Justification of Research in Humans Impossible to reach the important conclusions without studying humans Impossible to reach the important conclusions without studying humans Human physiologic studies, because Human physiologic studies, because animal responses often are not the same animal responses often are not the same Epidemiological studies, because Epidemiological studies, because they depend on human susceptibilities and human interactions and human interactions Drugs for treating humans because Drugs for treating humans because animal experiments don’t always predict animal experiments don’t always predict results results

Justification (2) If you’re going to treat humans, you must study humans If you’re going to treat humans, you must study humans Corollary: If you’re going to treat certain kinds of humans, then you must perform studies with them, for example Corollary: If you’re going to treat certain kinds of humans, then you must perform studies with them, for example Children, mentally impaired, ethnic groups, elderly, women, and pregnant women) Children, mentally impaired, ethnic groups, elderly, women, and pregnant women)

History of the Ethical Research Movement

The Nuremberg Code (World War II) Informed consent is absolutely essential Informed consent is absolutely essential Qualified researchers must use appropriate research designs Qualified researchers must use appropriate research designs There must be a favorable risk/ benefit ratio There must be a favorable risk/ benefit ratio Participants must be free to stop at any time Participants must be free to stop at any time

The Declaration of Helsinki World Medical Association (1964, 1975, 1983, 1989, 1996, 2002) “The well-being of the subject should take precedence over the interests of science and society” “The well-being of the subject should take precedence over the interests of science and society” Consent should be in writing Consent should be in writing Use caution if participant is in dependent relationship with researcher Use caution if participant is in dependent relationship with researcher Limited use of placebo, especially if treatment is available Limited use of placebo, especially if treatment is available Greater access to benefit once research is concluded Greater access to benefit once research is concluded

The Belmont Report (The U.S. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978) Ethical Principles and Guidelines for the Protection of Human Subjects of Research: Ethical Principles and Guidelines for the Protection of Human Subjects of Research: Respect for persons Respect for persons Beneficence Beneficence Justice Justice

Council for International Organizations of Medical Science (CIOMS) Guidelines 1993, 2002 Nuremberg => Helsinki => CIOMS Informed consent Informed consent Research in developing countries Research in developing countries Protection of vulnerable populations Protection of vulnerable populations Distribution of the burdens and benefits Distribution of the burdens and benefits Role and responsibilities of ethics committees Role and responsibilities of ethics committees

Basic Concepts for Ethical Research Ethical Research

Definition of Ethics (1) The discipline of dealing with what is good and bad, with moral duty and obligationThe discipline of dealing with what is good and 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 individual or groupThe principle of conduct governing an individual or group Webster’s Ninth New Collegiate Dictionary Webster’s Ninth New Collegiate Dictionary

Definition of Ethics (2) A Dictionary of Epidemiology, 4th ed, 2001 (J.M. Last (ed)) The branch of philosophy that deals with distinctions between right and wrong – with the moral consequences of human actions

Basic Principles of Research on Human Subjects (1) Human Subjects (1) (The Belmont Report) Respect for persons Respect for persons Beneficence Beneficence Justice Justice

Basic Principles of Research on Human Subjects (2) Respect for persons Choices of autonomous individuals should be respectedChoices of autonomous individuals should be respected People incapable of making their own choices should be protectedPeople incapable of making their own choices should be protected Voluntary subjects need adequate information for decision-makingVoluntary subjects need adequate information for decision-making

Basic Principles of Research on Human Subjects (3) Beneficence Participation in research is associated with a favorable balance of potential benefits and harmsParticipation in research is associated with a favorable balance of potential benefits and harms Maximize possible benefits, minimize potential harmMaximize possible benefits, minimize potential harm

Basic Principles of Research on Human Subjects (4) Justice Participation in research is associated with a favorable balance of potential benefits and harmsParticipation in research is associated with a favorable balance of potential benefits and harms May not exploit or exclude vulnerable individuals who may benefit without good reasonMay not exploit or exclude vulnerable individuals who may benefit without good reason

CONFLICTING PUBLIC HEALTH GOALS Protect the uninfected Protect the uninfected Protect the infected Protect the infected

Summary - Principles and Foundations of Research Ethics All codes and regulations advocate three All codes and regulations advocate three fundamental principles: Respect for personsRespect for persons BeneficenceBeneficence JusticeJustice Research is a privilege, not a right Research is a privilege, not a right The well-being of the participant is paramount The well-being of the participant is paramount

Assessment of Benefits and Risks

Assure That Benefits Outweigh Risks Research must be justified on the basis of a favorable benefit/risk assessment for the research participant. Benefits must outweigh risks Research must be justified on the basis of a favorable benefit/risk assessment for the research participant. Benefits must outweigh risks This is similar to the principal of beneficence or “do no harm.” Researchers must protect participants from harm and maximize their well-being This is similar to the principal of beneficence or “do no harm.” Researchers must protect participants from harm and maximize their well-being

