1 pharmacovigilance obligations - Sciformix...pharmacovigilance obligations quality standards and...

3
Among the multitude of challenges that face the global life science industry, the reduction in the number of new drug approvals has put tremendous pressure on innovator pharmaceutical companies. Despite the FDA announcing 39 new drug approvals in 2012 – a 16 year high 1 the past decade has been characterised by a severe innovation ‘drought’ that has seen the number of new medicines fall to little more than half previous levels. In addition to this, competition from generic manufacturers has exploded due to an increase in patent expiries. It is estimated that generic competition eroded US$67bn from top drug companies’ annual sales in the US between 2007–2012, with more than three dozen drugs losing patent protection during this period. 2 Big Pharma/generics partnerships Managing the complexity of drug development, approval and post-approval product maintenance processes, hiring specialists and the ability to manage fluctuations in resource demands are key issues that biopharma companies face. Traditional operating models are being pushed to breaking point because of cost pressures, emerging generic competition, governmental and political demands and the weight of supporting global distribution channels. In response, biopharma is exploring new growth opportunities in emerging markets, strengthening R&D by collaborating with industry and academic partners, moving towards a mixed portfolio of innovative and generic products and focusing on operational efficiency. As a result, even marketing of pharma products is being driven by partnerships between two or more companies. There has been a substantial increase in the number of licensing and supply partnerships between generic manufacturers based in countries in the emerging markets and large or mid-sized global pharma companies. For example, Mylan recently entered into a strategic collaboration with Biocon, acquiring the rights to develop and market generic versions of Biocon’s three insulin analog products: Glargine (the generic version of Sanofi’s Lantus), Lispro (the generic of Eli Lilly’s Humalog) and Aspart (the generic of Novo Nordisk’s NovoLog). Similarly, generic drug maker Cipla is currently partnering South Africa’s Aspen Pharmacare to cater to the Australian market, whereby Cipla will develop the generic products to be launched by Aspen in Australia. These mutually beneficial partnerships allow Big Pharma companies to grow, attain a mixed portfolio of innovator A successful path to fulfilling pharmacovigilance obligations quality standards and adverse event reporting. To minimise this risk, partners and contractors should be chosen with care, performing adequate due diligence before entering the contract. The impact of regulatory requirements on the structure of the agreement should be addressed early on. Having a contract to deal comprehensively with the issues of PV is paramount, along with actively managing the relationship in terms of auditing and implementing monitoring processes and issue management. A contract affords an opportunity to manage the risk, and a Safety Data Exchange Agreement (SDEA) serves this purpose. These agreements are written contracts developed between the partner companies to define the responsibilities of each party with reference to each PV activity. A well-drafted agreement ensures regulatory compliance and prevents the duplication of PV activities drugs and generics, and expand into emerging markets while providing generic manufacturers with marketing capabilities. However, the increase in regulatory vigilance and government pressures mean that the responsibility for safety reporting has to be clearly outlined and closely monitored in such relationships. The FDA and EMEA (which placed medical safety top of the EU legislative agenda when it released the new pharmacovigilance (PV) legislation in July 2012), hold the big innovator pharma companies legally responsible for PV within such licensing/outsourcing agreements. Although PV may not be the driver of an agreement, when it comes to safety reporting the Marketing Authorisation Holder (MAH)/Application Holder is ultimately responsible for maintaining compliance with the application itself, and applicable laws regarding GMP, As the number of innovator pharmaceutical and generic manufacturer partnerships grow, the lines of responsibility for meeting pharmacovigilance requirements can get blurred. Chitra Lele, of Sciformix Corporation, looks at routes to managing the issue PHARMACOVIGILANCE 24 manufacturing chemist July/August 2013 Figure 1

Transcript of 1 pharmacovigilance obligations - Sciformix...pharmacovigilance obligations quality standards and...

Page 1: 1 pharmacovigilance obligations - Sciformix...pharmacovigilance obligations quality standards and adverse event reporting. To minimise this risk, partners and contractors should be

Among the multitude of challengesthat face the global life science industry,the reduction in the number of new drugapprovals has put tremendous pressureon innovator pharmaceutical companies.Despite the FDA announcing 39 newdrug approvals in 2012 – a 16 year high1 –the past decade has been characterised bya severe innovation ‘drought’ that hasseen the number of new medicines fall tolittle more than half previous levels.

