managing the risks of therapeutic products: proceedings of a workshop

pharmacoepidemiology and drug safety 2005; 14: 619–628Published online 7 January 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pds.1060

ORIGINAL REPORT

Managing the risks of therapeutic products:proceedings of a workshop{

Judith M. Kramer MD, MS* for the Participants in the Centers for Education and Research onTherapeutics (CERTs) Workshop entitled: Managing the Risks of Therapeutic Products

Duke Center for Education and Research on Therapeutics, Duke University Medical Center, Durham, North Carolina, USA

SUMMARY

Traditional tools available to the Food and Drug Administration for managing known risks of therapeutic products(drugs, devices and biological products) have limited effectiveness. This report presents the recommendations of a multi-disciplinary workshop focused on managing these risks. This is the last in a series of five workshops coordinated by theCenters for Education and Research on Therapeutics (CERTs) on assessing, communicating and managing the risks andbenefits of therapeutic products. Workshop participants included experts from government, academia, industry and health-care organizations, including consumers. Using a modified nominal group process, participants developed a consensus onprinciples that should govern future risk management (RM) programs, specifically: in order to protect the public health,risk management programs (RMPs) should be evidence-based, science-driven and patient-focused. A plan to manage therisks of each new therapeutic product should be developed prior to its approval. Evaluation of both the processes and out-comes of RM is essential; these evaluations should be in the public domain. Participants also identified and prioritizedresearch and policy gaps related to RM. Recommended research areas included determining the effectiveness of eachelement of RMPs, finding the best ways to inform healthcare consumers and determining the best way to present risk infor-mation in drug labeling. Policy questions included defining the criteria for requiring a RMP, determining the effect of privacylegislation on RMPs and determining how the continuum of risk across therapeutic products should be classified. As thisworkshop demonstrated, it is possible to develop a prioritized research and policy agenda to meet the needs of all consti-tuencies. Collaboration across diverse government, academic, industry and constituency-based organizations can lead tosolutions for the perplexing problems involved in balancing the risks and benefits of therapeutic products. Patients deserveno less as we strive to protect their safety. Copyright # 2005 John Wiley & Sons, Ltd.

key words— risk management; therapeutics; pharmaceuticals; devices; patient safety

INTRODUCTION

The extraordinary advances over the past century inunderstanding the pathophysiology of disease haveled to a dramatic increase in the availability of treat-

ments to mitigate symptoms, cure illnesses and pro-long life. The increasing effectiveness of new drugtreatments is often paralleled by an increase inpotency of these pharmacologic agents. Similarly,therapeutic medical devices are becoming more com-plex and sophisticated, as evidenced by the devel-opment of implantable cardioverter defibrillators,artificial heart valves and even artificial hearts. Asthe potency of drugs and biological products and thecomplexity of medical devices have increased, therehas been a parallel increase in reported adverse drugexperiences (ADEs)1–3 and adverse device effects.4

In 2003, the U.S. Food and Drug Administration(FDA) received 370 887 reports of adverse drugevents5 and 125 000 adverse device events.6

Received 5 October 2004Revised 10 November 2004

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

* Correspondence to: Dr J. M. Kramer, Duke Center for Educationand Research on Therapeutics, Duke University Medical Center, POBox 17969, Durham, NC 27715, USA.E-mail: [email protected]{No conflict of interest was declared.

Contract/grant sponsor: Agency for Healthcare Research andQuality (AHRQ); contract/grant numbers: R13 HS13929-01 andU18HS013474 CERTs (Cooperative Grant) U18HS10548.

Patient care is optimized both by maximizing thebenefits and minimizing the risk of new therapeuticproducts (drugs, devices and biological products).The recent focus on safety and risk management (RM)reflects the increasing concern about the effec-tiveness and safety of these products under conditionsof general use beyond the FDA’s determination ofefficacy and safety at the time of initial drug or deviceapproval. Unanticipated adverse effects from thera-peutic products can arise for the first time afterapproval for marketing. More commonly, adverseevents seen during clinical trials are observed morefrequently after marketing, when larger numbers ofpatients are exposed, and the products are used inpatients with co-morbid illnesses or who are takingother medications concomitantly.7,8 In addition, once aproduct is on the market, practitioners may choose touse that product for indications that do not yet haveFDA approval.

