Ethics in international Ethics in international ResearchResearch

Justice across national Justice across national boundariesboundaries

Clinical Trials Group (ACTG) 076: Clinical Trials Group (ACTG) 076: Vertical Perinatal HIV TransmissionVertical Perinatal HIV Transmission

Antiretroviral drug zidovudine administered Antiretroviral drug zidovudine administered orally in the prenatal period, intravenously orally in the prenatal period, intravenously during labor, and administered orally to the during labor, and administered orally to the newborn reduced HIV infection in the newborn reduced HIV infection in the newborn by two-thirds newborn by two-thirds Study terminated at first interim analysisStudy terminated at first interim analysisWithin two months the Public Health Within two months the Public Health Service announced that HIV positive Service announced that HIV positive women should receive this treatment.women should receive this treatment.

Post-ACTG 076: USAPost-ACTG 076: USA

zidovudine was zidovudine was estimated to have estimated to have reduced neonatal HIV reduced neonatal HIV death by 50% in the death by 50% in the US and Europe.US and Europe.

Post ACTG-076: AfricaPost ACTG-076: Africa

In Africa, accounting In Africa, accounting for 70% of the global for 70% of the global HIV burden, therapy HIV burden, therapy played no role played no role because of cost because of cost

Therapeutic regimens Therapeutic regimens as effective but less as effective but less expensive than expensive than zidovudine needed for zidovudine needed for developing countriesdeveloping countries

Research design to search for a Research design to search for a less expensive regimen?less expensive regimen?

June, 1994, WHO convened expert panel to June, 1994, WHO convened expert panel to advise research agenda for perinatal HIV advise research agenda for perinatal HIV transmission transmission

““Placebo-controlled trials offer the best Placebo-controlled trials offer the best option for a rapid and scientifically valid option for a rapid and scientifically valid assessment of alternative antiretroviral assessment of alternative antiretroviral drug regiments to prevent [perinatal] drug regiments to prevent [perinatal] transmission of HIV.” (WHO 1994)transmission of HIV.” (WHO 1994)

18 trials to explore alternative 18 trials to explore alternative interventionsinterventions

** In trials conducted in the US, subjects in In trials conducted in the US, subjects in all study groups had full access to all study groups had full access to zidovudine or other antiretroviral drugs. zidovudine or other antiretroviral drugs. In 15 of the 16 trials in developing In 15 of the 16 trials in developing countries, some or all of the patients were countries, some or all of the patients were not provided with antiretroviral drugs. not provided with antiretroviral drugs. 9/15 studies conducted in other countries 9/15 studies conducted in other countries were funded by the US government were funded by the US government through the CDC or NIH. through the CDC or NIH.

Declaration of HelsinkiDeclaration of Helsinki

First written in 1962; First written in 1962; rewritten in 1975; rewritten in 1975; modified three times modified three times since its rewrite. since its rewrite.

All versions placed All versions placed the benefit and well-the benefit and well-being of the subject being of the subject as the pre-eminent as the pre-eminent concernconcern

Debate over Declaration RevisionsDebate over Declaration Revisions

establishment of general rather than local establishment of general rather than local ethical review committees ethical review committees

a more liberal view towards the use of a more liberal view towards the use of placebos; and placebos; and

allowing for local determination of access allowing for local determination of access to health careto health care

PolarizationPolarization

“ “Some argued that the Some argued that the proposed revision established proposed revision established a model for human biomedical a model for human biomedical research ethics that research ethics that encouraged utility and encouraged utility and efficiency at the expense of efficiency at the expense of patient autonomy and well-patient autonomy and well-being. Those who defended being. Those who defended the amendments said they the amendments said they were more in line with were more in line with contemporary ethical thinking contemporary ethical thinking ….”….”

Deutsch Edinburgh 2000 Deutsch Edinburgh 2000 633-641633-641

Declaration of Helsinki (2000) Declaration of Helsinki (2000)

Significant rewriteSignificant rewrite

Emphasizing again that the rights of the Emphasizing again that the rights of the individual should take precedence over the individual should take precedence over the interests of science and societyinterests of science and society

Emphasizes the protection of vulnerable Emphasizes the protection of vulnerable populations. populations.

Local versus international rule unclearLocal versus international rule unclear

Modification of Helsinki (2001)Modification of Helsinki (2001)

Para 29Para 29: “The benefits, risks, burdens and : “The benefits, risks, burdens and effectiveness of a new method should be effectiveness of a new method should be tested against those of the best current …tested against those of the best current …methods. This does not exclude the use of methods. This does not exclude the use of placebo, or no treatment in studies where placebo, or no treatment in studies where no proven…method exists”no proven…method exists”AmendmentAmendment: “: “a placebo-controlled trial a placebo-controlled trial may be ethically acceptable, even if a may be ethically acceptable, even if a proven therapy is availableproven therapy is available”(2001 revision) ”(2001 revision)

