1. Princeton, June 2004 © Risk Management Resources 1 The Risk Management Initiatives and Drug Development Felix M Arellano, MD, Dip Pharm Med, FISPE

2. 2Princeton, June 2004© Risk Management Resources Definitions. Pharmacovigilance Plan (PVP) All products launched with PVP Data from pre-clinical development Data from pre-clinical development Data from clinical development Data from clinical development Class or “family” safety “issues” Class or “family” safety “issues” Data from population intended to receive the agent Data from population intended to receive the agent Steps needed to gain further knowledge Steps needed to gain further knowledge PVP (ICH) = PV Specification + Action Plan

3. 3Princeton, June 2004© Risk Management Resources Risk Minimization Action Plan (formerly Risk Management Plan) RMP. Similar to PVP + Risk assessment/measurement Risk assessment/measurement Risk confrontation Risk confrontation Risk intervention (minimization or tools) Risk intervention (minimization or tools) Risk management evaluation Risk management evaluation Risk communication Risk communication RM (FDA) = Risk assessment + risk minimization

4. 4Princeton, June 2004© Risk Management Resources Risk Management

5. 5Princeton, June 2004© Risk Management Resources Where we are FDA PDUFA III. Pre NDA meeting packages should include safety information and proposal for Risk Management Plans (RMP) Pre NDA meeting packages should include safety information and proposal for Risk Management Plans (RMP) NDA Review. RMP must be submitted no later than one month prior to official action date NDA Review. RMP must be submitted no later than one month prior to official action date Guidance Papers. 2 nd draft released on May 5 th and is open for comments Guidance Papers. 2 nd draft released on May 5 th and is open for comments Implementation expected in 2004

6. 6Princeton, June 2004© Risk Management Resources Where we are (cont.) EMEA. EU Heads of Agencies developed a “EU Risk Management Strategy” in January 2003 Guidance on Risk Management can be obtained during “scientific advice” Guidance on Risk Management can be obtained during “scientific advice” By the time of approval all products are expected to have a RMP or a statement that no specific “safety measure” is needed By the time of approval all products are expected to have a RMP or a statement that no specific “safety measure” is needed

7. 7Princeton, June 2004© Risk Management Resources Where we are (cont.) ICH Guideline (E2E) has been adopted by FDA FDA will issue its guidelines in 2004

8. 8Princeton, June 2004© Risk Management Resources Where we are (cont.) RM concept has shifted RMP were originally designed to manage KNOWN risks (terfenadine, mebefranil, astemizole, bromfenac)

9. 9Princeton, June 2004© Risk Management Resources Where we are (cont.) RM concept now involves pre-marketing risk assessment during which, by definition, post-marketing risks are not known

10. 10Princeton, June 2004© Risk Management Resources Why is RM here? Perception vs. Reality General perception of an “increased regulatory pressure”: There are less regulatory approvals There are less regulatory approvals More drugs are withdrawn More drugs are withdrawn Agencies are more cautious in granting approvals Agencies are more cautious in granting approvals

11. 11Princeton, June 2004© Risk Management Resources Average Number of Drugs Approved per Year. FDA 1939-2000 DecadeNo. Drugs 1940s3 1950s10 1960s11 1970s17 1980s28 1990s41

12. 12Princeton, June 2004© Risk Management Resources Last 5 years of the 20 th Century (FDA) Almost a drug per week!!!

13. 13Princeton, June 2004© Risk Management Resources Number of NME/NDA Approved per Calendar Year 1990-2002 NDA Standard NME Expedited NME

14. 14Princeton, June 2004© Risk Management Resources Number of NMEs Withdrawn as a Percentage of NME Approved 1990-2002 Number Proportion

15. 15Princeton, June 2004© Risk Management Resources Proportion of Standard NDA Approved 1993-2002

16. 16Princeton, June 2004© Risk Management Resources Proportion of Standard NDA Approved 1993-2002 1998-2002 1993-1997

17. 17Princeton, June 2004© Risk Management Resources Number of Drug Safety Alerts (1996-2001) clinical alert of SAEs, black box warnings, voluntary recalls, counterfeits and market withdrawals CAGR 18% 1996 2001

