Ethics in Clinical Trials

1
Ethics in Clinical Trials

• Ethical concerns in general
• Ethical concerns in trials
• Interesting examples

2
Ethical Concerns in all Research

• RQ should be important and answerable
• Benefit should outweigh risk
• Participants should give consent
• Privacy should be protected
• Research report should be fair and honest

3
Ethical Perspectives

• Idealism
• human beings are special
• can never be a means only
• Utilitarianism
• greatest good for the greatest number

4
Roles

• Physician - Investigator
• Patient - Participant
• Treatment - Research

5
HISTORY

• Nuremberg Code (1947)
• Declaration of Helsinki, WMO (1964 - 97)
• NIH Ethical Review Policies (1966)
• National Commission for the Protection of Human
  Subjects (Belmont Report, 1979)
• DHHS Regulations, 45 CFR 46 (1981-91)

6
Nazi Experiments

• THE NUREMBERG PHYSICIANS TRIAL
• Participants were placed in freezing water and
  time to death was measured
• Participants drank sea water and adverse
  effects were measured

7
The Nuremberg Code (1947)

• Voluntary participation
• legal capacity to give consent
• free of force, fraud, deceit, duress
• free to withdraw at any time
• Fruitful results for society
• unprocurable by other means
• conducted by qualified persons
• Avoid unnecessary risk to subjects
• risk not greater than importance of RQ

8
Post WWII Trials

• US Atomic Energy Commission tests of the adverse
  effects of radiation exposure
• Clinical trials in federal and state prisoners

9
Tuskegee Syphilis Study (1932-72)

• Prospective cohort funded by USPHS
• 600 poor, illiterate, black men
• 399 with syphilis 201 without syphilis
• followed for 40 years for tertiary syphilis
• Never informed of condition
• Never treated

10
Ethical Principles

• Beneficence
• Respect for autonomy
• Truth-telling
• Justice
• Promise-keeping
• Privacy

11
World Medical AssociationDeclaration of Helsinki
(1964)

• Voluntary participation with consent in writing
• Design described in written protocol
• Review by an independent committee
• Responsible scientific publication
• Protection of vulnerable populations

12
Institutional Review Boards

• NIH required ethical review of internal studies
  in1953 and funded studies in 1966
• led to establishment of local IRBs
• Oversight by NIH Office of Human Research
  Protections based on Federal regulations
• risks to subjects minimized and reasonable
• informed consent in writing
• provisions for privacy
• safeguards for vulnerable populations
• selection of subjects equitable

13
Federal and Local Regulations

• UCSF - Committee on Human Research
• you can volunteer to serve!
• NIH - Office for Human Research Protection
• http//ohrp.osophs.dhhs.gov/polasur.html
• Code of Federal Regulations Title 45, Part 46
• http//ohrp.osophs.dhhs.gov/
• humansubjects/guidance/45cfr46.htm.

14
Whats Special about RCTs?

• Randomization - equipoise
• Intervention - relatively safe
• Placebo - acceptable clinical option
• Measurements - safe and tolerable
• Interim monitoring - careful and timely

15
Equipoise

• Question important and not answered
• Evidence of benefit, not conclusive
• trial of new drug treatment for advanced breast
  cancer
• trial of treatment for common cold

16
Intervention and Control

• Maximize benefit, minimize harm
• intervention (minimal effective dose)
• control (placebo acceptable?)
• Qualified staff and protections for known
  potential harms
• manage known adverse effects
• pay costs of known adverse effects
• Identify associated harm

17
Measurements Safe and Tolerable

• Trial of estrogen for fracture prevention
• substitute TVUS for endometrial biopsy
• Trial of accuracy of spiral CT for PE
• all get spiral CT and pulmonary angiogram
• Trial of effect of estrogen treatment on coronary
  atherosclerosis (ERA)
• randomized to estrogen or placebo
• coronary atherosclerosis on angiograms

18
Fecal Occult Blood TestingKronborg, et al., 1996

• Randomized, controlled trial
• 60,000 persons in Denmark
• identified via central records
• FOBT biannually or usual care
• request for FOBT mailed by PMD
• Outcome colon cancer
• based on national registry

19
Informed Consent

• Purpose of trial
• Why asked to participate
• Visits, procedures, time and costs
• Discomforts or risks
• Benefits to subject and society
• Alternatives
• Confidentiality
• Contact for questions, problems

20
Active Compression-Decompression for CPR, Schwab
et al., 1994

• Randomized, controlled trial
• 860 persons with cardiac arrest
• ACD CPR or standard CPR
• Outcome discharged alive
• No informed consent
• Trial halted by FDA

21
SPECIAL POPULATIONS

• Children
• Fetus
• Mentally disabled persons
• Institutionalized persons
• Prisoners
• Unconscious or severely ill persons

22
Alternatives to Informed Consent

• Waiver of consent
• life threatening situation
• consent not possible
• Permission from parent or guardian
• Deferred informed consent
• enter study without consent
• later consent or participation terminated
• Prospective consent

23
Cumulative Meta-analysis
Effect of beta-blockers on mortality after MI
24
Antibiotics for AbortionSawaya, et al, 1996

• Cumulative meta-analysis 12 RCTs
• after 5 trials (1985), summary RR 0.5, plt.05
• 7 additional trials performed
• findings of 5 trials non-significant
• trials continued up to 1993

25
Zalospirone for DepressionRickels, et al, 1996

• Randomized trial
• 287 people with major depression
• Placebo or 3 doses of drug
• Outcome - change in severity of depression
• High dose effective two lower doses not

26
Prevention of AIDS in Africa

• Standard care for HIV pregnant women in US
• zidovudine orally before delivery
• IV during labor, then orally for newborns
• RR .33 for infection in newborn
• Pregnant HIV African women
• randomized to oral AZT or placebo
• most funded by US agencies

27
Cardiac Arrhythmia SuppressionEcht, et al., 1991

• Randomized trial
• 1498 patients post-MI with PVCs
• Encainide, flecainide, or placebo
• Outcome death
• Trial stopped after 1 year due to increased
  deaths in treated group p .004

28
MORE TrialGrady, et al., 2003?

• Randomized, placebo-controlledtrial
• 7704 women with osteoporosis
• raloxifene or placebo
• Outcome morphologic spine fx
• Increased risk of VTE (RR2.5)
• first year RR6
• second year RR 5
• no increased risk thereafter

29
Conflict of Interest

• Professional judgement unduly influenced by other
  interests
• reputation
• promotion
• financial interests
• ownership, stock, gifts, consulting fees, travel
  and entertainment, research support

30
Ethics in Randomized Trials

• Informed consent isnt enough
• Important ethical issues in all stages of the
  design, conduct and presentation of findings of
  RCTs
• Easy to get sucked into thinking that your
  research is more important than participant safety