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Ethical issues in clinical trials

Bernard Lo, M.D.

February 10, 2010

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Case 1. PPIs in GI bleeding

IV esomprazole vs. placebo All then received oral esomeprazole

Major upper ulcer bleed Documented on endoscopy Variable endoscopic treatment

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Questions

1. Would you approve study as IRB

member?

2. Would you refer patients as MD?

3. Would you enroll as participant?

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Clinical equipoise justifies randomization

1. Experts find current evidence

inconclusive or conflicting• If experts disagree or uncertain, no harm to

participants

2. Clinicians willing to enroll patients

3. Informed participant agrees to be

randomized

Systematic reviews

H2 blockers not beneficial in DU

bleeding, may be beneficial in GU

(2002)

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Systematic reviews

PPI reduces rebleeding and surgery in

ulcer bleeding (2005) Robust conclusions

• Highest quality studies

• Randomize after endoscopic Rx

• Some used H2 blocker as control

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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

Views of sponsor

Deficiencies in prior studies

Differences from prior studies

Approved by regulatory agencies Variable response to placebo in clinical

trials in PUD, depression FDA not an ethics board

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Options for IRB

Do not approve trial

Require participants to be informed Meta-analysis results showing effectiveness Availability off study

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Case 1. PPIs in GI bleeding

Active

Control p

Major rebleed 72h 5.9% 10.3%

.03

Surgery 2.7% 5.4%NS

Death 0.8% 2.1%NS

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Use of placebo controls

Withholding effective therapy harms

participants and is unethical Unless patient fails or cannot tolerate Unless minor, self-limiting condition Unless great variation in efficacy from trial

to trial

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Questions?

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Background

Placebo controls

Withholding negative results from

clinical trials

BL experience with withdrawal and

challenge studies

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Clinical trials of antidepressants

Some patients with major depression

worsen on medications How to protect participants in clinical

trials?

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Opportunities to protect participants

At enrollment

During the trial

After cases are identified

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At enrollment

Exclude persons At high risk for suicide

• Previous attempts

Poor support systems• Require friend or relative

Poor access to psychiatric care

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During the study:If suicidality identified

Close monitoring for suicidality Pact with patient Monitoring by family or friend

Plan for how to respond Train staff Referral to psychiatric care

Count suicidality as treatment failure

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During the study:If suicidality identified

Remove participant from study Need personal physician to treat patient off-

protocol May need more intensive therapy

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After cases are identified

Medical monitor Are procedure to respond to suicidality

appropriate?

DSMB What increase in suicidality in one arm of

trial would be clinically significant and warrant stopping the trial if statistically meaningful?

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Questions?

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Take home points

Ethical issues occur at each stage of

clinical trial

Cannot rely on sponsor, FDA, IRB to

assure that ethical issues addressed Responsibility of investigator

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