1 ethical issues in global health research bernard lo, m.d. [email protected] september 9,...
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Tenofovir
Nucleoside RT inhibitor
Generally fewer side effects than other
HAART
Proximal tubular damage, ATN Reverses on discontinuation
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PrEP protests
Should receive standard interventions Prevention services
• Needle exchange, methadone for IDUs
Dialysis for renal failure ART for seroconverters
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PrEP protests
Access to drug after trial Manufacturer offered to sell at cost Still unaffordable
Lack of informed consent
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PrEP protests
Cultural / political context Poor care at government clinics
Involvement in planning New advocacy groups refuse to meet
Charges of exploitation
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Need research in developing countries
Burden of disease Some conditions primarily in South
Uncertainty over best Rx Optimal therapies not feasible
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Drug company interest in developing countries
Most clinical trials now offshore
Cheaper and quicker Lower labor costs Many “naive” patients
More hospitable regulatory
environment
Drug-company trials in developing countries
None for conditions that occur
disproportionately in developing world
Studies in allergic rhinitis, overactive
bladder
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Ethical issues also salient in US
Is background care appropriate?
Is consent adequate?
Will patients have post-trial access?
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Disclosure
NBAC
CAPS
HPTN
Gates
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Perinatal HIV studies
AZT standard of care in U.S. Starting 3rd trimester IV during labor and delivery Not feasible in South
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Perinatal HIV studies (1996)
Shorter course AZT vs. placebo in
Thailand, Africa
Criticized as exploitation, double
standard Proposed equivalency trial
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Tuskegee Revisited
“Those offended by the comparison of
the African research with Tuskegee
have yet to show how these studies
differ in their fundamental failure to
protect the welfare of human subjects.”
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Wall Street Journal. Oct 29, 1997
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Interventions for control group: Helsinki #29 (2000)
Interventions must be tested against
“best current prophylactic, diagnostic,
and therapeutic methods”
Rejected “highest attainable and
sustainable”
www.wma.net
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Interventions for control group: NBAC report (2001)
Studies must address priorities of host
country
Pertinent research question may be: is
a limited intervention better than
current (no) care?
http://bioethics.georgetown.edu/nbac/
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Interventions for control group: Helsinki (2008)
Placebo necessary to determine safety
and efficacy
Compelling and scientifically sound
methodological reasons
No serious and irreversible harm
www.wma.net
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Perinatal HIV study
Placebo established proof of principle
and efficacy
Efforts to make drugs more available Additional funding Lawsuits against manufacturers Price reductions
Issues of fairness to trial participants
Care during trial
Access to study intervention after trial
Redress for trial-related injuries Seroconversion in HIV prevention trial?
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Tenofovir vaginal gel
RCT of sexually active women in South
Africa
Before and after sex doses
Female-controlled prevention
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New HIV infections
Tenofovir suppository 5.6
Placebo 9.1
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Implications for other studies
Studies of oral tenofovir PrEP
Studies of daily tenofovir vaginal gel
Options Disclose results to participants Offer intervention to participants
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RCT of prenatal folate
Does folate during pregnancy prevent
birth defects?
Unethical to do placebo control in U.S.
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Prenatal folate trial in China
Subjects illiterate women in rural areas
Unethical to give folate in China? One child policy Government plot for sterilization Concerns that birth defects ascribed to drug
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Challenges in informed consent
Seek permission from mother-in-law Supplement, not replace patient consent
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Challenges in informed consent
In clinical care Not disclose diagnosis Not discuss uncertainty Not obtain consent
Defer to village leader, husband
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Challenges in informed consent
Different model of disease Blood draws = spell Phlebotomy not minimal risk?
Rumors, misinformation
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Challenges in informed consent
Detailed consent form
counterproductive Low health literacy Suspicion of signature or thumbprint
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What is culturally appropriate?
Respect for persons is universal
Tailor consent procedures to particular
situation
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Innovations in informed consent
Consult with community
representatives What are participants’ concerns? What will be difficult to understand? How best to explain study?
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Innovations in informed consent
Community-based education Street theater, group meetings
Imaginative explanations Randomization
Independent witness rather than
signature
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Innovations in informed consent
Participant may seek approval from
others Final choice by individual participant
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Innovations in informed consent
Questionnaire to assess participant
comprehension
Disclosing information is necessary but not
sufficient
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Similar innovations in U.S.
Consult community representatives
Check understanding of participants
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Oral antibiotic for meningitis
Intravenous antibiotics not feasible in
developing nations
RCT oral trovaflaxacin vs. ceftriaxone
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RCT during epidemic
Nigerian collaborators had no input
into study design
Need for care vs. research?
Study team flew in, flew out
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Ethical problems
No prior oral use in children
Not told that clinic nearby
No repeat LP
Failures not switched
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Ethical problems
Control drug given IM, lower doses
IRB approval forged
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Study outcomes
Mortality in both arms 6%, comparable
to US and local care
Later international multicenter study,
including US sites
Trovaflaxacin causes liver damage, use
restricted
Parents file suit against drug company
Allegations
Not told drug experimental, that
standard treatment available
Failure to evaluate after treatment
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Research oversight
Informed consent
IRB review at UCSF and in host country
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IRB challenges in international studies
U.S. IRB lacks expertise about host
country
Host country IRB lacks resources and
experience
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Challenges in international studies
IRB approval not ensure ethical issues
adequately addressed
Greater responsibility on investigator If something goes wrong, IRB approval is
no defense
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Context of international research
Vast disparities in wealth
Limited resources in host country
History of “exploitation”
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Partnerships in international research
Partnership with host country Scientists, officials, community leaders Start in design phase Not just present draft protocol
BMJ 2003; 327: 337
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Partnerships in international research
Capacity building Training host country staff and
collaborators Leave behind equipment Involve in data analysis and writing
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Ethical obligations of researcher
Good intentions not enough
Act as advocate, not guarantee change
Set high but not unrealistic standard
Make good-faith, reasonable efforts