1 ethical issues in global health research bernard lo, m.d. bernie@medicine.ucsf.edu september 9,...

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Ethical issues in global health research

Bernard Lo, M.D.

bernie@medicine.ucsf.edu

September 9, 2010

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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