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RMP: DEFINITIONS AND REGULATORY ASPECTS
Marc Czarka, MD, FBCPM
Managing Partner HM3A
(Market Autorisation and Access Associates)
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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…
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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.
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WHAT IS RISK ?
wikipedia.org/historical_background/ “the definition of risk”wikipedia.org/historical_background/ “the definition of risk”
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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
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• 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
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MOST OF US VIEW RISK AS EITHER ……ACCEPTABLE
…………..OR UNACCEPTABLE
IF AND WHEN WE HAVE A CHOICE!
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• 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
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GUIDELINE ON RMP
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GUIDELINE ON RMP
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
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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)
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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 […]
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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
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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
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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
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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)
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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
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AND IN BELGIUM?
• WHO?
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AND IN BELGIUM?
• WHAT?
• PROCEDURE:– WHAT TO SUBMIT– RECEIVABILITY– REVIEW BY THE MEDICINES’
COMMISSION– NOTIFICATION OF DECISION
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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
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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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