Pharmacovigilance Final

7/30/2019 Pharmacovigilance Final

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Unlocking the power o pharmacovigilance*

An adaptive approach to an evolving drug saety environmentPricewaterhouseCoopers Health Research Institute


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Executive summary 01Background 02The challenge to the pharmaceutical industry 02Increased media scrutiny 02Greater regulatory and legislative scrutiny 04Investment in pharmacovigilance 05The reactive nature o pharmacovigilance 06Unlocking the power o pharmacovigilance 07Organizational alignment 07Operations management 07Data management 08Risk management 10The three strategies o eectivepharmacovigilance 11Strategy 1: Align and clariy roles,responsibilities, and communications 12Strategy 2: Standardize pharmacovigilanceprocesses and data management 14Strategy 3: Implement proactive

risk minimization 20Conclusion 23Endnotes 24Glossary 25

Contents


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5/32PricewaterhouseCoopers Health Research Institute

The idea that controlled clinicaltrials can establish product saetyand eectiveness is a core principleo the pharmaceutical industry.Neither the clinical trials processnor the approval procedures o theU.S. Food and Drug Administration(FDA), however, can provide a perectguarantee o saety or all potentialconsumers under all circumstances.Despite this act, there are viablesolutions that pharmaceuticalcompanies can implement to support

pharmacovigilancethe systematicdetection, assessment, understandingand prevention o adverse drugreactions. When built into existingresearch and development practices,pharmacovigilance activities canenhance patient saety while reducingor even preventing costly saety-related withdrawals.

Currently, however, pharmaceuticalexecutives ace a number o challengesin the area o pharmacovigilance. Inthe our decades rom the thalidomidetragedy to the recent concernsabout Vioxx, companies have usedpharmacovigilance methods designedto identiy rare, easily identied saetyproblems At the same time, we haveseen the growth o a ragmentedhealthcare system that has lackeda uniying inrastructure. As a result,this system operates primarily inreaction to rather than in anticipationo major pharmaceutical saety events.

As drug consumption has increasedand the public has grown to expectgreater drug saety, the traditionalreactive approach has proven largely

incapable o addressing shits inpublic expectations and regulatoryand media scrutiny. This reality hasrevealed issues in the our areasinvolved in patient saety operations:organizational alignment, operationsmanagement, data management, andrisk management.

When appropriately aligned andsupported, these areas can worktogether to enable a fexible,adaptable, and proactive system

or addressing patient saetyissues. Companies can unlock thepower o their pharmacovigilanceactivities by creating an operationalramework that supports the keypatient saety inrastructures. Theollowing are recommendations orcompanies developing an adaptivepharmacovigilance ramework:

1. Align and clariy roles,responsibilities, and communications

Develop an objective, data-driven,team-based approach to riskmonitoring and evaluation

Implement well-dened decision-making models, escalationprocesses, and communicationchannels

Determine the pharmacovigilanceworkload and suciently resourcethe required eort

Designate a pharmacovigilanceoperating model and businessprocess owner

Ensure that appropriate process andorganizational checks and balancesare in place to limit bias and manageregulatory risk

2. Standardize pharmacovigilanceprocesses and data management

Align operational activities acrossdepartments and across sites

Implement process-driven standardoperating procedures, workinstructions, and training materials

Integrate saety data throughdata and system interoperabilitystandards

Implement workfow managementtechnology to ensure appropriatetransparency and accessibility o

saety inormation Select a vendor that best matches

the pharmacovigilance operatingmodel, business process andvendor/system selection criteria

3. Implement proactive riskminimization

Develop risk management actionplans based on pre-established riskscoring mitigation processes

Implement data mining techniquesto bolster saety analytics, reportingand investigation

Incorporate continuous improvemenactivities and standardized riskcommunication plans

Create a dashboard that summarizeand promotes timely awarenesso saety risks across the portolioand timely execution o saety riskminimization activities

Executive summary


6/322 | Unlocking the power o pharmacovigilance

Background

The challenge to thepharmaceutical industry

A chie problem that pharmaceuticalcompanies ace in the area opharmacovigilance is the possibilitythat a medicine may be taken ina manner or which it was neitherintended nor clinically tested.This can happen or a number oreasons: the number o participantsin the average clinical trial is dwaredby the thousands or even millions o

biologically unique patients who maytake a marketed treatment; medicinescan be taken in combination with othertherapies with which they have notbeen clinically tested; and medicinesmay be prescribed or an indicationdierent rom the one or which theywere approved. All o these actors,including preexisting conditions, mayincrease the odds that serious adverseevents absent in clinical trials mighteasily occur postmarket.

Neither these odds nor the risksthey represent are well understoodby consumers, the result being thata spate o saety-related productwithdrawals has hastened the recentsteep decline o public condencein the ability o pharmaceuticalcompanies and regulators to ensuresaety.

Increased media scrutiny

Growing public concern over drugsaety also has spurred the mediato ocus on this issue. Drug saetywas the top issue in PharmaceuticalExecutives Annual Media Audit 2005,with drug saety and developmentissues dominating more than halo the print media coverage (Exhibit1). Heightened media and public

Exhibit 1: Frequency analysis o ethical issues

Other

Medicare/MedicaidGeneric drugs

DTC advertising

Righ tot life/contraception

NIH ethics rule

Issues related to vaccines

Developing countries

New drug/treatment research

Reimportation/importation

Marketing sales and incentives

Data disclosureclinical and manufacturing

Cinical study design & sponsorship

Drug prices

Drug safety

25

33

8

9

9

12

12

13

13

14

26

30

54

114

Ethical issue Number of references

Source: Front Page Pharma, by Stephen J. Porth and George P. Sillup, Pharmaceutical Executive,

February 1, 2006.

Exhibit 2: Prescription drug adverse event report growth, U.S., since 1995

13%

-4%

7%

13%15%

14%

23%

11%12%averageannualgrowthrate

16%

200420032002200120001999199819971996

Source: CDER 2004 Report to the Nation: Improving Public Health Through Human Drugs, Cente

or Drug Evaluation and Research. August 22, 2005.



awareness has combined withgreater scrutiny by regulatorsand elected ocials to create arapidly evolvingand potentiallydangerousenvironment orpharmaceutical companies.

One reason or such media scrutinyis the release o reports rom the FDAand the World Health Organizations

Vigibase (a global adverse drugreaction database) o signicantincreases in the number o adverse

events reported in recent years. TheFDA, or example, shows an averagegrowth rate o 12% annually inadverse event reports to the agencyrom 1995 through 2004 (Exhibit 2).The causes and implications o theincrease are the subjects o muchdebate. Despite increases in adverseevent reports, saety-based drugwithdrawals in the U.S. have remainedessentially fat, at about 3 per 100New Chemical Entity approvals orthe past 35 years.1

The public may view the increase inreported adverse events negatively,but the growing number o reportsmay result, in part, rom increasedawareness in the medical communityand the sheer increase in drugconsumption. The industry couldbenet greatly i the public betterunderstood these actors and theirimpact on pharmacovigilance.

The impacts o saety issues are notlimited to perception alone. Saetyissues can lead to regulatory nes,litigation costs, reduced marketshare, diminished brand equity, anddecreased shareholder value. Suchimpacts may aect a companysability to nance saety initiatives andthereby induce a downward spiral ourther saety-related strategic andoperational issues (see Exhibit 3).