The traditional tools that the FDA uses to managethese risks include drug and device labeling, letters tohealthcare professionals, condition-of-approval studies,post-approval studies and withdrawal of products fromthe market. The term ‘labeling’ incorporates severaldifferent media:

1. Information for health care practitioners containedin the package insert (written by the manufacturerand approved by the FDA).

2. Information specifically for the patient in a ‘patientpackage insert’ (written by the manufacturer andapproved by the FDA): Although there are about200 products with patient package inserts, the FDAonly requires distribution of these inserts with oralcontraceptives and estrogens.

3. Medication guides: Approved FDA labelingrequired to be distributed at the time of dispensingfor products that pose ‘a serious and significanthealth concern’ (21CFR208, effective 1 June 1999).As of August 2004, FDA has issued medicationguides for 22 different marketed products.9

Among other important information needed to ap-propriately and safely prescribe a medication, thepackage insert contains information about the indications,dose, adverse events observed during the clinical trials,warnings and precautions. When the FDA deems thata serious or potentially life-threatening side effectdeserves special emphasis in the package insert, thisinformation is printed in boldface type in a box at thetop of the label (‘black-box warning’). The informationin the package insert serves as the foundation uponwhich the healthcare system and physicians managethe risks to patients. This may be supplemented by

other information the consumer may receive with themedication (e.g., a patient package insert or Medica-tion Guide) and by information distributed by thepharmacy. Most pharmacies use computerized data-bases to provide patients with leaflets of information onprescription drugs.

Sometimes after a medical product reaches themarket, adverse health effects come to light that areserious enough to alter the balance of benefit and riskassociated with that product. This situation promptsefforts to get this information into the hands of phy-sicians, pharmacists and consumers. FDA tools fordisseminating this information include changes in thelabel (including adding a black-box warning), letters tophysicians (‘Dear Healthcare Professional’ letters)and/or safety alerts (disseminated via the FDA Med-Watch program’s website (http://www.fda.gov/med-watch/). Often the aforementioned communicationefforts prompt another powerful avenue of dissemina-tion: media coverage.

A number of recent studies have shown that thesuccess of these methods available to FDA in changingmedical practice has been minimal.10–12 In fact, failureto adequately manage the risks of a marketed productmay have contributed in part to a number of high-profile removals of products from the market.13–15

In 1998, bromphenac (Duract1), a non-steroidal anti-inflammatory analgesic, was withdrawn from themarket because of multiple cases of severe hepatitisand liver failure resulting in four deaths and eightliver transplants.13 In all but one case, the drug wasprescribed longer than the recommended duration of10 days or less. A black box warning advising limitingduration of therapy to 10 days was not effective ineliminating longer courses of use. In 2000, the manu-facturer of cisapride (Propulsid1), a treatment forsevere nighttime heartburn in patients with gastro-esophageal reflux, withdrew the product from themarket because of cardiac arrhythmias that were fatalin 80 cases.14 Approximately 85% of these casesoccurred when the product was used in patients withknown risk factors. However, the FDA’s institutionof black box warnings in the label and sponsorededucational programs had been ineffective in stoppingthe prescribing of this agent to high-risk individuals.In 2001, cerivastatin (Baycol1), a cholesterol-lowering drug, was withdrawn from the market dueto 34 reports of fatal rhabdomyolysis, a condition ofsevere inflammation and damage to muscle tissue.15

Again, labeling was ineffective in eliminating co-prescription of a contraindicated product, gemfibrozil(Lopid1), thought to be associated with this ADE.These product withdrawals have contributed to a

620 j. m. kramer

Copyright # 2005 John Wiley & Sons, Ltd. Pharmacoepidemiology and Drug Safety, 2005; 14: 619–628

growing awareness of the need to appropriatelymanage the risks of drugs to protect the public healthand to keep valuable drugs on the market.

