In the near future, personalized medicine—where treatment is based on an individual’s characteristics rather than that of an average patient—will transform the delivery of health care. Elements of personalized medicine are already emerging in clinical practice: biomarkers are providing early diagnosis of diseases and genetic tests are helping physicians determine safe and effective medication dosages. A recent study estimated that nearly one-quarter of all prescriptions filled in the United States includes pharmacogenomic information on the label.1
In order to continue the advancement and acceptance of personalized medicine, it is vital that testing of biomarkers for their clinical effectiveness be conducted in a timely and cost effective manner. While the prospective randomized controlled trial (RCT) will continue to serve as the gold standard for determining the efficacy of most therapeutic treatments, in the field of pharmacogenomics, alternative approaches may be more suitable for determining biomarkers’ clinical effectiveness. Alternative approaches—such as case-control and cohort studies, as well as retrospective data analyses—may require less time and resources than RCTs, and most importantly, can provide results that may be translated more easily into clinical practice.
Prospective RCTs are used to test pharmaceuticals to ensure they are not only safe, but also effective. Typically, a RCT analyzes two types of treatments under otherwise identical conditions; a new treatment is compared to an existing treatment or a placebo. While the RCT provides valuable information about the new treatment, it is limited in its ability to address the applicability of that treatment in broader, non-controlled environments that are more representative of real clinical practice.
When RCTs are used to evaluate biomarkers, issues ranging from ethical concerns to logistical complications must be considered. For example, if evidence from preliminary retrospective genotyping suggests a certain sub-population may be at risk, would it be ethical to expose participants identified with the biomarker to harm by not considering it in the proposed treatment scheme? To date, clinical researchers appear to say “no.” Over the past four years, several research groups have been engaged in genotyping for the use of warfarin, an anticoagulant with a narrow therapeutic index. While several studies, including RCTs, are underway, none is designed to measure the effect of a full dose of warfarin in patients who have a higher than normal sensitivity to the drug. It would be unethical to do so. This suggests that prior knowledge of a participant’s genotype affects the treatment scheme.
The logistical complications associated with using RCTs to evaluate biomarkers can be substantial and at times they cannot be overcome, as was recently the case for Tegretol (carbamazepine), an anticonvulsant medication. Retrospective data provided the basis for the US Food and Drug Administration (FDA) to update Tegretol’s label to warn carriers of the HLA-B*1502 allele with Asian ancestry about the possible risk of sometimes fatal dermatologic reactions. Since most carriers of the HLA-B*1502 allele will not develop an adverse reaction, a sizeable and expensive RCT would have been required to appropriately study the biomarker.2 Due to the seriousness of the adverse reaction, regulators proceeded to take action without evidence from a RCT.
Given these concerns with RCTs, it is not surprising that researchers are using other analyses—for example, non-randomized case-control and cohort studies, along with retrospective data analyses—to support the translation and integration of biomarkers into clinical practice. In a case-control study, researchers identify two groups of participants: one is composed of individuals with a specific health problem (the ‘case’) and the other is composed of ‘similar’ individuals without the problem (the ‘control’). An analysis is then conducted either prospectively or retrospectively to determine factors that may contribute to the health problem. In a cohort study, a group of people exposed to a variable are followed over time and compared to a separate unexposed group.
While case-control and cohort studies are not new, the speed at which these studies can be conducted today, both prospectively and retrospectively, with a large population is revolutionary. Databases and information technology provide the opportunity to simulate case-control studies to identify characteristics of patients having the presence or absence of biomarkers and to analyze the effectiveness of a certain drug treatment or the likelihood of an adverse outcome based on a certain treatment. It is important to note that unlike RCTs, these studies allow for the observation of other factors (e.g., environment and co-medication) that can influence the outcome of the therapeutic treatment.
While prospective RCTs are the gold standard for regulatory approval of new drug therapies, they may not always be adequate to assess the clinical utility and effectiveness of biomarkers. For this purpose, non-randomized case-control or cohort studies may produce better results that are more reflective of the real clinical environment. Moreover, these proven and established approaches sidestep some of the ethical and logistical concerns that may be associated with RCTs, while offering potential benefits of expediency and lower cost. Results from case-control and cohort studies are usually easier to translate into clinical practice than results from RCTs because they more closely represent the real world. While RCTs were invented relatively recently to assess whether new drugs are safe and effective, these alternative approaches, which reflect how medical science has evolved over the years, may still be the more appropriate approach to assess how biomarkers should be integrated into clinical practice.
1. Frueh, Felix W., et al. “Pharmacogenomic Biomarker Information in Drug Labels Approved by the United States Food and Drug Administration: Prevalence of Related Drug Use,” Pharmacotherapy 2008;28(8) 992-998.
2. Novartis, Tegretol prescribing information
About the Author
Dr. Felix Frueh leads Medco Health Solutions’ personalized medicine and development organization. Previously he directed a genomics review team at FDA’s Center for Drug Evaluation and Research. He also has served on the faculty at Georgetown’s Departments of Pharmacology and Medicine.
Filed Under: Drug Discovery