Upstream risks

Business/financial

impactsSafety risks

Exhibit 3: The downward saety spiral



Partly in response to the GAOsreport, the FDA created the positiono associate center director or saetypolicy and communication withinthe Center or Drug Evaluation andResearch to oversee drug saetyissues and policies.5

The FDA also recently changedorthe rst time in more than 25 yearsthe requirements or pharmaceuticalpackage inserts and warning labels,released 11 new patient saetyguidance documents, and announcedplans to release guidance on eightother saety-relevant topics duringthe remainder o 2006.6

The March 2006 GAO report alsohas inspired Congress to work toward

enhancing the oversight authorityo regulatory agencies aroundpostmarket drug saety. Although ameasure that would have granted theFDA authority to compel drugmakersto conduct postmarket clinical trialsailed, similar legislation is in progressand the Senate Finance Committeehas adopted FDA oversightandspecically, patient saetyas parto its agenda.

The recent steps in the U.S. parallela heightened ocus on patient saetyin Europe, both within the EuropeanUnion and within individual states. Thinew emphasis on pharmacovigilance,while welcome, does pose challengesto U.S. pharmaceutical companiesdoing business in Europe.

Historically, the European authoritiesadopted a more philosophical viewo pharmacovigilance, but nowwere seeing them move toward

the compliance, surveillance, andqualiying data that the U.S. hastypically stressed, said Barry Arnold,ormer vice president o global patientsaety at AstraZeneca. And the

Americans are moving more towardevaluating the quality o systems andnot just the number o reports.

Consumers do not hold industry solelyresponsible or saety issues but blamegovernment as well. A 2005 consumersurvey conducted by the Henry J.Kaiser Family Foundation reportedthat 77% o respondents were veryor somewhat condent in the ability

o the FDA to ensure that prescriptiondrugs are sae. Even so, 22% werenot at all or not too condent inthe FDAs oversight ability.2

Unortunately, the public has beenled to believe that FDAs approval oa drug means that FDAs promise osae and eective is an absolute,said Judith M. Sills, Pharm.D., head oglobal saety intelligence at NovartisPharmaceuticals. Neither the FDAnor the industry has done a good

job in educating consumers thatthese terms are relative and not anabsolute guarantee.

And the publics level o condenceis slipping. A more recent Wall StreetJournal Online/Harris Interactive Pollpaints an even bleaker picture: 58%o respondents said they think theFDA does only a air or poor jobo ensuring the saety and ecacyo new prescription drugsupsignicantly rom the 37% who saidso just two years ago.3 To somedegree, these opinions are drivenby consumers misunderstanding othe relative nature o the sae andeective descriptions as they applyto pharmaceutical products.

The public perception that everyproblem can be solved by a pill hasto change, said Raymond L. Woosley,M.D., Ph.D., president o the CriticalPath Institute. Drugs are oreignchemicals, and while they havebenecial eects, they also have side

eects. The public must understandthat because o the biologicdierences between individuals, allside eects cannot be discovered priorto marketing. Thereore, it is to beexpected that drugs will be takeno the market rom time to time.

Nearly all medical treatments andproducts may carry some degreeo risk to patient health. The publicsignorance o the risk proles oprescription drug products can

signicantly aect its expectationsabout and reactions to saety events.

Greater regulatoryand legislative scrutinyScrutiny o the pharmaceuticalindustry also extends to the regulatoryand legislative arenas. Regulatorsand legislators are subject to publicopinion, and this has driven expandedactivity in the area o drug saety.

Despite the FDAs establishment o theDrug Saety Oversight Board in 2005and the consequent drating o a policyon major postmarket decision making,a March 2006 U.S. Government

Accountability Oce (GAO) reportcriticized the FDA or lacking clearand eective processes or makingdecisions about, and providingmanagement oversight o, post-marketsaety issues.4 In particular, the reportnoted the FDAs inability to ensure

that long-term, postmarket ollow-upstudies get conducted, noting thatonly 24% o agreed-upon studies wereactually conducted rom 1991 to 2003.



Until the International Conerence onHarmonization (ICH) has standardizedregulations across the globe,companies will grapple with dieringand evolving cross-border rules andsaety reporting requirements. Itsbecome clear that even i a countrys

regulatory authority signs onto ICH,theyll put their own spin on theregulations. This will continue to be achallenge, said Sills.

Investment inpharmacovigilance

Any discussion o drug saetymust acknowledge the act thatthere is relative underinvestment inpharmacovigilance. A 2003 study byDuke University and the University o

North Carolina at Chapel Hill peggedspending on patient saety monitoringollowing FDA approval at just 0.3%o sales revenue across the top 20pharmaceutical manuacturers, eventhough research and developmentspendinglargely in advance oproduct approvalconsumes 15.6% orevenue at these same manuacturers.7

There is no science that dictates that acertain percentage o revenue shouldbe allocated to pharmacovigilance,butin the ace o the potentially hugecost o saety-related withdrawalswithin the context o heightenedstakeholder expectations arounddrug saetycompanies shouldendeavor to strike a better balancebetween R&D spending andpharmacovigilance spending. The costo withdrawalswhen viewed againsta backdrop o annual drug spendinggrowth, that declined rom 18% in1999 to 8% in 2004 (see Exhibit

4)demonstrates that companiesace a rapidly diminishing margin orsaety-related error. And governmentactuaries recently predicted that drugconsumption could continue to declinein the uture, making it that muchharder to recoup losses due to saety-based withdrawals.8

Exhibit 4: The decline in prescription drug spending growth, 1999-2004

14.5%13.9%

10.0%

8.2%

18.5%

15.5%

200420032002200120001999

Year over year growth rate, perscription drug spending

Source: National Health Expenditures, Centers for Medicare & Medicaid Services.



The clear implication is that companiesshould invest more now to implementpharmacovigilance measures.The question, then, or rms willingto make this expanded commitment is:How best to deploy that additional timeand money? PricewaterhouseCoopers

interviewed 34 industry experts onpatient saety and pharmacovigilanceand consulted thought leaders whohave successully addressed similarchallenges in other disciplines bothwithin and beyond the pharmaceuticalindustry. Their insights providedthe basis or the recommendationsoutlined here.

The reactive natureo pharmacovigilance

The interviews ound thatpharmacovigilance programs atdierent companies are at variousstages o maturity. Regardless o their

degree o pharmacovigilance maturity,however, nearly all o the companiesinterviewed are working to improvetheir pharmacovigilance eorts.

The act that pharmacovigilance isin the spotlight is a mixed blessing,said Jean-Louis Saillot, M.D.,vice president and head o globalpharmacovigilance, Schering-Plough.The increased scrutiny makes thechallenges harder to surmount, butthat same scrutiny orces us to meet

those challenges head-on.

Companies ace this challengebecause the pharmacovigilancemethods developed in the ourdecades since the thalidomide tragedyhave been designed to identiy rare,easily identiable saety problems atthe same time as we have seen thegrowth o a ragmented health-caresystem that has lacked a uniyinginrastructure. As a result, this systemoperates primarily in reaction torather than in anticipation o majorpharmaceutical saety events.



As drug consumption has increasedand the public has grown to expecthigher levels o drug saety, thetraditional reactive approach hasproved largely incapable o addressingshits in public expectations andregulatory and media scrutiny.This reality has revealed issues inthe our areas, or inrastructures,involved in patient saety operations:organizational alignment, operationsmanagement, data management,and risk management.

