quite conducive to standard researchmethodologies. As Leaning notes, ‘the physical layout of thesecamps provides some accessibility and population density mostamenable to rapid systematic sampling and data collection.’These reasons, coupled with ‘a humanitarian justification basedon urgent human need’ contributes ‘to the mounting momen-tum for carrying out research in these settings.’23 Research involving mentally incompetent persons poses some-what different problems from those encountered with prisoners or refugees faculties. By virtue of lacking certain mental facilities,the mentally incompetent are innately vulnerable to exploitationby others.
22 J. Leaning. 1997. Annex – World Health Organization Ethics Template Website.
Whereas obtaining informed consent is at least possible with pris-oners or refugees (though likely hindered by the factors discussedabove), it is, by definition, impossible to obtain informed consentfrom the mentally incompetent. Informed consent necessarilydemands the capacity for rational, informed decision-making,characteristics the mentally incompetent do not possess.24 Informed consent, however, has often been touted as a neces- sary requirement for participant entry into clinical trials. Forexample, the Nuremberg Code, the first body of formalised guide-lines concerning research involving human participants, statesthat, ‘voluntary consent of the human subject is absolutely essen-tial’ for proper ethical research.25 As Schüklenk has observed,however, this ‘absolutely essential’ criterion ‘would render awhole range of research clinical trials involving incompetent men-tally ill patients impossible . . . Evidently if we wish to improve thesituation of those who suffer from diseases that impair their capac-ity to provide informed consent, it is necessary to conductresearch involving such people.’26 This same consideration ledthe World Medical Association, during its initial formulation ofthe Declaration of Helsinki (1964), to adopt proxy consent as anacceptable alternative for those research participants who areunable to directly give informed consent.27 But proxy consent can be problematic as well. Perhaps the most important question to ask is proxy consent by whom? Mostethics committees and national/international bioethics commit-tees recognise proxy consent conferred by legally authorisedauthorities.
Another important question is proxy consent for what? That is, what sort of clinical research is acceptable under the conditionsof proxy consent? At issue here is the difference between thera-peutic and non-therapeutic research. The former confers directbenefits to research participants, while the latter does not. By 24 M. Cuenod & J. Gasser. Research on the Mentally Incompetent. Journal of Medical Ethics 2003; 29: 19–21. Acontent/full/29/1/19 (accessed 19 September, 2003).
25 Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council Law. No. 10: Nuremberg, Oct. 1946–1949. 2 Volumes. Washington, DC.
Government Printing Office.
26 Schuklenk, op. cit. note 3.
27 Boleyn-Fitzgerald, op. cit. note 1.
extending the potential pool of research participants to includethe mentally incompetent, the Declaration of Helsinki permitstherapeutic research on these subjects, i.e. research that would bebeneficial, in particular, to mentally incompetent persons. Thisresearch might include testing of new psychiatric drugs, behav-ioural therapies, or surgical interventions.
Non-therapeutic research, however, does not help mentally incompetent persons qua their status as mentally incompetent.
Non-therapeutic research can usually be carried out using normaladults and does not demand the involvement of vulnerable popu-lations. With respect to mentally incompetent persons, non-therapeutic research might include testing the efficacy of a newvaccine against HIV or assessing the risks of side effects of a newdrug. Non-therapeutic research may also include research thatgathers relevant data specific for a given population but whichdoes not benefit the population in question. For example,researchers may be interested in learning about the incidence of erectile dysfunction among mentally incompetent persons.
Clearly the involvement of mentally incompetent persons is necessary for such a study, but no direct benefit will accrue to the research participants.
Following this distinction, and the underlying idea that thera- peutic research carries less risk and more benefits for vulnerableresearch participants, advisory groups like the US NationalBioethics Commission have argued that non-therapeutic clinicalresearch requires more extensive review at the federal level thantherapeutic clinical research of minimal risk.28 This reasoning reflects a more widely shared sentiment that proxy consent may not sufficiently protect mentally incompetentpersons from exploitative research agendas that lack positive ben-efits to participants and which are primarily directed at the men-tally incompetent because of their vulnerability. The removal offirst person informed consent may more readily serve the inter-ests of researchers than it does the interests of research partici-pants – after all, the importance of informed consent may oftenbe weakened when placed in the hands of an imperfect decisionmaking proxy. The mere presence of proxy consent thus cannotalways substitute for first person informed consent, and specialprecaution should therefore be taken with research involvingmentally incompetent individuals.
