The Case for Practical Clinical Trials in Psychiatry

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The Case forPractical Clinical Trials in
Psychiatry

• John S. March, MD, MPH
• Duke University Medical Center

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March JS, et al. (2004), The Child and Adolescent
Psychiatry Trials Network (CAPTN). J Am Acad
Child Adolesc Psychiatry March JS (2005), Using
and Teaching Evidence-Based Medicine (EBM) The
Duke University Child and Adolescent Psychiatry
Model. Ch Psychiatr Clin North Am March JS et al.
(2005), The Case for Practical Clinical Trials in
Psychiatry, J Amer Psychiatr Assoc
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Evidence-Based Medicine is the conscientious,
explicit and judicious use of current best
evidence in making decisions about the care of
individual patients. David
Sackett, MD
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EBM Requires Best Evidence

• Clinically meaningful
• Generalizable (Few filters)
• Real world patients
• Real world doctors
• Real world treatment(s)
• Real world outcomes
• Replicable (reliable estimator of the pop mean)

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Trial Types

• We need trials for decision makers
• Public health value
• Real effect sizes
• Subgrouping variables (moderators)
• We have mostly explanatory trials

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What Have We Learned?

• Not nearly enough
• Too few mostly acute studies
• Lack generalizability
• Dont adequately assess safety or moderators
• Very expensive and take a long time to complete
• Performed long after drugs are in widespread
  clinical use

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Measurement Error
R T / T e R Intraclass Correlation
Coefficient T True score e Error
Fleiss, J. (1986). The Design and Analysis of
Clinical Experiments. New York Wiley.
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Minimizing Error
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Alpha reliability Measures Stability Measures In
ter-rater QA Site variability QA
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TADS Manuals
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SEM and Power
CI population mean /- 2 SEM
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A Modest Proposal

• Abandon large efficacy/effectiveness trials
• Iteratively develop treatments and examine
  mechanisms (mediators) in small data intensive
  trials
• Switch to large practical clinical trials to
  study real world outcomes, including subgrouping
  variables (moderators), and to disseminate
  treatments

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Practical Clinical Trials
Practical clinical trials, which are almost
always larger and always simpler than typical
RCTs in psychiatry, provide reliable estimates
of health outcomes applicable to a broad patient
base treated under usual clinical conditions
without bias. Richard Peto
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Characteristics of PCTs 1

• A straightforward clinically relevant question
• Representative sample of patients and practice
  settings
• Sufficient power to identify modest clinically
  relevant effects
• Randomization to protect against bias
• Clinical uncertainty regarding the outcome of
  treatment at the patient level

March, J., Silva, S., Compton, S., Shapiro, M.,
Califf, R., Krishnan, K. R. (in press). The
case for practical clinical trials in psychiatry.
Amer J Psychiatry.
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Characteristics of PCTs 2

• Best clinical practice diagnostic assessment
• Best clinical practice treatments
• Simple and clinically relevant outcomes
• Limited subject and investigator burden
• High value per dollar spent

March, J., Silva, S., Compton, S., Shapiro, M.,
Califf, R., Krishnan, K. R. (in press). The
case for practical clinical trials in psychiatry.
Amer J Psychiatry.
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Typical PCTs

• Active comparator trials
• Treatment addition (adjunctive or augmentation)
  trials
• Population PK studies
• Subgroup analyses, e.g age, pharmacogenetics
• Expand to traditionally excluded or rare
  populations
• Distal outcomes (5 year survivals), e.g. course
  of illness, not just episode, so can evaluate
  prognosis

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The Child and Adolescent Psychiatry Trials
Network Web site www.captn.org
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Americans confidence in our academic research
enterprise will unravel if researchers are not
extremely cautious in their private interests and
absolutely truthful in their research results,
especially adverse events, in situations where
their research activities and personal interests
converge.
- Donna Shalala, Secretary of the Dept. of
Health Human Services May 7, 2000
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Conflicting Values - Common Interest
Conflicting Values - Common Interest
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A man who carries a cat by the tail learns
something he can learn in no other way.
Mark Twain
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Summary

• To maximize their public health value, RCTs
  should tilt toward either
• Explanatory trials that focus on treatment
  development and mechanisms
• Practical clinical trials for decision makers
  that focus on producing generalizable knowledge
• PCTs will require stable networks funded and
  governed by a consortium of stakeholders