Justification of Research in HumansJustification of Research in Humans

•• Impossible to reach the important Impossible to reach the important conclusions without studying humansconclusions without studying humans

•• Human physiologic studies, becauseHuman physiologic studies, becauseanimal responses often are not the sameanimal responses often are not the same

•• Epidemiological studies, becauseEpidemiological studies, becausethey depend on human susceptibilitiesthey depend on human susceptibilitiesand human interactionsand human interactions

•• Agents for treating humans becauseAgents for treating humans becauseanimal experiments donanimal experiments don’’t always predictt always predictresultsresults

Justification (2)Justification (2)

•• If youIf you’’re going to treat humans, re going to treat humans, you must study humansyou must study humans

•• Corollary: If youCorollary: If you’’re going to treat certain re going to treat certain kinds of humans, then you must perform kinds of humans, then you must perform studies with them, for example studies with them, for example

•• Children, mentally impaired, ethnic Children, mentally impaired, ethnic groups, elderly, women, and pregnant groups, elderly, women, and pregnant womenwomen

CONFLICTING PUBLIC HEALTH CONFLICTING PUBLIC HEALTH GOALSGOALS

•• Protect the uninfectedProtect the uninfected

•• Protect the infectedProtect the infected

ETHICS

The ethics of takingThe ethics of taking

action vs. the ethics of action vs. the ethics of avoiding actionavoiding action

Definition of EthicsDefinition of Ethics

•• Ethics: Ethics: •• The discipline of dealing with what is good The discipline of dealing with what is good

and bad, with moral duty and obligationand bad, with moral duty and obligation

•• A set of moral principles or valuesA set of moral principles or values

•• The principle of conduct governing an The principle of conduct governing an individual or group individual or group

•• WebsterWebster’’s Ninth New Collegiate Dictionarys Ninth New Collegiate Dictionary

History of the EthicalHistory of the EthicalResearch MovementResearch Movement

The Nuremberg Code The Nuremberg Code (World War II)(World War II)

•• InformedInformed consent is absolutely essentialconsent is absolutely essential•• Qualified researchers must use appropriate Qualified researchers must use appropriate

research designsresearch designs•• There must be a favorable risk/ benefit ratioThere must be a favorable risk/ benefit ratio•• Participants must be free to stop at any Participants must be free to stop at any

time time

The Declaration of HelsinkiThe Declaration of HelsinkiWorld Medical AssociationWorld Medical Association

(1964, 1975, 1983, 1989, 1996, 2002)(1964, 1975, 1983, 1989, 1996, 2002)•• ““The wellThe well--being of the subject should take being of the subject should take

precedence over the interests of science and precedence over the interests of science and societysociety””

•• Consent should be in writingConsent should be in writing

•• Use caution if participant is in dependent Use caution if participant is in dependent relationship with researcherrelationship with researcher

•• Limited use of placebo, especially if treatment is Limited use of placebo, especially if treatment is availableavailable

•• Greater access to benefit once research is Greater access to benefit once research is concludedconcluded

The Belmont Report (The U.S. The Belmont Report (The U.S. National Commission for the National Commission for the

Protection of Human Subjects of Protection of Human Subjects of Biomedical and Behavioral Biomedical and Behavioral

Research, 1978)Research, 1978)

Ethical Principles and Guidelines for the Ethical Principles and Guidelines for the Protection of Human Subjects of Protection of Human Subjects of Research:Research:

•• Respect for personsRespect for persons•• BeneficenceBeneficence•• JusticeJustice

Council for International Council for International Organizations of Medical Science Organizations of Medical Science

(CIOMS) Guidelines 1993, 2002(CIOMS) Guidelines 1993, 2002NurembergNuremberg => => HelsinkiHelsinki => => CIOMSCIOMS•• Informed consentInformed consent•• Research in developing countriesResearch in developing countries•• Protection of vulnerable populationsProtection of vulnerable populations•• Distribution of the burdens and benefitsDistribution of the burdens and benefits•• Role and responsibilities of ethics Role and responsibilities of ethics

committeescommittees

Basic Concepts forBasic Concepts forEthical ResearchEthical Research

Basic Principles of Research onBasic Principles of Research onHuman SubjectsHuman Subjects

((The Belmont Report)The Belmont Report)

••Respect for personsRespect for persons

••BeneficenceBeneficence

••JusticeJustice

Basic Principles of Research on Basic Principles of Research on Human Subjects (1)Human Subjects (1)

•• Respect for personsRespect for persons•• Choices of autonomous individuals should be Choices of autonomous individuals should be

respectedrespected

•• People incapable of making their own choices People incapable of making their own choices should be protectedshould be protected

•• Voluntary subjects need adequate information Voluntary subjects need adequate information for decisionfor decision--makingmaking

Basic Principles of Research on Basic Principles of Research on Human Subjects (2)Human Subjects (2)

•• BeneficenceBeneficence•• Participation in research is associated with a Participation in research is associated with a

favorable balance of potential benefits and favorable balance of potential benefits and harmsharms

