Opinion: Looking back and looking ahead: Vioxx, drug safety, and the legacy of Sen. Michael Enzi

The prescription painkiller originally known as Vioxx may be making a comeback after its maker, Merck, abruptly pulled it from the market in 2004 following studies that showed the drug roughly doubled patients’ risks of heart attack and stroke and may have contributed to an estimated 60,000 deaths.

According to STAT, Tremeau Pharmaceuticals, a privately held Massachusetts drug company, is about to begin clinical trials of rofecoxib (the generic name for Vioxx) as a treatment for hemophilic arthropathy, a persistent joint disease for which doctors often prescribed Vioxx off-label.

The timing of this new push for rofecoxib seemed quite the coincidence to me, given the pending retirement of Sen. Michael Enzi (R-Wyo.), whose investigation of the approval and subsequent withdrawal of Vioxx led to sweeping changes in how we ensure drug safety.

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Enzi, who is retiring this month after 24 years in Congress, is far from a household name. This is largely by his own design, considering the opportunities to generate publicity he’s had as chairman or ranking member of two high-profile Senate committees.

As he began to look into how and why the Food and Drug Administration and Merck missed certain safety signals related to Vioxx, Enzi was better known on Capitol Hill for his work on labor and employment issues than for any mark he had yet made on health policy. Yet his partnership with the late Sen. Edward Kennedy (D-Mass.) led to a comprehensive overhaul of FDA’s framework for evaluating the risks and benefits of prescription drugs, what a New England Journal of Medicine editorial called at the time “the most important drug-safety legislation in a century.”

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As a staffer to Enzi when he chaired the Senate Committee on Health, Education, Labor, and Pensions, I remember the pressure on him was intense. Merck had withdrawn Vioxx from the market just three months before he became the chair of the committee, which is responsible for FDA oversight.

The FDA was coming under heavy criticism, with some members of Congress and opinion leaders suggesting that preventing “another Vioxx” required a new FDA branch that would focus exclusively on the safety of drugs without consideration of their benefits or effectiveness.

This is where Enzi’s background on labor issues came into play. Before taking the gavel of the full committee, he had chaired its subcommittee on employment, safety, and training. From his oversight work there, and as a former owner of a small business, Enzi knew that no workplace could achieve absolute safety short of shutting down entirely. In the same way, he understood that no prescription drug could ever be approved with absolute certainty of safety — drugs are chemical substances, after all. Even common drugs like aspirin and ibuprofen can sometimes have harmful side effects.

During the committee’s investigations, it became clear to Enzi that while Vioxx had clear benefits for some people, it also posed some risks, and that neither the FDA nor the manufacturer had given enough thought to how to safely manage those risks after the drug entered the market and was being widely prescribed. At the time, the FDA’s only recourse post-approval to protect patient safety was to withdraw a drug completely from the market.

Following multiple hearings, Enzi and Kennedy directed their respective staff members to develop a concept through which the FDA and drug sponsors would collaborate more closely during the review process to identify known and potential risks of drugs and to implement product-specific plans for monitoring and managing those risks after approval.

This paradigm, which Enzi and Kennedy dubbed a “risk evaluation and mitigation strategy” (REMS), had multiple elements that could be tailored to any drug’s particular circumstances. For most drugs, clear and accurate labeling and medication guides, combined with standard post-marketing surveillance, would suffice.

For drugs whose benefits outweighed the risks, but whose risks were significant, the FDA would be empowered to require additional safety-focused elements as part of the requirements for approval. Some of these elements were quite strong, including restricted distribution programs and mandatory physician education programs, but they occupied an important space on the continuum between approval and withdrawal.

After 18 months of hearings and negotiations, Enzi and Kennedy formally introduced the risk evaluation and mitigation concept as the centerpiece of their Ensuring Drug Safety and Innovation Act of 2006. Two months later, a report on drug safety the FDA itself had commissioned from the Institute of Medicine (now known as the National Academy of Medicine) endorsed the central tenets of the Enzi-Kennedy bill.

It should come as no surprise that the Enzi-Kennedy bill was met with some trepidation by the pharmaceutical industry and even by some in the FDA who worried that the always-tenuous balance between safety and access to new medicines would shift too far in the direction of safety, limiting pharmaceutical innovation.

Undeterred, Enzi and Kennedy forged ahead. Although the committee process brought amendments and fine-tuning to the legislation, the REMS paradigm remained the cornerstone of a new approach to drug safety when Congress approved it by overwhelming bipartisan margins in the 2007 reauthorization of the Prescription Drug User Fee Act (PDUFA).

Despite the initial misgivings of many industry observers, a 2013 Brookings Institution paper acknowledged that risk evaluation and management programs had enabled the FDA “to facilitate access to a host of drugs that may not have otherwise been approved and allow products to remain on the market with greater confidence.”

The FDA deserves credit for building on the framework created by Enzi and Kennedy over the past decade. It has developed a more systematic methodology for benefit-risk assessment and a clearer approach to communicating its regulatory processes, considerations, and decisions. This effort has been supported by Congress through the two most recent reauthorizations of PDUFA and the 21st Century Cures Act.

To be clear, the deaths associated with Vioxx were tragic. Many people, however, took Vioxx as prescribed without incident and it meaningfully improved their quality of life. If the FDA had then the regulatory tools it has today, it might have been possible to avoid many of the deaths associated with Vioxx while preserving access to the drug for those who needed it and were at low risk of being harmed by it.

It will be due in large part to the work led by Sen. Michael Enzi if there is indeed another chapter — one with a happier ending — in the story of the drug formerly known as Vioxx.

Stephen Northrup is a founding partner of the policy and political consulting firm Rampy Northrup LLC. He was the health policy director for the Senate Committee on Health, Education, Labor, and Pensions under Sen. Michael Enzi’s chairmanship.

Source: STAT