Drug Safety: Managing Innovation in Rheumatology

Preface

Refining Drug Safety in

Rheumatology

John J. Cush, MD

Rheum Dis Clin N Amhttp://dx.doi.org/10.100889-857X/12/$ – see f

Kathryn H. Dao, MD

Guest Editors

An exciting era of rheumatology is upon us. Advances in pathobiology have producednovel advances in the treatment of rheumatoid arthritis, osteoarthritis, osteoporosis,gout, and lupus, to name a few. New and emerging therapeutics have substantiallyhelped control symptoms and may also alter the natural history of progression andallow a chance for remission. Paradigm shifts in therapeutics are often a consequenceof both novel drug development and wiser or more efficient use of existing therapies.While new treatment choices may be welcomed, they may also incite concern andcaution. In this issue of Rheumatic Disease Clinics of North America we shed lighton a variety of drug safety issues germane to the practice of rheumatology.

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

However, enthusiasm is ultimately trumped by concerns whether any agent “is trulysafe.” Pisetsky and others have stated that the safest risk is the one not taken.1 Duringtraining, young doctors are taught by their mentors that therapeutic adventurismshould be avoided. Rather than prescribe the “latest and greatest” new drug, thewise clinician should let others and time establish the safety of these novel therapies.2

Hence while large controlled studies have shown significant clinical and radiographicbenefits with new biologic agents in rheumatoid arthritis, the uptake of these agents byprescribers has been predictably slow. This change delay has been shown in manymedical disciplines. Despite evidence favoring the cardioprotective effects of beta-blockers, lipid-lowering agents, and low-dose aspirin, the uptake of these in routinepractice has also been disappointedly slow.3 Perhaps clinicians are sluggish to adopttreatment advances because of the perils of translating clinical trial recommendations

38 (2012) xi–xiv16/j.rdc.2012.10.001 rheumatic.theclinics.comront matter � 2012 Published by Elsevier Inc.

Prefacexii

into clinical practice––exemplified by experiences with hormone replacement therapy,rofecoxib (Vioxx), rosiglitazone (Avandia), and thalidomide.4

Patients are also reluctant to change. When it comes to the utilization of novel ther-apies, Wolfe and Michaud have shown that patients prefer “the devil you know” (theircurrent therapy) to “the devil you don’t” (a new drug).5 They found a sizeable discrep-ancy 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, andstudy may adjudicate safety concerns. Bringing a new drug to market in the UnitedStates may take 10 years and nearly a billion US dollars. Moreover, the conditionsrequired for change may only evolve with long-term safety data. Hence, safety doesnot come cheaply, quickly, or easily. As a regulatory requirement for drug approval,pharmaceutical manufacturers are heavily invested in pharmacovigilance to ensurethe long-term success of their product. Pharmacovigilance is the science of identi-fying, assessing, understanding, minimizing, and avoiding adverse effects and drug-related problems.6 Global pharmacovigilance spending in 2010 was nearly $12 billionUS. It begins during drug development (phase II and III trials) and is continued withlong-term trials, postmarketing trials, widespread clinical use, medical reports ofsafety and efficacy, and population or registry-based observational studies. Indeedit is the frequent and pervasive focus on safety by many stakeholders that will estab-lish the true safety and utility of a new agent.

The Food and Drug Administration (FDA) and other regulatory agencies arecharged with ensuring the public health by ascertaining the safety, efficacy, and secu-rity of new medical interventions and products. These agencies have evolved to meetsocietal demands and commercial advancements as they impact population safety.7

Recent changes at the FDA have focused on drug safety, especially with regard toproduct labeling clarity (boxed warnings, contraindications, warnings), postmarketingcommitments by manufacturers (Risk Evaluation and Mitigation Strategies), and newinitiatives designed to electronically gather more real-time information on drug safetyat the time of approval (Sentinel Initiative).8