In 1999, the FDA published a seminal documentrecognizing the challenges of managing risks ofmedical products in a complex healthcare system.16

This report called for the development of a systems-based approach to manage such risks. Recently,sponsor companies and the FDA have expanded effortsto better manage the risk of new drugs with potentiallyserious or life-threatening side effects. These ‘riskmanagement programs (RMPs)’ have been developedby drug manufacturers in collaboration with FDA tomore actively educate practitioners and, on occasion,to limit the prescription or distribution of such products.These programs have sought, for example, to preventthe administration of a known teratogen to a woman ofchild-bearing potential, to assure that critical labora-tory monitoring occurs or to avoid dangerous drug-disease and drug-drug interactions. Most of theseprograms were developed between individual drugsponsors and the FDA on an as-needed basis. Noconsistent approach has been taken as to when a RMPis needed or how it should be administered; evaluationof the effectiveness of these programs has been minimal.

In a similar time frame, the Centers for Educationand Research on Therapeutics (CERTs), were createdby the 1997 Food and Drug Administration Moder-nization Act, and permanently authorized by Congressin 1999. The CERTs program is charged, among otherthings, ‘to improve the quality of health care whilereducing the cost of health care through (I) an increasein the appropriate use of drugs, biological products ordevices and (II) the prevention of adverse effects ofdrugs, biological products and devices and the con-sequences of such effects, such as unnecessaryhospitalizations’. The Agency for Healthcare Researchand Quality (AHRQ) was given responsibility for thedevelopment of the CERTs programs in coordinationwith the FDA.

Several CERTs investigators have been involved inthe research that has documented the inadequacy ofstandard FDA tools to manage the risk of therapeuticproducts.10 Aware of the growing concern aboutpreventable adverse drug and device effects, and theevolving trend toward individualized RMPs for high-risk drugs, in May 2001 CERTs investigators begana series of multidisciplinary workshops focusing onassessing, managing and communicating risks andbenefits of medical therapeutics (Table 1).17–19 Thispaper presents the findings of the final workshop,‘Managing the Risks of Therapeutic Products’, held on12–14 January 2003 in Chapel Hill, NC.

METHODS

For the purpose of this workshop, RM was defined as‘an endeavor applied to the use of therapeutic pro-ducts that seeks to assure that benefits to patients out-weigh risks’.

The workshop brought together 53 leaders fromgovernment, academia, the pharmaceutical industry,healthcare providers (physicians, pharmacists andnurses) and consumer organizations to accomplishthe following objectives:

� to identify current methods of managing the risks oftherapeutic products;

� to explore innovative approaches to managing risk;

� to develop a prioritized research agenda to furtherthe science of RM; and

� to identify policy gaps that impede effectiveimplementation of RM efforts.

The list of meeting participants is available at www.certs.hhs.gov/programs/risk_series/think_tanks/risk_manage/rm_participants.pdf.

The format for the meeting involved brief presenta-tions to stimulate discussion and extract the views ofdifferent constituencies. This was followed by brain-storming of principles to govern future RM strategiesand development of a list of research and policy gapsrelated to RM. Participants were asked to nominateinnovative ideas for future RMPs. Finally, meetingparticipants jointly prioritized these research andpolicy gaps and innovative ideas to develop an agendafor future action.

Broad categories of discussion included the following:

� current techniques for managing risks of therapeutics;

� methods for measuring the effectiveness of RMtools; and

� methodological dilemmas in conducting RMPs andevaluating their overall effectiveness.