Organizational alignmentTraditional department boundariesimpede interaction on saetyissues, inhibit the sharing o bestpractices, and limit integrationamong departments (such as salesand marketing, manuacturing, andcustomer service) that have incentivestructures dierent rom thoseo the saety organization. Manyorganizations lack a single individualwith responsibility or the overall quality

and integrity o saety processes andsystems. Instead, authorityandaccountabilityare more diusethan is necessary. Developing ateam-based and product-ocusedstang model made up o sta romthe key unctionssuch as trialregistration, regulatory, testing, andinvestigationwith a dotted-line backto their unctional areas will breakdown departmental barriers and ostercollaboration.

Operations managementMany o todays postmarket saetyinitiatives were either created in anearlier era or built organically over timeThis ad hoc evolution has not resultedin a unied, structured, and adaptablevision to guide the management osaety-related processes. For examplethe generation and disseminationo reports may continue even aterthey have been rendered obsolete bychanges in regulation, technology,

or business processes. This issue iscommon and can be addressed bybuilding a continuous improvementramework into the organizationsoperating model.

Drug saety operations also requentlylack standardized and alignedactivities across product lines andacross geographic locations, andthereby ail to leverage opportunitiesor standardization or economies oscale made possible by similarities inthe overarching process. For examplewhen adverse event data arrives, itmust be investigated and evaluatedregardless o country, product, orsource o the report. Lack o aunied operations structure canresult in process redundancies or,worse, gapsall o which createunnecessary risk.

Unlocking the power o pharmacovigilance



Data management

Todays data systems oten ail tocapture, standardize, and integratesaety inormation eciently.Furthermore, current adverse eventreporting processes and systems

typically lack a clear standard orquality o content. Companiesoten nd that the saety data availableto them in spontaneous reportsis incomplete and lacks theinormation necessary to inormadequate analyses.

Physicians working on a hospitalsta use hospital-dened parametersor what constitutes an adverseevent. Reactions the drug sponsor oragency might be interested in could

be considered nonissues at specicacilities, said Beverly Kirchner,president and CEO o Genesee

Associates and member o the boardo directors o the Association oPerioperative Registered Nurses.

One estimate commonly cited byinterview participants is that onlyabout 10% o serious adverse eventsare reported. This underreportingis due to several actors: lack oclarity around what events should bereported, lack o available time, andpoor recognition o adverse eventsbecause o diering standards or lacko training. For example, because thereare many possible explanations oran adverse event, it is rarely possibleto demonstrate a causal relationshipbetween a compound and a specicadverse event.

Furthermore, the reporting ractionthe number o adverse events per

drug that enters the pharmacovigilancereporting systemis oten unknownor dicult to quantiy with certainty.I 50 people on a given drug reportchest pains, the number who actuallyexperience chest pains could be muchhigher. And the company has no wayo knowing just how much higher,which makes analysis dicult.

Postmarketing, spontaneous reports do not workin certain situations. For example, in the case o acommon condition like heart disease, it is impossibleto tell whether a case is related to a drug or whether

it would have happened anyway. When the adverseevent youre looking at is the same as or verysimilar to the maniestation or natural history o thevery disease you are trying to treat, assessment oindividual adverse events is not very helpul.

Joanna Haas, M.D.Vice president o pharmacovigilanceat Genzyme Corporation

With spontaneous reporting, you know youre seeingonly the tip o the iceberg. And rom this tip youcannot event-gauge the ull size o the iceberg.

Jean-Louis Saillot, M.D.Vice president and heado global pharmacovigilanceat Schering-Plough



Even when the data gathered areacceptably complete, analysis maystill prove to be a Herculean taskbecause o the myriad systems andinstitutions that store and report saetydata. For example, more than 85%o U.S. physicians store their patient

medical records on paper, and eventhose oces that are wired do notinterace easily with pharmaceuticalmanuacturers.9

Much pre- and postmarket inormationis collected and analyzed in separaterepositories. Data may be collectedby dierent therapy- or compound-specic groups, by dierent meansand or dierent purposes. Clinicaltrial data, or example, might not beleveraged or patient saety purposes

simply because the trial data were notcollected or stored with possible utureuses in mind. Integrated analysesacross departmental databasesanalyses that could identiy saetytrends and acilitate more integratedreportingare practically nonexistentsimply due to the manner in which dataare collected and stored (Exhibit 5).

The challenge is how to connectthe data that typically sits in dierentplaces; how to aggregate it intoinormation on which the companycan act, said Beth Ziemba, directoro compliance management atElan Corporation. As an example,pharmacovigilance departmentsoten use a dierent database thanclinical departments do; linking thesedatabases would allow a companyto conduct improved analysesthroughout product development,including postapproval.

Exhibit 5: Source o adverse event reports, 4Q04 through 3Q05

User facility

Distributor

Literature

Study

Company representative

Other

Foreign

Consumer

Health professional

0.5%

1%

7%

10%

12%

24%

27%

42%

59%

Source:AERS Latest Quarterly Data Files, FDA.



The hurdles in data sharing aresignicant not only within a company,but they also prevent data sharingbetween the company and the FDA,as well as across the broader scienticcommunity. Further complicating theissue is that the saety inormationgathered within a single companythat has locations in dierent countriesmay be owned and stored in theoriginating locations.

Risk managementRisk can take many orms: operational,nancial, regulatory, and reputational,to name a ew. To maintain stabilitywithin their core businesses,companies must be equipped toidentiy, evaluate, and manage thoserisks eectively. Too oten, however,a companys risk managementinrastructure is not integrated withits organizational, operational, anddata management systems; thereis overreliance on legacy policiesand procedures, training, anddocumentation systems; and thecompany applies risk managementin a reactive, inconsistent manner.The result o such inconsistent,nonsystematic, and uncoordinatedapproaches can be signicant nancialand reputational harm to the company.

Even those companies that have begunto use proactive risk managementtechniques in some unctional areas

have not used them consistently inareas pertinent to drug saety risk.For example, adverse event requencydata have been used or assessmento real-time risk. But these datatypically are not integrated withmeasures o event severity, and sodo not inorm decisions through apredened risk prioritization process.

There is a disconnect between R&D, clinical andpostmarket surveillance. There should be a singlerepository where all data points, both pre- andpostmarket, merge. This will drive more-ecaciousdrug saety monitoring and improve our ability toproactively discover potential saety issues beorethey become widespread.

Noemi Romero-KondosGlobal complaint managementlead process manager at Hospira


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The three strategies oeective pharmacovigilance

For a pharmaceutical company to be successul, drug saety has to be at the coreo all discussions across the organization. Pharmacovigilance has to be embeddedinto the day-to-day operations o the company. Similar to other systems, most othe issues around pharmacovigilance systems are not IT [inormation technology]issues but mainly process and people and organization issues. Tools, including IT

solutions, must be implemented in the context o addressing process improvementsand organizational needs.


Operations

management

Risk

management

Data

management

Organizational

management

Align

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roles

,responsib

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an

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communic

ati

ons

Imp

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ion

Standardizepharmac

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ica

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anddatamanagem

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3

1

2



Strategy 1: Alignand clariy roles,responsibilities,and communications

Appropriate organizational alignment

is a crucial enabler o the operatingand data management models thatgovern the eciency and eectivenesso a companys pharmacovigilanceactivities.

To establish an organization-wide pharmacovigilance program,companies should developclearly dened saety roles andresponsibilities that cover a drug romdevelopment through postmarket.This includes an unambiguous

chain o command and an explicitescalation process or saety-relatedissues to prevent problems romdropping o managements radar.Decision-making models that arenot hampered by poorly denedroles and responsibilitiesas wellas specic processes or handlingsaety-related issueswill drive clearaccountability that will greatly mitigatesaety risks beore they develop intocostly problems that could have beenavoided.

