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CLINICALHARMACOLOGYTHERAPEUTICS

VOLUME 75 NUMBER 6 JUNE 2004

OMMENTARIES

ostmarketing surveillance for drug safety:urely we can do better

Marie R. Griffin, MD, MPH, C. Michael Stein, MD, and Wayne A. Ray, PhDNashville, Tenn

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In this issue of the Journal, Bonnel and Graham1

eport peripheral neuropathy occurring in association witheflunomide treatment. This report addresses the questionf whether leflunomide causes peripheral neuropathy inome patients, but it also raises more fundamental ques-ions regarding how we obtain information about theafety of drugs after they have been marketed.

Leflunomide is one of several new drugs used to treatheumatoid arthritis, and it was approved in the Unitedtates in September 1998. Although peripheral neurop-thy was not specifically documented in prelicensing

rom the Departments of Preventive Medicine and Medicine andCenter for Research and Education on Therapeutics, VanderbiltUniversity Medical Center, and Geriatric Research and EducationClinical Center, Veterans Affairs Tennessee Valley HealthcareSystem.

his project was supported in part by an Agency for HealthcareResearch and Quality Centers for Education and Research onTherapeutics cooperative agreement (grant No. U18 HS 10384).

eceived for publication Jan 19, 2004; accepted Jan 30, 2004.eprint requests: Marie R. Griffin, MD, MPH, Department of Pre-ventive Medicine, Vanderbilt University Medical Center, A1124MCN, Nashville, TN 37232.

-mail: marie.griffin@vanderbilt.edulin Pharmacol Ther 2004;75:491-4.009-9236/$30.00opyright © 2004 by the American Society for Clinical Pharmacologyand Therapeutics.

loi:10.1016/j.clpt.2004.01.017

tudies, paresthesias were reported by 3% to 4% of pa-ients, about twice as commonly as among those random-zed to placebo and sulfasalazine but only modestlyreater than for patients randomized to methotrexate.2

timulated by a report of 2 cases of peripheral neurop-thy associated with leflunomide published in 2002,3

nvestigators from the US Food and Drug Administra-ion (FDA) reviewed reports of peripheral neuropathyssociated with leflunomide from their database of spon-aneous adverse reports from manufacturers, health careroviders, and consumers.1 Eighty nonduplicative re-orts that were temporally related to leflunomide ther-py were the ultimate subject of their review. Theuality of the data is limited by information provided inhe voluntary reports so that, for example, dose wasissing for 32% and onset of symptoms was missing

or 42%.The investigators argue for a causal relationship be-

ause the neuropathy is not typical of that associatedith rheumatoid arthritis, the neuropathy improved in

everal instances with early drug withdrawal, and thereas no other likely etiology in most cases. However, is

his the level of proof we need to make clinical deci-ions? A clinical trial with such incomplete data woulde unlikely to be published, let alone change clinicalractice. If indeed there is a causal relationship between

eflunomide and peripheral neuropathy, how often does

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CLINICAL PHARMACOLOGY & THERAPEUTICS492 Griffin, Stein, and Ray JUNE 2004

t occur? Should we monitor all users of leflunomide foreripheral neuropathy? If so, how? Should the drug beithdrawn at the onset of subjective paresthesias (a

elatively common symptom) despite otherwise goodfficacy and tolerance? Is another drug likely to be asfficacious and safer? How many other uncommon butotentially important reports of adverse events associ-ted with leflunomide, other new drugs for rheumatoidrthritis, or, indeed, any new drug reside undiscoveredn the FDA database until it is specifically interrogatedor those events? What are the long-term adverse ef-ects of new drugs for rheumatoid arthritis, a conditionhat generally requires lifelong treatment? Providersnd patients deserve answers to these questions, but theurrent system is not designed to provide them.