Issues behind the DeclarationIssues behind the Declaration

Local versus global standards of careLocal versus global standards of care

Informed ConsentInformed Consent

EquiposeEquipose

Placebo controlled studies versus no Placebo controlled studies versus no placebo (“Science versus Ethics”)placebo (“Science versus Ethics”)

Shared Burden of Risk/EquityShared Burden of Risk/Equity

Standard of care: local versus Standard of care: local versus globalglobal

““A global view of justice, A global view of justice, which endorses which endorses international equity, international equity, cannot be squared with cannot be squared with international research international research guidelines that allow guidelines that allow ‘local conditions’ to define ‘local conditions’ to define the scope of duty to the the scope of duty to the control group”control group”

de Zulueta P Bioethics 2001 de Zulueta P Bioethics 2001 289-311 289-311

Standard of care: local versus global Standard of care: local versus global (con)(con)

Should the standard be the standard of the Should the standard be the standard of the host country, the standard of the host country, the standard of the sponsoring country or some global sponsoring country or some global standard?standard?– Is it appropriate to assume that a standard set Is it appropriate to assume that a standard set

by industrialized countries can be/should be by industrialized countries can be/should be applied to developing countries? applied to developing countries?

– Should standards of care differ based on the Should standards of care differ based on the sponsoring country ?sponsoring country ?

Standard of care: local versus global Standard of care: local versus global (con)(con)

Many instances of possibly “unethical Many instances of possibly “unethical exploitation” occur in a two-tiered system exploitation” occur in a two-tiered system

** Local scientists and physicians argue that Local scientists and physicians argue that only because of the two-tiered system did only because of the two-tiered system did their country have any access to these their country have any access to these studies.studies.An argument has been made that even if An argument has been made that even if the funding is external, if the researchers the funding is external, if the researchers are local, local standards can be used. are local, local standards can be used.

Standard of care: local versus global (con)Standard of care: local versus global (con)

Are local investigators, who have much to gain both Are local investigators, who have much to gain both financially and by reputation, by receiving funding financially and by reputation, by receiving funding from the US, in the position to take an appropriate from the US, in the position to take an appropriate ethical stance?ethical stance? ““,,,[A] local standard may benefit participants and non-,,,[A] local standard may benefit participants and non-participants alike in impoverished countries, but it comes at participants alike in impoverished countries, but it comes at the cost of using a double standard for what is considered the cost of using a double standard for what is considered ethical human experimentation.”Rothman BMJ 2000 442-444ethical human experimentation.”Rothman BMJ 2000 442-444““...[t]he heated debate reflects a tension, if not an ...[t]he heated debate reflects a tension, if not an outright war, between two conflicting meta-ethical outright war, between two conflicting meta-ethical systems, or incommensurable paradigms, that underpin systems, or incommensurable paradigms, that underpin scientific research involving human subjects…” scientific research involving human subjects…” de Zulueta de Zulueta P Bioethics 2001 289-311P Bioethics 2001 289-311

Informed ConsentInformed Consent: :

What constitutes “informed consent”---especially What constitutes “informed consent”---especially among those who are vulnerable because of among those who are vulnerable because of age, mental or physical disability, level of age, mental or physical disability, level of education, or degree of poverty?education, or degree of poverty?Is it appropriate to ask a potential subject in a Is it appropriate to ask a potential subject in a developing country who lives under an entirely developing country who lives under an entirely different legal system to complete an informed different legal system to complete an informed consent that is consistent with the legal consent that is consistent with the legal expectations of the sponsoring countryexpectations of the sponsoring countryCan we explain concepts of risk and protection Can we explain concepts of risk and protection to persons with little education? to persons with little education?

Informed Consent, con.Informed Consent, con.

Study in the Gambia of 137 acceptors and Study in the Gambia of 137 acceptors and 52 refusors of Hemophilus influenza type 52 refusors of Hemophilus influenza type B conjugate:B conjugate:

** 90% knew purpose of vaccine was to prevent 90% knew purpose of vaccine was to prevent disease disease

** 93% of acceptors did so to receive the vaccine 93% of acceptors did so to receive the vaccine

** “placebo control” was understood by only 10%“placebo control” was understood by only 10%Leach et al Soc Sci Med 1999: 139-48Leach et al Soc Sci Med 1999: 139-48

Informed Consent, con.Informed Consent, con.

What does a vaccine that may have fifty percent What does a vaccine that may have fifty percent efficacy mean to an illiterate woman?efficacy mean to an illiterate woman?How do we establish that we have explained How do we establish that we have explained something clearly?something clearly?Are some populations so vulnerable, so Are some populations so vulnerable, so dependent that the concept of “informed, dependent that the concept of “informed, voluntary consent” may be unachievable?voluntary consent” may be unachievable?Are genuinely consensual relations possible Are genuinely consensual relations possible between the research community and between the research community and participants who otherwise have little or no participants who otherwise have little or no access to healthcare or other basic rights and access to healthcare or other basic rights and liberties?.... liberties?....