There is a pendulum movement right now to movebeyond the act that all medications have side eectsand move more towards a ocus on the benets aswell as the risks. We cannot assess the saety risks

without a calculation in benets.

Ludo Lauwers, M.D.Senior vice presidentGlobal head o benet risk management,medicines and nutritionals sectorJohnson & Johnson

There is a very limited pool o experienced people.Saety is moving to the oreront in companies, andcompanies are going to have to resource it better.

Judith M. Sills, Pharm.D.Head o global saety intelligenceat Novartis Pharmaceuticals



Companies should establish anescalation ramework that ensuresthat issues are identied, prioritized,tracked, reviewed, and resolved in atimely manner. The ramework wouldalso empower employees to escalateissues to management.

For example, the ramework woulddene a number o escalation criteriathatwhen matched togetherwould guide identied issues througha path rom registration through toclosure, with clear links to testing andinvestigation processes and regulatoryreporting mechanisms. The criteriashould be updated regularly basedon a continuous improvement phaseo the business process and ought tobe based on regulation and historical

experience with the particular product.

To operate eectively, both thedecision-making model and theescalation ramework requireestablished, ormalized communicationchannels. These channels enableemployees, including those withoutdirect drug saety responsibilities, toobtain necessary inormation romanywhere in the organization, tomake inormed saety decisions, andto communicate those decisions asappropriate.

Determine the pharmacovigilanceworkload, and suciently resourcethe required eort.Companies also should providesucient resources to supporttheir pharmacovigilance eorts,although individuals who possessthe specialized skills necessary toexecute drug saety activities arerelatively scarce. To address this issue,

some companies have embraceda stang model that leveragesdiversied advanced degrees inpharmacovigilance unctions such assignal detection, signal investigation,and risk management. Rather thanrelying solely on saety-relatedexperience, nurses, pharmacists, and

hospital technicians are enlisted or thmore operationally ocused unctionssuch as processing orms, reporting,and case investigation.

Companies also should considera mixture o xed versus fexible

resources, in which xed resourceswith deep subject-matter expertiseocus on specic products, whilefexible resources cover a greaterbreadth o products. This stangconcept allows or temporary increasein the saety workload or a particularproduct and also acilitates optimalstang in an environment in whichdrug saety is still viewed as acost center.

Designate a pharmacovigilance

operating model and business procesowner.One key resource is a designatedprocess owner (not to be conusedwith the head o drug saety, althoughthe drug saety head could be theprocess owner), who is responsibleor the saety prole o the productand who acts as an unbiased stewardo the overall operating model andprinciples o ensuring drug saety.

The individual would be accountableor the eective execution o thepharmacovigilance operating modeland business process, would ensurethat pharmacovigilance integrity andquality are kept consistently high, andwould promote an atmosphereo continuous improvement.

In addition, the process owner shouldoversee internal communicationsthat provide or connections betweenthe saety unction and marketing,

sales, and other units whose primaryresponsibilities do not include saety.The responsibility or creating andenorcing appropriate saety checks,balances, and controls must rest withthe process owner and be backedby senior managers who communicatthe importance o saety to theentire company.

Develop an objective, data-driven,team-based approach to riskmonitoring and evaluationUltimate decisions on how to managedrug saety risks should be madeby teams o key stakeholders.One approach would be to appoint

stakeholders to a Data SaetyMonitoring Board.

Another would be to establish a DrugSaety Risk Management Committee,ormed early in the developmentprocess. By including representativesrom discovery, drug saety, clinicaldevelopment, legal, compliance,marketing and manuacturing, sucha group enables more timely andcomplete saety issue identication,as well as more ecient and inormed

saety decisions.

Member identication, groupormation, and membership transition(as the product moves through itsliecycle) should be standardized.Groups should eature diversity operspectives based on criteria suchas disease area, mechanism o action,and stage in the product lie cycle.

Implement well-dened decision-making models, escalation processes,and communication channels.

A pharmacovigilance decision-making model should specicallydene employee roles in gatheringand analyzing inormation thatultimately infuences drug saetydecisions. Such a model allowsemployees to take greater ownershipo pharmacovigilance issues, ostermore collaborative relationships, andcontribute to continuous improvement.For example, the model would allow

employees to work autonomouslywithin their roles while ollowinga consistent method to determineappropriate action. In particular,a decision-making model wouldclearly establish ownership orspecic decisions and wouldreduce ambiguity.



event reporting and risk managementdecision making. Data standardizationis also important because muchinormation is collected and analyzedby discrete business units that havedierent therapy- or compound-specic working groups, dierent

means o collection, and dierent usein mind.

Several pharmaceutical companiesstandardize operational and datamanagement activities in otherareas, but very ew have appliedstandardization to pharmacovigilanceactivities.

Align operational activities acrossdepartments and across sites.

A well-structured operations model

provides a common and consistentplatorm upon which dierentgeographic locations, unctionalgroups, and product lines can renetheir own site-specic processes,compare operational dierences,and share best practices.

Saety proles and regulatoryrequirements may dier rom drug todrug and location to location. Howevethere are activities and decision pointsthat can be standardized and alignedregardless o product or location.

Additional levels o detail can bedeveloped depending on products,locations, and organizational rolesas one moves urther into any onearea (See Exhibit 6).

Accordingly, the undamentalsaety reporting process should becommon rom country to country,though it should also be able toaccommodate local regulatory

requirements or cultural imperatives.Such standardization can helppharmaceutical rms cope with theregulatory requirements o the multiple

jurisdictions within global markets andcan oster sharing obest practices.

level o internal review, investors cansee that an environment such asthis one, that promotes complianceand transparency, demonstratesan increased level o accountabilityby senior executives. This can, inturn, be particularly helpul in the

current environmentone in whichcorporate ethics, accountability, andresponsibility all have been called intoquestion.

The working relationship betweenpharmacovigilance and corporatecompliance should be supportedby quality assurance auditing andbusiness unit monitoring processesthat enable organizations to assesspharmacovigilance quality proactivelyand systematically, as well as by

the level o systems that provideemployees with an authoritative sourceo readily accessible and cross-reerenced compliance inormation.

Strategy 2: Standardizepharmacovigilanceprocesses and datamanagement

Standardization around well-dened,integrated operations and datamanagement processes is the salienteature o eective pharmacovigilanceprograms. This enables companies toensure more-ecient patient saety,consistent regulatory compliance,and controlled risk management whileensuring scalability by consistentlyollowing a set o procedures. By theuse o such consistent procedures,both trending and analysis can beperormed on the same data set, and

saety-related issues can thereore becompared easily.

Standardizing the sources, reports, andanalytics used in the translation o datainto saety signals allows or consistent

Ensure that appropriate process andorganizational checks and balancesare in place to limit bias and manageregulatory risk.Because departments outside drugsaety have dierent objectives andincentives, the importance o drug

saety may not necessarily beunderstood or acted upon equallyacross a company.

Companies have to be careul toensure that independent, medicallybased decision making is adequatelyprotected. Decisions on saety signalsmust be medically and science driven.In any situation, people have to bemindul o conscious and unconsciousbias, said Saillot. To ensure quality odecision making, we have to welcome

checks and balances.