Before drug companies can market a new prescrip-ion drug or biologic agent in the United States, the newroduct undergoes extensive testing and is rigorouslyvaluated by the FDA. These studies are necessarilyimited as to numbers of patients and duration of fol-ow-up; therefore a large part of the “experiment” be-ins after a product is marketed and a much largerumber of patients are exposed to the drug, often withomorbidities or in clinical situations very differentrom those in the clinical trials that led to approval. Athis time, when our need for data is great, we relyeavily on a system of voluntary reporting to detectotential problems. Advances in computer technologynd information systems can improve this importantesource, which may generate the first signal of a prob-em with a new drug. However, even with more com-lete reporting and fewer missing data elements, thisype of system cannot replace the population-based infor-ation needed to determine causality and to quantify risk.In addition to voluntary reporting, the FDA may ask

manufacturer to conduct a “phase 4” or “postmarket-ng study” before or after licensure if additional informa-ion is important in improving prescribing. The FDA

odernization Act of 1997 provided the FDA with addi-ional authority for monitoring the progress of these “post-arketing commitments” that drug and biologic appli-

ants have agreed to conduct. In addition, postmarketingtudies for products that were fast-tracked and those forhich further data are needed to establish safe use in

hildren are mandatory.4 For leflunomide, the manufac-urer committed to 6 postmarketing studies; because thereas not concern about peripheral neuropathy before li-

ensing, this was not a targeted adverse event for study.s of Oct 22, 2003, when the tracking system for these

tudies was last updated, none were recorded as havingeen started.5 This is similar to postmarketing commit-

ents for many other drugs. As of February 2002, only g

7% of the 2400 postmarketing commitments for newrugs had been completed and many had never beentarted. Despite changes in FDA procedures, potentialoncerns or “signals” generated before licensing cantill remain unexplored for years after marketing.

Are manufacturers the best group to measure andvaluate postmarketing safety? We think not. There aretrong disincentives for companies or contract researchrganizations to identify safety problems with licensedrugs quickly and efficiently. As pointed out by Stern,6

eeking out and sharing bad news about a product arenlikely to increase business.Many experts agree that the major problem with the

urrent system is the lack of an independent organiza-ion responsible for the systematic review of drugs forafety after marketing.7-10 Historically, the FDA hasad limited capacity to take a comprehensive view ofrug safety. Although valuable, information gleanedrom passive postmarketing surveillance is inherentlyimited and cannot address many of the relevant ques-ions. Voluntary reports of specific drug-disease asso-iations are extremely effective when a rare event, forxample, phocomelia, occurs in an exposed population.ase reports are also effective when a dramatic clinicalvent, for example, acute liver or renal failure, occursn close temporal association with exposure to a drug.owever, voluntary reports are less likely to be helpful

n determining whether a drug causes or increases theeverity of a condition that is relatively common in theackground population, for example, myocardial in-arction, heart failure, or, indeed, peripheral neuropa-hy. This is especially true when the increase in thesevents is modest, a doubling or less. A 50% increase incommon but serious adverse event such as myocardial

nfarction could pose a major public health problem ifhe exposure were relatively common, yet this would belmost impossible to detect without a population-basedeview of the drug’s safety.

Delayed recognition of the importance of an adversevent is not a theoretic concern. For example, despitehe availability of prescription nonsteroidal anti-nflammatory drugs since the 1960s, their causal role inerious peptic ulcer disease complications was unclear.n 1986 the FDA was stimulated to investigate thessociation by a petition from the Public Citizen’sroup. The labeling was changed in 1989, and further

vidence for the association, wide acceptance, anduidelines to limit risk followed slowly. In the mean-ime, thousands of patients in the United States diedach year from this adverse drug effect.11 Even now,

uidelines about appropriate use of gastroprotective

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CLINICAL PHARMACOLOGY & THERAPEUTICS2004;75(6):491-4 Leflunomide and postmarketing surveillance 493

gents in high-risk persons taking nonsteroidal anti-nflammatory drugs are frequently ignored.12

