New Medicines: too early/too late?

1. New Medicines:too early/too late? Thomas Lönngren EMEA Sweden, 3 July 2009

2. The drug regulator’s walk on the tightrope Protect public health … … against negative consequences from unsafe or ineffective medicines … against negative consequences from failing to meet unmet medical need When in doubt, be negative, “we need more information” When in doubt, be positive, “it might be a patient's only hope” Worry about false-negative decision “Type-2 error” Worry about false-positive decision “Type-1 error” Are the (dis-) incentives balanced right to influence regulators’ behaviour? no penalty for being negative! What are the consequences? What are the consequences?

3. or put another way…..

5. Benefit Risk Evaluation Definition: Risk benefit evaluation • The process by which the benefits and risks of a medicine are assessed and balanced, and to ensure that the adverse consequences of a medicine do not exceed the benefits within the population treated

6. Benefit-Risk balance is key Benefits Risks

7. Type of Approval • Normal • Comprehensive data to assess risk-benefit balance • Exceptional circumstances • Comprehensive data can normally never be provided because • Indication too rare • Contrary to medical ethics • State of scientific knowledge • Conditional Approval (NEW) • Comprehensive clinical data not yetavailable but… • benefit-risk balance positive, … • “early approval”

8. Conditional Approval (New) • Scope • Orphan drugs, emergency threats, serious and life-threatening diseases • Requirements • Positive benefit-risk balance • It is likely that comprehensive data can be provided • Unmet medical needs will be fulfilled • Immediate availability outweigh risks • Authorisation • valid for 1 year (renewable) Keypoint: level of certainty reduced but benefit risk is still judged positive

9. Benefit Risk Balance • Different perspectives: • Company - public health • Regulator - public health • Doctor - individual’s health • Patient - individual’s health

10. Benefit Risk Balance • The target diseases is key to the balance: • Self limiting – common cold • Chronic progressive - diabetes • Intermittent – multiple sclerosis • Morbidity - suffering • Mortality - death

11. Benefit Risk Balance • Population being treated: • Young vs. old • Ethnic differences

12. Benefit Risk Balance • Purpose of intervention: • Prevention - vaccines • Treatment – cancer txs • Diagnosis – contrast media

13. Benefit Risk – a Continuous Process Phase III MAA Phase II Marketing Renewal Phase I Reclassification Drug discovery …. where the outcome may differ….

14. Benefit Risk – Ever Changing • New data • New alternatives • New disease

15. From one-off licensing… MA Warning, DHPC Withdrawal backlash Level of under-standing of benefit-risk PhV, other sources PhV Drug Development Phase Time →

16. ExampleEvolution of Remicade (EU): Efficacy

17. ExampleEvolution of Remicade (EU): Safety - 1

18. ExampleEvolution of Remicade (EU): Safety - 2

19. Example RAPTIVAB/R: the starting point… • Authorised in EU in September 2004 to treat adults with moderate to severe plaque psoriasis who have failed to respond or cannot take other systemic treatments (2nd line therapy). • BENEFITS – efficacy in a ‘high-need’ group of patients, i.e. those with moderate to severe disease that do not have treatment alternatives • SAFETY – most frequent side effects: flu-like symptoms – limited data available for long-term therapy CONCLUSIONS: BENEFITS outweigh RISKS (in this restricted group of patients)

20. Example RAPTIVA B/R: the post-authorisation September 2008 – January 2009 • Three cases ofprogressive multifocal leukoencephalopaty (PML) identified • PML: • Rare brain infection caused by a virus • Virus commonly found in the general population but only leads to PML if the immune system has been weakened • Usually leads to severe disability or death • Raptiva no longer only therapeutic option for these high-need patients other products had meanwhile been approved for use in moderate to severe psoriasis

21. Example RAPTIVA B/R: the post-authorisation January 2009 • BENEFITS • (Modest) efficacy in the treatment of high-need patients in a condition that is disabling and causes social an psychological problems for patients • BUT the condition is very rarely life-threatening • AND other therapies are now available • RISKS • PML cases (three confirmed, one suspected) • Other serious side effects such as infections (meningitis, sepsis, tuberculosis) • INCLUDINGsome with a fatal outcome

22. Example RAPTIVA B/R: the post-authorisation January 2009 • BENEFITS vs RISKS? How to change B/R? • Difficult to identify patients at risk of PML • Not possible to identify restricted population for whom benefits outweigh the risk of PML Further restrictions to PI unlikely to reduce risk! BENEFITS NO LONGER OUTWEIGH RISKS SUSPENSION OF MA MA subsequently withdrawn (at request of MAH) in June 2009

23. Strengthening the system • Better science • Biomarkers to personalized medicines • Examples…

24. PROTECT Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium … improving the methodology of safety monitoring

25. How to improve benefit risk assessment • Enhance methodology of Benefit-Risk assessment • Goals: • Qualitative  Quantitative • Implicit criteria  Explicit criteria • Incorporate patients’ valuations of beneficial/adverse outcomes • Actions: • To revise/structure the current benefit-risk assessment section of the CHMP assessment report • To further research the methodology of benefit risk assessment

26. Risk Management Plan Risk Management: a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those interventions Proactive: Sponsor submits “EU Risk Management Plan” at time of MAA, updated throughout the lifecycle of the product

27. Focus on adverse reaction reportingand Eudravigilance • Eudravigilance = web based data-processing network and management system for electronic exchange, management and scientific evaluation of individual case safety reports (ICSR) • Current Eudravigilance functionality: • The Industry and all EU Member States and are electronically reporting to Eudravigilance • All Member States can analyse the data to conduct safety monitoring (pharmacovigilance) • Compliance with data protection legislation (notified to the DPS in August 2008) • Pooled data – detects ADRs earlier, detects rare ADRs, compare ADRs based on how medicines used: better protect health • More than 2 million case reports and 30,000 new reports per month

28. Post-Authorisation Safety Studies • Capacity building – ENCePP • European network for centers in pharmaepidemiology and pharmacovigelance

29. Conclusions • Regulating medicines: • Difficult judgements • We have many regulatory and scientific tools to help • We are investing to strengthen • Benefit risk balance is key