28 Schuklenk, op. cit. note 3.
Even if informed consent is met via proxies for mentally incom-petent persons, other considerations make their use in clinicaltrials particularly difficult. For example, it is probably more diffi-cult for mentally incompetent persons and their proxies to signalongoing consent for participation in clinical trials. Mentallyincompetent patients may be subject to prolongation of partici-pation against their will, if only because of difficulties in commu-nication with proxies or the inability of proxies to recognise achange of mind in their dependants.
Additionally, given that many researchers and proxies may be narrowly concerned with meeting standards of informed consentin the beginning of a trial, they may subsequently be less percep-tive to attitudinal shifts among mentally incompetent researchparticipants and could therefore be prone to ignoring participantcomplaints or signs of discontent with research involvement.
Unlike research with normal adults, in which procuring informedconsent is a once-off occurrence, research with mentally in-competent persons requires constant monitoring and intimate,continual communication between the participants and proxy toinsure that the former are always informed and consenting.
Mentally incompetent persons may also be more susceptible to outside influences, particularly by people close to them, such asfamily members or caregivers, who may coerce their judgement or inclinations regarding participation in a clinical trial. Forexample, such external influences might easily convince a men-tally incompetent person to participate in research, who in turninforms his proxy that he wishes to participate. Worse, such exter-nal influences could easily emanate from the proxy herself,placing increased responsibility on the clinical researcher toensure that informed consent is free from such manipulations.29 Impoverished people encompass a broad range of individuals,possibly including members of other vulnerable groups discussedabove. Research involving impoverished persons is a globalconcern of research ethics (poor people can be found every-where), but it is a particular problem for developing world coun-tries, especially when confronted with a barrage of developed 29 Cuenod & Gasser, op. cit. note 24.
world researchers seeking to conduct trials amongst the develop-ing world’s poor. As Dickens and Cook aptly note: Resource-poor settings are often found in economically devel-oping and disadvantaged countries, but they also exist in devel-oped countries, such as among inner-city ghettos and barrios,and aboriginal, immigrant, and refugee settlements. Concernshave arisen with special regard to developing countries,however, that commercially-inspired sponsors of studies fromdeveloped countries may take advantage of them as host sitesto test products intended for sale in affluent markets. Thesecountries may allow studies that recruit suitable participantswho are more willing to participate, perhaps for inexpensiveinducements, less understanding of study risks, and, forinstance, less likely and able to pursue grievances and litigationin the event of injury, than developed-country residents.30 Impoverished people are, above everything else, highly suscepti-ble to prospects of financial gain. Even small financial rewards canact as a coercive force, compelling the poor to do what the richwould be reluctant to consider. Like prisoners, refugees, and men-tally incompetent persons, the impoverished may be unable togive informed consent when confronted with compensation forresearch participation. The poor of the developing world areoften severely destitute and desperate for survival, literally livingday to day perpetually in the face of death.
Non-financial rewards that could potentially improve the stan- dard of living of impoverished individuals may also be overly coercive. These rewards might include food, shelter, clothing,medical treatment, etc. Again, the depressed level of economicsubsistence characterising the developing world can transformthese simple rewards/basic entitlements into forceful incentivesfor the poor. Researchers conducting trials among the poor of thedeveloping world must not assume that the incentive structurecharacterising the poor of their home (developed) countriesapplies equally.
The problem of coercive incentive structures in research protocols becomes compounded when one considers that the 30 B.M. Dickens & R.J. Cook. Challenges of Ethical Research in Resource- Poor Settings. International Journal of Gynecology and Obstetrics 2003; 80: 79–86.