No drug is completely safe, and, therefore, informa-ion about the safety and efficacy of a new drug com-ared with other therapeutic alternatives is critical forational prescribing. Such studies are not part of theegulatory process and, to the detriment of publicealth, are often not performed after marketing. Forxample, during the last 2 decades, older antihyperten-ive medications were gradually displaced by newerrugs.13 These new agents were promoted as havingreater benefits, on the basis of a variety of surrogatend points. Some of the newer drugs proved to be notnly more expensive but less safe. It is only recentlyhat results of needed comparative clinical trials withlinically meaningful end points were published.14 Cur-ent guidelines maintain the primacy of several olderrugs as first-line therapy for hypertension.This lesson is being repeated with a new generation

f oral hypoglycemic agents that have theoretic advan-ages but limited long-term safety data and no provendvantage. Troglitazone, the first in the new class ofhiazolidinediones, was enthusiastically embraced be-ore withdrawal after successive warning letters fromhe FDA about increased fatal liver toxicity.15 Premar-eting trials and postmarketing epidemiologic studiesf newer thiazolidinediones such as rosiglitazone andioglitazone revealed an increased risk for both fluidetention and heart failure compared with older drugs.16

omplex risk management guidelines have been pro-osed16; however, there is a need for large head-to-headrials assessing efficacy and safety compared with olderypoglycemic agents using clinically meaningful endoints (not solely glucose control).Finally, the lack of an organization with effective ties

o practitioners and consumers means that once a def-nite problem is identified there is no effective way tonfluence prescribing. Within 2 years of marketing, theDA issued a specific contraindication to the combinedse of cerivastatin and gemfibrozil, and the productnformation was amended in 1999.17 Despite escalatingarnings during the next 2 years, patients continued to

ake this combination, with patients and providersargely unaware of the emerging data up until the timef the drug’s withdrawal.18 The definitive FDA reviewf spontaneous reports of fatal rhabdomyolysis ap-eared as a letter in the New England Journal of Med-cine in 2002, 6 months after voluntary withdrawal.19

his investigation noted that the increase in reportselative to other statins was evident for cerivastatin bothhen used alone and when used in combination with

emfibrozil. This pattern of escalating but ineffective t

arnings and the accumulation of a number of prevent-ble deaths before voluntary withdrawal by the manu-acturer has been repeated too many times.

It is important to recognize that the safety profile ofdrug is not a variable that is defined in perpetuity by

he experiments that led to its being marketed. Weannot identify all of the adverse effects of a drugefore marketing; new and unexpected adverse eventsill occur, and mechanisms to detect and act on these

hould be part of a mandatory drug approval and re-ewal process.The ability to do appropriate postmarketing surveil-

ance rests on the capacity to mount studies rapidly inesponse to alerts and to conduct ongoing review ofccumulating postmarketing drug-disease data bothrom spontaneous reports and in other population-basedatabases. Investigators need to be able to performarge multicenter studies and use administrative andlinical practice computerized databases of populationsith prescription drug information or large cohorts withrescription drug information collected in a standard-zed manner. For more than 20 years, the FDA hasunded a small number of groups via cooperative agree-ents to conduct postmarketing surveillance studies,

oth those specifically requested by the FDA andnvestigator-initiated studies. In the last 5 years, 7 Cen-ers for Education and Research on Therapeutics haveeen established as a demonstration program, in part toalvanize more interest in and support for postmarket-ng drug studies. In addition, PDUFA III (Prescriptionrug User Fee Act III) has encouraged manufacturers

o develop “risk management” plans in consultationith the FDA to do additional studies to improve theirrugs’ risk profile during the first 2 to 3 years aftericensure.

These and other efforts are laudable; however, toate, we lack a systematic coherent approach to postli-ensing drug evaluation. There is a need for a distinct,ndependent entity with the mission of monitoring allew and existing drugs after marketing in a proactive,ystematic way. This entity should be independent ofndustry9 but could work cooperatively with federalgencies, including the FDA, Agency for Healthcareesearch and Quality, and Centers for Disease Controlnd Prevention; with groups representing practitioners;ith pertinent consumer organizations; and with other

takeholders. Alternatively, this board could be part ofn existing agency. The major mission of this organi-ation would be to conduct mandatory, proactive mon-toring of every new chemical entity. In addition, olderrugs would receive periodic review. As in clinical

rials, the level of monitoring should be appropriate to

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CLINICAL PHARMACOLOGY & THERAPEUTICS494 Griffin, Stein, and Ray JUNE 2004

he potential risk. This drug safety board could beuided by a number of advisory committees with ex-ertise in specific areas and with broad representationncluding researchers, clinicians, and patients, muchike committees the FDA has for decisions regardinghe licensing of new drugs. This board would system-tically review premarketing and postmarketing data onll new chemical entities and determine which postmar-eting studies are needed and ensure that they areerformed. The Centers for Disease Control and Pre-ention Advisory Committee on Immunization Prac-ices is an example of a committee that systematicallyeviews data on vaccines, identifies gaps in knowledge,nd makes recommendations about appropriate use.imilar committees for drugs could better define theafety of individual drugs, improve rational prescrib-ng, protect manufacturers from unwarranted litigation,nd improve the public health.