The responsibility or creating andenorcing pharmacovigilance checks,balances, and controls must rest,thereore, on management thathas cross-unctional oversight. Forexample, as part o a continuousimprovement process, managementwould review the checks, balances,and controls with the process ownerto ensure the process is workingoptimally. In addition, by activelysupporting and communicating theimportance o pharmacovigilance tothe entire enterprise, executives canensure organizational alignment aroundstrong pharmacovigilance.

To ensure that these checks andbalances are properly understoodthroughout the enterprise, urthermore,the cross-unctional managementteam should oster a transparentcollaborative working relationship

between pharmacovigilance andcorporate compliance programs.

In addition to the ensuring that thesaety risks o the drugs in theirportolios receive the appropriate



Exhibit 6: Operations model or pharmacovigilance processes

Process: represents a

specific or roll-up activity in the

overall process

Communication: represents

process communications (e.g.,

phone, intranet, e-mail)

Input/Output:represents the

direction of process activities

and handoffs

Document/Report/System

Form: Indicates item created/

used in a given process step

Receive Report Investigate Case Report Case Mitigate Risk

Drug Safety Operations Information SystemsOther Functional Areas

Conduct

Investigation

Report Findings

Clinical

MedicalOthers

ClinicalMedicalOthers

Legend:



Implement process-driven standardoperating procedures, workinstructions, and training materials.Standardization o work instructions,training materials, and documentationdrives greater adherence to qualityprocesses and enables companies to

cope with the loss o key employees,which is especially important in theace o a relatively limited drug saetytalent pool.

Pharmacovigilance model and processundamentals trainingtraining on thehighest level in the pharmacovigilancemodel and processshould coverthe overall processes, organizations,and systems and should remain thesame regardless o a persons role inthe saety organization. This can also

be a useul tool in raising awarenessthroughout the organization.

More-customized training or each rolein the saety organization should drilldown rom the undamentals traininginto specic roles and responsibilities.Trainers, thereore, can ecientlymix and match training modules asappropriate to create role-specic andproduct-specic training materials thatbuild upon what employees learnedduring undamentals training.

It is extremely dicult to nd pharmacovigilance-qualied M.D. candidates. You really have to build aninrastructure that can train and mature them in-house.


We dont view drug saety rom a postmarket orpremarket perspective but, rather, as a continuumrom the time the compound is identied and the timeo animal studies on through when companies arehoping to get approval. This is ar more involved thanlooking separately at postmarket and premarket.

Alan GoldhammerAssociate vice president oregulatory aairs or thePharmaceutical Research andManuacturers o America (PhRMA)



Work fow management systemsensure that only the appropriateemployees receive the datarequired to inorm the decisionsthey are authorized to make withinthe pharmacovigilance model.The technology also ensures that

the appropriate decision, sign-o, communication, and retentionrequirements are executed anddocumenteda process known aswork fow close out. The technology,thereore, allows or more-controlledmanagement o tasks, thusensuring that all saety events arehandled appropriately.

Select a vendor that best matches thepharmacovigilance operating model,business process, and vendor/system

selection criteria.Companies recognize that sotwareand technology vendors havemade signicant advances in saetydata mining, in analytics, and inother tools required or successulpharmacovigilance programs.Technology solutions must not drivecompanies pharmacovigilanceprocesses or operating models,however.

Technology should instead bind theoperating model with the organizationmodel, supporting risk managementactivities throughout the saetyorganization. To identiy the toolsand technologies that are mostappropriate to an organizations uniquneeds, companies should derivesystem requirements rom process-based business rules and eed thoserequirements into a systematic vendorselection process.

Integrate saety data through data andsystem interoperability standards.

A single database should include dataacross the entire product lie cycleboth premarket and postmarket.By viewing postmarket saety as acomponent o a continuum and by

perorming analysis o saety dataacross this continuum, organizationscan identiy more saety signals.

Integration o data is important toperorm signal detection across aproducts development lie cycle, saidZiemba. Integration would includethe tools to pool data rom the varietyo data sets across the companyincluding data on product complaintsand sales and marketing inormationand rom data sets housed externally,

so as to create an aggregate data setthat is as close to complete and asinclusive as possible.

There are, however, several challengesto integration across the saetycontinuummostly around data andsystem interoperability standards. Inboth pre- and postmarket operations,multiple databases may contain similarinormation, but these databasestypically are neither linked nor linkableto each other. Each database isdesigned and populated or dierentobjectives and thereore containsnominally dierent but inherentlysimilar saety data elements. Forexample, some databases may becreated or preclinical toxicology andpharmacology studies, some may becreated or each clinical trial and somemay be created or each postmarketuse (e.g., complaint management,customer service, or medicalcommunications).

Despite the act that dierentdatabases have dierent uses, theirdata contains many common saety-relevant elements. Companies canlink these databases (and therebyacilitate integrated saety analyses)by creating standards around the

database elements as well as dataormats, terminology and systeminteroperability.

Many o the same standardizationissues posed by data sets housedinternally are similar to the issuesposed by external data sets suchas automated claims databases,physician records, pharmacy records,and clinical registries. As within thecompany, a common ormat, commondata elements, common terminology

(such as MedDRA), and systeminteroperability standards can acilitatelinkages among saety data. While littlecan be done to standardize externaldata without the eorts o groupssuch as the ICH, companies canimprove their own management o dataobtained rom internal and externalsources by adopting in-house data andinteroperability standards.

Implement work fow managementtechnology to ensure appropriatetransparency and accessibility o saetyinormation.Work fow management technologyalready has created value in otherareas o the pharmaceutical valuechainsuch as in help desk unctionsand electronic capital expenserequestsand consequently is gainingwidespread industry acceptance.

Applied to pharmacovigilance, thistechnology can identiy and distributeinormation to stakeholders according

to a predetermined set o rulessuchas product amily, type o saety event,and event severityand therebyacilitate eective and consistentmanagement o saety reporting anddata sharing.



Within the industry, two concerns havearisen about inormation technologyvendors. First, sotware solutions areexpensive, and second, o-the-shelsolutions are neither customizable norfexible enough or an organizationsunique requirements. Companies

planning to customize technologyshould undergo a thorough searchprocess or the right vendor andproduct. Some companies will nd thata homegrown technology solution isthe best option, while others will ndthat o-the-shel solutions work better.

Saety is an evolving area, which iswhy sotware is such a challenge.I you build a tool or todaysrequirements, the system is static.Saety regulations and saety thinking

continue to evolve, so a system thatwill serve that area has to be dynamicand fexible, said Sills. Vendors areout there, but I dont know i there areany dominant vendors. I think thatcompanies, as they get rustrated,resort to building their own systems.

In the event o technology gaps,process workarounds can ensurethat the integrity o the process andtechnology solution remains intact,whether the product is o-the-shel, customized, or homegrown.

Comprehensive sotware is just now slowly developingand has not yet matured. However, it is still importantor companies to query technology companiesabout developing sotware to link and evaluate all

saety data.

Tobias Peschel, M.D., Ph.D.Vice president o drug saetyand public healthat Gilead Sciences



Best practices: Technological conceptsor enhanced pharmacovigilance

System Capabilities

Systems should accommodate saety inormation in multiple ormats

rom both direct sourcessuch as consumers, physicians, pharmacies,and other third partiesand indirect sources, which include regulatoryagencies, electronic medical records, and payer automated claimsdatabases. Systems should also share drug saety inormation acrossdepartments and route that inormation to the right stakeholders at theright time, in the right ormat and with the right level o privilege. Furthercapabilities should include the perormance o leading-edge saetydiagnostics and analytics as well as the generation o periodic and ad hocreports or both internal and external consumption.