Table 1. CERTs risk series think tanks

Risk CommunicationImproving communication of drug risk information toprevent injury17 (29 April–1 May 2001)

Risk AssessmentPostmarketing assessments of pharmaceutical risk18

(29–31 May 2002)Benefit Assessment

Overcoming difficult issues in characterizing therapeuticbenefit (17–19 September 2002)

Risk Communication and the mediaThe importance of the media in pharmaceutical riskcommunication19 (7–8 January 2003)

Risk ManagementManaging the risks of therapeutic products (12–14 January 2003)

managing risks of therapeutics 621


Case studies using the Lotronox1 and Tikosyn1

RMPs as examples served to stimulate discussion andillustrate several of the issues.20,21

In a prioritization exercise, meeting participantswere presented with a summarized list of nominatedresearch and policy gaps. Participants were asked toassign a priority of high, medium, low or zero to allnominated gaps, with zero indicating that the gap oridea should not be included. To give participants asense of others participants’ views and to stimulatediscussion both for clarification of meaning and foradvocacy, a public showing of hands was solicited forgaps considered high-priority; a discussion of theseitems ensued.

Written votes prioritizing all research gaps, policygaps and innovative ideas were submitted at the end ofthe meeting. A quantitative analysis of priorities wasperformed by calculating a weighted score for each gapor idea by assigning to priorities the followingrankings: high¼ 5, medium¼ 3, low¼ 1 and zero¼ 0.0. If nH¼ number of ‘high’ votes; nM¼ number of‘medium’ votes; nL¼ number of ‘low’ votes; andnz¼ number of zero votes, then the weighted score foreach gap or idea was equal to

P(nH � 5þ nM�

3þ nL� 1þ nz� 0) divided by the number of partici-pants voting on that gap/idea. This resulted in aweighted score for each gap or idea with a maximum of5.0 and a minimum of zero. The top ten research gaps,policy gaps and innovative ideas by weighted scoreswere then reviewed for redundancy and consolidatedinto non-overlapping items.

RESULTS

Table 2 summarizes various tools currently employedby the FDA and pharmaceutical sponsors to managerisk. Approaches have generally been either educa-tional in nature or directed at restricting distributionof a product to enhance control of its use. More recentprograms have added evaluation components. Thereare no standard criteria for tool selection, and evalua-tion of the effectiveness of individual tools is in-complete. A review of existing programs revealsconsiderable variation in the tools used (Table 3). Afurther challenge for implementing RMPs is the lackof consensus in the healthcare community about therespective roles of the FDA and the drug manufacturerin post-marketing RM.

Principles to govern future RMPs

After discussions about current techniques for mana-ging risks of therapeutic products, meeting partici-

pants jointly developed a list of principles to guide thefuture development of RM approaches for therapeuticproducts (Table 4). There was unanimous agreementon the need to balance considerations of a product’sbenefits and risks when RM interventions are consid-ered. Participants agreed that the primary objective ofRMPs should be protecting the public health.

In order to be proactive in anticipating risks ofproducts at the time of initial approval, sponsors shoulddevelop, in collaboration with FDA, a plan to managethe risks for every new product. Any preliminary safetyconcerns identified during development of the productshould be carefully evaluated prior to the product’srelease for use in a broader population of patientsthan those exposed during controlled clinical trials.Similarly, FDA and sponsors must consider potentialoff-label use by practitioners after marketing ap-proval in weighing potential risks. Potential sourcesof useful safety information include clinical databasesand patient registries.RMPs should be evidence-based, science-driven and

patient-focused. Since the science of changing beha-viors of patients and providers is evolving, evaluationof both the processes and outcomes of RMPs isessential. All recognized that there could be unantici-pated consequences of well-intended RM approaches.So that mistakes are not repeated in subsequent RMPs,these evaluations must be in the public domain.

In order to be sensitive to the needs of patients toaccess important medications and the needs of busyhealthcare practitioners, RMPs should minimize barriers

Table 2. Current inventory of RM tools

Prescriber toolsMandatory registration: physician, patient, pharmacy/pharmacist,institutionPhysicians’ agreement to reporting of adverse drug reactionsMonitoring of patients at specified intervalsEducational programs

Distribution toolsDispensing of drug in limited pharmacy settingsCentralized dispensing of drugLimited number of drug units per prescriptionLimited quantity or no refillsSpecial packagingPharmacy dispensing contingent on: required registration,physician specialty, physician ‘qualifications’, indication foruse, presence/absence of risk factors, authorized prescribercheck or sticker on prescription

Patient-directed toolsMedication guidesPatient package insertsPatient informed consent or patient agreementEducational programs

622 j. m. kramer


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to access and reduce complexity in implementation forhealthcare professionals and patients.