Risk and Benefit Defined A “risk” refers to a harm or likelihood of a harm. The degree of severity of a possible harm may be unclear A “risk” refers to a harm or likelihood of a harm. The degree of severity of a possible harm may be unclear A “benefit” refers to a positive value that accrues to the participant and/or to the society. The precise degree of gain that might accrue to the participant and/or to the society may be uncertain A “benefit” refers to a positive value that accrues to the participant and/or to the society. The precise degree of gain that might accrue to the participant and/or to the society may be uncertain

Types of Risks and Benefits Risks or harms and benefits may be physical (pain or injury), psychological, social, economic, or legal Risks or harms and benefits may be physical (pain or injury), psychological, social, economic, or legal Risks or benefits of research may apply to individual participants, families, groups or organizations, communities, or nations Risks or benefits of research may apply to individual participants, families, groups or organizations, communities, or nations Risks and benefits to the research participant usually carry the most weight Risks and benefits to the research participant usually carry the most weight

General Principles There is absolutely no justification for inhumane treatment of participants There is absolutely no justification for inhumane treatment of participants Risks to participants should always be reduced to the maximum extent possible Risks to participants should always be reduced to the maximum extent possible If a significant risk is involved, justification of the research must be examined with particular care If a significant risk is involved, justification of the research must be examined with particular care Whenever vulnerable persons are participants, the need to involve them must be carefully demonstrated Whenever vulnerable persons are participants, the need to involve them must be carefully demonstrated

Informed Consent

What is Informed Consent? Informed consent is … “consent given by a competent individual who: has received the necessary information has received the necessary information has adequately understood the information has adequately understood the information after considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, or after considering the information, has arrived at a decision without having been subjected to coercion, undue influence or inducement, orintimidation”

Informed Consent as a Process Informed consent is a communication process: Between the researcher and the participant Between the researcher and the participant Starts before the research is initiated Starts before the research is initiated Continues throughout the duration of the study Continues throughout the duration of the study

Essential Elements of Informed Consent (1) Study involves research Study involves research Purpose of study Purpose of study Duration of subject’s participation Duration of subject’s participation Description of the procedures Description of the procedures Foreseeable risks and discomforts Foreseeable risks and discomforts Reasonably expected benefits to subject or others Reasonably expected benefits to subject or others Alternatives, if any Alternatives, if any

Essential Elements of Informed Consent (2) Confidentiality Confidentiality Compensation for injury (>minimal risk) Compensation for injury (>minimal risk) Contacts for information about the research, research-related injury, subject’s rights Contacts for information about the research, research-related injury, subject’s rights Voluntary participation, refusal without loss of benefits, can withdraw at any time Voluntary participation, refusal without loss of benefits, can withdraw at any time

Essential Elements of Informed Consent: Description of the Research That it is a research study That it is a research study Objectives of the study Objectives of the study Expected responsibilities of participant Expected responsibilities of participant Procedures involved Procedures involved Study duration (and possibility of early termination) Study duration (and possibility of early termination) Explanation of features of the research design, such as randomization or placebo Explanation of features of the research design, such as randomization or placebo

Essential Elements of Informed Consent: Description of Benefits “Benefit to subject or others reasonably expected to result from the research” (Common Rule) “Benefit to subject or others reasonably expected to result from the research” (Common Rule) This can include direct medical benefit to participants and expected benefits of the research to the community or larger society, or contributions to scientific knowledge This can include direct medical benefit to participants and expected benefits of the research to the community or larger society, or contributions to scientific knowledge Whether, when and how any products or interventions proven by the research to be safe and effective will be made available to subjects once research is ended, and whether they will be expected to pay for them Whether, when and how any products or interventions proven by the research to be safe and effective will be made available to subjects once research is ended, and whether they will be expected to pay for them

Essential Elements of Informed Consent: Description of Risks Includes physical, social, and psychological risks Includes physical, social, and psychological risks Anticipated or foreseeable risks, pain or discomfort, or inconvenience to the individual (or others) associated with the research Anticipated or foreseeable risks, pain or discomfort, or inconvenience to the individual (or others) associated with the research Include risks to health or well being of subject’s spouse, partner, and/or family Include risks to health or well being of subject’s spouse, partner, and/or family Culturally appropriate format Culturally appropriate format

Essential Elements of Informed Consent: Confidentiality Provisions that will be made to ensure respect for privacy of subjects and confidentiality of records in which subjects are identified Provisions that will be made to ensure respect for privacy of subjects and confidentiality of records in which subjects are identified Limits of confidentiality, what persons or organizations may have access to the information, and possible consequences of breaches of confidentiality Limits of confidentiality, what persons or organizations may have access to the information, and possible consequences of breaches of confidentiality When appropriate, policies about disclosure of results of genetic tests; e.g., certificate of confidentiality When appropriate, policies about disclosure of results of genetic tests; e.g., certificate of confidentiality Special cultural circumstances Special cultural circumstances

