INTERNATIONAL ETHICAL GUIDELINES: CIOMS

Robert J. Levine, MD Director: Donaghue Initiative in Biomedical and Behavioral Research Ethics; Professor of Medicine; Lecturer in PharmacologyYale University New York: March 20, 2008

PURPOSE OF THIS TALK

• To expose the process of design of international codes of research ethics.

• CIOMS 2002 as an example.– The most satisfactory.

• Long-range goal: to facilitate the better understanding of international ethical codes so that they may be more skillfully applied.

OUTLINE OF TALK

• Historical note on CIOMS link to Declaration of Helsinki.

• The design of a satisfactory document.

• Specific applications to the design of the 2002 (most recent) revision.

• Distribution of the World’s resources and its relevance to Guidelines.

THIS SHOULD NOT BE THE WEALTHY DICTATING ETHICS TO THE WORLD

CIOMS Guidelines are designed primarily to guide sponsors and investigators from the wealthy

countries as they carry out research in developing countries.

HELSINKI LINK

• Purpose in 1982: to advise how the principles of Helsinki “could be effectively applied, particularly in developing countries.”

• 1982: Minor deviations; e.g., consent through ‘intermediary’.

CIOMS 1993

• Substantial deviations: circumlocutions.

• On phase I drug testing: “The requirement…of Article III.2, ‘subjects should be volunteers – either healthy persons or patients for whom the experimental design is not related to the patient’s illness’ is not to be disregarded lightly.”

Short Duration AZT Trials 1997

• Criticism in New England Journal of Medicine.

• The most acrimonious debate on ethics of clinical trials since 1970s.

• WMA and CIOMS each launched document revision projects.

• A major objective of each organization was ‘harmony’.

HELSINKI 2000

• Accomplishments– Clarification of language.– Removal of the language of ‘therapeutic’ and

‘nontherapeutic’ research.

• Remaining to be done– Clarification of position on placebo controls– Removal of remnants of ‘therapeutic’ and

‘nontherapeutic’ logic.

CIOMS 2002

• There is more harmony with Helsinki than there was in 1993.

• There are no circumlocutions as regards differences with Helsinki.

• WMA 2001 clarification on placebos failed to secure consensus:– Some think it went too far.– Some deplore loss of substantive standard.– Some think it incomprehensible.

DESIGN of SATISFACTORY GUIDLEINES

• Idealism vs pragmatism.

• Procedural vs substantive guidelines.

• Micromanagement.

• Paternalism.

• Unreconciled controversy.

IDEALISM vs PRAGMATISM

• Idealism must be expressed:– Emphasized in introduction and appendices.

– Emphasized that these are long range goals, not today’s expectations.

• Pragmatism must be reflected in Guidelines themselves– This is the behavior expected today.

– Idealism in Guidelines encourages noncompliance

ETHICS AS PRACTICAL REASONING

• Principlism: the mistake of the 1960s.– Applied ethics must not be purely theoretical.

• Ethical guidelines must be informed by a thorough empirical knowledge of the field.– Anthropologists.– It is not ethics vs science.– Ethics cannot be dissociated from economic

considerations.

PROCEDURAL vs SUBSTANTIVE GUIDELINES

• Substantive guidelines: actions required (or forbidden) because they are morally right (or wrong).

• Procedural guidelines:– To assure compliance with substantive

guidelines.– To determine what is morally right or wrong in

particular circumstances.

PROCEDURAL GUIDELINES

• Most numerous in guidelines designed to cover diverse projects and cultures.

• Enable decision-making that is especially suited to particular cultures or fields of research.

• May allow exploitation of individuals in corrupt regimes.

SUBSTANTIVE GUIDELINES

• Most numerous in guidelines designed for homogeneous cultures or single fields of study.

• Restrict the use of judgment to adapt to circumstances unanticipated in the guidelines. – Micromanagement.

• Reduce the probability of exploitation in corrupt regimes?

PATERNALISM

• CIOMS 1993 designed to prevent exploitation of developing countries.

• UNAIDS Guidance Document attempted to correct this.– Enabling low resource countries more freedom

to be self-determining.

• Is the pendulum swinging back toward protectionism?

IRRECONCILEABLE CONTROVERSY

• The goal is consensus, not unanimity.• No consensus:

– 1993: Genetics, embryo and fetal research.

– 2002: Proposed Guideline 16 on products of conception.

• Consensus without unanimity:– Compensation for research induced injury.

– Nonbeneficial procedures that present more than minimal risk in research involving children.

GUIDELINE 11

• General requirement to provide each subject with ‘established effective intervention’ [EET].

• Replaced standards:– Best proven therapeutic (preventive or

diagnostic) method. [Helsinki]– Best current intervention. (CIOMS drafts).

PLACEBO MAY BE USED1

• 1. No proven intervention exists.

• 2. Withholding EEI results in only temporary discomfort and no serious harm.

• 3. EEI as comparator would not yield scientifically reliable results.

PLACEBO MAY BE USED2

• 4. Studies designed to develop an effective alternative to an EEI that is not locally available.– Usually for economic or logistic reasons.

• Ethical justification:– Responsive to health needs.

– EEI as comparator would not yield scientifically reliable results.

– Reasonably available; sustainable.

DOUBLE STANDARD?

• No!

• The single standard is that the results of the research should be responsive to the health needs and priorities of the community of the subjects and the products developed must be made ‘reasonably available’.

FIDUCIARY VIOLATION?

• Pathogenesis

• Pathophysiology

• Epidemiology

Global injustice: The distribution of wealth among the nations of the world is inequitable. Research did not cause this and research cannot fix this. There is a temptation to use international research documents as devices to correct inequities; to some extent this is a reasonable and constructive activity. However, we must avoid development of guidelines that would impede the efforts of sponsors and investigators in industrialized countries to assist countries with lesser resources in their efforts to develop treatments and preventions that they can afford.

RECOMMENDATION FOR INTERNATIONAL AGENCY*

• Serves as interpreter.

• Serves as a monitor to identify needs for revision of Guidelines.– Infinite malleability.

• New procedure

* Remains to be done