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Title: Ethical issues in the use of placebo control groups in water intervention trials UC Berkeley School


1
Ethical issues in the use of placebo control
groups in water intervention trials UC Berkeley
School of Public HealthJack Colford, MD PhDBen
Arnold, MPHSwiss Tropical Institute
University of BaselDaniel Maeusezahl,
PhDBerkeley Water CenterNovember 9, 2006
2
Motivation
  • Design crisis / by the numbers
  • Has our field reached a point at which it is no
    longer ethical in trials of drinking water
    interventions for comparison group subjects to be
    assigned to receive no active intervention?
  • No active intervention here implies groups
    randomized to receive either placebos OR groups
    randomized to continue current drinking water
    practices.

3
Choices
  • What should future trials of drinking water
    interventions choose as comparison groups?
  • No active intervention (conditional on first
    question)
  • Placebos
  • Current drinking water practices (traditional
    use)
  • By randomization
  • By natural experiment
  • Active interventions
  • Equivalence trials
  • Stepped wedge design

4
Outline
  • The Berkeley WET studies
  • PilotWET (CDC,Emerg Infect Dis 8(1) 29-36)
  • BigWET (CDC, Am J Epidemiol 161(5) 472-82)
  • HIVWET (CDC/UC, J Water Health 3(2) 173-84)
  • Sonoma-WET (NIH, analysis beginning)
  • Bolivia-WET (NIH, analysis beginning)
  • Rec-WET (Calif Wat Brd, in press, Epidemiology,
    Jan 07)
  • Rec-WET II (NIH, begins June 2007)
  • Placebos in domestic drinking water studies
  • Role of water in the history of the development
    of randomized, blinded, placebo-controlled
    trials?
  • The vertical transmission prevention debate and
    its analogy

5
Outline (2)
  • Choices for comparison arms in water trials
  • Superiority designs
  • Placebo groups
  • Participants current standard of drinking water
    (traditional use)
  • Equivalence / (non-inferiority) designs
  • Active device (with previously proven efficacy)
  • Conclusions and suggestions
  • Your assignment on leaving the room today

6
Blind IRBs
7
Bolivia-WET
  • Natural experiment taking advantage of NGO
    roll-out of SODIS near Cochabamba
  • Funding from NIH (R01)
  • 22 villages (660 children lt5y) randomized 5050
    to SODIS vs. current practices in a natural
    experiment
  • Villages matched on baseline diarrhea incidence
  • NGO roll out staggered
  • Community-based participatory training followed
    by monthly motivational visit

8
SODIS -- Design
8-12
9
Bingo!
10
Declaration of Helsinki
  • The benefits, risks, burdens, and effectiveness
    of a new method should be tested against those of
    the best current prophylactic, diagnostic, and
    therapeutic methods. This does not exclude the
    use of placebo, or no treatment, in studies where
    no proven prophylactic, diagnostic, or
    therapeutic method exists

11
HIV Vertical Transmission Trial Debate
  • Long course (076) AZT treatment was proven
    method known to reduce vertical transmission
  • Proposed short courses (either short AZT or
    single dose nevirapine in peripartum period) were
    compared to placebos in most studies
  • One side argued that the short course should have
    been compared to long course AZT therapy and not
    to a placebo
  • The study investigators argued that it was
    unethical to conduct the study without a placebo

12
Vertical transmission arguments
  • A ban on the use of less than the best worldwide
    methods would prevent evaluation of less
    effective, but practical methods
  • 75 of vertical transmission occurs during
    delivery and post-partum 25 occurs before
    labortherefore short course automatically will
    leave some women/children at risk
  • Nevirapine (one dose) was believed to be
    effective during delivery (but such a regimen
    would have no effect on the 25 of cases
    transmitted earlier in pregnancy)
  • Testing nevirpaine would necessarily result in
    more cases of transmission than the standard long
    course

13
Wendler, D., E. J. Emanuel, et al. (2004). "The
standard of care debate can research in
developing countries be both ethical and
responsive to those countries' health needs?" Am
J Public Health 94(6) 923-8.
14
Analogy to waterborne disease trials
  • Are waterborne diseases as great a public health
    burden as HIV/AIDS?
  • Are waterborne disease interventions as effective
    at reducing mortality/serious illness as HIV
    treatments are at reducing HIV transmission in
    pregnant, HIV-infected women?
  • If the ethics of placebo (or not treatment)
    controlled trials are being debated in the
    setting of vertical transmission of HIV, should
    the use of placebos (or no treatment) trials be
    re-considered in trials of waterborne disease
    interventions?

15
WHO standard
  • The ethical standards applied should be no less
    exacting than they would be in the case of
    research carried out in the sponsoring country
  • WHO. International ethical guidelines for
    biomedical research involving human subjects.
    Geneva Council for International Organizations
    of Medical Sciences, 1993.

