PHARMACOVIGILANCE

44 manufacturing chemist May 2015

In recent years, the combination ofgreater public awareness of drug safetyissues and emerging informatics-basedmethods for acquiring and analysingmedical information have sparked globalresearch initiatives to transform ourpresent largely reactive safety systeminto one that is proactive, robust, andmore useful clinically1. In addition, theemerging importance of patient centricityand increase in publicly available safetydata are also driving this change2. As aresult, the need for proactivepharmacovigilance or ‘productvigilance’(PV) is being increasingly acknowledgedby all companies, irrespective of their sizeand product mix.

Regulatory expectations around thesafety and risk management of productsare undergoing a period of extensivechange, with regulations in developedregions becoming more stringent andregulations in emerging markets evolvingrapidly. Growing importance of theemerging markets has caused a shift inthe geographic focus of the marketplace.This has led to partnerships amongmultiple stakeholders across the globe,including generics manufacturers,distributors, service providers andtechnology providers, thus making thePV scenario quite complex.

Another factor adding to thecomplexity is the shift in the mix of smalland large molecules as well as thetherapeutic area focus, and the rigourrequired to capture safety experience fornewer classes of products.

Therefore, while diverse regulationsand guidelines govern PV practices, it isalso critical to ensure that all safetysystems and PV practices employed by anorganisation firmly tie into a unified andtruly global PV framework, which is animportant pre-requisite of proactive PV.Establishing such a framework involves alot more than simply capturing safetydata from affiliates, partners anddistributors.

A global PV system: what, why and how? A PV system is characterised by itsstructure, processes and desiredoutcomes. It is defined as a system usedby an organisation to fulfil its legal tasksand responsibilities in relation to PV anddesigned to monitor the safety ofauthorised medicinal products and detectany change to their risk/benefit balance.

Good Pharmacovigilance Practices(GPV) modules, various guidancedocuments from the US FDA, ICHguidelines and guidance from otherregulatory bodies require that theMarketing Authorisation Holder (MAH)should have a system where all aspectscomply with requirements of the

applicable regulatory authorities, andsafety data on similar products and fromgeographies other than where theproducts are licensed, be included.

The principal directive is that a robust,global system has to be in place tocapture and manage all Adverse DrugReactions (ADRs) for all licensedproducts, in the markets where they arelicensed and wherever in the worldsimilar products are sold. In addition tothis, a global system has to carry out allof the downstream activities on the safetydata that are captured, such as periodicreporting and safety surveillance. Thereare both commercial and legal

“A global PV system has to be anintegral part of a company’sCorporate Quality System. It iscomplex by nature and requires anumber of entities to work togetherin a seamless manner”

implications of non-compliance that couldaffect current licences, pending approvalsand new submissions.

A global PV system has to be anintegral part of a company’s CorporateQuality System. It is complex by natureand requires a number of entities to worktogether in a seamless manner.

Therefore, the system has to take intoconsideration the accountabilities andresponsibilities of all these entities interms of how they relate to safety directlyor indirectly, the interdependenciesbetween them and the harmonisationand standardisation of processes thatmay be required.

MAHs may use speciality safetyconsulting and service providers who canrecommend and put in place thefollowing key elements that are essentialfor a successful global PV system:● Best-in-class processes andStandard Operating Procedures(SOPs) for 1) the collection, databasing

In addition to proof of drug effectiveness, pharmacovigilance hasbecome an important safety requirement laid down by theregulators. Dr Chitra Lele, CSO, Sciformix Corporation, discussesthe importance of establishing an effective global safetyframework to meet today’s needs

