Protecting human subjects

in research

Pawel Stefanoff

Key issues

• Historical perspective

• Guiding principles

• Guidance for protocol preparation

• Informed consent

• Ethical committee review

• Conducting the study

• Reporting the study

Ethical guidance for research: Milestones

• Nuremberg code– War crimes tribunal at Nuremberg (1947)

• Universal declaration of human rights– United Nations General Assembly (1948)

• Declaration of Helsinki (1964)– World Medical Association

• International technical guidelines– Council for International Organisations of Medical

Sciences (CIOMS)

• World health Organization WHO

The Tuskegee syphilis study (1/2)

• Cohort study conducted in the first part of the 20th century

• Patients recruited with syphilis and followed up for decades to study the natural history

Tuskegee, Macon County, AL, USA

The Tuskegee syphilis study (2/2)

• Issues– No treatment given

– No information

– No consent

• Dramatic consequences

• Epilogue– President Clinton’s

apology (1997) to survivors

Spinal taps

Burial stipends

Basic ethical principles

• Autonomy – Respect for the person who is a study subject

• Justice– Burdens and benefits should be equally

distributed

• Beneficence – “Do good”

• Non-maleficence – “ Do no harm”

Research vs. non-research

• Research– Produces results that are generalizable

• Non-research– Programme evaluation

– Surveillance

– Emergency operations (e.g., outbreak investigation)

Ensuring the protection of human subjects in epidemiology

• All projects – Minimize risks

• Ensure confidentiality

– Maximize benefits

– Obtain informed consent

• Research projects– The same general principles apply

– Ethical committee clearance required in addition

Exercise 1: Is this research?

? A case-control study of tick-borne encephalitis risk factors

? A telephone survey collecting information on attitudes towards vaccination

? An evaluation of a surveillance system for aseptic meningitis

Criteria that a research protocol must meet

• Useful research question

• Scientifically sound approach

• Appropriate procedures

• Planned analysis

• Vulnerable populations protected

• Low risks, maximum benefits

• Good tools

• Informed consent

Only good studies are ethical!

Example of vulnerable populations

• Pregnant women

• Adolescents

• Children

• Elderly

• Refugees

• Prisoners

• Those who can't give consent (unconscious)

• Persons with mental or behavioural disorders

Research in vulnerable populations

• Must not be studied if unnecessary– Do not study a new drug among prisoners

• May be studied if the research question is of direct relevance to the population– Harm reduction strategies might be relevant

to prisoners among which illicit drug use is common

– Provide evidence that the vulnerable population will not be exploited

Low risks and maximum benefits (1):

Study participants

• Risks and benefits for the participants

• Weight them honestly – Do not under-estimate risks

– Do not over-estimate benefits

Low risks and maximum benefits (2):

Study population and other populations

• Benefit / harm for communities from which the participants are drawn

• Benefit / harm for communities beyond the research population

Maximize the welfare of participants

• Counsel participants

• Protect privacy and psycho-social needs

• Deal with adverse reactions

Exercise 2: Minimizing risks, maximizing benefits

• You would like to conduct a study on the factors associated with anemia among adolescent girls

• You propose to conduct a survey, to collect blood samples and to identify the factors that are associated with being anemic

• List two critical steps you would take to:– Minimize harm

– Maximize benefits

Informed consent

• Ban undue inducements to participate

• Ensure free participation

• Make provision for:– Those who can’t read / sign

– Those who can’t give personal consent

How does a person give an informed consent?

• Information received

• Information understood

• Decision made without:– Coercion

– Undue influence / inducement,

– Intimidation

The consent form (1/5)

• Attached to protocol

• Lay language

• Complete /adequate

• Clear mention of research

• Rationale for the study

• Details of what is asked from participants

• Duration of the research

The consent form (2/5)

• Nature, sequence and frequency of procedures

• Nature and likelihood of anticipated discomfort or adverse effects– Physical risks

– Psychological and social risks

– Clarifications

• What has been done to minimize risks

• Action to be taken if they occur

• Outlines the possible benefits, if any

The consent form (3/5)

• Outline of the procedure to protect confidentiality

• Mention if confidentiality is not possible

• Mention that:– Participation is voluntary

– Refusal to participate (or discontinue participation) involves no penalty / loss

• Description of alternatives to participation

The consent form (4/5)

• Nature of any compensation /reimbursement– Time

– Travel

– Person-days lost from work

• Plans for feedback to participants if any

• Contact information

The consent form (5/5)

• Provision for subjects incapable of reading and signing

• Provision for participants incapable of giving personal consent

Referring to the biological specimens

in the consent form (1/2)

• Nature, number and volume

• Procedures to be used– Routine or experimental

– Invasive or not

• Use to which specimens will be put– For the study

– In the longer term (e.g., left over)

Referring to the biological specimens

in the consent form (2/2)

• Will results will be returned to subjects?

