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22. Dr. Niels Vermeer - Utrecht University (The Netherlands)

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“EU Risk Management Plans within the Life-cycle Management of Biologicals” …

“EU Risk Management Plans within the Life-cycle Management of Biologicals”

Provides an overview of the current EU Risk Management Plan and presents results of upcoming study describing the evolution of the RMP after marketing authorization


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  • 1. EU Risk Management Plans within theLife-cycle Management of BiologicalsNiels Vermeer1,2IFPMA/AIPM Biotherapeutics WorkshopAcknowledgements to co-researchers in project:Ruben Duijnhoven1,2; Sabine Straus2; Aukje Mantel-Teeuwisse1;Stella Blackburn3; Toine Egberts1; Bert Leufkens1,2; Marieke De Bruin1,21. Utrecht University, Utrecht, The Netherlands2. Medicines Evalulation Board (MEB), Utrecht, The Netherlands3. European Medicines Agency (EMA), London, United Kingdom
  • 2. DisclosureThe department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute forPharmaceutical Sciences, has received unrestricted research funding from the NetherlandsOrganisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board(CVZ), the Royal Dutch Pharmacists Association (KNMP), the private-public funded Top InstitutePharma (www.tipharma.nl, includes co-funding from universities, government, and industry), the EUInnovative Medicines Initiative (IMI), EU 7th Framework Program (FP7), the Dutch Medicines EvaluationBoard, the Dutch Ministry of Health and industry (including GlaxoSmithKline, Pfizer, and others).
  • 3. DisclaimerThe views expressed in this article are the personal views of the author(s) and may not be understoodor quoted as being made on behalf of or reflecting the position of the European Medicines Agency orone of its committees or working parties.
  • 4. EU Risk Management Plan (EU-RMP)• Introduced to meet demand for strengthened coordination of on-goingsafety assessment and risk minimization post marketing- Limitations of safety data from trials increasingly appreciated- High profile safety withdrawals (e.g. rofecoxib)- Increasing pressure for early access to new medicines• Idea first proposed by Japanese Ministry of Health Labour & Welfare in2001, backbone by ICH E2E Pharmacovigilance PlanningICH E2E concept paper September 2002Duijnhoven e.a. PLOS Medicine 2013
  • 5. EU Risk Management Plan (EU-RMP)• Integral part of regulatory approval of biologicals (includingbiosimilars), since November 2005• Requirements described in guideline on good pharmacovigilance practice(GVP), formerly Volume 9A guideline• EU-RMP comprises three main sections:i. Safety specificationii. Pharmacovigilance planiii. Risk minimization plan
  • 6. EU-RMP, Safety specification• Synopsis of safety profile on basis of non-clinical and clinical data• Defining important safety concerns:1. Important identified risk- Adequate evidence of association (e.g. heart failure)2. Important potential risk- Basis for suspicion of association (e.g. malignancies)3. Important missing information- Information about safety which is not available (e.g. renal impairment)Results from 9 biologicals and 9 smallmolecules (Nov 2005 – May 2007)Giezen e.a. Drug Safety 2009
  • 7. EU-RMP, Pharmacovigilance plan• Structured plan to identify/ characterize safety concerns, including:- Further characterization of risk factors- How data on important missing information will be collected- Investigate whether a potential safety concern is real or not• For each safety concern, the planned PhV activities are listed:- Routine pharmacovigilance- Additional activitiesi. Post-authorization safety studiesii. Drug utilization studiesiii. Registry studiesiv. …Giezen e.a. Drug Safety 2009
  • 8. EU-RMP, Risk minimization plan• For each safety concern the need for addition risk minimisation measures isdetermined- Routine risk minimization (information in product information)- Additional risk minimization:i. Educational programsii. Controlled distribution• Example of risk minimization activitiesfor Soliris (eculizumab)
