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The Case for Practical Clinical Trials in Psychiatry

The Case for Practical Clinical Trials in Psychiatry John S. March, MD, MPH Duke University Medical Center March JS, et al. (2004), The Child and Adolescent Psychiatry Trials Network (CAPTN). J Am Acad Child Adolesc Psychiatry

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The Case for Practical Clinical Trials in Psychiatry

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  1. The Case forPractical Clinical Trials in Psychiatry John S. March, MD, MPH Duke University Medical Center

  2. 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

  3. “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

  4. 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)

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

  6. What Have We Learned? • Not nearly enough • Too few mostly acute studies • Lack generalizability • Don’t adequately assess safety or moderators • Very expensive and take a long time to complete • Performed long after drugs are in widespread clinical use

  7. 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.

  8. Minimizing Error e Alpha reliability Measures Stability Measures Inter-rater QA Site variability QA

  9. TADS Manuals

  10. SEM and Power CI population mean = +/- 2 [SEM]

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. The Child and Adolescent Psychiatry Trials Network Web site: www.captn.org

  17. 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

  18. UNIVERSITY INDUSTRY Knowledge for Knowledge’s Sake Management ofKnowledge for Profit Teaching Profits Research Commercializationof New and UsefulTechnologies Service Product R&D EconomicDevelopment Academic FreedomOpen Discourse ConfidentialityLimited Public Disclosure Conflicting Values - Common Interest Conflicting Values - Common Interest

  19. A man who carries a cat by the tail learns something he can learn in no other way. Mark Twain

  20. 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

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