• How will the leftovers be handled?

• Will there be genetic/genomic testing?

Confidentiality of data

• Do not collect identifiers on data collection instruments– Use study codes

• Do not enter identifiers in electronic data files

Identifiers logs

• Contain identifying information

• Collected on paper

• Separated from the data collection instruments after field verifications

• Kept under lock and key

• Destroyed after data analysis

Line listing and identifier log

• Electronic data file– Not confidential, can be analyzed

Uni. ID OnsetDate Ward Block City AgeYearsSex Hospital Death HEVIgM HAVIgM1 01.mar.05 18 2 HYD 12 1 1 2 1 92 03.mar.05 22 1 HYD 25 2 1 2 2 13 05.mar.05 23 3 HYD 36 1 2 9 9 94 06.mar.05 - - SEC 23 2 1 1 1 2

Uni. ID Name Address Phone 1 Salif Keita 234 Defense colony 044 12 34 56 782 K Suresh 234 Nugambakam High Road 044 87 65 43 213 A.D. Singh 234 Ring road 044 98 87 65 41 4 R.T. Balaj 678 Vadapalani 044 14 25 36 78

• Separate identifier log– Confidential, cannot be analyzed, kept on paper

Confidentiality of specimens

• Clinical specimens for investigations (e.g., outbreaks)– Identifier may be on the specimen

– Results given back to patient/ provider

• Research specimen– Study code on the specimen

– Results given back or not, as relevant

Ethical committees

• Basic responsibilities

• Composition

• Terms of reference

• Review procedures

• WHO guidelines available– http://www.who.int/tdr/publications/

publications/ethics.htm

Responsibilities of the ethical committee

• Safeguarding the dignity, rights, safety, and well-being of research participants

• Consider principles of justice

• Review ethics of proposed studies

Composition of ethics committees

• Multidisciplinary / multi-sectoral

• 5-7 to 12-15 members

• External chairperson

• Member secretary – Operates routine business

• Members from diverse origins

• Adequate age, gender and community representation

Initial approval and follow up

• Review of proposed research – Before its initiation

• Regular evaluation of ongoing studies – All that received a positive decision

Ethical committee review

• Presentation of protocol

• Discussions / questions (quorum)

• Clear decision– Clearance

– Conditional clearance

– Deferral

– Refusal

• Documentation of all processes– Checklist / standard operating procedures

Exemption from ethical review

• Teaching

• Educational tests

• Research on existing data

• Programme evaluation

• Consumer satisfaction survey for food

Conducting the research according to the protocol

• Follow protocol

• Ensure protection of human subjects as part of the field work quality assurance– Train field workers

– Standardize field work procedures

– Supervise

– Check forms and reports

Actually collecting informed consent

• Present the study

• Offer participation

• Collect consent if the patient agrees

• Leave a copy of the signed document

Data analysis

• Do not analyze files containing identifiers

• Make sure that the analysis would not disclose personal information– E.g., surveillance reports identifying cases

in a small community

Exercise 3: Ethical review needed?

? A case-control study of tick-borne encephalitis risk factors

? A telephone survey collecting information on attitudes towards vaccination

? An evaluation of a surveillance system for aseptic meningitis

Elements to mention in the final report

• Risks and benefits to participants

• Measures taken to protect human subjects

• Clearance obtained (or exemption)

Take home messages

• Follow principles of autonomy, justice, beneficence and non-maleficence

• Use a checklist to prepare your protocol

• Conduct the study according to protocol

• Only well planned, valid studies are ethical!

• Apply country rules, but act according to universal ethical principles

Useful resources

• www.wma.net

• www.who.int/rpc/research_ethics/en/

• http://www.cioms.ch/

• http://www.hhs.gov/