Considerations for Comparing a Test Drug with Standard of Care in Phase 2 Clinical Trials of Central Nervous System Diso
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Craig H. Mallinckrodt, PhD Eli Lilly 6.Co.. Lilly Corporate Center, Indianapolis, Indiana Micboel J. Detke, MD, PhD MedAvante. Hamilton. New jersey; Departments of Psychiatry. Harvard Medical School, Boston; McLean Hospital. Belmont. Massachusetts; Indiana University School of Medicine. Indianapolis, Indiana William R. Prrcka, PhD Eli Lilly S. Co.. Lilly Corporate Center, Indianapolis. Indiana Stephen J. Rrberg, PhD Eli Lilly S. Co.. Lilly Corporate Center. Indianapolis. Indiana Geert Molenberghs, PhD I-BioStat, Hasselt University. Diepenbeek. Belgium: Katholieke Universiteit Leuven, Leuven. Belgium
Key Words Clinical trial: Active comoaratoc Standard of care Correspondence Address Dr. Craig H. Mallinckrodt. Lirly CorporateCenter, Indidnapolis. IN 46285 (email: [email protected]).
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Considerations for Comparing a Test Drug With Standard of Care in Phase 2 Clinical Trials of Central Nervous System Disorders An increasing need exists to understand the benefits of a test drug compared with standard of care (SoC)earlier in development. Even if a drug is superior to placebo, it may not be worthwhile to continue development unless it has advantages over SoC. However, eficacy and safety comparisons versus SoC in early phase studies can be challenging. Analytic studies were conducted to illustrate that in common scenarios simply randomizing a few patients to SoC will frequentlyyield misleading results. It may take samples sizes at least fivefdd greater to achieve reliable comparisons of a test drug with SoC than when comparing versus placebo. Therefore, it is important that the rate of false positive and false negative results be quantitatively evaluated before determining
IN T R O D U C T l O N The goals of phase 2 development have traditionally included exploring use for the targeted indication (establishing proof of concept, PoC) and estimating dosage for subsequent studies (dose-response) (1,2).One of the changes in recent years in the health care industry is that key stakeholders are demanding evidence not only that drugs are safe and effective, but that they are safer or more effective than alternatives. Therefore, greater need exists to understand the risks and benefits of a test drug compared with a standard of care (SoC). Ideally, this information would be available early in development. For example, even if a test drug were superior to placebo in a PoC study, it might not be worthwhile to continue developing the drug unless it also provides benefit beyond a currently available cheaper, generic therapy. However, efficacy comparisons versus SoC in a PoC study can be challenging (3,4). For example, reliably establishing a difference be-
the sample size and the criteria upon which the test drug and SoC will be compared. Because test drugs often have no benefit, comparing a test drug with SoC may unnecessarily use resources that could be devoted to investigating other drugs. Moreover, it can be difficult to construct valid comparisons of a test drug versus SoC without expetience with the test drug regarding ap
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