In addition to this, competition fromgeneric manufacturers has exploded dueto an increase in patent expiries. It isestimated that generic competitioneroded US$67bn from top drugcompanies’ annual sales in the USbetween 2007–2012, with more thanthree dozen drugs losing patentprotection during this period.2

Big Pharma/generics partnershipsManaging the complexity of drugdevelopment, approval and post-approvalproduct maintenance processes, hiringspecialists and the ability to managefluctuations in resource demands are keyissues that biopharma companies face.Traditional operating models are beingpushed to breaking point because of costpressures, emerging generic competition,governmental and political demands andthe weight of supporting globaldistribution channels. In response,biopharma is exploring new growthopportunities in emerging markets,strengthening R&D by collaborating withindustry and academic partners, movingtowards a mixed portfolio of innovativeand generic products and focusing onoperational efficiency.

As a result, even marketing of pharmaproducts is being driven by partnershipsbetween two or more companies. Therehas been a substantial increase in thenumber of licensing and supplypartnerships between genericmanufacturers based in countries in theemerging markets and large or mid-sizedglobal pharma companies. For example,Mylan recently entered into a strategiccollaboration with Biocon, acquiring therights to develop and market genericversions of Biocon’s three insulin analogproducts: Glargine (the generic version ofSanofi’s Lantus), Lispro (the generic ofEli Lilly’s Humalog) and Aspart (thegeneric of Novo Nordisk’s NovoLog).Similarly, generic drug maker Cipla iscurrently partnering South Africa’sAspen Pharmacare to cater to theAustralian market, whereby Cipla willdevelop the generic products to belaunched by Aspen in Australia.

These mutually beneficial partnershipsallow Big Pharma companies to grow,attain a mixed portfolio of innovator

A successful pathto fulfillingpharmacovigilanceobligations

quality standards and adverse eventreporting.

To minimise this risk, partners andcontractors should be chosen with care,performing adequate due diligence beforeentering the contract. The impact ofregulatory requirements on the structureof the agreement should be addressedearly on. Having a contract to dealcomprehensively with the issues of PV isparamount, along with actively managingthe relationship in terms of auditing andimplementing monitoring processes andissue management.

A contract affords an opportunity tomanage the risk, and a Safety DataExchange Agreement (SDEA) serves thispurpose. These agreements are writtencontracts developed between the partnercompanies to define the responsibilitiesof each party with reference to each PVactivity. A well-drafted agreementensures regulatory compliance andprevents the duplication of PV activities

drugs and generics, and expand intoemerging markets while providinggeneric manufacturers with marketingcapabilities. However, the increase inregulatory vigilance and governmentpressures mean that the responsibilityfor safety reporting has to be clearlyoutlined and closely monitored in suchrelationships.

The FDA and EMEA (which placedmedical safety top of the EU legislativeagenda when it released the newpharmacovigilance (PV) legislation inJuly 2012), hold the big innovatorpharma companies legally responsible forPV within such licensing/outsourcingagreements.

Although PV may not be the driver ofan agreement, when it comes to safetyreporting the Marketing AuthorisationHolder (MAH)/Application Holder isultimately responsible for maintainingcompliance with the application itself,and applicable laws regarding GMP,

As the number of innovator pharmaceutical and genericmanufacturer partnerships grow, the lines of responsibility formeeting pharmacovigilance requirements can get blurred. Chitra Lele, of Sciformix Corporation, looks at routes tomanaging the issue

PHARMACOVIGILANCE

24 manufacturing chemist July/August 2013

Figure 1

024-026 mc0713sciformix v2:Layout 1 18/7/13 12:24 Page 24

Page 2: 1 pharmacovigilance obligations - Sciformix...pharmacovigilance obligations quality standards and adverse event reporting. To minimise this risk, partners and contractors should be

PHARMACOVIGILANCE

by various partners. They are oftenreviewed during regulatory inspections toensure there are written procedures forsafety data exchange between thepartners, and the communicationtimelines are adequate to meetregulatory compliance.

Managing pharmacovigilanceThe challenges associated withmaintaining compliance with safetyreporting are rooted in the framework ofthe agreements – liability is placed on thebiopharmaceutical company, and theresponsibility for PV placed in the handsof the generic manufacturer. In many ofthese agreements, the genericmanufacturer is based in an emergingmarket and often does not have theunderstanding or sufficient knowledge ofthe regulatory and legal obligations inhighly regulated markets. These areasare relatively new to them, andmanufacturing partners are often naïveabout PV compliance requirements, andthus have limited access to expertise andto resources such as safety databases.