The safe use of drugs requires knowledge and experience butmay also be bolsteredby guidelines or rules. Chalkidou and coworkers9 suggest that when considering newtherapies we should ask the 3 following questions: (1) Does current evidence suggestthat the innovation is better than current practice?; (2) Is more information or studynecessary?; and (3) Should we wait for more information? Schiffand colleagues2

have offered these principles for safe prescribing: (1) think beyond drugs (considernondrug therapy; treatable underlying causes; and prevention); (2) practice strategicprescribing (defer nonurgent drug treatment; avoid unwarranted drug switching; becircumspect about unproven drug use; start treatment with only 1 new drug ata time; know who should not receive a drug); (3) maintain heightened vigilanceregarding adverse effects (suspect drug reactions; be aware of withdrawal syndromes;and educate patients to anticipate reactions); (4) exercise caution and skepticismregarding new drugs (seek out unbiased information; wait until drugs have sufficienttime on themarket); (5)work with patients for a shared agenda (address nonadherence;patient preferences; education); and (6) consider long-term, broader impacts (weighlong-term outcomes and recognize that improved systems may outweigh marginalbenefits of newdrugs). Last, the clinician should recognize commonpitfalls that includeprescribing a drug: (1)when no drug is needed; (2)when no drug is indicated; (3) that thedrug is poorly chosen for the disease or patient; (4) that the drug is incorrectly dosed orused; (5) when no drug education or essential information is supplied; (6) when drugsare not monitored; or (7) when the patient is already receiving too many medications.10

Preface xiii

SUMMARY

This issue explores several important safety concerns that currently plague the rheu-matologist and health care providers who care for patients with rheumatic diseases.Weighing safety against efficacy can be a complex task that is best alleviated byunderstanding the issues, nature, and breadth of problems associated with druguse. Therapeutic decision-making must be evidence-based, judicious, and appro-priate for the patient and situation. Understanding drug safety is paramount toensuring both success of therapy and benefit to the patient. Similarly, it is importantnot to underestimate the impact of uncontrolled disease activity in decision-making.Drug safety must be weighed against the severity and risks of the disease under treat-ment. Clearly the benefit/risk ratio has improved for many of the therapies discussed inthis book.11 The use of both conventional and novel therapies mandates an under-standing of the mechanisms of action, unique toxicities, screening and monitoringmeasures, and rules for drug avoidance.

John J. Cush, MDBaylor Research Institute

Baylor University Medical CenterDallas, TX, USA

Kathryn H. Dao, MDBaylor Research Institute

Dallas, TX, USA

E-mail addresses:jjcush@gmail.com (J.J. Cush)

daokathryn@yahoo.com (K.H. Dao)

REFERENCES

1. Pisetsky D. Pisetsky’s rules vs. the Peltzman effect: pondering drug safety. TheRheumatologist. 2009. Available at: http://www.the-rheumatologist.org/details/article/872139/Pisetskyrsquos_Rules_vs__the_Peltzman_Effect.html.

2. Schiff GD, Galanter WL, Duhig J, et al. Principles of conservative prescribing.Arch Intern Med 2011;171(16):1433–40.

3. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardialinfarction, stroke, heart failure, and death in elderly Medicare patients treatedwith rosiglitazone or pioglitazone. JAMA 2010;304(4):411–8.

4. Lenfant C. Clinical research to clinical practice—lost in translation? N Engl J Med2003;349:868–74.

5. Wolfe F, Michaud K. Resistance of rheumatoid arthritis patients to changingtherapy: discordance between disease activity and patients’ treatment choices.Arthritis Rheum 2007;56(7):2135–42.

6. The safety of medicines in public health programmes: pharmacovigilance: anessential tool. Geneva: WHO; 2006.

7. Hilts PJ. Protecting America’s health: The FDA, business, and one hundred yearsof regulation. New York: Alfred A. Knopf; 2003.

8. Moore TJ, Singh S, Furberg CD. The FDA and new safety warnings. Arch InternMed 2012;172(1):78–80.

9. Chalkidou K, Lord J, Fischer A, et al. Evidence-based decision making: whenshould we wait for more information? Health Aff 2008;27(6):1642–53.

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10. Cush JJ, KavanaughA, SteinM. Prescribing guidelines. In: Cush JJ, KavanaughA,Stein M, editors. Rheumatology diagnosis and therapeutics. 2nd edition. Philadel-phia: Lippincott Williams & Wilkins; 2005. p. 399–402.

11. Pincus T, Kavanaugh A, Sokka T. Benefit/risk of therapies for rheumatoid arthritis:underestimation of the “side effects” or risks of RA leads to underestimation of thebenefit/risk of therapies. Clin Exp Rheumatol 2004;22(5 Suppl 35):S2–11.