•• Maximize possible benefits, minimize potential Maximize possible benefits, minimize potential harmharm

Basic Principles of Research on Basic Principles of Research on Human Subjects (3)Human Subjects (3)

•• JusticeJustice•• Participation in research is associated with a Participation in research is associated with a

favorable balance of potential benefits and favorable balance of potential benefits and harmsharms

•• May not exploit or exclude vulnerable May not exploit or exclude vulnerable individuals who may benefit without good individuals who may benefit without good reason reason

Summary Summary -- Principles and Principles and Foundations of Research EthicsFoundations of Research Ethics

•• All codes and regulations advocate 3All codes and regulations advocate 3fundamental principles:fundamental principles:•• Respect for personsRespect for persons•• BeneficenceBeneficence•• JusticeJustice

•• Research is a privilege, not a rightResearch is a privilege, not a right•• The wellThe well--being of the participant is being of the participant is

paramountparamount

Assessment of Benefits Assessment of Benefits and Risksand Risks

Assure That Benefits Assure That Benefits Outweigh RisksOutweigh Risks

•• Research must be justified on the basis of a Research must be justified on the basis of a favorable benefit/risk assessment for the favorable benefit/risk assessment for the research participant. Benefits must research participant. Benefits must outweigh risks.outweigh risks.

•• This is similar to the principal of This is similar to the principal of beneficence or beneficence or ““do no harm.do no harm.”” Researchers Researchers must protect participants from harm and must protect participants from harm and maximize their wellmaximize their well--being.being.

Risk and Benefit DefinedRisk and Benefit Defined

•• A A ““riskrisk”” refers to a harm or likelihood of a refers to a harm or likelihood of a harm. The degree of severity of a possible harm. The degree of severity of a possible harm may be unclear.harm may be unclear.

•• A A ““benefitbenefit”” refers to a positive value that refers to a positive value that accrues to the participant and/or to the accrues to the participant and/or to the society. The precise degree of gain that society. The precise degree of gain that might accrue to the participant and/or to might accrue to the participant and/or to the society may be uncertain. the society may be uncertain.

Types of Risks and BenefitsTypes of Risks and Benefits

•• Risks or harms and benefits may be physical Risks or harms and benefits may be physical (pain or injury), psychological, social, (pain or injury), psychological, social, economic, or legal. economic, or legal.

•• Risks or benefits of research may apply to Risks or benefits of research may apply to individual participants, families, groups or individual participants, families, groups or organizations, communities, or nations.organizations, communities, or nations.

•• Risks and benefits to the research participant Risks and benefits to the research participant usually carry the most weight. usually carry the most weight.

General PrinciplesGeneral Principles•• There is absolutely no justification for There is absolutely no justification for

inhumane treatment of participants.inhumane treatment of participants.•• Risks to participants should always be Risks to participants should always be

reduced to the maximum extent possible.reduced to the maximum extent possible.•• If a significant risk is involved, justification of If a significant risk is involved, justification of

the research must be examined with the research must be examined with particular care.particular care.

•• Whenever vulnerable persons are Whenever vulnerable persons are participants, the need to involve them must participants, the need to involve them must be carefully demonstrated.be carefully demonstrated.

ETHICAL PROCEDURES FOR INTERNATIONAL

RESEARCH (U.S. PUBLIC HEALTH SERVICE)

FWAsFWAsInstitutions that want to engage Institutions that want to engage in research that do not have an in research that do not have an IRB/IEC may submit a IRB/IEC may submit a FederalwideFederalwide Assurance form that Assurance form that designates one or more approved designates one or more approved IRBsIRBs that are already registered that are already registered with OHRPwith OHRP

IRB AuthorizationIRB AuthorizationReliance on another institution's IRB/IEC Reliance on another institution's IRB/IEC must be documented by a written must be documented by a written agreement that is available for review by agreement that is available for review by OHRP upon request. OHRP upon request. OHRP'sOHRP's sample IRB sample IRB Authorization Agreement may be used for Authorization Agreement may be used for this purpose, or the institutions involved this purpose, or the institutions involved may develop their own agreement. Future may develop their own agreement. Future designation of other IRB(s)/IEC(s) designation of other IRB(s)/IEC(s) requires update of the FWArequires update of the FWA..

Foreign IRB ApprovalForeign IRB ApprovalFollowing approval of the FWA by Following approval of the FWA by OHRP, the research project must be OHRP, the research project must be reviewed by the designated IRB/IEC reviewed by the designated IRB/IEC and an approval letter issued listing and an approval letter issued listing the IRB number and the FWA the IRB number and the FWA number of the institution conducting number of the institution conducting the research, and signed by the the research, and signed by the IRB/IEC chair.IRB/IEC chair.