This can lead to compliance difficultieswith PV agreements. Problems can arisewhen documents are written byindividuals who do not fully understandPV. The documents may be ambiguous orcan produce timelines that are toostringent for one or more parties. Thismay result in a lack of support fromstakeholders within the genericmanufacturer and inability to makedecisions for activities such as labellingdocuments, safety committee leadership,aggregate report writing and regulatoryaffairs.

Further problems may result fromparties being unable to provide reasoningfor specific requirements. This mayresult in frequent changes in theprocedures and if the agreement has a lotof operational level detail and is writtenlike an SOP, frequent updates to theagreement will be required.

Generic manufacturers, specificallythose based in emerging markets, aretypically not adequately set up to copewith the intense regulatoryrequirements from the start.Consultancy and education areessential for mitigating suchchallenges, and outsourcing PVto a neutral third party offersgreater opportunity for itssuccessful management. Pharmacompanies were traditionallyreluctant to partner with a third-party for PV due to concerns aroundsharing safety data and availability of therequired level of drug safety and medicalexpertise. However, they are becomingmore comfortable with outsourcing to

help fulfil PV obligations as many serviceproviders have qualified and experiencedteams.

There are three strategic imperativesto consider when adopting a model forsuccessful PV outsourcing:● Capability – Access to PV andregulatory knowledge to ensurecompliance.● Capacity – Access to scalable andresilient sources of talent andinfrastructure.● Cost – Ability to establish global PVcentres in a low cost destination.

With regard to the above imperatives,various sourcing models may beconsidered. At one extreme is the captivemodel and at the other is the fullyoutsourced model. In the captive model,the MAH company will set up global PVoperations in-house. Though this wouldprovide more control to the MAH, it is ahigh risk and high cost option given thelack of infrastructure, expertise andreadiness on the part of the company atthe outset. The fully outsourced model isattractive if adequate controls aredefined and implemented, theoutsourcing partner is competent and isalso sufficiently flexible to accommodaterequirements arising from futurepartnerships of the MAH.

Other intermediate approaches may beconsidered in place of the fullyoutsourced model if the manufacturerwants to retain direct control overspecific aspects of the global PVoperations or is mandated by the SDEAto do so. The Build-Operate-Transfermodel (BOT) is a relatively low risk andlow cost outsourcing model, whereby thethird party takes full responsibility forregulatory compliance and safetyreporting for a pre-determined period of

time before handing over responsibilityto the generic manufacturer who isgeared up by then to take it on.

This model can be a challenge for thethird party provider unless the genericmanufacturer has a few key seniormanagers who understand the criticalityof the safety obligations and can facilitateand support decisions to enable theprovider to act towards attainingcompliance. There is also a risk that thecompany may not be ready to bringeverything in-house by the agreed time.

Hence a hybrid model may be anattractive option. The manufacturer canidentify elements that could be managedby third party providers (case processing,aggregate reporting, literaturesurveillance). For the elements that areidentified to be retained in-house, themanufacturer can get the third partyprovider to consult and help set it up in acaptive model, or these elements could gothrough the BOT model and betransferred in-house after a definedperiod of time. Such a modelencapsulates the shared approach withcontinued long-term consultancy. As theresponsibility is shared between thegeneric manufacturer and the third partyand is not completely handed back, themodel de-risks compliance with long-term regulatory obligations.

The choice of model also dependsheavily on the scale of the partnership(number of products and countries/regions that will determine the volume ofwork) and projected increase in thecomplexity of the portfolio.

A multi-partner ecosystem is becomingmore common and adds a differentdimension of complexity. This additionalcomplexity requires high levels ofexpertise, both on domain and onprocess. For example, cases received fromone partner need to be sent toanother partner. Suchinvolvement of multipleparties and multiplehand-offs may ▼

July/August 2013 manufacturing chemist 25

024-026 mc0713sciformix v2:Layout 1 18/7/13 12:24 Page 25

Page 3: 1 pharmacovigilance obligations - Sciformix...pharmacovigilance obligations quality standards and adverse event reporting. To minimise this risk, partners and contractors should be

Figure 2: Companiesseeking third partysourcing vendors mayconsider specialisedservice providers withproven support andexpertise. This modeldepicts the capabilitiesthat Scientific ProcessOrganisation (SPO) suchas Sciformix can provide

result in insufficient turnaround time forcases or even worse,compliance/reporting risk.