18. 18Princeton, June 2004© Risk Management Resources Number of Safety – Related Label Changes (1997-2001) CAGR 21% Flat after 1997 – 1998 Skepticism over effectiveness of label changes as RM tool 1997 2001

19. 19Princeton, June 2004© Risk Management Resources Why is RM here? Perception vs. Reality General Perception of an increased regulatory pressure: There are less regulatory approvals +/- There are less regulatory approvals +/- More drugs are withdrawn + More drugs are withdrawn + Agencies are more cautious in granting approvals + Agencies are more cautious in granting approvals + Overall increase in regulatory pressure over label changes ++ Overall increase in regulatory pressure over label changes ++

20. 20Princeton, June 2004© Risk Management Resources Why do companies need RM? It is the right thing to do It is here, whether you like it or not R & D reasons: R & D reasons: Leaner Pipelines Leaner Pipelines Less “unmet medical needs” Less “unmet medical needs” Narrower indications Narrower indications Higher R & D Costs Higher R & D Costs

21. 21Princeton, June 2004© Risk Management Resources Why do companies need RM? (cont) Regulatory Reasons Agencies (and society) are becoming increasingly risk-averse Agencies (and society) are becoming increasingly risk-averse Smaller benefits; make benefit: risk analysis challenging Smaller benefits; make benefit: risk analysis challenging “Err on caution” translates in restrictions, delays, withdrawals (or all the above) = lower revenues “Err on caution” translates in restrictions, delays, withdrawals (or all the above) = lower revenues Opportunity is to translate challenge to advantage

22. 22Princeton, June 2004© Risk Management Resources What to Expect Compliance must be a given Focus on life cycle management Peri-launch and post-marketing periods are simply part of a continuum Peri-launch and post-marketing periods are simply part of a continuum Sponsors cannot be expected to predict completely the safety profile… But they will be expected to follow up on the identified ones, and… But they will be expected to follow up on the identified ones, and… Actively look for new ones Actively look for new ones

23. 23Princeton, June 2004© Risk Management Resources PVP/RMP in Development Pharmacovigilance Plans (PVP) starting in exploratory development and being followed through development

24. 24Princeton, June 2004© Risk Management Resources Risk Communication Of all the components of the RMP this is the most complex, multidisciplinary and challenging Balance between adequate, and exaggerated Communication of risk falls on underlying perceptions of the receiver

25. 25Princeton, June 2004© Risk Management Resources

26. 26Princeton, June 2004© Risk Management Resources Risk Communication

27. 27Princeton, June 2004© Risk Management Resources Issues Monumental task impossible to tackle pleasing everyone Categorization of drugs was removed from new version Risk minimization, not avoidance. Risk reduction better Endorses RM as part of life-cycle Endorsees and guides on RM in pre and post-marketing

28. 28Princeton, June 2004© Risk Management Resources Issues. Cons Lack of precision regarding when to prepare PVP and RMAP as well as “routine PV” Confusion around whether RM will narrow exposure to drugs Older drug issue not tackled Avoiding need for PVP Contradiction with ICH E2E (endorsed by FDA) Label as risk communication tool and cornerstone Exclusion of industry from certain forums

29. 29Princeton, June 2004© Risk Management Resources Issues Will companies take RM seriously without clear guidelines? Precedents are not reassuring Precedents are not reassuring Traditionally, pharmacovigilance is considered an expense, not an investment

30. 30Princeton, June 2004© Risk Management Resources Issues Distribution of burden among society members Including patients, and its “informed” consent

31. 31Princeton, June 2004© Risk Management Resources Issues (cont) Implementation of RM concept cannot be harmonized Information overload Not a panacea. E.g. toxicity in elderly due to misadministration

32. 32Princeton, June 2004© Risk Management Resources THANK YOU

33. 33Princeton, June 2004© Risk Management Resources 4 Oak Lane Califon, NJ 07830, USA +1.908.832.5550 www.riskmr.com arellano@riskmr.com www.riskmr.com