irbs and ethics in emerging markets
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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
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