pharmacoepidemiology and drug safety 2005; 14: 665–667Published online 18 February 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.1072

ORIGINAL REPORT

Points to consider: the roles of surveillance and epidemiologyin advancing drug safety{,z

Ralph Edwards1, Gerald Faich2 and Hugh Tilson MD3*

1WHO Collaborating Centres, Upsala, Sweden2Pharmaceutical Safety Assessments, Inc., Narberth, PA3University of North Carolina School of Public Health

INTRODUCTION

Understanding the roles of pharmacovigilance andpharmacoepidemiology and the relationships betweenthe core disciplines of the two fields is necessary forthe effective progress of each field. Thus a first-everjoint session of the two international societies forthese fields, the International Society of Pharmacov-igilance (ISoP) and the International Society for Phar-macoepidemiology (ISPE), was held as part of theannual ICPE in 2003. At the joint session, a proposaldeveloped in an ISoP meeting (Paris, 2003) wasreported, commentary from ISPE provided, and broadaudience input solicited. This report summarizes, as aseries of ‘Points to Consider,’ the ICPE discussionsand proposes a ‘way forward’ for the two specialtysocieties.These points are intended to summarize the views of

attendees at the special joint session of the Interna-tional Conference on Pharmacoepidemiology aboutthe roles and best uses of the tools of surveillance andepidemiology applied to the challenges of drug safety,and do not reflect the official position of ISOP or ISPE.The attendees affirmed that global approvals and

marketing of pharmaceuticals have resulted in everincreasing numbers of people being exposed to new

drugs in a short time following approval. This results inan increased likelihood that safety signals, investiga-tive opportunities, and regulatory actions will arise,differing from those in the past, and presenting newchallenges to the fields of pharmacovigilance andpharmacoepidemiology. Because of these challenges,a number of issues need to be considered by thePharmacovigilance and Pharmacoepidemiology com-munities internationally. The recent movement in theUnited States toward official regulatory agencyguidance on the components of Risk Management,notably on pharmacovigilance and epidemiology,underscores the importance of moving toward thisinternational consensus.Two general basic principles were agreed to underlie

these considerations:First, surveillance and epidemiology are interrelated

and complementary activities.Second, the complexities and importance of phar-

macovigilance and pharmacoepidemiology demandan experienced workforce, well-prepared decisionmakers, and an informed public.The meetings and discussions have resulted in the

following ten Points to Consider for the Roles ofSurveillance and Epidemiology in Advancing DrugSafety:

1. Spontaneous post-marketing reports of possibleadverse drug reactions (ADRs) are key to detectingor signaling possible new drug risks:

– The volume of reporting has increased substan-tially in recent years, without necessarily anincrease in quality, making the review burden

Received 25 June 2004Revised 15 November 2004

Copyright # 2005 John Wiley & Sons, Ltd. Accepted 15 November 2004

*Correspondence to: Dr H. Tilson, Senior Advisor to the Dean,University of North Carolina, School of Public Health, Chapel Hill,NC 27599-7400, USA. E-mail: hugh_tilson@unc.edu{No conflict of interest was declared.zResults of a special joint session of ISoP and ISPE at the AnnualInternational Conference on Pharmacoepidemiology (ICPE), Phila-delphia, August, 2003.

more difficult and making a virtual necessity oftriage systems [automated or not], all of whichhave limitations.

– Each report should be viewed as having thepotential for raising a concern of a possiblerelationship between a drug and an event.

– The most important reports are those withadequate descriptions of new (unlabeled) andserious events associated with a drug. Otherreports may indicate medical errors, systematicerrors in drug use, and defective or counterfeitproducts. These issues require attention, and are anew dimension of pharmacovigilance.

2. The volume of reports for a given drug is affected bymany important forces, among them:

– Volume of use.

– Publicity including regulatory and manufacturercommunication and lay media.

– Recency of marketing.

– Type and severity of the event.

Therefore, the reporting rate is not a true measureof the rate or the risk.

3. The quality of reports is important:

– The circumstances (including enhanced or stimu-lated reporting) of reporting should be stated. Thequalification of reporter is important in interpret-ing the report.

– The utility of the report depends to a great extenton the content of the information included.

– The arbitrary 15-day limit should be re-visitedsince it often precludes adequate followup andthus results in an avoidable large volume offollowup reports.

– Understanding such reports requires professionalinsight of the analyst (clinical evaluation); this, inturn, requires well-trained and adequately avail-able analysts.