Creating proactive ‘productvigilance’ systems

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PHARMACOVIGILANCE

and reporting of all ADRs; 2) continuousand proactive monitoring of safety data,scientific evaluation of benefit-risk basedon global use, including detection andevaluation of new signals; 3) internalcommunication and escalationmechanisms for safety concerns; 4)effective communication with regulatorsof new risks, risk minimisation measures,periodic safety reports, post-approvalsafety studies; 5) updates to productinformation with new knowledge of risksand benefits; and 6) for tracking newregulations and updates to existingregulations and managing changesrequired in the system for sustainedcompliance.● A comprehensive PV QualitySystem made up of documentedprocesses, including recordsmanagement, proactive Root CauseAnalysis (RCA), audits of all entities inscope, Corrective and Preventive Actions(CAPAs), and review at regular intervalsto verify effectiveness. (GVP 1 requires awritten 2–5 year risk-based strategy planto audit all PV activities).● Adequate number of competentand trained resources across allareas of operations● Effective partnershiparrangements with distributors,business partners and vendors.These would include Safety DataExchange Agreements (SDEAs), businesspartner agreements and agreements withvendors. ● EU-specific requirements such asthe PV Systems Master File (PSMF),availability of Local Safety Officers(LSOs) as required by local regulations,Qualified Persons in PV (QPPV),including ensuring required level ofempowerment, authority, visibility andinvolvement, and finally RiskManagement Plans (RMPs) for newsubmissions.● Corporate level structure is thefinal and overarching element in the PVsystem that: 1) aligns the various in-scope entities; 2) enables compliancefrom all Business Units (BUs),Therapeutic Areas (TAs) and franchises;and 3) reinforces the bond between thecentral PV function and individualaffiliates. Effective oversight of safetyrelated activities across all entities inscope is essential to the system alongwith responsiveness to emerging trends

diverse regulation requirements, as wellas the global organisational structure andoperating model that would facilitate theessential level of oversight and control.The synthesis of a strategic plan that isbased on a sound understanding of safetyregulations and global operations willlead to an optimal framework fordeploying a successful global PV system.

In summary, globalisation of themarketplace and the impact of 21stcentury technologies on healthcaredelivery will create significant challengesand opportunities for all stakeholders inlife sciences. PV is in transition, withnew sources of medical information andmethods for its analysis being exploredthat will transform the current reactivesystem into proactive benefit-riskmanagement. Regulations across theglobe are gradually evolving towards amore proactive approach, but remain tooprocedurally focused, often inhibitinginnovation, while the technical resourcesrequired for effective benefit-riskassessment are still at an earlydevelopment stage.

For organisations to be successful intoday’s environment, it is critical thatthey ensure all safety systems and PVpractices employed are firmly tied into atruly global PV framework. Establishingsuch a framework requires a carefullythought-out strategy that takes intoconsideration the accountabilities andresponsibilities of all entities, how theyrelate to safety directly or indirectly andthe harmonisation and standardisation ofprocesses that may be required.

REFERENCES1. Kahn, S. (2013). ‘Proactive pharmacovigilance –A new model for the 21st century.’ InternationalPharmaceutical Industry, 5(3), pp. 62–662. Moe Alsumidaie, 2014. ‘Highlights from the 2014Patient Centered Clinical Trials Symposium.’ AppliedClinical Trials. Online atwww.appliedclinicaltrialsonline.com/highlights-2014-patient-centered-clinical-trials-symposium[Accessed 06/02/2015]

chitra.lele@sciformix.comwww.sciformix.com

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of new operating structures, emergingpublic data sources, such as blogging orsocial media and greater access toconsumers, payers and providers.

Establishing a carefully planned GlobalPV System StrategyEstablishing a global PV system posesmany challenges to all organisations,both small and large, though thechallenges may vary with the type of theorganisation. For a small company withonly a limited number of products, therisk of non-compliance and in-houseavailability of safety expertise may be abig challenge. For a genericsmanufacturer, the focus and diligence onproduct safety and the number ofdistributors and business partners couldbe the major challenges. For largecompanies that have a diverse productmix and vast global reach, ensuringstandard global SOPs related to safetyand risk management across productcategories and regions, and effectiveoversight of all parties may be the mostimportant challenges.

A carefully planned strategy that takesinto consideration both the short-termand long-term business plan of theorganisation is fundamental to setting upan effective system. An in-depth analysisof the current state and gap analysis interms of people, process and technologymust be conducted.

Careful attention must be paid to the

“Careful attention must be paid tothe diverse regulatory requirements,as well as the global organisationalstructure and operating model thatwould facilitate the essential level ofoversight and control”

Table 1: Entities involved in a corporate quality system

Various company divisions from drug/product safety to regulatory and medical affairs, andcentralised functions from commercial, corporate, customer service, complaint intake to IT;and the entire company leadershipAll affiliate offices

The QPPV office

All distributors and business partners

Vendors (providing services to any of the company divisions and centralised functions)

Data centres

Dr Chitra Lele, CSO, Sciformix Corporation

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