In the meantime, it is time for a closer look at all ofhe newer disease-modifying drugs for rheumatoid ar-hritis. But who is going to determine what is needednd ensure that it gets done?

Drs Griffin, Stein, and Ray are Centers for Education and Re-earch on Therapeutics investigators and have identified no otheronflicts of interest. Dr Ray has consulted for attorneys involved inerivastatin lawsuits.

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tients treated with leflunomide. Clin Pharmacol Ther2004;75:580-5.

2. Approval package Arava. Medical review, pt 2, Table 8.Available from: URL: http://www.fda.gov/cder/foi/nda/98/20905_arava.htm. Accessed April 20, 2004.

3. Carulli MT, Davies UM. Peripheral neuropathy: an un-wanted effect of leflunomide? Rheumatology 2002;41:952-3.

4. Report to Congress. Reports on postmarketing studies(FDAMA 130). Available from: URL: http://www.fda.gov/cber/fdama/pstmrktfdama130.pdf. AccessedApril 20, 2004.

5. Postmarketing study commitments Arava. Availablefrom: URL: http://www.accessdata.fda.gov/scripts/cder/

pmc/index.cfm. Accessed April 20, 2004.

6. Stern RS. A promising step forward in psoriasis therapy.JAMA 2003;290:3133-5.

7. The Centers for Education and Research on Therapeutics(CERTs) Risk Assessment Workshop Participants. Riskassessment of drugs, biologics and therapeutic devices:present and future issues. Pharmacoepidemiol Drug Saf2003;12:653-62.

8. Mitchell AA. Systematic identification of drugs thatcause birth defects. A new opportunity. N Engl J Med2003;349:2556-9.

9. Wood AJ, Stein CM, Woosley R. Making medicinessafer—the need for an independent drug safety board.N Engl J Med 1998;339:1851-4.

0. Ray WA, Griffin MR, Avorn J. Evaluating drugs aftertheir approval for clinical use. N Engl J Med 1993;329:2029-32.

1. Fries JF. Gastrointestinal toxicity of nonsteroidal antiin-flammatory drugs. N Engl J Med 1999;341:1397-8.

2. Smalley W, Stein M, Eisen G, Ray WA, Griffin MR.Underutilization of gastroprotective measures in patientsreceiving nonsteroidal anti-inflammatory drugs. ArthritisRheum 2002;46:2195-200.

3. Ubel PA, Jepson C, Asch DA. Misperceptions about�-blockers and diuretics. J Gen Intern Med 2003;18:977-83.

4. The ALLHAT Officers and Coordinators for the ALL-HAT Collaborative Research Group. Major outcomes inhigh-risk hypertensive patients randomized toangiotensin-converting enzyme inhibitor or calciumchannel blocker vs diuretic: the Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial(ALLHAT). JAMA 2002;288:2981-97.

5. Gale EAM. Lessons from the glitazones: a story of drugdevelopment. Lancet 2001;357:1870-5.

6. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM,Horton ES, et al. Thiazolidinedione use, fluid retention,and congestive heart failure. Circulation 2003;108:2941-8.

7. Farmer JA. Learning from the cerivastatin experience.Lancet 2001;358:1383-5.

8. Schiff GD, Keehr LM, Sai TT, Bult J. High rates ofadverse effects and patient unawareness of withdrawnlipid-lowering drug combination in a public hospitalclinic. Pharmacoepidemiol Drug Saf 2002;11:643-5.

9. Staffa JA, Chang J, Green L. Cerivastatin and reports offatal rhabdomyolysis [letter]. N Engl J Med 2002;346:

539-40.