4. Signal detection is often exceedingly complex.Spontaneous reports may be used for the detectionof drug related hazards, subject to some limitationsand pre-conditions including:

– Spontaneous reporting is a method with a some-times very high but sometimes low and generallyundeterminable sensitivity and low specificity.

– In a single case, decision making on the nature ofthe relationship between the drug and the ADRfollows clinical diagnostic logic which is distinct

from the probability inferences of clinical trialsand epidemiology.

– An observed event may be due to the indicationfor therapy rather than the therapy itself (e.g.,suicide after anti-depressant); therefore, observedassociations should be viewed as signal raising,and causal conclusions drawn with caution.

– Signals on thebasis of spontaneous reportsmainlyprovide information on the quality of anADR, butgenerally do not reflect its frequency.

– Comparisons of reporting rates across drugs andcountries should be done primarily for explora-tory purposes. Extreme differences in reportingrates may also pose a signal.

5. ADR reports alone may suffice for regulatorydecision making under certain circumstances:

– When there is no proven or borderline effective-ness of the drug, for example with an untesteddrug or ‘natural’ remedies.

– When found early post-approval and no othersource of relevant information is available.

– When the event is rare and not otherwisequantifiable by structured studies.

– Where the event is uniquely identified with drugtherapy and not otherwise explainable.

– In the absence of contradictory data.

– In the presence of well-described clinical infor-mation.

– For finding drug interactions in untested combi-nations.

6. Epidemiologic studies done prior to approval of theindication for the new drug may provide informa-tion of the expected rates of events which will befound in association with the treated disease.Therefore, they may assist in interpretation of theADR data. Pharmacoepidemiologic studies of othertherapies for the same disease are also very usefulfor the same reason.

7. Analytic epidemiologic studies of large numbers ofexposed patients (or cases) and appropriate com-parators after approval of a drug can provideimproved evidence of risk and should be donewhenever appropriate (e.g. to assess a signal in trialsor from spontaneous reports) and feasible in a timelymanner. Generally, when available, informationfrom such studies outweighs evidence from sponta-neous reports of the same problem within therestrictions of the power of the study.

8. Large simple safety trials and structured cohorts areimportant:

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Copyright # 2005 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2005; 14: 665–667

– Large simple safety trials (LSSTs) and struc-tured cohorts, such as Prescription EventMonitoring (PEM) and ad hoc studies, startedin the peri-approval period, can provide relevantrisk information for anticipated ADRs andshould be encouraged.

– Circumstances in which they may be mostuseful include: relatively common disease beingtreated; simple treatments and regimens beingstudied; straightforward entry criteria for thestudy; and current therapies not entirely satis-factory.

9. Decision-making by companies, providers, andregulators should use all appropriate evidence.Data validity, transparency, and data sharingbetween regulators, academics, and industry arecrucial.

– Ageneral effort to improve risk communication,both in particular instances and in the generaleducation of the public, should be a highpriority.

10. A proactive approach to Risk Management shouldbe a component of all PMS efforts.

� Such risk management should:

– Be planned for all new drugs at the time ofmarketing.

– Include a proactive Risk Assessment Planwith a strategic (targeted) approach to collec-tion and monitoring of specific spontaneousreports (if these can be specified beyondthe usual broad coverage of spontaneousreporting).

– Specify methods and resources for rapid collec-tion of systematic population based information,and a plan to further develop them if needed.Proactive strategies are essential to assure thatsuch data are in place before the concern israised, for example, by the Spontaneous Reportsif undue public concern is to be avoided,individual patient risks minimized, and theunnecessary loss of valuable drugs avoided.

– Coherent efforts are needed by the field todevelop appropriate, effective methods toadvance this important area of pharmacovigi-lance, and pharmacoepidemiology policy.

The points above are here presented to the broaderreadership of Pharmacoepidemiology and Drug Safetyfor discussion in these pages.While they have hadwidediscussion within each of the responsible InternationalSocieties, they are offered under our individualauthorship to stimulate broad discussion and furtherenhancement before more formal presentation to andadoption by our respective Societies.

ACKNOWLEDGEMENTS

The authors acknowledge with thanks the unrestrictededucational grant from Bayer in support of the ISoPThinkTank and the educational grants supporting theICPE. The authors express special thanks to all facultyfrom the ThinkTanks and particularly to JuergenBeckmann, from the German Medicines EvaluationAgency, for his leadership in developing the initialPoints to Consider and his constructive critique of thiswork.

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Copyright # 2005 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2005; 14: 665–667