System Requirements

To support these capabilities, systems should employ data standards

such as the CDISC saety data standardsthat acilitate the transer odata and multisystem analysis o distributed saety data, as well as amedical data dictionary such as MedDRA to support the classication,retrieval, presentation, and communication o medical inormation tointernal and external stakeholders.

Technology Features

Branching that uses initial responses and specic conditions reportedduring data entry to collect specic diagnosis inormation

Prepopulated data elds that acilitate the diagnosis o suspected saetyeventssuch as specic reactions or symptoms o the eventand thatlead to data that is more useul during investigations, analytics, andmonitoring

Data lters that adhere to and satisy specic regulations such as HIPAAprivacy rule regulations

Data analytics that link data sets and acilitate pattern recognitionand detection

Work fow eatures that acilitate the controlled routing o events andsaety data to the appropriate organizational and scientic stakeholders

Event- and threshold-based triggers, with a prescribed corrective actionand approval process



Strategy 3: Implementproactive risk minimization

In the context o pharmacovigilance,a risk management ramework shouldhave three undamental traits:

Ability to quickly identiy risks basedon internal and external inormation,through processes that identiy andextract compound- and indication-specic inormation rom acrossthe organization

Categorization and ranking o theoverall organizational impact osaety risks based on the companysrisk appetite and tolerance

A predened process that manages

risks and that involves internalstakeholders who both developthe risk management plans andperiodically revalidate pertinentalgorithms and decision criteria

An essential rst step is to ensure thatappropriate controls or regulatorycompliance are in place. Companiesshould careully document and drivecompliance with all policies andprocedures. Maintenance o recordsis important, especially those o pastaudits and corrective and preventiveaction plans (CAPAs). Companiesshould enorce policy and procedureretirement dates and update processesto ensure that they meet current legaland regulatory requirements.

Beyond these undamental compliancemeasures, companies must injectobjectivity and standardization intorisk management by identiyingrisk tolerances and priorities anddeveloping comprehensive mitigationplans in advance o drug saety events.

For eective risk management, thepharmacovigilance risk identicationunction alone is ar rom beingenough, said Saillot. Its just oneo the rst steps. For risk minimizationactivities to be eective, everyonemust be aligned and acting onidentied risks.

Develop risk management action plansbased on preestablished risk scoringand mitigation processes.

Established risk scoring and mitigationprocesses can ensure objectivityand standardization. Risk scoringshould be based on a combination oindustry benchmarking, corporate risktolerance, and internal assessmentsvia a set o predened algorithmsthat allow or objective evaluationo specic issues and actions. Forexample, the risk impact on individualproducts may be determined by themeasurement o diverse data pointssuch as number o adverse events perproduct amily, patient demographics,and overall portolio value o theproduct and product amily. Issues maybe assessed either or each productindividually or or a class o productsand should be continuously updated asthe environment necessitates. As parto the assessment, companies shouldevaluate both external risk actorssuch as regulatory, reputation, andproduct liability riskand internal riskactorssuch as portolio, strategic,

and nancial riskwhen examiningspecic risk events.

Companies similarly may assign scoreto inorm the risk tolerance and riskappetite levels or specic types odrug saety issues across the productportolio. Based on these predenedlevels, the company can developappropriate risk mitigation plans.

For example, pharmacovigilance groupcan work to develop an objective,standardized approach to investigationo saety signals rom the point oinitial detection. Standardization o theinvestigation approach is essential,rom hypothesis generation throughhypothesis testing and, ultimately,to the process o making nal riskmitigation decisions. Companies thatemploy analyses and reports via astandardized, predetermined approach

can make consistent and appropriatedecisions regarding risk communicatioand action. Such an approach to riskmanagement will help companiesreduce reactionary measures andpotentially costly and ineectivedecisions made under real-time duress

Implement data mining techniques tobolster saety analytics, reporting, andinvestigation.

As mentioned earlier, eectivemanagement o saety data acrossmultiple platorms is critical to eectivemanagement o saety events. Thissame data can be mined to supplementexisting saety detection methodsand help assess the patterns, timetrends, and events associated withdrug interactions. Dynamic andfexible analytic sotware and the useo new tools, such as biomarkers orpharmacodynamic markers, also canhelp companies maximize the benetso medicines while minimizing saety ris



The rationale or data mining is clear:Detection o most saety signals isdicult. While serious and unlabeledadverse event signals are relativelystraightorward, the more dicultsignals require analysis across anumber o data sets. This is an

extremely time-consuming task iperormed without the aid o datamining technology, which allows orthe systematic examination o datawith statistical or mathematical toolsto determine whether a potential saetysignal warrants urther investigation.10

Data mining typically supplementsand supports existing saety signaldetection methods and is especiallyuseul in assessing the patterns, timetrends, and events associated with

drug-drug interactions. It is an eectiveexploratory and hypothesis-generatingtool that can provide insights intothe adverse event reporting patternsor a given product relative to otherproducts in the same therapy class.11It also can indicate the existenceo issues around the mechanism oactionsuch as receptor specicityand selectivity, signaling pathways,and intracellular protein interactions.It is the integration o the saety signaldata combined with an introspectiveevaluation o known risks based oninternal data that provides the greatestvalue in an analysis o the true impacto drug saety issues.

Using the problem-oriented approach as apharmacovigilance business model

Several companies have incorporated the spirit

and intent o proactive risk management into theirdevelopment processes. Joanna Haas, M.D., vicepresident o pharmacovigilance at Genzyme Corporation,calls Genzymes system the problem-orientedapproach to drug saety and pharmacovigilance. Inessence, the company looks or the potential riskso its compounds rom the time o discovery throughpreclinical development, and thereater via postmarketingsurveillance. I you think drug interactions may be anissue, youd make that something you look or, Haas

said. To designate something as a potential saetyproblem presumes youre trying to nd the answer, whichmay be that there is in act no problem. Haas went onto say that including risk concerns as well as benets inlings and discussions with the FDA makes the approvalprocess go more smoothly.



One o the most eective practicesor dealing with this challenge is acustomized saety risk dashboardthat provides a single, real-time,authoritative inormation source orall risks across the companys portolio products.

The dashboard should include overallsaety histories, short- and long-terminormation on use, case-by-casereporting, expected reactions versusactual adverse events, and a product

regulatory reporting history. Basedon data gathered rom the dashboardspecic risk mitigation procedurestailored to a given type and levelo risk may be accessed andollowed or guidance in a timely andeective manner.

Dashboards acilitate proactivemanagement o saety risks bysummarizing saety inormation acrossthe product portolio in real time andby identiying the types o data thatshould and should not be used in drugsaety decision making. Dashboardsare key means o ensuring that riskmanagement and communicationplans are executed in a timely andeective manner.

Incorporate continuous improvementactivities and standardized riskcommunication plans.Continuous improvement activitiesshould include new saety riskinormation to inorm changes to therisk prole that might urther minimizeproduct risks and maximize benetsor the targeted patient population.Continuous improvement activitiesalso should include reevaluation o riskcriteria around new internal or externalactors that may infuence overall risk

appetite and tolerance.

Communication o drug saetyrisk inormation both internallyand externally is perhaps the mostcritical output o pharmacovigilancerisk management activities.Communication plans should describethe risk escalation and communicationprocesses both within and outsidethe company. To ensure that messagesdisseminated are accurate, consistent,and not subject to misinterpretation,the drug saety ocer, the chiemedical/scientic ocer, andthe public relations, legal, regulatory,and compliance executives shouldbe involved in message designand deployment.

