Risk Management Plan

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

2. What is a Risk Management Plan Implications for post marketing activities Who, When and How Conclusions 3 5 4 6 Regulatory environment Motivation: Examples of withdrawals 2 1 Agenda

3. Rofecoxib (VIOXX) • Merck & Co • Introduced: 1999 Withdrawn: 2004 • Indications: Osteoarthritis and Acute Pain • Withdrawn due to : Heart attack and stroke Cerivastatin • Bayer A. G. • Introduced: Late 1990’s Withdrawn: 2001 • Cholesterol lowering • Withdrawn due to: Rhabdomyolysis leading to renal failure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. 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

5. 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

13. 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. Risk Management Plan Development

15. 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

16. 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.

17. 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.

18. When to start the work with the RMP? Phase IV Exposure Phase III (Potential Denominator) Phase II Phase I FIM ProductLife Cycle Approval Drug Discovery/Preclinical Clinical Development Post Marketing h h h Pharmacovigilance

19. 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

20. 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

21. 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

22. Any questions or comments?