Registries, research, and regrets: is the FDA’s post-marketing REMS process not adequately protecting patients?

Abstract

Regulatory science in the United States is barely a century old, with its genesis in the 1906 Pure Food and Drugs Act [Hamburg, 2010]. In 1993, the US Food and Drug Administration (FDA) initiated the MedWatch program, with the aim of ‘embedding reporting into the culture of medicine’ [Kessler, 1993a, 1993b]. The remedy for shortcomings in that program [Smith et al. 2006], targeting medical products with specific safety concerns, were RiskMAPs (risk minimization action plans), established in 2002 (see Table 1) [FDA, 2005]. Table 1. Possible formats for RiskMAPs (the strength of the safeguard increases from top to bottom of list). The 2006 Institute of Medicine report [Shane, 2009], and subsequent efforts by the FDA, the Agency for Healthcare Research and Quality, and the translational research community, resulted in RiskMAPs being superseded by the Risk Evaluation and Mitigation Strategies (REMS) program, incorporated into the 2007 FDA Amendments Act [FDA, 2008a]. REMS programs, as currently mandated, can incorporate several components, including registries, medication guides, patient package inserts, communication guides for healthcare providers and educational material to ensure safe use of the product [FDA, 2008b]. The reporting of serious adverse events to the FDA is still not a mandatory aspect of the REMS strategy per se, although the FDA is required to file quarterly reports based on biweekly screening of its Adverse Event Reporting System concerning REMS-associated therapies. To improve the postmarketing quality improvement process, it included optimizing input into the MedWatch program, more black box warnings and the Sentinel Initiative [FDA, 2008b; Federal Register, 2007]. As Leiderman has pointed out, ‘The “new” risk management approach expands the historic roles of industry and government as providers of product safety and prescribing information [through the product label] to a more “active” approach introducing special tools and programs to support safe use of selected products’ [Leiderman, 2008, Page 1]. Diplomatically skirted in this innovation process (and the FDA Commissioner’s recent Shattuck lecture) [Hamburg, 2010] is a critical issue: the opportunity to gather medical information about the product and its risks from the entire postmarketing at-risk population. Given that option, it is possible to use this patient cohort’s experience as the study group for new questions posed concerning that experience after commercial release. When is the exploitation of such remarkably rich datasets to be considered research, and thus amenable to the reporting requirements, along with checks and balances on control of that reporting, that protect human clinical research subjects? And, in the internet age of instant access to large amounts of data, instant feedback and communication over large networks of people and resource assets, can we do with anything less? I write as an academic medical center-based neurologist actively involved in clinical research of the causes and treatments for multiple sclerosis (MS). I am concerned about the lack of policy guidance, in certain special circumstances, to those who finance and conduct the translational research that brings drugs to market. There are economic and ethical reasons, some defensible, and some not, for the present way we survey for toxicity in the postmarketing treated population. This essay is offered as one physician’s position on the way to best establish ongoing patient safety in using new therapies with rare but high-risk complications. The following issues will be discussed: First, that here is a place for considering research aims in the context of the REMS process for certain drugs. Natalizumab’s (Tysabri, Biogen Idec, Cambridge, MA) example of an MS therapy with a novel mechanism of action and a rare and very serious complication is used to argue for such an expansion of the legitimate aims of a mandated registry. Second, that there are important differences in policy, financing, design and implementation between clinical trials with predefined endpoints and restrictive qualifying criteria to reduce confounding variables, and studies done on a prospectively accruing population. However, the present and increasingly more complex state of MS therapeutics – clinically, immunologically, ethically, financially and politically – demands a renewed approach to differentiating the passive REMS registry and the exploitation of the population at risk to further scientific and healthcare goals. Recommendations are made concerning the ways the patient, scientific, healthcare and policymaking communities can operationalize and synergize their goals and communication. While our purposes do not always coincide, we all should agree, along with Sherman and colleagues that the programs are ultimately in place in an attempt by all stakeholders to supply novel drug therapies while ensuring the highest level of patient protection [Sherman et al. 2011].