Finally, since there is a recognized need to improveoverall patient safety in the healthcare system, RMmust be integrated into a broader system of medicalquality assurance activities.

Research gaps

Research gaps prioritized most highly by meeting par-ticipants are presented as researchable questions inTable 5. Several themes emerged from this exercise.We clearly need to have more information aboutwhich components of RMPs are effective. In orderto do this, the sponsor and FDA need to articulatethe goals of a RMP, and identify methods to bothassess effectiveness and identify possible unintendedconsequences. We need more published data on whichresearch tools and strategies will help us better evalu-ate these programs. Existing RMPs should be studiedto identify the parameters of a successful RMP and todevelop general indicators of success that could beextrapolated to other programs.

Another theme among the research gaps is the needto better understand effective ways of communicatingrisk information to patients and healthcare practi-tioners in the context of a RMP. We need to identify the

best way to portray risk information in labeling and todetermine what methods work best in conveyingquantitative expressions of risk. Subgroups amongpatients who may need tailored communication—suchas the elderly and those with low levels of literacy—require particular attention.

Finally, lessons based on the existing literature on thebest methods to change patient and provider behaviorsshould form a basis for new efforts. Although manyaspects of RMPs are unique for the particular therapyor patient population, there are general principles thathave been validated in the literature and should assist indeveloping effective means of modifying behavior tominimize risk and maximize benefit.

Policy gaps

Table 6 summarizes the policy gaps that were consid-ered high priority by meeting participants. Developingcriteria for instituting a formal RMP was an importantarea of focus. This issue is closely related to the ques-tion of how we should classify the continuum of riskacross therapeutic products. Once that is accom-plished, the next challenge is to define criteria thatlink the type of RM intervention to a product’s levelof risk. If this were possible, it would provide a morestandardized approach to RM interventions, allowinghealthcare providers to become familiar with differentlevels of RM and the details of implementation. Thenext step would be the development of uniform defini-tions and guidelines for RMPs.

An operational challenge for RMPs that requiresfurther research is the impact of privacy legislation onthe ability to conduct the programs. Participants notedthe tension between attaining full ascertainment inpregnancy registries and balancing patients’ rights toprivacy. If, for example, only 50% of patients agree toparticipate in a registry, it is not possible to fully char-acterize the population of patients using the product ofinterest.22 Just as challenging is the tendency of healthcare providers and organizations to be so risk-averse

Table 4. Principles for future development of RMPs

The primary objective of RMPs should be protecting thepublic health.A plan to manage the risks of each new product should be developedprior to its approval.RMPs should be evidence-based, science-driven andpatient-focused.Evaluation of both the processes and outcomes of RMPs is essential;these evaluations should be in the public domain.RMPs should minimize barriers and complexity for healthcareprofessionals and patients.RM must be integrated into a broader system of medical qualityassurance activities.

Table 5. Research gaps expressed as researchable questions

Question Weighted score

What is the effectiveness of each individual element of a RMP? Which RM tools work best in which situation? 4.72/4.14What are the best ways to inform patients? What are effective interventions at a patient/consumer level forhigh-risk groups (e.g. elderly, low literacy)?

4.49/4.40

What are the best ways to present risk information in labeling? What quantitative ways work best to portray risk? 4.23What is the best way to change behavior of the various actors (e.g. providers, patients)? What is already knownabout this?

