Drug Safety

Drug safety—or, more precisely, drug non-safety—is an issue that gets frequent and intense public scrutiny and media coverage. From Vioxx to heparin, the dangers of prescription medications have captured the attention of doctors, patients, journalists, politicians, and lawyers. The Food and Drug Administration (FDA), a convenient and often unfairly maligned scapegoat, is under almost constant attack. And patients, not always trusting the judgment of their physicians, rely on a variety of sources for information about drugs, some of dubious value. For rheumatology, the escalating turmoil about drug safety has been juxtaposed with the rapidly changing approaches to therapy of rheumatic diseases. At a time when our use of pharmaceuticals is evolving at a much faster pace than ever before, rheumatologists and their patients have more questions about drug safety than ever before. What are the elements that have created this crisis? And what is the ACR doing on behalf of its members and their patients to address drug safety issues?

Before commenting further, a disclaimer is needed. I’m not an expert on pharmacology, drug development, or drug safety. The little I know comes from treating patients with rheumatic diseases since 1981 (which includes my fellowship training), reading both the medical literature and the lay press, and whatever my colleagues in the ACR who are real experts in this area have been able to teach me. But one of the perks of being ACR president is that once a month you get to write a column in The Rheumatologist (TR) about a topic of your choice, even if you don’t know that much about it! (And without even having to stay at a Holiday Inn Express.)

So, in no particular order, here are what I see as some of the roots of the drug safety mess:

• The high cost of drug development and the opportunities for blockbuster profit push manufacturers to expand usage of drugs too quickly after approval—both through intensive marketing to physicians and direct advertising to consumers—before enough time has elapsed to get a sufficient understanding of the safety issues.
• The FDA has become seriously understaffed and underfunded in the face of an expanded mandate that now also includes worldwide supervision of pharmaceutical manufacturing practices, a necessity that has been dramatized by the adulterated heparin episode. Only this year, after numerous fatalities from contaminated heparin, are additional funds being appropriated that will allow the FDA to hire more regulatory staff.
• In some cases, pharma has been slow to fully reveal safety concerns, or has manipulated the writing of scientific papers and reviews (as discussed in June’s ”President’s Perspective,” p. 4). Regulatory penalties and lawsuits are the inevitable consequences of such incidents.
• Patient expectations are at times too high. The notion that dangerous diseases can be cured by innocuous remedies, a perception that is fueled by the way that medical advances are often reported in the mass media, is rarely accurate.

But as important and concerning as these issues may be, it seems to me that the more fundamental reason for a drug safety problem is the existence of enormous gaps in our knowledge, due to enormous gaps in the data that is available. An important reason for this has to do with the way that drugs are studied during the drug development and approval process. Patients who are too young or too old, or who have any of a long list of co-morbid conditions, are excluded from clinical trials, yet these groups represent most of the patients whom we treat. And, often, these are the people who experience more frequent, more severe, more diverse, and more unexpected drug toxicities. It’s obvious that either clinical trials need to be designed in a different way and/or post-approval data collection from real-world practice settings needs to improve.

ACR Actions

1. Treatment guidelines: Under the supervision of the ACR Quality of Care Committee (QOC), chaired by Daniel Hal Solomon, MD, (an expert in drug safety and a TR editorial board member), groups of experts are updating treatment guidelines for a variety of rheumatic diseases. The new guidelines for the treatment of rheumatoid arthritis were published in June’s Arthritis Care & Research, together with an editorial commentary. (See p. 1 to read more about the guidelines.) These guidelines provide guidance for clinicians in both disease management and safe use of drugs, while pointing out important safety questions for which sufficient data is simply not yet available. Updated guidelines for management of osteoarthritis and glucocorticoid-induced osteoporosis are due out next year.

2. Timely communication to ACR members about safety issues: One of the main uses of the ACR Hotline is providing expert guidance to members within days to weeks when a new drug safety issue explodes. Other educational strategies include sessions at the ACR Annual Scientific Meeting devoted to drug safety and ACR white papers, like the one on NSAIDs.

3. Support for the development of new knowledge: The ACR Research and Education Foundation (REF)—both through its core programs and through Within Our Reach, its targeted RA research initiative—seeks to foster translational and clinical research that includes development of better outcomes measures and improved drug safety monitoring.