  • 9. EU-RMP foraflibercept (Eylea)European PublicAssessment ReportNovember 2012
  • 10. EU-RMP within life cycle management• Ongoing benefit/risk assessment during full life cycle of drug- Rather than point of approval being last point of major regulatory action• Hence, EU-RMP should evolve as safety profile becomes further defined- Regular updates within product’s life cycle• No insight in advancement (knowledge gain) over time, and contribution ofRMP to public health
  • 11. Study aimPrimary aim:To describe the evolution of the RMP after marketing authorization, byquantifying changes in listed safety concerns Insight into the knowledge gain of medicinal products over timeSecondary aim:To study factors associated with change, in particular with respect to theadditional pharmacovigilance actions proposed Insight into contribution of RMP to public health
  • 12. Study methods• Cohort study- Study population: 56 new medicinal products (Nov ‘05 – Dec ‘09)- Follow-up until Dec ’12• Outcomes of interest- Change in safety concern- Newly added concerns
  • 13. Study methods (2)• All baseline RMPs and subsequent RMP updates through EMA• Data extraction from RMPs (baseline/ updates)- Information on determinants (categorized)- Former and current status of safety concern collected for every RMP update
  • 14. Preliminary results• 23 biologicals initially selectedfrom community register- 17 biologicals included- 253 baseline concerns• Median follow-up:- 49 months (range: 35-75)- 8 RMP updates (4-11)23 biologicals identified overperiod: Nov ‘05 – Dec ‘0920 biologicals eligible for inclusion18 biologicals eligible for follow-upExcluded:- Vaccines (n=2)- Cell therapy (n=1)Excluded:- No RMP (n=1)- Poor quality (n=1)Followed-up until 31 Dec ‘12Excluded:- No follow-up (n=1)17 biologicals included;safety concerns at baseline:49 Identified risks99 Potential risks103 Missing information
  • 15. Preliminary results (2)• 43 out of 253 baseline safety concerns changed during follow-up:– 20 safety concerns were omitted– 19 potential risks changed to identified risk
  • 16. Preliminary results (3)Reason for omitting safety concern (determinant of change):- 9 resulted from completion of PhV activities in the RMP:• Completion of clinical trials (n=8), e.g. use in paediatric patients,interaction with vaccination (vaccination response)• Completion of active surveillance study (n=1), for safety in homeadministration– 3 resulted from completion of studies outside RMP– 4 upon reassessment / no new data on risk– 4 unknown
  • 17. Preliminary results (4)Timing of missing information being omitted (n=20)
  • 18. Preliminary results (5)• During follow-up, 59 concerns newly added for the 17 biologicals:– 21 identified risks, 23 potential risks, and 15 missing information• Reason/ data source* for newly added risk:* Unknown for 6 productsSource Frequency NotesClinical studies 20 (34%) 12/ 20 studies were proposed in RMPSpontaneous reports 10 (17%)Related to new indication 9 (15%) e.g. risk due to characteristics (co-morbidities) of new populationNo new data 6 (10%) e.g. upon EMA request, study reanalysisData from other products 3 (5%) Class effectsOther/combination 5 (9%)
  • 19. Discussion• Risk Management Plans can play a pivotal role in the life cyclemanagement of biologicals– Ongoing B/R assessment post marketing• EU regulatory framework has provided backbone– Integral part of approval of new drugs• Establishment of safety concerns and required pharmacovigilanceand risk management activities– Regular updates during life cycle once safety profile becomes furtherdefined
  • 20. Discussion• The observed development of RMPs after approval supports theirrole in a medicine’s life cycle• The vast majority of concerns from baseline remain unchanged– 20 out of 253 baseline concerns (8%) omitted during life cycle– Relative short follow-up might not allow for sufficient characterization ofconcern (median = 49 months)– Particularly difficult for regulators to decide that a safety concern mightbe omitted from the RMP• Five years post-approval, the emphasis seems to be on newlyemerged concerns, rather than on changes in baseline concerns
  • 21. Thank you for your attention