1 How to Review a Protocol. 2 Reference Documents WHO/TDR Operational Guidelines for Ethical...

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How to Review a Protocol

How to Review a Protocol

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Reference DocumentsReference Documents

• WHO/TDR Operational Guidelines for Ethical Committees that Review Biomedical Research, 2000.

• International Conference on Harmonization, Good Clinical Practice: Consolidated Guidelines, 1997.

• World Medical Association, Declaration of Helsinki, 2004.

• CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects, 2002.

• Code of Federal Regulations: 21CFR50&56; 45CFR46

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The Ethics CommitteeThe Ethics Committee

• The Ethics review systems are important societal mechanisms involved in the protection of human subjects. Their work should be characterized by:

– Competence of members as per requirements– Quality of the implementation of regulations and

policies– Transparency of procedures– Consistency in review both at the Ethics Committee

level and between committees– Independence from all those having an interest in the

research

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Need to Review Research ProtocolsNeed to Review

Research Protocols

… This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence.

Helsinki Declaration, B13

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Respect for Persons FirstRespect for Persons First

In medical research on human subjects,

considerations related to the well-being

of the human subject should take

precedence over the interests of science

and society.

Helsinki Declaration, A5

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Respect for Persons FirstRespect for Persons First

Does it still hold true that respect for individuals will

still come firstwhen a deadly epidemic

hits the country?

… and what happens then with ethics review?

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What Must the Ethics Committee Assess?

What Must the Ethics Committee Assess?

1. Scientific Design and Conduct of the Study

• Risks and Potential Benefits

• Budget and Trials Agreement

2. Recruitment and Retention of Research Participants

3. Care and Protection of Research Participants

4. Protection of Research Participants Confidentiality

5. Informed Consent Process

6. Community Considerations

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Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.

Helsinki Declaration, B11 and GCP 2.3

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Scientific Design and Conduct of the StudyScientific Design and Conduct of the Study

• The evaluation of the scientific merits of

the trial are part of the mandate of the

ethics committee (GCP 3.2.1)

• Clinical trials should be scientifically

sound, and described in a clear, detailed

protocol. (GCP 2.5)

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Please NotePlease Note

• Even if the evaluation of the science is clearly a function of the Ethics Committee, if a committee feels it does not have all of the necessary expertise around the table, it should ask for external advice or endorse a previous independent scientific evaluation providing enough information is available.

• Ethics committees should have access to the necessary resources to ensure appropriate functioning and access to external consultation as needed.

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Please NotePlease Note

• A scientifically sound protocol which respects all ethical requirements may not be allowed to proceed for other reasons.

• For example, a hospital may not wish to see a novel expensive treatment introduced through a research project if there exists a satisfactory treatment far less expensive.

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The Ethics Committee should consider:

• the appropriateness of the study design in relation to the

objectives of the study (is this design capable of

answering the research question?)

• the statistical methodology (including sample size

calculation), and

• the potential for reaching sound conclusions with the

smallest number of research participants;

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• the nature, magnitude and probability of the risks

and benefits, as well as ways to minimize risks

and maximize benefits

• the justification of predictable risks and

inconveniences weighed against the anticipated

benefits for the research participants and the

concerned communities;

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• the justification for the use of control arms;

– Will placebo be used? Is it justified?

• criteria for prematurely withdrawing

research participants;

• criteria for suspending or terminating the

research as a whole;

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Clinical EquipoiseClinical Equipoise

•“… at the start of the trial, there must be a state of genuine equipoise regarding the merits of the regimens to be tested, and the trial must be designed in such a way as to make it reasonable to expect that, if it is successfully conducted, clinical equipoise will be disturbed.“

Freedman, B. Equipoise and the Ethics of Clinical Research,

NEJM, 1987, 312, 141-145

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An Ideal Lost?An Ideal Lost?• Clinical Equipoise embodied a conception of justice

which was affordable in developed countries• As research moved in developing countries, the use of

control arms, especially using placebo, became more common, even when the existence of clinical equipoise was impossible to argue

