1. 06/05/2015 Risk Management Plan 24. April 2008 Helge Gydesen Epidemiology Novo Nordisk A/S

2. Slide no 206/05/2015 Agenda Regulatory environment 2 What is a Risk Management Plan 3 Implications for post marketing activities 5 Who, When and How 4 Conclusions 6 Motivation: Examples of withdrawals 1

3. Slide no 306/05/2015 Rofecoxib (VIOXX) Merck & Co Introduced: 1999 Withdrawn: 2004 Indications: Osteoarthritis and Acute Pain Withdrawn due to : Heart attack and stroke Cerivastatin Bayer A. G. Introduced: Late 1990’s Withdrawn: 2001 Cholesterol lowering Withdrawn due to: Rhabdomyolysis leading to renal failure

4. Slide no 406/05/2015 Regulatory guidance Three guidelines from FDA The ICH E2E Guideline EU risk management Guideline All can be found on International Society for PharmacoEpidemiology (ISPE) homepage www.pharmacoepi.org under the left hand heading resources www.pharmacoepi.org

5. Slide no 506/05/2015 EU-RMP EU-RMP required at MAA submission: New active, biosimilar or generic with risk minimisation for reference substance New dosage form, route, indication, manufacture process for biotech product On request of authorities If Marketing Authorization Holder (MAH) identifies a safety concern Other situations for centrally authorised product. e.g. bibliographical applications, fixed combination, certain hybrid products

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13. Slide no 1306/05/2015 Risk management - Definition and purpose A Risk Management system is a set of pharmacovigilance activities and interventions designed to proactively identify, characterise and prevent or minimise risks relating to medicinal products, including risk communication and the assessment of the effectiveness of risk minimisation interventions. The purpose of the Risk Management Plan (RMP) is:  to identify the risks associated with a medicinal product  develop methods to clarify further the safety profile of a product  plan ways to minimise risk to individual patients in clinical use.

14. Slide no 1406/05/2015 Risk Management Plan Development

15. Slide no 1506/05/2015 Epidemiology in The Risk Management Framework Risk assessment / measurement estimation and evaluation of risk Risk confrontation determining acceptable level of risk Risk intervention risk control action Risk communication interactive exchange of risk information Risk management evaluation evaluating effectiveness of activities  Epidemiology – population based evidence  Public Health perspective  Epidemiology – population based evidence Safety Risk Management provides a formal framework in which epidemiological activities and public health perspective are integrated in the development and life-cycle management of therapies Managing the risks from Medical Products Use. Creating the framework for Risk Management. Report to the FDA Commissioner May 1999 – 164 pages http://www.fda.gov/oc/tfrm/riskmanagement.pdf

16. Slide no 1606/05/2015 Who is contributing International Product Safety (IPS) is the owner of the document Contributions from the pre-clinical and clinical development area BIG contribution from Epidemiology Discussions with Marketing on the Post Marketing Activities

17. Slide no 1706/05/2015 Risk management - The role of Epidemiology Author and maintain the epidemiological sections of a Risk Management Plan (RMP) as per guidelines from regulatory authorities and NN SOP on ongoing basis. Support the updating of RMP periodically. Provide epidemiological expertise in Risk management activities throughout the life cycle of NN products. Provide timely epidemiology support to project teams to design and implement epidemiological studies, to review study proposal from internal and external sources, to analyze adverse events reporting data, and to interpret and report on data analysis results to other line functions. Contribute in safety risk evaluation once a safety signal has been detected and in communication of safety information and thereby propose and implement risk minimization activities. Provide epidemiology support in preparation of Periodic/ Annual Safety Reports (PSUR/ASR) if required by the regualatory authorities.

18. Slide no 1806/05/2015 Risk management - Future Global Epidemiology will be involved in all Risk Management Activities in NN Input to design and protocol Timely epidemiology support to project teams to design and implement epidemiological studies to evaluate safety issues. Setup an organised collaborative team with IPS as an Integrated Risk Management Expert Group (IRMEG) within NN. Responsible for study design, analysis, interpretation and publication of studies related to safety issues of NN products. Conduct epidemiological studies to support risk management activities Review and Meta analysis of LTR to address safety issues Make sure resources are allocated when new post approval safety studies (PASS) are initiated and required Resources in budget to conduct or for outsourcing for epidemiological studies to gather knowledge about target indications.

19. Slide no 1906/05/2015 When to start the work with the RMP? Approval Pharmacovigilance Product Life Cycle Exposure (Potential Denominator) FIM Phase I Phase II Phase III Phase IV Drug Discovery/PreclinicalClinical DevelopmentPost Marketing 

20. Slide no 2006/05/2015 RMP: A change in approach Proactive in stead of reactive Not a defensive approach, in stead: demonstrate safety Focus on different type of epidemiological studies in stead of normal pharmacovigilance Pharmaco epidemiology in stead of standard pharmacovigilance

21. Slide no 2106/05/2015 Risk management Plans – examples of identified risks: EXUBERA Smoking-induced alterations in Pharmacokinetics (drug interaction studies/passive smoking) Changes in Pulmonary Function (Long term PASS, Special Asthma study, Paediatric studies) Increased Insulin Antibody Levels (Long term PASS, Paediatric studies) Rare Pulmonary Events (Epi Lung Cancer study) 11 studies running until 2019, covering more than 75000 patients

22. Slide no 2206/05/2015 CONCLUSIONS Risk Management is a new area under development Clinical Epidemiology is a crucial area of information Will create discussions of the right level of post marketing activities: Observational studies, utilization of databases (internal/external) BUT ABOVE ALL: Epidemiological/statistical expertise will be needed in the future development of this area

23. Slide no 2306/05/2015 Any questions or comments?

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