4. An informed leadership: Repeated appearances by Janet Woodcock, MD, one of the highest ranking officials in the FDA (and also a rheumatologist), at ACR board meetings have gone a long way toward creating a better informed ACR leadership. Dr. Woodcock’s presentations have been substantive, forward-looking, and targeted to our interests and concerns. Other pertinent activities of ACR officers, Government Affairs Committee (GAC) volunteers, staff, and advocacy consultants include careful study of the many bills introduced into Congress over the past two years that bear on drug safety.

5. Establishment of an ACR Committee on Drug Safety: This subcommittee of the QOC was established two years ago and is tackling a challenging agenda of drug safety issues.

Key roles for this committee are to maintain a dialog with the FDA on drug safety concerns that pertain to rheumatology, develop training opportunities in drug safety research for rheumatology fellows and faculty, and devise ways to keep ACR members informed on a broad spectrum of drug safety developments. (A survey on these issues may be finding its way to your e-mail box soon.) This subcommittee will also assist the GAC and staff to monitor legislation related to drug safety and help develop drug safety educational sessions for ACR meetings.

6. Formulation of position statements: The ACR has developed a position statement on the issue of generic biologics (also called biosimilars or follow-on biologics), which is available on the ACR Web site and has been communicated to key members of Congress who are active on this issue. It emphasizes the need for ensuring safety as well as efficacy as new agents are brought forward, and the importance of handling this as a scientific issue, not a political one.

7. Participation in future cardiovascular guidelines that impinge on rheumatology: ACR members are well aware of the recent publication of guidelines for use of NSAIDs in treating arthritis by the cardiovascular community that, from our perspective, did not reflect sufficient understanding of rheumatic diseases or their appropriate treatment. Earlier this year ACR and REF leadership met with Elizabeth Nabel, MD, Director of the National Heart, Lung, and Blood Institute (NHLBI), to explore opportunities for funding rheumatic disease research through the NHLBI. An unexpected bonus outcome of this very successful meeting was an invitation to designate rheumatologists to serve on oversight committees that the NHLBI is establishing to supervise cardiovascular guidelines development. Two ACR members have already been placed into these positions, and we view this as a substantial step towards an appropriate voice for the rheumatologist—and for patients with arthritis—in the creation of future guidelines on topics such as use of NSAIDs.

8. Full disclosure, and an emphasis on ethics: Potential conflicts of interest are an ever-growing concern of the ACR, and the issues surrounding drug safety provide an excellent example of why this is important. In the development of treatment guidelines, Hotlines, white papers, and activities of officers, board members, and committee members, disclosure of potential conflicts of interest is strictly enforced. Sometimes such conflicts exclude participation by specific individuals, even if they are otherwise well qualified. Industry funding and influence is not permitted for any ACR advocacy activities. Our relationship with our Industry Roundtable partners provides us—in my view—with an opportunity to make inroads into the practices of ghostwriting, data manipulation, and other undesirable activities that can cloud our understanding of drug safety issues. Our legal counsel tells us that, to his knowledge, no other professional society is as vigilant on conflict of interest issues as the ACR, and we intend to stay ahead of the curve as ethical standards continue to evolve.

9. Development of an ACR patient data registry: If the need for better real-world data is the most important reason for a drug safety problem, then the development of an ACR registry is likely to be the boldest and most effective step that we can take. Most ACR members don’t know it yet, but intense planning is underway—through a task force led by Jim O’Dell, MD—to develop a plan for an ACR patient data registry that would allow all ACR members to participate. Creation of better drug safety and toxicity data is only one potential benefit of such a registry—others include providing a pathway for meeting recertification requirements, quality improvement, quality measure reporting, and clinical research. Many questions still need to be addressed before the ACR board can authorize full implementation of this project, and ACR members will be kept updated as this initiative unfolds.

Is the ACR doing enough about drug safety? Probably not yet, but this issue is certainly getting plenty of attention. As we move forward, we can be confident that all of our initiatives in this area are not only for the benefit of our members, but also for the benefit of our patients. In this effort—and indeed in everything that the ACR does—aligning the interests of our members and our patients will be essential to our future success.

Dr. Fox is president of the ACR. Contact him via e-mail at [email protected].