1. RMP: DEFINITIONS AND REGULATORY ASPECTS Marc Czarka, MD, FBCPM Managing Partner HM3A ( Market Autorisation and Access Associates )

2. IS IT A NEW ITCH? Nature 296, 387 - 390 (01 April 1982); doi:10.1038/296387a0 AN END TO THE SEARCH FOR NEW DRUGS? M. WEATHERALL, DIRECTOR OF ESTABLISHMENT, WELLCOME RESEARCH LABORATORIES, BECKENHAM, KENT UNTIL 1979. 73 REFERENCES…

3. IS IT A NEW ITCH? PUBLIC DEMAND FOR TOTALLY SAFE DRUGS HAS LED TO EXCESSIVE, COSTLY AND MISLEADING TOXICITY TESTING. SUCH TESTING DRAINS THE RESOURCES WHICH HAVE BEEN AVAILABLE FOR DISCOVERING MUCH NEEDED NEW DRUGS. BETTER PUBLIC UNDERSTANDING OF THE LIMITATIONS OF TOXICITY TESTING AND THE HAZARDS OF MEDICATION IS SORELY NEEDED IN ORDER TO IMPROVE THE PROSPECTS FOR DISEASES STILL NEEDING EFFECTIVE TREATMENTS.

4. WHAT IS RISK ? wikipedia.org/historical_background/ “the definition of risk”

5. RISK/BENEFIT RATIO WHEN RESULTS OF THE CLINICAL DEVELOPMENT PLAN ARE AVAILABLE, ONE HAS TO QUESTION THE BENEFIT/RISK (B/R) RATIO ADVERSE EVENTS ARE NOT INFREQUENT: –10-20% OF PATIENTS IN AN EMERGENCY UNIT, –SOME QUITE SERIOUS OR EVEN LETHAL (QUENEAU ET AL. BULL ACAD NAT MED; 2003; 187: 647) –GENERALLY ACCEPTED RULE-OF-THUMB ESTIMATE FOR PEOPLE INJURED BY HEALTHCARE IS ABOUT ONE IN TEN ANSWER TO B/R RATIO QUESTION WILL DIFFER IN FUNCTION OF –PATHOLOGY, –GENDER, –AGE, –POSSIBLY CULTURE

6. DRUG REGULATORY AGENCIES (FDA, EMEA…) HAVE A LEGAL OBLIGATION TO ENSURE A POSITIVE B/R IN ALL PATIENT (SUB) POPULATIONS EXPOSED EXPERTS EVALUATE AVAILABLE PRE-CLINICAL AND CLINICAL DATA AND EXPRESS IN THE LABEL (SPC) THE SPECIFIC CONDITIONS OF USE ONLY A CERTAIN AMOUNT OF UNPREDICTABILITY/ UNCERTAINTY IS ACCEPTABLE BEFORE MA AND IT DEPENDS MOSTLY ON THE LEVEL OF UNMET MEDICAL NEED MISSION OF REGULATORY AGENCIES

7. MOST OF US VIEW RISK AS EITHER ……ACCEPTABLE …………..OR UNACCEPTABLE IF AND WHEN WE HAVE A CHOICE!

8. A PART OF VARIABILITY CAN BE HANDLED POST-MA THROUGH A RISK MANAGEMENT PLAN (RMP), ESPECIALLY FOR POPULATIONS NOT SUFFICIENTLY STUDIED IN THE PRE-MA PHASE VARIABILITY IS A GROWING CHALLENGE TO REGULATORY AUTHORITIES SINCE THERE IS STRONG REQUEST FOR: –RAPID ACCESS TO INNOVATIVE MEDICINES (MEETING UNMET MEDICAL NEEDS) –PROTECTION FROM DRUG INJURIES –BOTH FOR THE GENERAL POPULATION AND MINORITIES (CHILDREN, ELDERLY…) MISSION OF REGULATORY AGENCIES

9. GUIDELINE ON RMP

10. 1.SITUATIONS WHEN EU-RMP IS REQUIRED 2.METHODS TO IDENTIFY RISK 3.METHODS TO CHARACTERISE RISK 4.PREVENTION OR MINIMISATION OF RISK 5.ASSESSMENT OF THE EFFECTIVENESS OF INTERVENTIONS

11. RISK CATEGORISATION IMPORTANT IDENTIFIED RISKS: SAFETY ISSUES THAT HAVE BEEN IDENTIFIED IN CLINICAL TRIALS (CTs) OR DUE TO THE DRUG CLASS IMPORTANT POTENTIAL RISKS: SAFETY ISSUES THAT HAVE NOT BEEN SEEN IN CTs BUT ARE KNOWN FOR OTHER DRUGS IN THE CLASS OR SEEN IN PRECLINICAL DATA MISSING INFORMATION: POPULATIONS NOT STUDIED (E.G. PREGNANT OR BREASTFEEDING WOMEN)