Ownership of the global safetydatabase has to be determined upfrontand interoperability of different safetydatabases ensured. There is also a needto drive agreement on document formatfor receipt (source documents, e2b,MedWatch, CIOMS, etc.). Working with athird party provider that specialises in allof these elements may prove to be thebest solution in such scenarios.

Defining the roadmap: a case study A hybrid-BOT model for PV outsourcinghas recently been implemented in apartnership between a well-known globalpharma company and an Indian genericmanufacturer. The model embodies aroadmap that other similar partnershipsmay well find useful, specificallyhighlighting the questions and processesthat must be actioned.

Firstly, the strategic objectives of themodel are identified, which shouldinclude access to capability, efficiency andleadership. Through the employment of acurrent state/situational analysis,together with a thorough understandingof organisational limitations, it is thenpossible to establish the scope involvedand what needs and issues requireimmediate attention. With the scope inplace, an efficient operating model can bedefined by asking questions about theprocess, technology and organisationalchanges that are required, and how plansfor current initiatives will change onimplementation of an operating model.

It is essential to employ a changemanagement process to meet the setobjectives. This may involve establishinga completely new working environmentor amending current practices, and mustallow for the measurement andmanagement of success throughquantifiable metrics around regulatorycompliance and operational efficiency.Such issues can be raised through the useof a risk/benefit analysis, which is animportant process in identifying the levelof investment required, what risks mustbe managed, and how the probability ofrealising the objectives can be increased.

This initial planning process shouldtake approximately 4–9 months andshould be undertaken beforeimplementing the strategy. It isimportant to ask questions about whichareas should be implementedimmediately, which pilot programmesshould be instigated to ensure the successof the implementation strategy, and if theevaluation process is viable andsustainable. Questions should also beasked about which business units or

geographies require involvement, andwhether implementation should occur inphases over a given timeframe.

In terms of execution, metrics, servicelevel agreements (SLAs) andmeasurement are vital, but it is alsoimperative to derive a strategy to scalethe model across different geographiesand the entire organisation. Thetimeframe is obviously dependent on thescale of activity, which in the case of ourpartnership example is over a few years.

The implementation of the roadmapinvolves planning, systems andinfrastructure, recruitment and training,and process development (Figure 1). Inthis example, certain responsibilitieswere transferred to the manufacturer atthe end of the agreed period andSciformix continued to own other tasksand responsibilities, such as aggregatereporting, safety surveillance and QA.

Critical success factorsIn any partnership, successfulmanagement of PV is essential formeeting regulatory obligations.Sciformix has recognised that there are afew key factors that are critical to ensurethe effectiveness of PV operations,especially in partnerships involvingglobal pharma companies and genericmanufacturers. First and foremost is thatthere must be a single, global processowner and it should be clear that theultimate responsibility for fulfilment ofPV obligations and its integrity resideswith the MAH. A high level of

management commitment, specifically inensuring that all departments are alignedon the vision and goals, is critical.

Management cannot be outsourced.SOPs have to be global and there has tobe a centralised team for operations andoversight. This will help ensureconsistency in processes and qualitycriteria across regions. Key metrics suchas compliance and workload should bemeasured and monitored. Theperformance management system andworkflow management system should betransparent and visible to all.

In summary, setting up global PVoperations for manufacturing andmarketing partnerships is a challengethat calls for special considerations.Though some considerations are similarto setting up PV operations for anypharma company, there are certaincomplexities and challenges that need tobe carefully addressed.

REFERENCES1. http://www.reuters.com/article/2012/12/31/us-pharmaceuticals-fda-approvals-idUSBRE8BU0EK20121231 Accessed 20/05/132. DeRuiter, J. and Holston, P. L. (2012). US Pharm37 (6) (Generic suppl): pp.12-20.

CONTACTSChitra Lele PhD, Chief Scientific Officer,Sciformix Corporation1500 West Park Drive, Suite 250,Westborough, MA 01581, USAT +1 877 576 [email protected] www.sciformix.com

PHARMACOVIGILANCE

26 manufacturing chemist July/August 2013

“Genericmanufacturers,specifically thosebased inemergingmarkets, aretypically notadequately setup to cope withthe intenseregulatoryrequirementsfrom the start”

024-026 mc0713sciformix v2:Layout 1 18/7/13 12:24 Page 26