Multiple Multiple FWAsFWAsFunded projects may be required to Funded projects may be required to get multiple get multiple FWAsFWAs if they "engage" if they "engage" other institutions or their employees other institutions or their employees as partners or participants in the as partners or participants in the project (see OHRP website for project (see OHRP website for definition of "engagement"). definition of "engagement"). Permitted use of other institutions' Permitted use of other institutions' facilities does not constitute facilities does not constitute engagement.engagement.

Ethics Course RequirementEthics Course RequirementAll investigators (including nonAll investigators (including non--U.S. U.S. investigators) must complete an investigators) must complete an approved ethics training course and approved ethics training course and obtain a certificate of completion obtain a certificate of completion (approved courses and completion (approved courses and completion certificates are available on the web) certificates are available on the web) before their proposals can be before their proposals can be approved by the IRB/IECapproved by the IRB/IEC

RESEARCH IN RESEARCH IN POPULATIONS AND POPULATIONS AND

COMMUNITIES WITH COMMUNITIES WITH LIMITED RESOURCESLIMITED RESOURCES

TWO RESPONSIBILITIES•• Prior to conducting research in a Prior to conducting research in a

population or community with population or community with limited resources the limited resources the researcher/sponsor should:researcher/sponsor should:1) Ensure the research responds to 1) Ensure the research responds to the health needs and priorities of the the health needs and priorities of the target community.target community.2) Ensure any product developed will 2) Ensure any product developed will be made available to the community.be made available to the community.

RESPONSIVENESS TO RESPONSIVENESS TO COMMUNITY HEALTH COMMUNITY HEALTH

NEEDSNEEDS•• It is not sufficient to determine It is not sufficient to determine

disease prevalence and that new disease prevalence and that new research is needed.research is needed.

•• If successful interventions result If successful interventions result from the research they must be made from the research they must be made available to the community.available to the community.

•• If this is not done, the research is If this is not done, the research is exploitative.exploitative.

MAKING A PRIOR AGREEMENTMAKING A PRIOR AGREEMENT

•• Before the research begins, a plan Before the research begins, a plan should be offered in which the should be offered in which the proposed product is made available to proposed product is made available to the host nation upon completion of the the host nation upon completion of the study.study.

•• Participants should include Participants should include representatives of the nationrepresentatives of the nation’’s s government, local authorities, government, local authorities, community members, and NGO groups.community members, and NGO groups.

COMPREHENSIVENESS OF THE COMPREHENSIVENESS OF THE AGREEMENTAGREEMENT

•• The agreement should include The agreement should include payments, royalties, distribution payments, royalties, distribution costs, subsidies, technology, and costs, subsidies, technology, and intellectual property.intellectual property.

•• In some cases, international In some cases, international organizations, public and private, organizations, public and private, may also be included in the may also be included in the discussions.discussions.

THE ETHICS OF CONDUCTING THE ETHICS OF CONDUCTING RESEARCH IN DEVELOPING RESEARCH IN DEVELOPING

COUNTRIESCOUNTRIES•• When, if ever, should investigators use the When, if ever, should investigators use the

standards of care/ethics of developing countries vs. standards of care/ethics of developing countries vs. developed countries (e.g., Tanzania drug trials)?developed countries (e.g., Tanzania drug trials)?

•• Are investigators responsible for the health of their Are investigators responsible for the health of their participants?participants?

•• Can participants in developing countries understand Can participants in developing countries understand informed consent (e.g., is there an expectancy of informed consent (e.g., is there an expectancy of benefit or treatment even if not stated in the benefit or treatment even if not stated in the informed consent)?informed consent)?

•• Is it ethical to do research in developing countries Is it ethical to do research in developing countries on issues relevant to developed countries but not on issues relevant to developed countries but not relevant to developing countries? relevant to developing countries?

REQUIREMENTS FOR REQUIREMENTS FOR COMMUNITY APPROVALCOMMUNITY APPROVAL

•• Community must have legitimate, Community must have legitimate, empowered empowered spokesperson(sspokesperson(s) )

•• Community must have a common healthCommunity must have a common health--related culturerelated culture

•• A communication network for the A communication network for the community must be in placecommunity must be in place

FACTORS INFLUENCING FACTORS INFLUENCING VOLUNTARY CONSENTVOLUNTARY CONSENT

•• Vulnerability to incentivesVulnerability to incentives•• Impact of community pressureImpact of community pressure•• Power of investigators to influencePower of investigators to influence•• Ability of participants to understand goals Ability of participants to understand goals

and risksand risks

RESEARCH CONTROVERSIES RESEARCH CONTROVERSIES IN DEVELOPING COUNTRIESIN DEVELOPING COUNTRIES

•• Are placebo groups ethical?Are placebo groups ethical?•• Should placebos reflect international or Should placebos reflect international or

local standards of care?local standards of care?•• Should participants be assured care Should participants be assured care

beyond the trials beyond the trials –– if so, for how long?if so, for how long?•• Should care be provided to the trial Should care be provided to the trial

community?community?•• Should trials be evaluated for scaleShould trials be evaluated for scale--up up

feasibility before implementation?feasibility before implementation?