EquipoiseEquipoise

The state in which we have no reason to The state in which we have no reason to believe that one experimental condition or believe that one experimental condition or intervention is superior to another intervention is superior to another ““The necessity for investigators to be in The necessity for investigators to be in this state of equipoise applies to placebo-this state of equipoise applies to placebo-controlled trials, as well. Only when there controlled trials, as well. Only when there is no known effective treatment is it ethical is no known effective treatment is it ethical to compare a potential new treatment with to compare a potential new treatment with a placeboa placebo”. ”. Angell NEJM 1997 847-849Angell NEJM 1997 847-849

Placebo Control versus no Placebo Control versus no control (“Science versus ethics”)control (“Science versus ethics”)

Equipoise: the gateway to and the foundation Equipoise: the gateway to and the foundation for a placebo-controlled trial.for a placebo-controlled trial.

The randomized, placebo-controlled trial is The randomized, placebo-controlled trial is upheld as the paradigm of the excellence in upheld as the paradigm of the excellence in sciencescience

If there is not equipoise, there is not a basis for If there is not equipoise, there is not a basis for genuine scientific querygenuine scientific query

Is the overarching need for a placebo-controlled Is the overarching need for a placebo-controlled trial “placing science ahead of ethics”? trial “placing science ahead of ethics”?

Placebo Control versus no control Placebo Control versus no control (“Science versus ethics”) (con.)(“Science versus ethics”) (con.)

Placebo group provides the benchmark Placebo group provides the benchmark

Placebo-controlled trials withhold existing Placebo-controlled trials withhold existing therapy in order to further observe the therapy in order to further observe the natural course of infection and diseasenatural course of infection and disease

Placebo=a fixed and reliable reference Placebo=a fixed and reliable reference point ? point ?

At times already approved medications At times already approved medications can be ineffective can be ineffective

Reasonable riskReasonable risk

Central component of justice: individual or Central component of justice: individual or group should neither shoulder a group should neither shoulder a disproportionate percentage of risk nor disproportionate percentage of risk nor receive more than “fair share” of benefits receive more than “fair share” of benefits

~90% of medical research conducted on ~90% of medical research conducted on diseases that cause only 10% of the global diseases that cause only 10% of the global burden of disease burden of disease

Reasonable Risk, con.Reasonable Risk, con.

Is this a fair sharing of the burden of risk? Of the Is this a fair sharing of the burden of risk? Of the possible benefit? possible benefit? If he were to receive a If he were to receive a higher sum, would this make the study higher sum, would this make the study more ethical—or less ethical?more ethical—or less ethical? Would Would offering him a lower stipend for participation offering him a lower stipend for participation make it more ethical? make it more ethical? Is there a different Is there a different way that he could be compensatedway that he could be compensated? ? Would the “ethics” change if the disease Would the “ethics” change if the disease prevalence remained the same in his prevalence remained the same in his country, but relative to other diseases, it country, but relative to other diseases, it was more prominent?was more prominent?

Reasonable Risk, con.Reasonable Risk, con.

Would it change if his education level Would it change if his education level were higher?were higher? Are we concerned that he Are we concerned that he cannot understand the concept of a cannot understand the concept of a vaccine that is 65% efficacious? vaccine that is 65% efficacious? Would it Would it change if he were not a peasant farmer change if he were not a peasant farmer but were a US soldier stationed abroad but were a US soldier stationed abroad would the situation be more ethical?would the situation be more ethical? If If the sponsoring agency were not the US the sponsoring agency were not the US but his own country, would this change the but his own country, would this change the ethics of the situation?ethics of the situation?

““Fair Benefits": An ethical solution Fair Benefits": An ethical solution or a utilitarian compromise?or a utilitarian compromise?

Benefits to Participants During the ResearchBenefits to Participants During the ResearchImprovements to health and health careImprovements to health and health careCollateral health services unnecessary for research studCollateral health services unnecessary for research studBenefits to Population During the ResearchBenefits to Population During the ResearchCollateral health services unnecessary for research Collateral health services unnecessary for research Public health measuresPublic health measuresEmployment and economic activityEmployment and economic activityBenefits to Population After the ResearchBenefits to Population After the ResearchReasonable availability of effective Research and medical Reasonable availability of effective Research and medical care capacity developmentcare capacity developmentPublic health measuresPublic health measuresLong-term researchLong-term researchSharing of financial rewards from research resultsSharing of financial rewards from research results

Supplemental components to “Fair BenefitsSupplemental components to “Fair Benefits** Collaborative PartnershipCollaborative Partnership

Community involvement at all stagesCommunity involvement at all stagesFree, uncoerced decision-making by populationFree, uncoerced decision-making by populationbearing the burdens of the researchbearing the burdens of the research

** TransparencyTransparencyCentral, publicly accessible repository of benefit Central, publicly accessible repository of benefit agreements agreements Process of community consultationsProcess of community consultations

Ethical aspects of Research in Developing Countries Science 2002 21Ethical aspects of Research in Developing Countries Science 2002 21