Regulatory Benefit-Risk Assessment and Comparative Effectiveness Research

Abstract

Over the past 5 years, we have witnessed growing interest in both comparative effectiveness research (CER) and regulatory benefit-risk assessment (BRA). Both deal with benefits and harms, although at different stages of the product lifecycle. There are growing pressures for a more systematic and quantitative approach to regulatory BRA. However, there is also a need for CER - beyond the evidence that can reasonably be generated during pre-launch product development. Important regulatory and policy questions include the following: What would be a level playing field across disease areas and companies? Who should bear the costs of these studies? What role can benefit-risk modelling play? What is the value of research and how is it related to the prevalence of disease? What is the relationship between uncertainty and the value of evidence? We need to recognize the lifecycle nature of evidence generation, moving from the regulatory setting to the real world and affecting potentially hundreds of thousands, or even millions, of patients worldwide. We need to emphasize not only the public goods nature of information embedded in innovations, but also that it is global. Finally, we need to more systematically explore the benefits and costs of gathering further information - the value of research - recognizing that doing this requires a model or methodology, which we have, for systematically appraising our current state of knowledge and what could be gained from further research. All said, it would seem that BRA and CER should be neither strangers nor strange bedfellows, but may need to be coaxed into being bedfellows.

Modelling the Cost Effectiveness of Disease-Modifying Treatments for Multiple Sclerosis

“…With the growing focus on evidence-based medicine and on enhancing the quality and efficiency of healthcare delivery systems, the need for information about comparative effectiveness of alternative treatment strategies is increasing 74, 86, 87 . However, with the increase in the number of available treatments in the market as well as the growing cost of clinical trials designed to test health interventions, more researchers turn to decision analytic modelling to make decisions in the presence of uncertainty 21 .…”

Perspectives on Comparative Effectiveness Research

“…As discussed recently by Martin et al, [25] numerous challenges must be overcome in conducting publicly financed comparative effectiveness Prevalence and characteristics of published comparative effectiveness studies, among studies evaluating medications. [18] 2 As discussed by Garrison [19] in this special issue, a public good is not diminished by others' use and no one can be effectively excluded from using the good. studies, including coordination of multiple government agencies as well as public and private payers, all of which may present barriers not typically encountered by pharmaceutical companies in the context of clinical study execution (e.g.…”

“…Several articles in this special issue address challenges in effectively applying this knowledge, [19,[42][43][44] in particular, focusing on what decision rules might be used for CER in the context of public policy analysis. Cutler and Ericson [43] consider a situation where price is substantially above marginal cost (viz.…”

“…This work implies that application of costeffectiveness analysis in a policy setting (for example, using a cost-per-QALY threshold such as the one adopted by NICE) would be improved by considering true social costs. Garrison [19] focuses on the use of quantitative benefit-risk analysis and health outcomes modelling as a method to assess evidence developed from CER and to support regulatory decision making. The author uses the case of the type II diabetes mellitus treatment rosiglitazone (with noted elevated cardiovascular risk) and discusses the December 2008 US FDA guidance [45] on safety testing in diabetes.…”

Should benefit–risk assessment have its own drug “label”?

“…A marginally effective but “safe” drug may still have harms that exceed its benefits and, conversely, an unequivocally effective but “unsafe” drug may have benefits that exceed its harms. Magnifying confusion about these two distinct ideas, the FDA considers available information about benefit–risk balance at the same time that it assesses safety and efficacy for approval decisions, although risk/benefit information is applied implicitly and unsystematically rather than explicitly, systematically, and quantitatively 8,9. Consequently, the FDA does not require “proof ” that benefits exceed harms, whereas it does require proof of safety and effectiveness.…”