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WEEK OF JUNE 18, 2007 • VOL. XXX, NO. 25 New Risks, New PlanDrug safety concerns show need for sophisticated risk management. BY STEPHEN PAUL MAHINKA
AND KATHLEEN M. SANZO
rcoxia, Vioxx, Acomplia, Zelnorm, and Tysabri; Aranesp, Procrit, Avandia and Lucentis. The concerns raised about these drugs illustrate the unprecedented focus on both safe- ty and costs not only at the Food and Drug Administration but also in Congress and at the Centers for Medicare and Medicaid Services. sales for Zelnorm at the FDA’s request. An outside reviewer’s From the FDA’s enhanced concerns about safety to Congress’ post hoc analysis of clinical trials revealed an increased risk of consideration of bills authorizing the FDA to impose ongoing cardiovascular events for Zelnorm users. But that analysis risk management programs and post-market studies, as well as showed that only 13 patients (0.1 percent) had serious events, the CMS’ increasing interest in requiring pharmaceutical compa- nies to demonstrate cost and comparative effectiveness, the land- The FDA has been evaluating whether additional safety warnings scape of drug and biologic development is rapidly and irrevoca- for other products—including the diabetes drugs Avandia from bly changing. These changes will have dramatic consequences GlaxoSmithKline and Actos from Takeda—are needed to highlight a for the process of selecting drug candidates, the scope and type possible risk of congestive heart failure in certain patients. of clinical studies, and the market value of products and compa- Similarly, the FDA convened its Oncologic Drugs Advisory nies. Pharmaceutical companies must respond by better integrat- Committee to reassess the risk-benefit profile of certain anemia ing their own risk management strategies. drugs, such as Amgen’s Aranesp and Johnson & Johnson’sProcrit, to address new concerns over their use with cancer THE FDA’S NEW FOCUS
patients. The advisory committee unanimously recommended The market has seen the highly publicized withdrawals of that additional safety studies be conducted. It also voted in favor several widely used drugs—including Merck’s Vioxx and of added “black box” warnings on the product labels.
Pfizer’s Bextra—because of significant safety issues that arose Another way in which the FDA has reacted to growing public after FDA approval. Not surprisingly, this has had ripple effects concern about drug safety is by imposing risk minimization at the FDA itself. In a host of ways, the agency has been increas- action plans, or RiskMAPs. The agency in 2005 issued guidance ing its oversight of new and already-approved drugs.
documents on RiskMAPs, which can effectively limit the scope For example, there has been a substantial increase in health of the distribution and sale of products. For example, the recent advisories. In 2001, the FDA issued four. By 2005 and 2006, the RiskMAP adopted for Biogen Idec/Elan’s multiple sclerosis drug Tysabri required that the drug makers create a mandatory Greater evidence of comparative safety or efficacy may be patient registry, mandate a preliminary MRI, and make the drug required for approval of new drugs where other therapeutic available only through authorized doctors or centers. products are on the market. The FDA’s “not approvable” deci- In addition, the agency has increasingly obliged drug developers to sion on Merck’s arthritis drug Arcoxia, for example, has been agree to undertake post-market clinical studies, generally referred to widely seen as indicating a more conservative approach. as Phase IV studies. (The efficacy of this requirement, including the That same conservativism appears to have affected the agency’s effectiveness of the FDA’s oversight, has been widely questioned.) weighing of the risks and benefits of Sanofi-Aventis’ diet drugAcomplia. After issuing an initial “approvable” letter, the agency CONGRESSIONAL EFFORTS
reversed its determination that an “obesity management” indication While the FDA has been doing more with its current authority, for Acomplia could be approved without an advisory committee public outcry over drug safety has stimulated congressional inter- 2007 ALM Properties Inc. All rights reserved. This article is reprinted with permission from Legal Times (1-800-933-4317 • LTsubscribe@alm.com • www.legaltimes.com).
