Justification of Research in Humans

Justification of Research in Justification of Research in HumansHumans

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

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

• Epidemiological studies, becauseEpidemiological studies, becausethey depend on human susceptibilitiesthey depend on human susceptibilities

and human interactionsand human interactions

• Agents for treating humans becauseAgents for treating humans because animal experiments don’t always predictanimal experiments don’t always predict resultsresults

Justification (2)Justification (2)

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

• Corollary: If you’re going to treat certain Corollary: If you’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 CONFLICTING PUBLIC HEALTH GOALSHEALTH GOALS

•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

• Webster’s Ninth New Collegiate DictionaryWebster’s Ninth New Collegiate Dictionary

History of the EthicalHistory of the Ethical

Research MovementResearch Movement

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

• InformedInformed consent is absolutely essential consent 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 well-being of the subject should take The well-being of the subject should take

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

• Consent should be in writingConsent should be in writing

• Use caution if participant is in dependent relationship Use caution if participant is in dependent relationship with researcherwith 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 concludedGreater access to benefit once research is concluded

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

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

Research, 1978)Research, 1978)

Ethical Principles and Guidelines for Ethical Principles and Guidelines for the Protection of Human Subjects of the 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, 2002

NurembergNuremberg => => 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 for

Ethical ResearchEthical Research

Basic Principles of Basic Principles of Research onResearch on

Human SubjectsHuman Subjects((The Belmont Report)The Belmont Report)

•Respect for personsRespect for persons

•BeneficenceBeneficence

•JusticeJustice

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

• Respect for personsRespect for persons

• Choices of autonomous individuals Choices of autonomous individuals should be respectedshould be respected

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

• Voluntary subjects need adequate Voluntary subjects need adequate information for decision-makinginformation for decision-making

Basic Principles of Basic Principles of Research on Human Research on Human

Subjects (2)Subjects (2)• BeneficenceBeneficence

• Participation in research is associated Participation in research is associated with a favorable balance of potential with a favorable balance of potential benefits and harmsbenefits and harms

• Maximize possible benefits, minimize Maximize possible benefits, minimize potential harmpotential harm

Basic Principles of Basic Principles of Research on Human Research on Human

Subjects (3)Subjects (3)• JusticeJustice

• Participation in research is associated Participation in research is associated with a favorable balance of potential with a favorable balance of potential benefits and harmsbenefits and harms

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

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

• All codes and regulations advocate 3All codes and regulations advocate 3

fundamental principles:fundamental principles:• Respect for personsRespect for persons• BeneficenceBeneficence• JusticeJustice

• Research is a privilege, not a rightResearch is a privilege, not a right

• The well-being of the participant is The well-being of the participant is paramountparamount

Assessment of Assessment of Benefits and RisksBenefits and Risks

Assure That Benefits Assure That Benefits Outweigh RisksOutweigh Risks

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

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

Risk and Benefit Risk and Benefit DefinedDefined

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

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

Types of Risks and Types of Risks and BenefitsBenefits

• Risks or harms and benefits may be Risks or harms and benefits may be physical (pain or injury), psychological, physical (pain or injury), psychological, social, economic, or legal. social, 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 Risks and benefits to the research participant usually carry the most weight. participant 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 reduced to the maximum extent possible.possible.

• If a significant risk is involved, If a significant risk is involved, justification of the research must be justification of the research must be examined with particular care.examined with particular care.

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

ETHICAL PROCEDURES FOR INTERNATIONAL

RESEARCH (U.S. PUBLIC HEALTH

SERVICE)

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

IRB AuthorizationIRB Authorization

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

Foreign IRB ApprovalForeign IRB Approval

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

Multiple FWAsMultiple FWAs

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

Ethics Course RequirementEthics Course RequirementAll investigators (including non-All investigators (including non-U.S. investigators) must complete U.S. investigators) must complete an approved ethics training an approved ethics training course and obtain a certificate of course and obtain a certificate of completion (approved courses completion (approved courses and completion certificates are and completion certificates are available on the web) before their available on the web) before their proposals can be approved by the proposals can be approved by the IRB/IECIRB/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 from If successful interventions result from the research they must be made 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 MAKING A PRIOR AGREEMENTAGREEMENT• 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 proposed product is made available to the host nation upon available to the host nation upon completion of the study.completion of the study.

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

COMPREHENSIVENESS OF COMPREHENSIVENESS OF THE AGREEMENTTHE AGREEMENT• 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 standards of care/ethics of developing countries vs. developed countries (e.g., Tanzania drug vs. developed countries (e.g., Tanzania drug trials)?trials)?

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

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

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

REQUIREMENTS FOR REQUIREMENTS FOR COMMUNITY APPROVALCOMMUNITY APPROVAL

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

• Community must have a common Community must have a common health-related culturehealth-related 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 Ability of participants to understand goals and risksgoals and risks

RESEARCH CONTROVERSIES RESEARCH CONTROVERSIES IN IN DEVELOPING IN IN DEVELOPING COUNTRIESCOUNTRIES• 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 – if so, for how long?beyond the trials – 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 scale-up Should trials be evaluated for scale-up

feasibility before implementation?feasibility before implementation?