IRBS AND ETHICS IN EMERGING MARKETS

John Isidor, J.D.Sr. Director and Co- Founder, Institutional Official

Schulman Associates IRBjisidor@sairb.com

ACPUOctober 19, 2010

OUTLINE

Overview of Research in Developing Countries

Ethics Committees in DCsPlacebo Issue Informed ConsentAZT Trial Issues

OIG REPORT, JUNE 2010 FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN TRIALS (JUNE 2010)80% of marketing applications for drugs and biologics in FY08 contain data from ex/U.S. studies

Over 50% of trial sites in FY08 were ex/U.S.

78% of all subjects in FY08 were enrolled ex/U.S.

87% of all subjects in biologics trials in FY08 were enrolled ex/U.S.

OIG REPORT: FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS (JUNE 2010)Although sponsors can submit data from trials not conducted under an IND, sponsors must follow FDA’s GCP regulations

FDA is allowed to inspect for adherence to IND or GCP regulations

FDA inspects 1.2% of all U.S. based sites, but only 0.7% of ex/U.S. sites

OIG REPORT: FDA’S ABILITY TO MONITOR AND INSPECT FOREIGN CLINICAL TRIALS (JUNE 2010)Western Europe accounted for the most sites and subjects outside of the U.S. but large numbers of sites and subjects also were in the developing world

Central and South America have highest average of subjects per site

Large and growing numbers of sites and subjects from Peru, Colombia, Chile, Panama, Venezuela, Nicaragua, Argentina, Brazil, Costa Rica

Other large numbers from South Africa, Russia, Poland

REASONS FOR DOING TRIALS IN DCs Better address neglected diseases Countries such as Nigeria, South Korea, China and India require significant local data for product approval

Target diseases that disproportionately affect DCs such as HIV/Aids, Malaria and TB

May help assess the relevance and applicability of the treatment with the local healthcare system

Include a more diverse range of patients/participants

Access untapped PIs and treatment naïve patients

Develop broader base of qualified PIs Increase health/medical infrastructure in low resource countries

WHY MOVE CLINICAL TRIALS INTO THE DEVELOPING WORLD?Lower site costsFewer competitive trialsTreatment-naïve subjectsMotivated subjects and investigatorsDisease-specific study needsCountries trying to attract clinical research• e.g., Singapore, India, Malaysia, China, Eastern Europe, Brazil

TRIALS IN THE DEVELOPING WORLDReasons Why Clinical Trials

Move to the Developing World

Corresponding Complications

Lower site costs Undue financial benefits to subjects and researchers?

Fewer competitive trials Poor background standard of care for patients/subjects; inexperienced local research team

Treatment naïve patients If there was no care before trial, what happens after trial is over?What standard to use for control group?

Motivated subjects and researchers

Data integrity challengesCutting ethical corners in study conduct

Disease-specific study needs Availability of intervention, if proven, after trial ends

National governments encouraging clinical trial setting

Do all levels of government and health institutions agree? Governments that promote clinical trials can be governments that change their minds

LAWS, REGULATIONS, ETHICAL PRINCIPLES GOVERNING CLINICAL RESEARCH IN DCsNuremberg CodeDeclaration of Helsinki ICH/GCPsCIOMSBelmont PrinciplesFDA GCPs

LAWS, REGULATIONS, ETHICAL PRINCIPLES GOVERNING CLINICAL RESEARCH IN DCsMany DCs have national laws governing research• Costa Rica• Peru• India• Brazil• Argentina

INDEPENDENT/LOCAL ETHICS COMMITTEES (IECs)Ask the PI for information about local IECs• Review Policies & Procedures• Inquire whether the IEC is government required or independent IECs exist

Ask the Public Health Minister about IECs

CONCERNS ABOUT IECs IN DCs

Inadequate Training Inadequate Resources Inadequate SOPs Inadequate Understanding of Informed Consent issues

Lack of Understanding of Ethical Issues such as Placebo Control

TRAINING RESOURCES FOR IECs

Internet Programs such as CITIPRIM&R Offers Training such as IRB 101 & 102

Hiring a ConsultantPartnering with a University or Government IEC

TRAINING RESOURCES FOR IECs

International Bioethics organizations that provide training and information• FERCAP• SIDCER• ICMR• PABIN

CONFRONTING A SUBSTANDARD LOCAL IECDiscuss with Local PIDiscuss with Ministry of HealthPossible Second Layer Review with a recognized Ethics Committee

GCP Compliant IEC

CONCERNS ABOUT INFORMED CONSENT IN DCsBasic Principles• Identify proper subject for consent• Written or verbal consent• Provide appropriate information about the research• Adequately understand the information• Voluntarily decide to participate• Explicitly consent to participate

IDENTIFYING PARTY TO CONSENT

In addition to research subject may need to• Discuss with local government or

Principal Investigator• Involve community person such as

community or tribal leader• Involve domestic and/or sexual partner• Involve family member or grandparent• Be multiple levels of consent

CONCERNS ABOUT WRITTEN CONSENTConsent form can be threateningToo longBreach of trust relationshipProvide identification of subject Take something from subject

APPROPRIATELY INFORM ABOUT THE RESEARCHDifficult concepts to explain such as randomization and placebo

Concerns about alternative treatmentConcerns about risks and compensation for injury

Payment to participant/coercive

ADEQUATE UNDERSTANDING

What is adequate understanding?How is understanding measured?Understanding the study as a whole or every detail?