Essential Elements of Informed Consent: Compensation Available compensation in case of research- related injury, and whether there is any uncertainty about funding; whether there is compensation for death or disability Available compensation in case of research- related injury, and whether there is any uncertainty about funding; whether there is compensation for death or disability What treatment is available and cost What treatment is available and cost Whether payment will be provided for participation, and if so, how much (fair payment for time, travel or inconvenience) Whether payment will be provided for participation, and if so, how much (fair payment for time, travel or inconvenience) Must not be coercive Must not be coercive

Essential Elements of Informed Consent: Contacts for information Provide contact for research-related questions Provide contact for research-related questions Provide contact for concerns about rights as a participant Provide contact for concerns about rights as a participant Contacts must be realistic and viable Contacts must be realistic and viable

Essential Elements of Informed Consent: Voluntary Participation Absolutely voluntary Absolutely voluntary Right to discontinue at any time Right to discontinue at any time No penalty for refusal No penalty for refusal

Circumstances Must… Give subject sufficient opportunity to consider the decision Give subject sufficient opportunity to consider the decision Minimize possibility of coercion or undue influence Minimize possibility of coercion or undue influence

Language Must… Be understandable to subject or representative Be understandable to subject or representative Language must NOT Language must NOT Waive subject’s rightsWaive subject’s rights Release investigator, sponsor, or institution from liabilityRelease investigator, sponsor, or institution from liability Need to test for comprehension Need to test for comprehension

Available Alternatives Alternative procedures or treatment Alternative procedures or treatment Advantages and disadvantages Advantages and disadvantages Availability Availability

Additional Elements from CIOMS (1) Must include: The nature and sources of funding of the research, the sponsors of the research, the institutional affiliation of the investigators, and financial incentives to the investigators The nature and sources of funding of the research, the sponsors of the research, the institutional affiliation of the investigators, and financial incentives to the investigators The possible research uses, direct or secondary, of the participant`s medical records and of biological specimens taken in the course of clinical care; whether commercial products will be developed The possible research uses, direct or secondary, of the participant`s medical records and of biological specimens taken in the course of clinical care; whether commercial products will be developed Whether it is planned that biological specimens collected in the research will be destroyed at its conclusion, and, if not, details about their storage and possible future use, and that participants have the right to decide about such future use, to refuse storage, and to have the material destroyed Whether it is planned that biological specimens collected in the research will be destroyed at its conclusion, and, if not, details about their storage and possible future use, and that participants have the right to decide about such future use, to refuse storage, and to have the material destroyed

Additional Elements from CIOMS (2) That, after the completion of the study, participants will be informed of the results That, after the completion of the study, participants will be informed of the results Whether the researcher is serving only as a researcher or as both researcher and the subject`s health-care professional Whether the researcher is serving only as a researcher or as both researcher and the subject`s health-care professional The extent of the researcher's responsibility to provide medical services to the subject The extent of the researcher's responsibility to provide medical services to the subject That the research protocol has been approved by an ethical review committee That the research protocol has been approved by an ethical review committee

PRIVACY, CONFIDENTIALITY AND STIGMATIZATION

DEFINITION OF PRIVACY PRIVACY = FREEDOM FROM UNSANCTIONED INTRUSION PRIVACY = FREEDOM FROM UNSANCTIONED INTRUSION (American Heritage Dictionary, 7 th edition, 1992)

PRIVACY Respect for persons guarantees the participants RIGHT to privacy Respect for persons guarantees the participants RIGHT to privacy Lack of privacy causes unwillingness to participate in research Lack of privacy causes unwillingness to participate in research Assertion of investigator that privacy is guaranteed is insufficient Assertion of investigator that privacy is guaranteed is insufficient Participant must perceive that privacy is guaranteed Participant must perceive that privacy is guaranteed

CONFIDENTIALITY VS. ANONYMITY

CONFIDENTIALITY Name and identifying information are recorded Name and identifying information are recorded Investigator guarantees that identifying information will not be shared with unauthorized persons Investigator guarantees that identifying information will not be shared with unauthorized persons Guarantee of confidentiality is only as good as the integrity and care of the investigator and staff Guarantee of confidentiality is only as good as the integrity and care of the investigator and staff

ANONYMITY Name and identifying information are not recorded Name and identifying information are not recorded Impossible to trace back results to informant Impossible to trace back results to informant

DEFINITION OF STIGMATIZATION Stigmatization = characterizing or branding (a person) as disgraceful or ignominious (American Heritage Dictionary, 7 th Edition, 1992)

STIGMATIZED GROUPS (1) Marginalized groups Marginalized groups The poorThe poor Ethnic minoritiesEthnic minorities Sex workersSex workers Drug usersDrug users The uneducated (illiterate)The uneducated (illiterate) Men who have sex with other menMen who have sex with other men

STIGMATIZED GROUPS (2) HIV-infected persons HIV-infected persons Persons infected with sexually transmitted organisms Persons infected with sexually transmitted organisms Sexually promiscuous persons Sexually promiscuous persons

Lack of confidentiality creates a risk of stigmatization Investigator has the responsibility to guarantee freedom from stigmatization as a result of the research for all participants