est as well. Congress has undertaken hearings both on safety The first comparative effectiveness trial of a pioneer drug issues affecting specific drugs (such as Avandia) and on broad undertaken by the National Institutes of Health was legislation to enhance FDA authority. Proposals have exploded in announced in February this year. The trial will compare two number. From 1989 to 1998, no bills containing the words “drug Genentech drugs, Lucentis (which costs $2,000 a dose) and safety” were introduced. From 2003 to 2004, there were 19. And Avastin (which costs $40 a dose). The potential Medicare sav- ings from use of the less expensive drug are estimated at as This year the Senate passed the Food and Drug Administration Revitalization Act, which requires a particularized “risk evalua-tion and mitigation strategy” if serious risks are uncovered during NEW STRATEGY NEEDED
a drug’s clinical trials and post-approval studies or through the This unprecedented confluence of interest among the FDA, FDA’s adverse event reporting system or outside studies. The bill Congress, and the CMS on drug safety, comparative effective- also mandates that the agency create an active post-approval drug ness, and cost issues makes it imperative that pharmaceutical surveillance system and provides significant civil penalties—up and biotechnology companies develop their own more sophisti- to $2 million—for companies that fail to comply with the risk The effects of all these government efforts on drug developers Mark McClellan, the former head of both the FDA and the are likely to be substantial. They include more restricted distribu- CMS, has commented that this legislation would constitute “the tion, and consequently sales, of some drugs; reductions in cover- biggest set of changes in post-market drug regulations since at age and reimbursement by the government and private payers least 1962,” with the FDA “doing no less than entering a new based on new comparative clinical effectiveness and cost-effective- ness studies; and the resulting effects on the market’s valuation of McClellan has also observed that more generally, new drug drugs and their manufacturers, which could, in turn, affect negotia- safety laws could be expected to create new interactions between tions over collaboration agreements, mergers, and acquisitions.
the FDA, the CMS, and private payers as part of the development Traditionally, drug developers have narrowly focused their of cost containment mechanisms under the Medicare prescription clinical trials on generating sufficient safety and efficacy data to drug benefit. Legislation has recently been introduced in the obtain FDA approval as quickly as possible. Pricing and reim- House, for example, to provide additional funding to compare the bursement issues were rarely addressed before that approval.
cost and effectiveness of various treatments for particular illnesses. Indeed, they seldom needed to be addressed at all, because near-ly every approved drug was reimbursed at whatever price level CMS ACTIVITIES
Perhaps most surprisingly—in view of its traditional lack of That system is no more. In this new era of greater focus on involvement in this area—the CMS has begun to consider a role in safety and cost, developers of drugs and biologics must make drug safety and effectiveness matters. The driving force is the their own risk management plans up front. strongly felt need to contain the costs of the Medicare drug benefit. For example, clinical trials today should include tests designed So far, the CMS has proposed restrictions on coverage and to establish comparative safety and efficacy as well as cost-effec- reimbursement for anemia drugs, such as Aranesp and Procrit, tiveness. Such evidence must be ready at the time of FDA in view of the new label warning for certain cancer patients.
approval to answer government and private payer challenges. The CMS is also reviewing its coverage policy for these drugs Drug developers should also be prepared with their own data when they are used to treat kidney disease. Because these and communications strategies to respond to the results of gov- drugs are the single largest expenditure for Medicare, limita- ernment-directed studies of comparative efficacy. The implica- tions on the scope of coverage or reimbursement could result tions of making supporting data more publicly available at an in substantial savings for the government. A Wall Street phar- earlier stage in a product’s life cycle must also be addressed. maceutical industry analyst observed, “We could never have Companies will also want to prepare plans to respond to ques- anticipated that the extent of the regulatory and reimbursement tionable calls for the market withdrawal of a product and to address the risk of class actions, which will surely follow. There is a similar substantial interest in developing mechanisms Proving the clinical safety and efficacy of a pioneer drug is to research the comparative effectiveness of medical treatments.
thus only the beginning. Drug companies must also adjust to The Congressional Budget Office is preparing a report on the these new cost and safety demands with their own improved, potential for such research to reduce costs and improve treatment.
better-integrated risk management strategies.
And Gail Wilensky, the head of the CMS’ predecessor agency, hasproposed a new quasi-governmental entity to oversee such Stephen Paul Mahinka is a partner and chairman of the life research. Private insurer groups have also supported the idea. sciences interdisciplinary practice at Morgan, Lewis & Bockius in This quasi-governmental entity might be modeled after the Washington, D.C. Kathleen M. Sanzo is a partner in the firm’s United Kingdom’s National Institute for Health and Clinical D.C. office and leader of the FDA/health care regulation practice. Excellence, which has become active in evaluating clinical Contact them at smahinka@morganlewis.com and ksanzo@mor- effectiveness and cost-effectiveness. The U.K. agency conclud- ganlewis.com. Their firm represents several of the drug compa- ed, for example, that Tysabri is not cost-effective for routine nies mentioned here. The authors thank Jun Li, a law clerk and regulatory scientist, for his assistance. 2007 ALM Properties Inc. All rights reserved. This article is reprinted with permission from Legal Times (1-800-933-4317 • LTsubscribe@alm.com • www.legaltimes.com).

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