All communication plans shouldconsider the audience involved,especially when that audience iscomposed o the patient- or physician-centric communities that have such

a high impact on industry reputation.

Sales representatives, or example,can play a key role in communicatingrisks to physicians. There is arole or sales reps to objectivelygive inormation to physicians onthe benets along with the risks oproducts, said Ludo Lauwers, M.D.,senior vice president and globalhead o the benet risk management,medicines, and nutritionals sector atJohnson & Johnson. I a product hasan issue, it is important to educate.I know it sounds like a contradiction

as sales reps have an incentive tosell, but we have used sales repsin the past to go to physicians witheducational saety messages. It worksvery well because it is a strong wayto make sure that an important saetymessage is conveyed to physicians.

Create a dashboard that summarizesand promotes timely awareness osaety risks across the portolioand timely execution o saety riskminimization activities.

A robust signal detection and actionplatorm, enhanced by data miningtechniques and enabled by a cross-unctional team-based approach andthe right communication plans, still hasa number o limitations. It is dicult orthe pharmacovigilance process ownerto ensure that all the correct actionsare taken in a given situation.



Timely communication o emerging risks to physiciansand patients, as well as regulators, is extremelyimportant. Everyone who is prescribing, dispensing,or taking a drug needs to be inormed o potentialrisks as early as possible.

Tobias Peschel, M.D., Ph.D.Vice president o drug saetyand public healthat Gilead Sciences

Conclusion

The time or companies to reexaminetheir pharmacovigilance practicesand to develop and implementeective, best-in-class solutions isnow. Many organizations have alreadybegun to evaluate and enhancetheir pharmacovigilance practicesor ecacy and eciency, andthrough that experience many haveencountered signicant obstacles.

We believe that the practical approachwe have discussed in this paper can

provide a resh perspective, both tothose companies that have just begunthe journey and to those that haveencountered obstacles along the way.We have provided a ramework thatwill enable companies to nd successby concentrating on the integration ooperations, risk management and thesupporting organization. The powero this approach lies in the alignmento strategy with accountability and inthe linkage o unctional areas within asingle integrated operating model thatadapts more easily to the changingcharacterizes o the industry, regulatorsand the public alike.

By concentrating on integration acrossthe key inrastructures, companieswill enable themselves to avoid thechallenges companies typically acewhen building toward the uture. Theywill create a sustainable inrastructureand a highly adaptive culture, both owhich can lead to greatly diminished

costs and risks, as well as greatlyimproved outcomes or patients.



Endnotes

1 CDER 2004 Report to the Nation: Improving

Public Health through Human Drugs, Center

or Drug Evaluation and Research, August 22,2005.

2 HealthPoll Report, Henry J. Kaiser FamilyFoundation, February 2005.

3 Americans Growing Less Condent in FDAsJob on Saety, Poll Shows, The Wall Street

Journal Online, May 24, 2006.

4 Drug Saety: Improvement Needed in

FDAs Post-Market Decision-Making andOversight Process, Report to Congressional

Requesters, GAO, March 2006.

5 FDA Appoints New Associate

Center Director or Saety Policy andCommunication, FDA News, April 26, 2006.

6 FDA Announces New Prescription DrugInormation Format to Improve Patient

Saety, FDA News, January 18, 2006.

7 Is More Money the Answer to ImprovedPatient Saety Monitoring? Lisa Roner, ed.,

March 9, 2006.

8 Health Spending Projections through 2015:

Changes on the Horizon, by Christine

Borger, Sheila Smith, Christopher Truer,Sean Keehan, Andrea Sisko, John Poisal,

and M. Kent Clemens, Health Aairs, Feb.

22, 2006.

9 Electronic Medical Records Get Closer, by

Julie Schmit (citing Eric Brown o Forrester

Research), USA Today, June 7, 2005.

10 Portions rom Good Pharmacovigilance

Practices and PharmacoepidemiologyAssessment, FDA Guidance to Industry.

11 Portions rom Good PharmacovigilancePractices and Pharmacoepidemiology

Assessment, FDA Guidance to Industry.



ADR: Adverse Drug Reaction (see AdverseEvent).

AERS: Adverse Event Reporting System FDAs

database o reported adverse events.

Adverse Event:Any undesirable experience

associated with the use o a medical product in a

patient

Background Rate: Reers to the background rateo occurrence or an adverse event in the general

population or in a subpopulation with

characteristics similar to that o the exposedpopulation. Oten compared against the

Incidence Rate. (See also Incidence Rate,Reporting Rate and Saety Signal).

Biomarkers: Physiologic indicators (e.g. blood

protein levels) that can be used to measure theprogress o a disease, outcomes o

administration, and/or the positive/negative

eects o a treatment, sometimes long beoreother indications or symptoms are apparent.

(See also Critical Path Initiative).

CAPA: Corrective and Preventive Action

CDISC: Clinical Data Interchange Standards

Consortium Organization that establishes and

supports worldwide, platorm-independentindustry data standards to support the electronic

acquisition, exchange, submission, and archiving

o clinical trials data and metadata that enable

inormation system interoperability or medicaland pharmaceutical research and development

and related areas o healthcare. [www.cdisc.org]

Clinical Registry: (see Registry).

Data Mart: (see Data Warehouse).

Data Mining: Systematic examination o data

using statistical or mathematical tools to

determine a potential saety signal warrantingurther investigation. Typically used to

supplement existing saety signal detection

strategies, data mining is especially useul orassessing patterns, time trends, and events

associated with drug-drug interactions. It is not

used to establish causal relationships betweenproducts and adverse events, but rather as an

exploratory or hypothesis generating tool that

may provide insights into the patterns o adverseevents reported or a given product relative to

other products in the same class or to all other

products. (see also Saety Signal)

Data Warehouse: (Sometimes reerred to as a

data mart) a repository o integratedinormation, extracted rom heterogeneous data

sources, available or eicient querying and

reporting that supports data analysis anddecision making tasks.

EDC: Electronic Data Capture

EDR: Electronic Data Record

EMR: Electronic Medical Record

Expected Adverse Event: (see Adverse Event)

Good Pharmacovigilance Practices: FDA

Guidance on current generally accepted goodpharmacovigilance practices or post-market

saety vigilance activities [www.da.gov/cber/

gdlns/pharmacovig.htm]

HIPAA: Health Insurance Portability and

Accountability Act (1996), which required theDepartment o Health and Human Services

(HHS) to adopt national standards or electronic

healthcare transactions. The HIPAA Privacy Ruleprovides ederal protection or the privacy o

individually-identiiable health inormation (also

known as protected health inormation [PHI]) byprohibiting the use and disclosure o PHI except

to the individual subject and to HHS unless

speciically permitted. (See also HIPAA).

HL7: Health Level Seven, an ANSI-accredited

Standards Developing Organization whichproduces standards, speciications, and/or

protocols or clinical and administrative

healthcare data. [www.hl7.org] (see also NCPDP).

ICH: International Conerence or Harmonisation Organization where regulatory authorities o

Europe, Japan, and United States and experts

rom the pharmaceutical industry discussscientiic and technical aspects o harmonizing

activities across the liecycle o pharmaceutical

products. International harmonization eortsaround Medical Terminology (MedDRA), the

Common Technical Document (CTD), and

Electronic Standards or Transmission oRegulatory Inormation (ESTRI) have been

coordinated under the sponsorship o the ICH.