12. RMP FOR SPECIAL POPULATIONS « SAFETY SPECIFICATION »: SHOULD DISCUSS WHICH POPULATIONS HAVE ONLY BEEN STUDIED TO A LIMITED DEGREE IN THE PRE-SUBMISSION PHASE […] AND THEIR IMPLICATIONS WITH RESPECT TO PREDICTING THE SAFETY OF THE PRODUCT IN THE MARKETPLACE […]

13. RMP IN PRACTICE SO, SINCE NOVEMBER 2005, COMPANIES SUBMITTING A NEW DOSSIER FOR A MA IN THE EU HAVE TO PREPARE A RMP THE RMP OUTLINES THE DRUG’S SAFETY PROFILE AND WHAT THE COMPANY INTENDS TO DO IN TERMS OF –PHARMACOVIGILANCE (PV), –POST-MARKETING STUDIES AND –RISK MINIMISATION ACTIVITIES

14. MANAGING RISK THROUGH PV AND PASS PV AIMS TO LOOK FOR ADVERSE EVENTS (AE) RELATED TO THE DRUG POST-AUTHORISATION SAFETY STUDIES (PASS) DELIVER INFORMATION ON POTENTIAL RISKS AND MISSING INFORMATION

15. MANAGING RISK THROUGH RISK MINIMISATION RISK MINIMISATION AIMS TO MITIGATE RISKS AND, WHEREVER POSSIBLE, PREVENT ADVERSE REACTIONS AND/OR INAPPROPRIATE USE. ACTIVITIES MIGHT INCLUDE: RESTRICTED DISTRIBUTION/PRESCRIPTION/ACCESS EDUCATIONAL TOOLS / SCIENTIFIC COMMUNICATIONS

16. WHERE TO FIND THE KEY INFORMATION ON RMP? EVERYTHING YOU ALWAYS WANTED TO KNOW ABOUT A SPECIFIC RMP (BUT WERE AFRAID TO ASK) IS TO BE FOUND IN THE SUMMARY OF PRODUCT CHARACTERISTICS (SPC) THE SPC IS THE KEY SAFETY INFORMATION RESOURCE FOR ALL DRUGS, ALL RISK MINIMISATION TOOLS MUST BE BASED ON ITS CONTENT (SEE ANNEX II-B)

17. AND IN BELGIUM? LAW 25/03/1964 – Art. 6, §1 bis, 9 and 10 ROYAL DECREE 14/12/2006 – Art. 64, §2 and 190 CIRCULAR n° 532 – 17/12/2008

18. AND IN BELGIUM? WHO?

19. AND IN BELGIUM? WHAT? PROCEDURE: –WHAT TO SUBMIT –RECEIVABILITY –REVIEW BY THE MEDICINES’ COMMISSION –NOTIFICATION OF DECISION

20. AND IN BELGIUM? OWN EXPERIENCE WITH TIMELINES: –PLAN AT THE SAME TIME AS PRICING AND REIMBURSEMENT DOSSIERS –ABOUT 1-2 MONTHS OF PREPARATION, INCLUDING A PRE-SUBMISSION MEETING IF DEEMED APPROPRIATE –SUBMISSION TWO WEEKS BEFORE COMMISSION’S MEETING –IF APPROVED (EVEN WITH SMALL AMENDMENTS), NEEDED TO WAIT NEXT COMMISSION’S MEETING FOR FINAL MINUTES FOR FORMAL APPROVAL –ANOTHER 2-4 WEEKS TO GET WRITTEN APPROVAL FROM THE MINISTER’S DELEGATE (GENERAL ADMINISTRATOR) –SO, IF EVERYTHING RUNS SMOOTHLY, BETWEEN 3 AND 4 MONTHS, IF BUMPIER, UP TO 6 MONTHS –NOT A BOTTLENECK FOR MARKET ACCESS IF PLANNED AT THE SAME TIME AS PRICING AND REIMBURSEMENT DOSSIERS

21. AND IN BELGIUM? LATEST NEWS: –RMP SUBMISSION CAN TAKE PLACE AFTER CHMP POSITIVE OPINION – BEFORE MA –WHENEVER POSSIBLE, APPROVAL WILL TAKE PLACE DURING THE SAME COMMISSION MEETING AS THE REVIEW –CIRCULAR DOES NOT CONTAIN ANY TIMELINES ALTHOUGH THERE IS A COMMITMENT FROM THE AGENCY TO MAINTAIN STATISTICS AND DISCUSS THEM WITH THE INDUSTRY –HENCE, THE WHOLE PROCESS SHOULD NOT TAKE MORE THAN 3 TO 4 MONTHS

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