impoverished of many developing world countries belong to cul-tures where reciprocity is the norm. That is, researchers areexpected to offer something in return for subject participation.31In principle, this is not problematic, since there is nothinginnately unethical about offering compensation in exchange forparticipation. The problem arises for the researcher, however, intrying to meet such conditions of reciprocity without offeringcompensation that is coercive. Nonetheless, for many impover-ished communities reciprocity is an important criterion to satisfythat should not be ignored: In cultures founded less on market principles than on reciprocity, however, it is offensive to seek an advantage without affording a reciprocal advantage in return. Powerfuloppressors may indeed demand, take, or steal from the poor,but where mutual respect and esteem prevail, an advantagerequested must be reciprocated by an advantage given. What issought and given need not be of equal value since this assimi-lates the exchange to marketplace bargaining. The purpose isthe offering not of goods or services, but of respect, esteem,and recognition of dignity.32 As this passage suggests, incentives may be structured to meet cul-tural demands of reciprocity – which, incidentally, satisfy devel-oped countries’ precaution against commodification – withoutpre-empting informed consent. The impoverished, like any other vulnerable group, should not be discriminated against and removed from research because they are vulnerable. Rather,vulnerability and susceptibility of the poor to incentives meritsthem special protection and oversight in clinical trials – not totalexclusion.
Researchers must also refrain from using the disadvantaged statusof impoverished people as an excuse to engage in sub-standardclinical research procedures, as exemplified in the ZDV (AZT)clinical trials discussed previously. Because the poor (particularlythe poor of the developing world) are unable to afford standardtreatment protocols that might be quite common in the other 31 Cuenod & Gasser, op. cit. note 24.
32 Ibid.
richer, developed countries does not exclude their provision inclinical trials.
The arguments put forth justifying the placebo arm of the ZDV trials (and all other clinical research in which some participantsreceive non-standard treatment that would be deemed unaccept-able in developed countries) usually invoke ‘local standards ofcare’, that is, the participants in the study are left to be no worsereceiving sub-standard treatment (like placebos) since this is whatthey would have received anyway (being poor they would beunable to afford the standard treatment protocols, so it is ethi-cally acceptable to deny them this treatment during clinical trials– so the argument goes). Unfortunately this reasoning misses acrucial point – that the local standards of care in question are adirect result of profit-oriented, developed world drug pricing,which has no particular moral status and which could set drugprices for standard treatment protocols at much more cost-friendly rates for the developing world. It is thus ethically unjustifiable to argue as though impoverished people must make do with what they have (i.e. doing without) simply becausethey are poor, since their diminished purchasing power is theresult of morally arbitrary pricing schemes of the developedworld. Clinical research involving impoverished people musttherefore guarantee participants the best absolute standards ofcare available and should ignore the wealth of the participantsthemselves.
Concern about potential harm to the foetus and harm to themother underlies much of the reluctance of investigators torecruit and enroll pregnant women.33 Guideline 17 of the 2002CIOMS International Ethical Guidelines for Biomedical ResearchInvolving Human Subjects notes that pregnant women are eligi-ble for participation in such trials, given that they ‘are adequatelyinformed about the risks and benefits to themselves, their pregnancies, the foetus, and their subsequent offspring, and totheir fertility.’ The CIOMS guidelines further recommend that 33 A. Kornblum. Trial and Error: Should Pregnant Women Be Research Participants. Environmental Health Perspectives 1994; 102: 1–5. Available at:September, 2003).
research should be therapeutic and restricted to issues regardingwomen/maternal/foetal health, with evaluation and emphasisplaced on assessing risks for teratogenicity.34 The CIOMS guidelines highlight the relevant concerns of usingpregnant women in clinical research. Again, the basic objectionis that informed consent becomes hindered because of lack of sci-entific knowledge on research with pregnant women (and womenin general, for that matter). Because pregnant women have beensystemically excluded from scientific research, the effects of drugson the mother and foetus pose greater risks (due to increaseduncertainty of their effects) than do equivalent studies carried outwith male participants. (For a comprehensive look at this topic,see Mastroianni et al.35) Unfortunately, strict protectionist policies prohibiting or discouraging pregnant women from participating in clinicalresearch only perpetuate this vicious cycle, for if the justificationfor not allowing pregnant women to participate is that little sci-entific evidence exists to assess the risks of their participation,then how will pregnant women ever become acceptable researchparticipants? Similarly, advocates of including pregnant women point out another important dilemma. Because of protectionist attitudespreventing pregnant women from participating in clinical trials,subsequent drug design and development rely heavily on data collected from adult men. However, when these drugs are intro-duced into the market, they are meant to be consumed by every-one – including pregnant women. The exclusion of pregnantwomen from clinical trials, during which these drugs are tested,means that the effects of these drugs are unknown within thepregnant women population. In this manner, the benefits ofbarring pregnant women from participating in research may, inthe end, harm expecting mothers and their foetuses more thantheir inclusion in clinical trials.
