Why Trials Are Often Negative

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  • 01/16/2008
From an editorial in the American Journal of Psychiatry.

Demonstrating Drug Action
Carol A. Tamminga, M.D.

The questions that have arisen in the public and scientific literature lately about the use of SSRIs in children and adolescents are addressed for one of the currently available SSRIs by Wagner et al. The issue of whether it is effective to use SSRIs in childhood and adolescent depression has been repeatedly raised over the last years in the context of our field failing to produce clear efficacy answers in children. Depressed children are being treated with SSRIs in greater and greater numbers, without demonstrated efficacy in the age group. The difficulty of demonstrating efficacy with tricyclic antidepressants in children has fueled suspicions that there may exist an age-dependent resistance to treatment. The importance of this well-designed large study for therapeutic strategies in children and adolescents cannot be overstated. It is important that the methodology of this study is solid and the numbers adequate to test the efficacy question asked. The result that citalopram reduced depression more than placebo in this child and adolescent population provides a clear answer for physicians that will (in combination with results from additional studies) guide treatment decisions. It is especially gratifying to see an early onset of action at 1 week of treatment, suggesting an advantage that can be followed up in future studies. This study also set a high methodologic standard for psychiatric diagnosis in pediatric studies. It would be an understatement to say that more such studies are needed.

One would always wish for more in terms of information from drug trials in psychiatric diseases. A common physician complaint about these trials is that they fail to sufficiently inform clinical practice because of restricted entry criteria, fixed-dose design, and limited duration of treatment. It is true that initial registration trials have a goal of demonstrating superiority over placebo to become approved for the market. But this does not rule out additional Phase 4 studies done in large enough patient cohorts to fully inform pressing clinical issues. How do comorbid conditions alter drug response? What treatments are effective in medication nonresponders? What kinds of actions can be expected with long-term treatment? It will be important for industry to address these kinds of Phase 4 questions for clinical use as well as the registration trials.

One particular issue in our field makes informative clinical trials particularly difficult. This is that we do not know what exactly we are treating in terms of its biology. Psychiatric diagnoses are not based on molecular pathology (rather, phenomenology), and new drugs are not directed toward known, disease-related molecules (rather, toward hypotheses). Therefore, we may not be recruiting the correct patient populations for a particular treatment nor have a drug directed toward the disease pathophysiology. Moreover, we may not be measuring anywhere near the optimal outcome measures in our trials (e.g., consider the constraint of only measuring "fatigue" in the treatment of anemia, and not having a RBC count). Nonetheless, even though we do not yet have our molecular targets, we cannot give up on drug development. Indeed, we already have treatments for our diseases, and these may be better treatments than we deserve, based on the state of our knowledge. We need now to hone the treatments that we have and develop the valuable clinical trial methodologies to carry us into the future. Meanwhile, we need to translate the rich basic knowledge accumulating in neuroscience into advances for therapeutics.


Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.

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