4.16

What are the parameters of a successful RMP, and what indicators of success should we use? 4.10What research tools and strategies should we use to evaluate RMPs? 4.03

624 j. m. kramer


with respect to the Health Insurance Portability andAccountability Act of 1996 (HIPAA) that they refuse todo things that are actually specifically provided for inthe HIPAA legislation (e.g., a health plan refusing toparticipate in FDA-sponsored research that requiresphysicians to report adverse events associated witha therapeutic product). Fear of the punitive conse-quences associated with HIPAA legislation has ledmany to ignore the public health dimensions of theseresearch programs and to act on their exaggeratedperception of risk rather than on the intent and text ofthe legislation.

An important policy issue is who should bear thefinancial burden for the design, testing, conduct andevaluation of RMPs. Indirectly tied to costs and incen-tives is the issue of how we assure appropriate RM forolder therapies that are off-patent (i.e., generic) andhave multiple industry sponsors. Issues of equity areclearly important to industry representatives. Chal-lenges will include assuring equity among differentsponsors for products with similar risk and balancingsponsor responsibility and public health need.

Finally, criteria need to be developed for phasingdown or discontinuing RMPs if additional data ac-cumulate that mitigate safety concerns or, conversely,for intensifying a RMP if unacceptable unanticipatedconsequences are identified.

Innovative ideas

Table 7 summarizes the innovative ideas that partici-pants supported for future RMPs. They felt stronglythat tools should be tested prior to deployment in aprogram. They also favored proactive surveillanceby establishing safety targets in advance of productrelease and monitoring these targets once the productis marketed. They favored the use of electronic clini-cal databases for such monitoring. Participants alsoagreed that leveraging technology such as electronicprescribing held promise to drive good therapeutics,assuming the content for prescribing alerts could beimproved to increase the signal-to-noise ratio. Healthprofessionals such as nurses and pharmacists wereconsidered an important resource to be utilized in RMPs.Additional ideas included developing educationalstandards for patient education and developing cultu-rally-sensitive and needs-sensitive educational materi-als. Finally, participants made a plea for keeping RMsimple. All felt that restrictive tools and programsshould be applied only when clear criteria indicatethe need.

DISCUSSION

Workshop participants were successful in outlining aframework for future RM initiatives: a list of guiding

Table 6. Policy gaps expressed as researchable questions

Question Weighted score

What are the criteria for requiring or strongly encouraging a formal RMP? 4.24/4.11What is the impact of privacy legislation on the ability to conduct RMPs? 3.81How should the continuum of risk across therapeutic products be classified? Can we define criteria that link thetype of RM intervention with a product’s level of risk?

3.78/3.42

Who should pay/bear the burden for the design of RMPs, the design and testing of instruments used in RMPs, theconduct and the evaluation of RMPs?

3.68

Can stakeholders develop uniform definitions and guidelines for RMPs? 3.61How do we assure appropriate RM for existing therapies (e.g. older products)? 3.53What are the criteria for phasing down a RMP? 3.50Can we balance sponsor responsibility and public health need? Can we assure equity among different sponsors forproducts with similar risk?

3.43

Table 7. Innovative ideas

Idea Weighted score

Test educational tools before deployment in a RMP 4.26Use proactive surveillance: in advance of product release, establish safety targets to be monitored after approval;make optimal use of electronic databases

4.19

Use electronic prescribing to drive good therapeutics; improve the content for prescribing alerts to increase the‘signal to noise’ ratio

4.14

Involve other health professionals (e.g. nurses and pharmacists) in support of RM approaches 3.67, 3.44, 3.22Develop educational standards for patient education; develop culturally sensitive materials(e.g. different languages, differing format for blind and others who cannot follow written instructions)

3.29, 3.27

Keep it simple; only apply tools and programs when needed 3.22



principles, prioritized agendas for research and policyand views on innovative directions for RMPs. Theapproach used in this workshop was consistent withthe premise put forward by FDA in 1999: the needfor a systems-based approach.16 It is unrealistic toput the full burden of managing the risks of therapeu-tics on the shoulders of the industry or on the FDA.Once a drug, device or biological product is marketed,the safe use of the product ultimately involves health-care practitioners and patients. The multidisciplinarysetting created by this workshop offered the opportu-nity to share the perspectives of individuals affectedby these programs (doctors, nurses, pharmacists,patients and their families) with regulators and drugmanufacturers. These views need to be considered increating RMPs that do not add undue burden on con-sumers or healthcare professionals in our attempts toprotect them.

