Ethics and International Collaborations

Jeremy Sugarman, MD, MPH, MAHarvey M. Meyerhoff Professor of Bioethics & MedicineBerman Institute of Bioethics and Department of MedicineJohns Hopkins UniversityBaltimore, Maryland USA

Multinational Clinical Research

Registration Participation rates Treatment naïve populations Research costs*

US: $125 million India: $70 million

Meet global health care needs

*Mean cost of Ph I-III. Gale Group, 2006.

A Growing Epidemic 39.5 million people infected with HIV In 2006

2.9 million people died of AIDS related illnesses

4.3 million people were infected with HIV

Baltimore Sun, 11-22-06

UNAIDS 2006 Report on the Global AIDS Epidemic

Efforts Scandalized

Popular cultureThe Constant Gardner

Popular mediaWashington Post series: The Body Hunters

Professional journalsNEJM concerning placebo-controls in the

vertical transmission of HIV

Overview

Using data to inform debates and policy Perspectives on multinational collaboration Ethics guidance for research

An Empirical Imperative Clinical research is predicated on the notion that we

need data to determine ‘truth’ and facilitate sound decision-making

Ironically, methods of clinical research, including those designed to protect participants such as conclusions about appropriate trial design in particular cases and informed consent, are introduced without data regarding safety or efficacy

Where relevant we need to evaluate these protections as we would any proposed clinical intervention

Lavori, Controlled Clinical Trials 1999; 20:187-193.

Ethical Oversight

Multiple bodies recognize the need for guidelinesWorld Medical AssociationCIOMS International Conference on HarmonizationNuffield TrustNational Bioethics Advisory Commission

Lack of consensus and conflicting guidance

International Perspectives on Protecting Human Subjects

Jeremy Sugarman, MD, MPH, MABenjamin Popkin, JD, MPHJudith Fortney, PhDRoberto Rivera, MD

[ISBN 1-931022-14-3]. Bethesda, MD: National Bioethics Advisory Commission, May 2001, E1-30.

Empirical Projects to Inform NBAC’s Deliberations

Ethnographic study Quantitative survey Focused site visits

Focused Site Visits

Chile Guatemala Haiti Kenya Mexico Taiwan Thailand United Kingdom

Process

Key respondent in each site Identify others with relevant experience and knowledge

• Investigators• IRB members (local, regional, and national)• Persons who obtain informed consent

Oral informed consent Standardized discussion guidelines

Discussion Guidelines Experiences with US regulations regarding research (e.g.,

how they function, who carries them out, and the relevance of standard US elements of informed consent)

How US regulations correspond to international investigators’ own moral rules and how situations of conflict are reconciled

Recommendations for changes or improvements in current US regulations and research practices

Analysis

Qualitative analysis• Site visit reports• Group debriefing sessions

Domains• Informed Consent• Institutional Review Boards• Justice• Research Design• Contrasting Approaches to Oversight• Trust

Overall Findings

There is a high degree of commitment to conducting ethically sound research.

There is much consonance between the values of international researchers and US guidelines.

When there is discordance, local researchers and IRB members tended to see these as opportunities for negotiation and compromise. However, their well intentioned offers for negotiation and compromise can be met with a lack of trust.

On the Review Process

The review process is rather burdensome – time consuming and often quite difficult, despite its importance in doing research.

The specific procedures outlined in US regulations regarding how this review should take place and be documented posed substantial challenges due to staffing, space, and resources.

It is sometimes perceived that there is almost no flexibility in the face of cultural variability.

On Informed Consent

There was widespread concern that US regulations regarding informed consent place undue emphasis on detailed documentation formulated to serve foreign rather than local needs

Recommendations to NBAC

1. Work with local colleagues to make the research relevant to local issues and priorities.

2. In designing research, assess whether there are any relevant cultural barriers (such as whether placebos are culturally appropriate) to conducting it in a given location.

3. Develop informed consent documents in collaboration with local colleagues paying particular attention to potential problems in translation of particular concepts.

Recommendations to NBAC

4. Exercise a degree of flexibility with regard to written consent documents which might be awkward for research participants unaccustomed to receiving documentation of any important transaction.

5. Develop means of simplifying requirements for documentation that retain the ability to audit, both for the oversight of research (initial review, direct oversight, and continuing review) and for informed consent.

Recommendations to NBAC

6. Consider having a local ombudsman available to answer subjects’ concerns about the study as well as their rights as research subjects.

7. Encourage international discussion about the role of trusting the integrity of local investigators and those charged with the oversight of research to adopt and enforce mechanisms for ensuring that the rights and interests of human subjects are protected.

Recommendations to NBAC

8. Provide education and training for local investigators and IRB members about US regulatory requirements that includes information about the rationale for them.

Incorporating Findings

Design research in accord with local priorities Distinguish substance and procedures of obtaining

informed consent Culturally appropriate means of disclosure Support research about appropriate mechanisms of

obtaining consent Consult with community leaders while recognizing the

individuals involved Waivers for written documentation of consent for minimal

risk research

Evolving Science, Evolving Guidance Research in HIV prevention and treatment

is associated with an array of ethical issues

Guidance, rhetoric, and scholarship have been responsive to both successes and failures

Unfortunately, these efforts may conflict and/or may be inadequately sufficiently sensitive to facts and nuance

Format

15 guidance points span the continuum of research

Unlike other guidance documents, some of the points are morally required, while others are aspirational, reflecting the realities and constraints inherent to practice

Each point identifies those accountable for it

Before Research Ensuring high-quality scientific and ethical

research Setting research objectives and priorities Engaging communities Building local capacity and partnerships Ethical issues in study design Consent, assent, permission and re-consent Addressing vulnerabilities Ethical review of research

During Research

Standard of prevention Standards of care and treatment Independent data safety and monitoring

After Research

Disseminating research results Sustaining capacity-building and

infrastructure into the future Continuing care for research participants Provision of successful research

interventions

Concluding Comments

International collaborative research will involve practical and ethical challenges

Explicit deliberation, informed where possible by data, about these issues across the continuum of research promises to enhance collaborations