34 Council for International Organizations of Medical Sciences. 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects.
Geneva. A(accessed 19 September, 2003).
35 A. Mastroianni, R. Faden & D. Federman, eds. 1994. Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies. Washington, DC. National Academy Press.
Critics like Ruth Macklin, for instance, believe exclusion amounts to nothing less than paternalism on behalf of the widermedical community, who have implicitly discounted the personalknowledge, cognisance, and intimate decision-making ability apregnant mother has over herself and her unborn child: ‘If notpaternalistic, then what is exclusion? . . . Why should some distantscientist whose relationship lasts a brief time make the ultimatedetermination rather than a woman who presumably cares moreabout her unborn child?’36 Ultimately, the issue of whether pregnant women should be involved in clinical research remains divisive, entangled with different risks and benefits. Therapeutic research of direct, rele-vant importance to the health of pregnant women per se is lesscontentious than non-therapeutic research that may as easily becarried out with other, less vulnerable populations, and yet theintegration of pregnant women into the latter is important toachieve higher efficacy in drug design and development across allpopulations. The decision to include or exclude pregnant womenfrom clinical trials decisively hinges on obtaining informedconsent. Whether this can occur in the absence of pertinentknowledge regarding the risks, benefits, and harms surroundingclinical research with pregnant women is questionable.
The same arguments to include/exclude pregnant women alsoapply to research involving (non-pregnant) women and children.
Again, whether informed consent can be obtained or not is thecritical issue, given that women and children have likewise beengenerally excluded from clinical research because of risk anduncertainty. This marginalisation has left them, like pregnantwomen (and foetuses) at a significant disadvantage in terms ofprescription drug efficacy, since comparatively little is knownabout the dosages and effects of prescription drugs in thesegroups.
The discussion above highlights the difficulties of clinicalresearch involving a number of vulnerable populations. The first 36 Ruth Macklin cited in: A. Kornblum, op. cit. note 33.
step in addressing these vulnerabilities is, importantly, recognis-ing that such vulnerabilities do indeed exist.
Beyond this, however, there are no ‘hard and fast’ rules. The ethical acceptability of including or excluding members from anyvulnerable populations cannot easily be derived from a set ofguidelines or normative ethical theory. However, there are someconstraints that any clinical research involving vulnerable popu-lations should satisfy: Informed consent must always be secured from potentialresearch participants, either directly or indirectly from a legallydesignated proxy.
The research must never seek to inflict actual harm on participants.
The research should maximise possible benefits and minimisepossible harm.
The last two constraints are laid out in the influential BelmontReport produced by the National Commission for the Protec-tion of Human Subjects of Biomedical and Behavior Research in 1978.37 Though these same constraints apply to non-vulnerable populations, their relevance for vulnerable popula-tions is greater since they are more likely to fall victim to one or more forms of exploitation. Notice that these constraints are not novel to the discussion presented here – the pitfalls associated with research involving vulnerable populations have occurred when these constraints have not been satisfied. The concerns and recommendations specific to each of thegroups discussed above revolve around these constraints, whichhave only been made more explicit here for the purposes of erudition.
As this module has indicated, clinical research involving vul- nerable populations must proceed with extreme caution. Adher-ing to these principle constraints is an important first step in thisprocess. Proper clinical research must never ignore the potentialfor exploitation of vulnerable populations. Research involvingthese groups is not innately unethical but can certainly become 37 National Commission for the Protection of Human Subjects of Biomedi- cal and Behavioral Research. 1978. Ethical Principles and Guidelines for the Protec-tion of Human Subjects. The Belmont Report. Washington, DC. Government PrintingOffice.
so in the absence of proper oversight and the continual recogni-tion of population vulnerability.
