SAN FRANCISCO—Advances in biologic and nonbiologic DMARDs have transformed the lives of many patients with rheumatic diseases. At the same time, balancing the risks of these therapies with the benefits has rendered treatment decisions more complex. The ACR’s Drug Safety Subcommittee, in partnership with the ARHP, sponsored an afternoon panel discussion at the October 2008 ACR/ARHP Annual Scientific Meeting. The session, “The Big Picture—Balancing Risk and Benefit fro the U.S. Food and Drug Administration, Physician and Patient Perspectives,” updated rheumatologists about current Food and Drug Administration (FDA) postapproval safety monitoring activities and clarified techniques for helping patients weigh risks and benefits of treatment choices.
The impetus for presenting the panel came from results of an ACR member survey, reported subcommittee chair and co-moderator Daniel J. Lovell, MD, MPH, interim director of the division of rheumatology at Cincinnati Children’s Hospital Medical Center, in his introduction. (Arthur Kavanaugh, MD, professor of medicine at the University of California, San Diego, also a subcommittee member, shared moderator duties with Dr. Lovell.) Results of the survey showed that 85% of survey respondents were “highly” or “extremely” concerned about drug safety, while 65% were less than “satisfied” about their own knowledge about drug safety.
FDA’s Current Initiatives
Paul Seligman, MD, MPH, associate director of safety, policy, and communication at the FDA Center for Drug Evaluation and Research, began by noting that the FDA recognizes that there are practical as well as ethical constraints in the agency’s ability to answer all questions related to a product prior to its approval. Among those constraints: all drugs have risks, premarket clinical trials are not large enough to detect rare safety events, and uncertainty is inherent in clinical trials.
Responding to increasing demands for more transparency and timeliness about postmarket safety issues, the FDA, in the past two to three years, has stepped up its outreach to consumers and providers. The Consumer Health Information Web site (www.fda.gov/consumer) disseminates information about a wide range of food, health, and safety topics; also, the FDA now partners with WebMD (www.Webmd.com/fda) to expand its public health advisories and ongoing safety reviews. For providers, the FDA publishes a quarterly Drug Safety newsletter (www.fda.gov/cder/dsn); maintains a MedWatch listserv (www.fda.gov/medWatch.elist.htm) with a current subscriber list of over 120,000; and partners with healthcare organizations to distribute electronic product safety updates. A recent example of information for providers was a September 4, 2008, FDA Alert regarding inconsistent recognition of histoplasmosis and other invasive fungal infections in patients taking TNF blockers, prompted by a case report and a subsequent FDA search of the Adverse Event Reporting System (AERS) database.
The FDA Amendments Act (FDAAA) of 2007 significantly extended the FDA’s regulatory authority regarding postmarket drug safety. Among other provisions, the act requires that drug labeling changes based on new safety information be done in accordance with strict timelines. New programs, including the Sentinel Initiative launched in May 2008, are part of the FDAAA-mandated thrust to develop a nationwide system for monitoring postmarket medical product safety. “The current system of voluntary reporting, through AERS, isn’t adequate to the task that we as a society face today,” stated Dr. Seligman. During postpresentation discussion, Dr. Seligman conceded that the FDA’s efforts to increase transparency and provide more safety information often carry unintended consequences.
Getting the Gist of Risks
With the increasing complexity of treatment options and wide availability of drug safety information, physicians must continue to play a key role in helping patients weigh risks and benefits of treatment, asserted second presenter Valerie Reyna, PhD, professor of human development and psychology at Cornell University in Ithaca, N.Y., and director of the Center for Behavioral Economics and Decision Research. This can be a difficult task, she said, because most people—including physicians—are uncomfortable when having to make trade-offs between risks and benefits of a given treatment. One reason for this is, because they occur in noncommensurate dimensions, benefits (relief from pain) cannot be directly compared with risks (possibility of increased infection). It can be helpful, therefore, to understand what cognitive research has revealed about risk perception, which consists of four main components:
- Knowledge: This includes not just background information but life experiences that inform the comprehension of that knowledge;
- Representation: The gist or essence of the information, and how is that understood, or represented;
- Retrieval: How one accesses information in order to make a decision; and
- Processing: Combining one’s representation of information with what is retrieved to generate a decision.
Each of these components can present difficulties, and result in risk perception errors. For instance, Dr. Reyna said, verbatim representation of risk, often a featured component of informed consent, can present problems for clinical trial enrollees. Investigators have been cautioned to test potential participants’ comprehension of risks by asking them to repeat information verbatim. But, she noted, if patients are not given the gist of the information—that is, the interpretation of its essence—this can result in a misperception of risk, as Dr. Reyna noted in her paper1 commenting on a 2001 study by Lloyd et al that tested understanding of risk in those scheduled for carotid endarterectomy.2 In that study, patients often correctly recalled the gist of risk (22% risk of dying from a stroke if they didn’t have the surgery), but many got the verbatim estimates wrong (some thought they had a 100% chance rather than a 22% chance of dying without the surgery).
It is not only patients who can vary in their estimates of risk and benefit. Dr. Reyna described results from a survey she recently conducted based on four increasingly complex patient scenarios. Rheumatologists were asked to rate the degree of medication risk (none, low, medium, or high) for patients receiving an NSAID plus one of the following: methotrexate (MTX); MTX plus etanercept; MTX plus rituximab; or MTX plus prednisone, hydroxycholoquine, and sulfasalazine. Although the physician respondents had consensus regarding the gist of these patients’ treatment regimens, there was a great degree of variability regarding the exact probability estimates they had for medication risks. When it comes to estimating risk, human brains do not function like computers. They rely on gist, not verbatim numbers.
What most current evidence has shown, said Dr. Reyna, is that the traditional view of decision making—that patients simply needed the right tools or measures to put risk into a quantitative context—is not a correct model. “It’s helpful to know what a computer would decide, and what a well-ordered set of preferences would look like,” she said, but cognitive science now shows that patients make decisions about their health qualitatively rather than quantitatively. “The bottom line,” she said, “is that it’s the gist, not the numbers” that forms the basis for most medical decision making. Physicians can keep this in mind when discussing treatment options with patients.
The Patient and Public Health View
Published U.S. and European surveys validate that people with rheumatoid arthritis perceive disease modifying antirheumatic drugs (DMARDs) as central to the management of RA, stated Janet S. Austin, PhD, director of the Office of Communication and Public Liaison at National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and this year’s recipient of ARHP’s Abbey Thomas Service Award, at the start of her portion of the presentation.
“And yet,” Dr. Austin added, “people with rheumatoid arthritis feel a constant tension due to strong concerns about potential long-term effects of DMARDs.” This was one of the conclusions that came out of the RA patient focus groups she conducted at NIAMS.
Because of her experience of dealing with RA for over 40 years, Dr. Austin touched not only on the public health but also the patient perspective on balancing risks and benefits of treatment. She encapsulated the crux of the session with this statement: “I decided many years ago that my quality of life was just as important today as it was tomorrow. Therefore, I take my medications, listen to my doctor, and choose not to worry about potential long-term side effects. I trust that in the future, should complications arise, that the medical and scientific discoveries of tomorrow will hold the answer.”
Although Dr. Reyna lauded the current era of patients becoming active decision makers, she cautioned that physicians must not abrogate their responsibility in helping patients make informed choices. “Healthcare providers have to think very carefully about ‘the bottom line’ of the information they communicate to patients. They are in a very important role of conveying that information,” she concluded.
Gretchen Henkel covered the 2008 ACR/ARHP Annual Scientific Meeting for The Rheumatologist.