VOLUNTARINESS

Does consent = freedom to refuse?What if study treatment is only available healthcare option?

EXPLICIT CONSENT

Intertwined with voluntarinessFreedom to refuse due to differing social status with physician/PI/healthcare workers

Great deference to physicians/conflict of interest

Signature of participant/witness and possibly family member or community member

Use of independent witness where there are literacy problems

ETHICAL ISSUES FOR PHARMA SPONSORS CONDUCTING RESEARCH IN DCsTrials should only be conducted where the medicines will likely be suitable and available for widespread use after the trial ends

Is local healthcare system able to provide continued post trial care for participants

Will licensed and or investigational medicines be made available post trial to participants with a chronic disease where there is no suitable alternative treatment

ETHICAL ISSUES FOR PHRMA SPONSORS CONDUCTING RESEARCH IN DCS Is the standard of care for the host country

measured by a worldwide standard or the standard that exists in the host country

Can we use placebo as a control when no standard treatment exists in the host country or must you use the best available treatment in the world

Some arguments for using local standard of care Research can determine if a new treatment is

better than one currently used in the host country It ensures continued post trial treatment to the

same standard in the host country In many therapeutic areas there is no consensus

on the best available treatment In some cases the best treatment may be a

surgery not available in the host country

JUSTIFICATION OF THE SHORT COURSE AZT TRIAL

A QUESTION OF JUSTICE IN THE SHORT COURSE AZT

TRIAL

POINTS TO CONSIDER

There was never any intent to exploit a vulnerable population

The Short Course AZT Trial could not be conducted in the U.S.

The health ministries of the host countries endorsed the study

Health care justice in Sub Sahara Africa did not exist

Justice in U.S. clinical research is a myth despite the Belmont Report

A QUESTION OF BENEFICENCE IN

THE SHORT COURSE AZT TRIAL

POINTS TO CONSIDER

The standard of practice in Sub Sahara Africa was no treatment for the prevention of perinatal HIV

A placebo control did not place mothers or infants at increased risk compared to no treatment

Subjects randomized to AZT incurred only a minor risk of toxicity

The potential benefit of assignment to AZT was prevention of perinatal HIV

POINTS TO CONSIDER CONT’D

All subjects could potentially benefit by better prenatal care provided by the study

If the Short Course AZT proved to be efficacious, other HIV infected women in the 3rd world may benefit

HIV infected women in developed countries will not benefit unless the Short Course AZT is as effective (highly unlikely) as the 076 Regimen

It is unrealistic to demand that every subject receive the best proven therapy available anywhere in the world

A QUESTION OF RESPECT FOR PERSONS IN THE SHORT

COURSE AZT TRIAL

POINT TO CONSIDER

Consent was obtained by local physicians familiar with the culture

A QUESTION OF PRACTICALITY, ECONOMIC REALITY AND CULTURAL

LIMITATIONS IN THE SHORT COURSE AZT

TRIAL

POINTS TO CONSIDER

The 076 Regimen was not affordable and a cheaper treatment was needed

The 076 Regimen was too complicated to implement in undeveloped countries

WHY?

BECAUSE…

Most women in Sub Sahara Africa do not seek prenatal care

Most women breast-feed, which is the cultural norm

Formula is not affordable or culturally acceptable

The necessary medical infrastructure to support the 076 Regimen was non-existent

POINTS TO CONSIDER CONT’D

Use of the 076 Regimen as an active control instead of placebo would extend the trial

The Short Course AZT regimen is relatively simple and “inexpensive”

Scarce resources in Sub Sahara Africa are invariably devoted to economic needs

Drug companies and/or developed countries will not assume the cost of expensive treatments for 3rd world countries

WHAT’S THE BOTTOM LINE?

THE BOTTOM LINE

Unqualified and rigorous application of the principles of The Belmont Report to 3rd world clinical research may ultimately prove to be harmful and, therefore, unethical.

Epilogue

The Short Course AZT Trial was shown to reduce perinatal HIV transmission by approximately 50%.

CONCLUSION

Research will continue to grow in DCsMany important reasons to conduct research in DCs

Many ethical challenges remain such as identifying qualified researchers, IECs and ongoing informed consent challenges

Ethical research offers the potential for great benefits for the host country and its citizens as well as world healthcare