The principles put forth by the group are ambitious.Instead of viewing RM as aversion of risk for a fewhigh-risk therapeutic products, the group took abroader perspective by defining RM as ‘an endeavorapplied to the use of therapeutic products that seeks toassure that benefits to patients outweigh risks’. Theywent on to recommend that every new productshould have a plan that analyzes and proactively seeksinformation that puts a product’s risks in the context ofits benefits. They envisioned a RM plan as a thoughtfulapproach for all products, not just those with docu-mented risk. Even for a new product with no seriousrisk identified in the pre-marketing phase, a RMplan could analyze potential areas for scrutiny aftermarketing. For example, if exposure to a drug prior tomarketing was limited to a population of patientswithout comorbid illnesses, or if a new therapeuticdevice has a significant operator/device interactionthat could put patients at risk when less experiencedoperators start using the device, a plan could bedeveloped to carefully monitor the safety of such a drugor device as it comes under broader conditions of use.In some circumstances, such as when there is a signi-ficant concern over operator/device interactions, anepidemiologic study might be designed for the post-marketing phase to monitor outcomes in practice.

Another key component of the principles governingRMPs is the need for evaluation—evaluation of theoverall outcome, as well as the impact of variouscomponents of the program. Furthermore, the results ofthese evaluations for specific RMPs should be in thepublic domain. There are legitimate public healthconcerns about the effect of RMPs on access topotentially beneficial treatments and on the safety ofspecific treatments. The need for this information to be

in the public domain is not unlike the precedent thatspontaneous reports of adverse drug events in the post-marketing period are in the public domain.

Participants also recognized that to be effective, RMmust be integrated into the broader system of medicalquality assurance activities. If each product sponsorwith a RMP develops a list of prescribing require-ments that are unique for their product(s), it may beuntenable for a practitioner to integrate these differentprocedures into the workflow of daily practice. Timeand human resources are limited at the point of care.The aggregate impact of quality improvement initia-tives and multiple RMPs on a practice’s workflowcould be quite significant. The overall impact of aRMP on practice patterns may well determine thesuccess of a program.

The research and policy gaps identified by workshopparticipants address fundamental yet difficult ques-tions. Future RM initiatives should be evaluated on thebasis of whether they shed light on these identifiedgaps. Answering these questions promptly will benefitall constituencies by avoiding waste of resources onineffective approaches, and encouraging an evidence-based and fair approach to manage the spectrum of riskacross therapeutic products.

A key policy gap is how to classify the continuum ofrisk across therapeutic products. A related question iswhether uniform criteria can be developed to link thetype of RM intervention with a product’s level of risk.Addressing these questions would address the dilemmaof when to require a formal RMP and would promotea level playing field for pharmaceutical sponsors. Auniform approach would also aid communication andimplementation with practitioners. Participants ofthis workshop encouraged the use of multidisciplinaryworkgroups under the aegis of the Agency for Health-care Research and Quality and the CERTs programto develop solutions to such complex questionscollaboratively.

There are clear themes underlying the ideas putforward for future RM approaches.

� Pre-test programs prior to implementation

� Encourage proactive surveillance

� Make optimal use of information technologyresources

� Make optimal use of human resources (e.g., nurses,pharmacists)

� Address needs of patient subgroups (e.g., elderly,low literacy, children)

Considerable groundwork was laid in this meetingfor future RM initiatives. The meeting’s format was

626 j. m. kramer


successful in allowing a diverse group of individualsfrom different constituencies, including consumers,to engage in a dialogue about difficult issues, developguiding principles for future RMPs and devise aresearch and policy agenda to improve our futurecapabilities to balance risk and benefit.