Suppose, for example, that a team of clinical researchers wants to conduct a study examining the potential side effects of a new, non-invasive medical diagnostic device that pulses high intensityradiation through human tissues to produce an X-ray type image. The researchers have decided they wish to conduct thisstudy on a prisoner population and have made arrangements withthe prison officials so that any prisoner who participates receivesspecial prison allowances (more family visitation time, less prisonduties, more frequent access to the prison gym and other enter-tainment facilities, etc.) You have the final decision about whetheror not the research should proceed.
Is this research ethically acceptable? What specific con-cerns should be addressed when dealing with prisoners in thisexample? Do these same concerns apply equally to normal, non-incarcerated adults? Why might have the researchers chosen towork with prisoners instead of normal, non-incarcerated adults?If the prisoners insist that they can indeed give informed consent– even in the presence of incentives – should they be allowed todo so? Is the heightened precaution and increased oversight ofclinical research endeavours dealing with prisoners really just aform of (unjustifiable) discrimination? Suppose a team of clinical researchers begins testing a newvaccine for the West Nile virus amongst a group of Sudaneserefugees currently residing in Algeria. Suppose further that therewere no local internal review boards or other regulatory bodiesthat oversees clinical research endeavours involving theserefugees, and thus the vaccine team simply enters the Sudanese refugee camps, explains to the Sudanese the methods andpurpose of the research, and begins testing the new vaccineagainst a placebo (there is currently no vaccine against the WestNile virus). As a result of their efforts, the vaccine team discoversthe new vaccine was far more clinically effective and drasticallyreduces the number of new West Nile cases within the refugeecamps.
Should the researchers have continued to pursue clinical trialswhen obtaining local ethics approval was impossible? What factorsmay have prevented the refugees from giving informed consent,even after the nature and purpose of the research was explainedto them? Did the fact that the refugees experienced an overallbenefit from participating in the clinical research make it moreethically acceptable? Would other clinical research that offeredno therapeutic benefit to the refugees pose more ethical prob-lems, and if so, what are they? Why might conducting research onthe Sudanese refugees be more pragmatically appealing thanresearch on native (resident) Algerians? Consider again the Willowbrook State School hepatitis experi-ments, in which Dr. Southam deliberately infected mentallyincompetent schoolchildren with hepatitis to study the progres-sion of the disease.
Suppose it is unclear whether proxy consent was obtained in thisstudy. Would any form of proxy consent be ethical in this situa-tion? Is clinical research that leaves participants clearly worse offthan they were before ethically acceptable, and is this study anexample of such research? Would the same research be ethicallyacceptable if mentally competent children were chosen insteadfor the study? Does the fact that the actual participants were men-tally incompetent matter when determining whether the studywas ethical or not? Suppose a group of poor black South Africans are being specifi-cally recruited from local townships for a clinical research studyexamining the efficacy and potential side effects of a new drug tocombat high blood pressure. The team of physicians conductingthe study is from a local research hospital and is intimately familiar with the customs, culture, attitudes, and beliefs of their research participants. The team has chosen to test the newdrug in the townships because poor blacks living there frequentlysuffer from high blood pressure.
What are the relevant considerations of working with im-poverished persons that may hinder this research? How does the fact that the research has therapeutic value affect your deci-sion? How does the fact that the researchers are very familiar with their subject population affect their ability to procureinformed consent? Does the fact that most of the potential clini-cal trial participants will be unable to buy the new blood pressuremedication (if indeed it is proven effective) affect your decisionto allow or disallow the research? If you decide the trial is not ethically acceptable, is this discrimination against impoverishedpeople? Consider again the ZDV (AZT) study involving pregnant, HIV-infected mothers described above, but now suppose that insteadof conducting a placebo arm of the study, the mothers in the control group now received the standard HIV treatment protocol.
How does the absence of a placebo arm affect the ethical accept-ability of the clinical trials? Suppose later it was discovered thatthe new ZDV (AZT) regimen being tested increases the risk ofbirth defects in newborns. Should the trials proceed in light ofthis new information? How does this new source of potential harm affect the ability of HIV-infected mothers to give informedconsent? Jason Lott, MA (Oxon)Medical School Student, Year OneUniversity of Pennsylvania School of Medicine295 John Morgan Building3620 Hamilton WalkPhiladelphia, PA [email protected]

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