John J. Cush, MD, Guest Editor

Kathryn H. Dao, MD, Guest Editor

The need for change is driven by the lack of preventative or curative measures, clinical trial evidence of limited efficacy, and the ever-present practice of cycling patients through numerous therapies––either because of lack of efficacy, tolerability, or finances. It is not surprising that patients and physicians alike express enthusiasm over new treatments––as these may be “the magic bullet” we seek.

However, enthusiasm is ultimately trumped by concerns whether any agent “is truly safe.” Pisetsky and others have stated that the safest risk is the one not taken. During training, young doctors are taught by their mentors that therapeutic adventurism should be avoided. Rather than prescribe the “latest and greatest” new drug, the wise clinician should let others and time establish the safety of these novel therapies. Hence while large controlled studies have shown significant clinical and radiographic benefits with new biologic agents in rheumatoid arthritis, the uptake of these agents by prescribers has been predictably slow. This change delay has been shown in many medical disciplines. Despite evidence favoring the cardioprotective effects of beta-blockers, lipid-lowering agents, and low-dose aspirin, the uptake of these in routine practice has also been disappointedly slow. Perhaps clinicians are sluggish to adopt treatment advances because of the perils of translating clinical trial recommendations into clinical practice––exemplified by experiences with hormone replacement therapy, rofecoxib (Vioxx), rosiglitazone (Avandia), and thalidomide.

Patients are also reluctant to change. When it comes to the utilization of novel therapies, Wolfe and Michaud have shown that patients prefer “the devil you know” (their current therapy) to “the devil you don’t” (a new drug). They found a sizeable discrepancy between the patient’s treatment satisfaction and disease activity measures, which could be attributed to loss of disease control or fear of side effects.

If fear (or risk aversion) is the foundation of safety concerns, time, experience, and study may adjudicate safety concerns. Bringing a new drug to market in the United States may take 10 years and nearly a billion US dollars. Moreover, the conditions required for change may only evolve with long-term safety data. Hence, safety does not come cheaply, quickly, or easily. As a regulatory requirement for drug approval, pharmaceutical manufacturers are heavily invested in pharmacovigilance to ensure the long-term success of their product. Pharmacovigilance is the science of identifying, assessing, understanding, minimizing, and avoiding adverse effects and drug-related problems. Global pharmacovigilance spending in 2010 was nearly $12 billion US. It begins during drug development (phase II and III trials) and is continued with long-term trials, postmarketing trials, widespread clinical use, medical reports of safety and efficacy, and population or registry-based observational studies. Indeed it is the frequent and pervasive focus on safety by many stakeholders that will establish the true safety and utility of a new agent.

The Food and Drug Administration (FDA) and other regulatory agencies are charged with ensuring the public health by ascertaining the safety, efficacy, and security of new medical interventions and products. These agencies have evolved to meet societal demands and commercial advancements as they impact population safety. Recent changes at the FDA have focused on drug safety, especially with regard to product labeling clarity (boxed warnings, contraindications, warnings), postmarketing commitments by manufacturers (Risk Evaluation and Mitigation Strategies), and new initiatives designed to electronically gather more real-time information on drug safety at the time of approval (Sentinel Initiative).

The safe use of drugs requires knowledge and experience but may also be bolstered by guidelines or rules. Chalkidou and coworkers suggest that when considering new therapies we should ask the 3 following questions: (1) Does current evidence suggest that the innovation is better than current practice ?; (2) Is more information or study necessary ?; and (3) Should we wait for more information ? Schiffand colleagues have offered these principles for safe prescribing: (1) think beyond drugs (consider nondrug therapy; treatable underlying causes; and prevention); (2) practice strategic prescribing (defer nonurgent drug treatment; avoid unwarranted drug switching; be circumspect about unproven drug use; start treatment with only 1 new drug at a time; know who should not receive a drug); (3) maintain heightened vigilance regarding adverse effects (suspect drug reactions; be aware of withdrawal syndromes; and educate patients to anticipate reactions); (4) exercise caution and skepticism regarding new drugs (seek out unbiased information; wait until drugs have sufficient time on the market); (5) work with patients for a shared agenda (address nonadherence; patient preferences; education); and (6) consider long-term, broader impacts (weigh long-term outcomes and recognize that improved systems may outweigh marginal benefits of new drugs). Last, the clinician should recognize common pitfalls that include prescribing a drug : (1) when no drug is needed ; (2) when no drug is indicated ; (3) that the drug is poorly chosen for the disease or patient ; (4) that the drug is incorrectly dosed or used ; (5) when no drug education or essential information is supplied ; (6) when drugs are not monitored ; or (7) when the patient is already receiving too many medications.