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Letters to the Editor

Reply to Failure Rate and "Professional Subjects" in Clinical Trials of Major Depressive Disorder

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Dr Khin and Colleagues Reply

To the Editor: We acknowledge the potential contribution of "professional patients" to the rising placebo response, declining treatment effect over time, and persistently high failure rate seen in placebo-controlled major depressive disorder (MDD) trials.1 Unfortunately, there are no systematic data to document the impact that such subjects might have. The US Food and Drug Administration (FDA) has little capacity to investigate this concern, because patients are deidentified in the data submitted as part of new drug applications. Even site inspections by FDA’s Division of Scientific Investigations do not provide an opportunity to address this potential problem, because these typically focus on only a few sites selected from multicenter trials. FDA Center for Drug Evaluation and Research clinical investigator inspectional databases2 (eg, subjects receiving simultaneous investigational drugs as the deficiency code) have so many limitations that these also would not be a particularly useful source for a comprehensive look at this issue.

Trying to assess patient compliance with taking the assigned treatment is useful independent of the concern about "professional patients," so we agree with Dr Shiovitz and colleagues regarding the suggestion of collecting pharmacokinetic samples during these trials. The FDA has in fact encouraged sponsors to include pharmacokinetic measurements in the design of these trials. It is unclear, however, that such assessments would help in definitively identifying "professional patients," because even legitimate patients may sometimes fail to take assigned treatment.

The suggestion of groups independent of the FDA setting up central databases for tracking participation of professional patients in clinical trials is worthy of consideration. Close attention is needed, however, to a variety of factors in the construction of this type of individual patient-level database, including, importantly, legal issues on patient privacy3,4 and human subject protection.5 These considerations become increasingly important as globalization of clinical trials continues to increase.

References

1. Khin NA, Chen Y-F, Yang Y, et al. Exploratory analyses of efficacy data from major depressive disorder trials submitted to the US Food and Drug Administration in support of new drug applications. J Clin Psychiatry. 2011;72(4):464-472. PubMed doi:10.4088/JCP.10m06191

2. US Food and Drug Administration Center for Drug Evaluation and Research Clinical Investigator Inspection List. http://www.fda.gov/Drugs/InformationOnDrugs/ucm135198.htm. Accessed July 5, 2011.

3. Kulynych J. HIPAA compliance in clinical trials. J Oncol Pract. 2008;4(1):9-10. http://jop.ascopubs.org/content/4/1/9.short

4. US Department of Health and Human Services, Office of the Secretary. Part V, Standards for Privacy of Individually Identifiable Health Information; Final Rule. 45 CFR §160, 164. http://www.hhs.gov/ocr/privacy/hipaa/administrative/privacyrule/privrulepd.pdf. Accessed July 5, 2011.

5. US Department of Health and Human Services. Protection of Human Subjects. 21 CFR §50. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=50. Revised April 1, 2010. Accessed July 5, 2011.

Ni A. Khin, MD

ni.khin@fda.hhs.gov

Yeh-Fong Chen, PhD

Yang Yang, PhD

Peiling Yang, PhD

Thomas P. Laughren, MD

Author affiliations: Division of Psychiatry Products, Office of Drug Evaluation I, Office of New Drugs (Drs Khin and Laughren); and Division of Biometrics I, Office of Biostatistics, Office of Translational Science (Drs Chen, Y. Yang, and P. Yang), Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland. Potential conflicts of interest: None reported. Funding/support: None reported. Disclaimer: The views expressed in this letter are those of the authors, and do not necessarily represent FDA.

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