(see also MedDRA) [www.ich.org]

Incidence Rate: Rate at which new cases o

adverse events occur in the product-exposedpopulation. The numerator consists o the

number o new cases. The denominator consist

o the number o exposed patients and time oexposure/time at risk. There are inherent

diiculties in calculating incidence rate or

spontaneous events due to the uncertaintyaround the number o adverse events not

reported. Otentimes compared against the

Background Rate (see also Background Rate,

Reporting Rate, and Saety Signal).

Labeling: (see PI Prescribing Inormation /Package Insert)

Labeled (Expected) Adverse Event:An adverse

event that is one o the known adverse events

listed on the product package insert (PI)

Large Simple Saety Studies: (see LSSS)

LSSS: Large, Simple, Saety Studies

Randomized clinical studies designed to asses

limited, speciic saety outcomes in a largenumber o patients. These outcomes generall

important saety endpoints or saety concerns

suggested by earlier studies are deined a priowith the study speciically designed to assess

them.

MedDRA: Medical Dictionary or Regulatory

Activities International standard o medicalterminology, developed under the auspices o

ICH, used or regulatory activities. MedDRA isparticularly important in the electronic

transmission o adverse event reporting, both inthe pre- and post-marketing areas, as well as th

coding o clinical trial data. [www.ich.org] (see

also ICH).

Glossary



MedWatch: FDA Saety Inormation and Adverse

Event Reporting Program that allows healthcare

proessionals and consumers to report seriousproblems that they suspect are associated with

the drugs and medical devices they prescribe,

dispense, or use. Reporting can be done online,

by phone, or by submitting the MedWatch 3500orm by mail or ax. [www.da.gov/medwatch/]

NCPDP: National Council or Prescription Drug

Programs ANSI-accredited Standards

Development Organization (SDO) which createsand promotes standards or the transer o data

to and rom the pharmacy services sector o the

healthcare industry. [www.ncpdp.org] (see also

HL7)

Non-Serious Adverse Event: All adverse eventsnot classiied as a serious adverse event

Pharmacoepidemiology: Study o the utilization

and eects o drugs in large numbers o people.

To accomplish this, pharmacoepidemiology

borrows rom both pharmacology (study o theeect o drugs) and epidemiology (study o the

distribution and determinants o diseases in

populations). [www.pharmacoepi.org]

Pharmacovigilance: Scientiic and data gatheringactivities relating to the detection, assessment,

understanding and prevention o adverse events

including, to the extent possible, understanding

the nature, requency, and potential risk actorso the adverse events.

PHI: Protected Health Inormation (see also

HIPAA Privacy Rule).

PI: Prescribing Inormation / Package Insert Prescription drug products FDA approved

labeling which contains a compilation oinormation about the product, including

inormation necessary or sae and eective use.

READ Codes: United Kingdoms National Health

Service (NHS) Clinical Terms. Combined with

SNOMED-RT to create SNOMED-CT (SNOMEDClinical Terms). [www.nhsia.nhs.uk/terms/pages/]

(See also SNOMED).

Registry: An organized system or the collection,

storage, retrieval, analysis, and dissemination o

inormation on individual persons exposed to acommon actor that predisposes them to the

occurrence o a health-related event. This

common actor may include exposure to aspeciic medical intervention, a particular

disease, condition, or risk actor, or substances

(or circumstances) known or suspected to cause

adverse health eects.

Reporting Rate: (see Incidence Rate).

RiskMAP: Risk Minimization Action Plan Astrategic saety program designed to meet

speciic goals and objectives in minimizing

known risks o a product while preserving its

beneits. A RiskMAP targets one or more saety-related health outcomes or goals and uses one

or more tools to achieve these goals.

[http://www.da.gov/cber/gdlns/riskminim.htm]

Saety Signal: An excess o adverse eventscompared to what would be expected to be

associated with a products use. Signals

generally indicate the need or urther

investigation, which may or may not lead to theconclusion that the product caused the event,

whether the product represents a potential saety

risk, and/or whether other risk mitigation actionsshould be taken. (See also Incidence Rate,

Reporting Rate and Background Rate).

Serious Adverse Event (SAE):An adverse event

that results in any o the ollowing outcomes:death, a lie-threatening adverse drug

experience, inpatient hospitalization or prolonged

hospitalization, a persistent or signiicant

disability/incapacity, or a congenital anomaly/

birth deect, or requires intervention to preventpermanent impairment and/or damage. [www.

da.gov/medwatch/]

Signal Detection: Detection o a saety signal

(see also Saety Signal).

SNOMED: Systemized Nomenclature o

Medicine Universal healthcare terminology thaenables clinicians, researchers, and patients to

share healthcare knowledge worldwide across

clinical specialties and sites o care. SNOMED

RT and NHS Clinical Terms Version 3 (READCodes) were combined into SNOMED CT

(Clinical Terms) a single, global health

terminology with a comprehensive structure tosupport electronic health records). [www.

snomed.org] (see also READ Codes).

Spontaneous Report: Unsolicited communicatio

by healthcare proessionals or consumers to a

company, regulatory authority or otherorganization (e.g. WHO, Poison Control Center)

that describes one or more adverse drug

reactions in a patient (not deriving rom a studyor organized data collection scheme) who was

given one or more medicinal products.

Unexpected Adverse Event: (see Adverse Even

Unlabeled (Unexpected) Adverse Event:An

adverse event that is not one o the known

adverse events listed on the product packageinsert (PI)


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and Associate, Health Industries Advisory

[email protected]

+[1] (703) 918-3391

Alison Detwiler


and Manager, Tax Services

[email protected]

+[1] (703) 610-7459

Health Research Institute Advisory

Team

Anthony L. Farino

Partner, U.S. Pharmaceutical and Lie Sciences

Advisory Services Leader

[email protected]

+[1] (312) 298-2631

Michael Mentesana

Director, U.S. Pharmaceutical and Lie Sciences

Advisory R&D Services Leader

[email protected]

+[1] (646) 471-2268

Simon Friend

Partner, Global Pharmaceutical Industry [email protected]

+[44] (20) 7213 4875

Mark Simon

Partner, U.S. Pharmaceutical Industry Leader

[email protected]

+[1] (973) 236-5410

Eddy Schuermans

Partner, EMEA Pharmaceutical Advisory Services

Leader

[email protected]

+[32] (0)2 710 4004

Steve Arlington

Partner, Global Pharmaceutical and Lie Sciences

Advisory Services Leader

[email protected]

+[44] (0) 20 780 43997

Michael Swanick

Partner, Global Pharmaceutical Tax Leader

[email protected]

+[1] (267) 330-6060

Attila Karacsony

Director, Global Pharmaceutical Industry

Marketing

[email protected]

+[1] (973) 236-5640

Sandy Johnston

Director, European Pharmaceutical and Lie

SciencesR&D Advisory

[email protected]

+[44] 20 7213 1952

Mike Cunning

Director, Pharmaceutical Data Management

Group

[email protected]

+[1] (973) 236-4493

Kate N. Maloney

Manager, U.S. Pharmaceutical and LieSciencesClinical Advisory

[email protected]

+[1] (267) 330-1450

Anup Kharode

Senior Associate, U.S. Pharmaceutical and Lie

Sciences Advisory

[email protected]

+[1] (267) 330-1357

Frank P. DePaoli

Senior Associate, U.S. Pharmaceutical and Lie

Sciences Advisory

[email protected]

+[1] (973) 236-5267


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Documents

Pharmacovigilance Final