• The justification for control arms is now governed by concepts like :– Established medical intervention (CIOMS)– Existing proven therapy (Helsinki)– The non-availability of a suitable control for economic reasons

should not discharged the sponsor of creating a situation of genuine Clinical Equipoise

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• the adequacy of provisions made for monitoring and auditing the conduct of the research, including the constitution of a data safety monitoring board (DSMB);

• the adequacy of the site, including the supporting staff, available facilities, and emergency procedures;

• the manner in which the results of the research will be reported and published;

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2. Recruitment and Retention of Research

Participants

2. Recruitment and Retention of Research

Participants

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Recruitment and Retention of Research Participants


• the characteristics of the population from

which the research participants will be

drawn (including gender, age, literacy,

culture, economic status, and ethnicity);

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• Inclusion and exclusion criteria– Should ensure the protection of vulnerable people– Should ensure the just distribution of research risks

and benefits

– Should not automatically leave out populations

susceptible to benefit from research results (pregnant

woman, children, incompetent) unless the risk is

disproportionate since the new treatment could not be

applied to them because they were not part of the trial

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• the means by which initial contact and

recruitment is to be conducted;

• the means by which full information is to

be conveyed to potential research

participants or their representatives;

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• inclusion criteria for research participants:

are they clear, warranted and fair?;

• exclusion criteria for research participants:

are they clear, warranted and fair?;

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Care and Protection of Research Participants


• the suitability of the investigator(s)’s (and research team) qualifications and experience for the proposed study;

• any plans to withdraw or withhold standard therapies for the purpose of the research, and the justification for such action;

• the medical care to be provided to research participants during and after the course of the research;

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• the adequacy of medical supervision and psycho-social support for the research participants;

• steps to be taken if research participants voluntarily withdraw during the course of the research;

• the criteria for extended access to, the emergency use of, and/or the compassionate use of study products;

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• the arrangements, if appropriate, for informing the research participant’s general practitioner (family doctor), including procedures for seeking the participant’s consent to do so;

• a description of any plans to make the study product available to the research participants following the research;

• a description of any financial costs to research participants;

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• the rewards and compensations for research

participants (including money, services, and/or

gifts);

• the provisions for compensation/treatment in the

case of the injury/disability/death of a research

participant attributable to participation in the

research;

• the insurance and indemnity arrangements;

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4. Protection of Research Participants

Confidentiality

4. Protection of Research Participants

Confidentiality

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Protection of Research Participants Confidentiality

Protection of Research Participants Confidentiality

• a description of the persons who will have access to personal data of the research participants, including medical records and biological samples;

• the measures taken to ensure the confidentiality and security of personal information concerning research participants;

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Informed Consent ProcessInformed Consent Process

• a full description of the process for obtaining

informed consent, including the identification of

those responsible for obtaining consent;

• the adequacy, completeness, and

understandability of written and oral information

to be given to the research participants, and,

when appropriate, their legally acceptable

representative(s);

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• clear justification for the intention to include in the

research individuals who cannot consent, and a full

account of the arrangements for obtaining consent or

authorization for the participation of such individuals;

• assurances that research participants will receive

information that becomes available during the course of

the research relevant to their participation (including their

rights, safety, and well-being);

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• the provisions made for receiving and responding to queries and complaints from research participants or their representatives during the course of a research project;

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6. Community Considerations6. Community Considerations

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Community ConsiderationsCommunity Considerations

• the impact and relevance of the research on the local community and on the concerned communities from which the research participants are drawn;

• the steps taken to consult with the concerned communities during the course of designing the research;

• the influence of the community on the consent of individuals;

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• proposed community consultation during

the course of the research;

• the extent to which the research

contributes to capacity building, such as

the enhancement of local healthcare,

research, and the ability to respond to

public health needs;

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• a description of the availability and affordability of any successful study product to the concerned communities following the research;

• the manner in which the results of the research will be made available to the research participants and the concerned communities.

1 How to Review a Protocol. 2 Reference Documents WHO/TDR Operational Guidelines for Ethical...

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