16
The comparison group debate
  • The sole point of disagreement is the best
    comparison group to use in assessing the
    effectiveness of less-expensive interventions
    once an effective intervention has been
    identified. The researchers conducting the
    placebo-controlled trials assert that such trials
    represent the only appropriate research design,
    implying that they answer the question Is the
    shorter regimen better than nothing?

Lurie, P. and S. M. Wolfe (1997). "Unethical
trials of interventions to reduce perinatal
transmission of the human immunodeficiency virus
in developing countries." N Engl J Med 337(12)
853-6.
17
The church of placebo orthodoxy
  • Placebo orthodox
  • Placebos (when feasible) mandatory on the basis
    of methodologic concerns
  • Problems
  • Criteria for ethical use not formally stated
  • no permanent adverse consequences or
  • only temporary discomfort or
  • will not be harmed

18
Placebo advocates
  • Placebos are necessary to ensure validity
  • Without placebos a finding of no difference is
    difficult to interpret since the active control
    may have been no better than placebo
  • All agree that placebos are unethical in
    life-threatening or serious morbidity situations

19
Active control advocates
  • Claim that placebo orthodoxy sacrifices ethics
    and patient welfare
  • Helsinki seems to embrace this
  • Argues that when effective therapies exist they
    must be used
  • States that the clinically relevant question is
    whether the new treatment is better than (or
    equivalent to) the existing treatment

20
Examples
  • Traditional use
  • Clasen, T., G. Garcia Parra, et al. (2005).
    "Household-based ceramic water filters for the
    prevention of diarrhea a randomized, controlled
    trial of a pilot program in Colombia." Am J Trop
    Med Hyg 73(4) 790-5.
  • Active group received a ceramic water filter
    system designed for use at the household level.
  • Control group continued to use their
    customary practices for collecting, storing, and
    drawing drinking water.
  • Result Odds ratio 0.40 (95 CI 0.25 - 0.63)

21
Examples
  • Placebo use
  • Conroy, R., Elmore-Meegan, M, et al. (1996).
    Solar disinfection of drinking water and
    diarrhoea in Maasai children a controlled field
    trial. Lancet 3481695-97.
  • Active group told to fill the bottle with
    water and leave it in full sunlight on the roof
    of the hut
  • Control group instructed to keep their filled
    bottles indoors in the shade
  • Result Odds ratio 0.66 (95 CI 0.50 - 0.87) for
    treated vs. placebo

22
Placebo use in trials of waterborne disease
intervention trials
23
Comparison arms used in drinking water trials
Data extracted from Clasen T, et al.
Interventions to improve water quality for
preventing diarrhoea. (A Cochrane Review).
Cochrane Library, Issue 3, 2006
24
Study design alternatives
  • Alternate designs avoiding placebo use
  • Superiority trials (either active control or
    placebo)
  • Parallel
  • Cross-over trials
  • Natural experiments
  • Equivalence and non-inferiority trials
  • Active control
  • Natural experiments
  • Stepped wedge

25
Superiority vs. equivalence trials
  • Superiority trials
  • Intended to determine if new treatment is
    different from (better than) placebo or existing
    treatment (active control).
  • Null hypothesis is that there is no difference
    between treatments.
  • Alternative hypothesis is that the new treatment
    is either different from (two-sided) or better
    than (one-sided) control.
  • Equivalence trials
  • Intended to determine that new treatment is no
    worse than active control.
  • We can never assess absolute equivalence.
  • We can only assess no difference within a
    prescribed margin.
  • Null hypothesis and alternative hypotheses are
    reversed.
  • Null hypothesis is that difference between
    treatments is greater than X.
  • Alternative hypothesis is that difference between
    treatments is less than X.

26
Equivalence margin
27
Related issues
  • Sample size as an ethical issue
  • Efficacy vs. effectiveness
  • Marginal structural models and the death of the
    trial
  • Stepped wedge design

28
Stepped wedge
  • Crossover cluster design in which clusters switch
    treatmentsbut only in one direction
  • Clusters are randomized with respect to the time
    of switch
  • Useful in situations with limited resources or
    geographical challenges
  • All clusters eventually receive the intervention

Hussey, M. A. and J. P. Hughes (2006). "Design
and analysis of stepped wedge cluster randomized
trials." Contemp Clin Trials. 2006 Jul 6 Epub
ahead of print PMID 16829207
29
Conclusions
  • Our field needs to face the issue of comparison
    group choice in trials
  • Greater pre-trial consideration should be given
    to alternatives such as
  • Equivalence designs
  • Natural experiments
  • Stepped wedge design
  • Examination of the role of newer, marginal
    methods of inference in observational data
  • Your assignment
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