Since the conclusion of the CERTs workshop, therehas been much activity in the area of RM. In March2003, the FDA issued the following concept papersrelated to risk assessment and management.

1. Premarketing Risk Assessment2. Risk Management Programs3. Risk Assessment of Observational Data: Good

Pharmacovigilance Practices and Pharmacoepide-miologic Assessment

In addition to soliciting written comments aboutthese Guidances, the FDA held a public workshop on9–11 April 2003 to discuss the concept papers. Afterconsidering these comments, FDA issued the follow-ing revised draft guidances in May 2004: PremarketingRisk Assessment, Development and Use of Risk Mini-mization Action Plans (RiskMAP) and Good Pharma-covigilance Practices and PharmacoepidemiologicAssessment.23–25

The public comment period on these Guidancesended at the beginning of July 2004. We now await theFDA’s final Guidances on these topics. The guidanceon the Development and Use of Risk MinimizationAction Plans (RiskMAP) is most relevant to the re-commendations of the CERTs Risk ManagementWorkshop. It will be interesting to consider the FDA’sGuidances in the context of the principles set forwardby participants in the CERTs Workshop.

CONCLUSION

Despite the complexity of managing the risks of ther-apeutic products in the context of their benefit, thisWorkshop has demonstrated that a collaborative ap-proach involving all constituencies, with a prominentplace for consumers, can make progress on develop-ing relevant solutions. Many times a solution involvesgathering more information through research andbroader input, but developing a consensus on the topicsfor this further research is useful as we approach thisdaunting challenge. When applied to RM, this ap-proach can further improve the positive impact ofinnovation in the drug, device and biological industry,while better protecting the public from unintendedadverse consequences.

ACKNOWLEDGEMENT

Special thanks to Paul J. Seligman, MD, MPH, of theOffice of Pharmacoepidemiology and Statistical Sci-ence in the Center for Drug Evaluation and Research,U.S. Food and Drug Administration, Rockville, MD,for assistance in writing the background for this article.

APPENDIX 1. PLANNING COMMITTEEMEMBERS

Judith M. Kramer, MD, MS, ChairPrincipal Investigator, Duke CERTsChief Medical OfficerDuke Clinical Research Institute

Elizabeth Andrews, PhD, MPHVice PresidentResearch Triangle Institute (RTI) Health Solutions

Jim Battles, PhDSenior Service FellowPatient Safety and Medical ErrorsAgency for Healthcare Research and Quality

KEY POINTS

� Collaboration across diverse government,academic, industry, and constituency-basedorganizations can lead to solutions for the per-plexing problems involved in balancing therisks and benefits of therapeutic products.

� A plan to manage the risks of each newtherapeutic product should be developed priorto its approval.

� Evaluation of both the processes and outcomesof risk management is essential; these evalua-tions should be in the public domain.

� Research into risk management programs shouldbe aimed at determining the effectiveness of eachelement of the programs, finding the best ways toinform healthcare consumers, and determiningwhat quantitative ways work best to portray risk.

� Policy efforts should be directed toward de-veloping a more systematic approach to riskmanagement interventions (thus facilitatingtheir adoption into medical practice), includingclassifying the continuum of risk across ther-apeutic products, developing criteria for insti-tuting formal risk management programs, andlinking level of risk with type of risk manage-ment intervention.



Jonca Bull, MDDirector, Office of Drug Evaluation VCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration

Alan Goldhammer, PhDAssociate Vice President, US Regulatory AffairsPharmaceutical Research and Manufacturers ofAmerica

Linda HostelleyExecutive Director, Adverse ExperienceReporting WorldwideWorldwide Product Safety and EpidemiologyMerck and Company, Inc.

Paul Seligman, MD, MPHDirectorOffice of Pharmacoepidemiology andStatistical ScienceCenter for Drug Evaluation and ResearchU.S. Food and Drug Administration

Ex officio member: Hugh Tilson, MD, DrPHChair, CERTs Steering Committee

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