Rapid evaluations of safety signals using RWD: a case example and discussion

Transcription

1 Rapid evaluations of safety signals using RWD: a case example and discussion Maja Hellfritzsch Poulsen, MD Clinical Pharmacology and Pharmacy University of Southern Denmark Maja Hellfritzsch Poulsen 27 September 2017

2 Outline The pharmacoepidemiological research group at SDU The safety signal, the regulatory and the public reaction Our study: evaluation of the safety signal using RWD Rapid safety evaluations using RWD data: when and how? 2

3 The pharmacoepidemiological research group at University of Southern Denmark Staff 2 professors, 1 associate professor, 8 ph.d.-students, 3 datamanagers 9 physicians, 2 pharmacists, 3 other Research areas Evaluation of the safety of drugs in real-world use Specific hypotheses vs. hypothesis generation 3

4 Shortly about me Physician (graduated in 2009) Medical specialty: Clinical Pharmacology Medical sub-specialty: Thrombosis and Haemostasis Current position: PhD student Main research area: oral anticoagulants 4

5 The safety signal April spontaneous adverse drug reaction reports Drug: Warfarin Orion Events: INR-increase, bleeding, death Setting: following switching from brand-name warfarin 5

6 Automated generic substitution in Denmark: an economic tool Interchangeble drugs substitution groups Brand-name drug Parallel-imported brand-name drug Generic drugs Overall purpose Ensures low drug prices and rational use of state finances In practice Pharmacies are obligated to hand out the cheapest drug in the group 6

7 Warfarin substitution group Marevan Waran Warfarin Orion 7

8 The safety signal April spontaneous adverse drug reaction reports Drug: Warfarin Orion Events: INR-increase, bleeding, death Setting: following switching from brand-name warfarin 8

9 Regulatory considerations Potential mecanisms Suboptimal bioeqivalence? Coincidence? Extra attention on warfarin therapy? Available evidence Spontanous adverse drug reaction reports Bioequivalence study: Warfarin Orion vs. Marevan 9

10 Regulatory decision Better safe than sorry Warfarin Orion immediately excluded from the substitution group Automated generic substitution to and from Warfarin Orion repealed 10

11 The Danish Medices Agency warns against popular drugs: Your heart medication can be deadly 90,000 Danes at risk The regulator: No need to panic Head of the Danish Heart Association: This is very concerning 11

12 Shared > times Seen by > 1 mio. facebook users 12

13 (Potential) negative consequences of the regulatory decision Fear and insecurity among patients Patients stop taking warfarin Distrust to drugs in general and to the health authorities Higher health care costs Immediate: extra GP visits Long-term: Generic substitution of narrow therapeutic index drugs in general is threatened 13

14 Sale of Warfarin Orion Defined daily doses (DDD) Q Q Q Q

15 Mis-match Level of available evidence RWD-based evidence Consequences of wrong decision 15

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17 For regulators and other researchers To provide an example of the use of the Danish nationwide health registries in the evaluation of a specific safety signal For patients and treating physicians To close the case: Had there actually been a threat to safety? But also To qualify future discussions on the appropriateness of generic substitution of narrow therapeutic index drugs 17

18 Study hypothesis Switching from brand-name warfarin to Warfarin Orion increases the risk of excessive anticoagulation Overall approach Compare the risk of admission with excessive anticoagulation in periods with and without a preceding generic switch 18

19 Cohort study Danish National Prescription Registry Danish National Patient Registry Data on prescriptions Cohort identification Exposure status Use of other medication CPR Vital status Migrations LINKAGE! Data on hospital diagnoses Outcomes Indication for treatment Information on other comorbidities 19

20 Main exposure: recent switch from brandname warfarin to Warfarin Orion Exposed person-time: 60 days after switch Unexposed person-time: time of continuous use of brand-name warfarin 20

21 Exposure assesment Warfarin users n= Person-time: PY Exposed Unexposed Other 21

22 Primary outcome: Excessive anticoagulation Hospital diagnosis Increased INR OR Bleeding Important limitation: Specific INR values were not available 22

23 Risk of excessive anticoagulation following a generic switch PT in years (PY) Events Rate (/1000 PY) Adjusted HR (95%CI) Continuous brand-name Reference Switch to generic ( ) switches from brand-name to generic warfarin 23

24 Other outcomes OR (95% CI) Hospitalization with increased INR 1.2 ( ) Hospitalization with bleeding 1.0 ( ) Fatal excessive anticoagulation 1.0 ( ) 24

25 Study conclusions No increased risk of hospitalization with excessive anticoagulation following generic switching = do not support the hypothesis Minor INR fluctuations not leading to hospitalization cannot be ruled out No major safety threat 25

26 Process Start Study protocol final Data in house Analysis final Manuscript submitted May 15th June 1th June 15th July 1th September 1th Manuscript published January 1th (2016) 26

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31 Not really..changes in INR could not be ruled out. We are unlikely to allow generic substitution for warfarin and other vitamin-k-antagonists in the future. 31

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33 Considerations Do we even need to be more certain? 33

34 Degree of seriousness High 3rd dimension: Consequences of a wrong decision? Low High Degree of certainty 34 Low

35 Considerations Do we even need to be more certain? Will the study be able to provide the necessary information with acceptable certainty? 35

36 Necessary information, acceptable certainty? STUDY QUESTION! Are (enough) essential data available? Clear pre-planned thresholds for decisions 36

37 Considerations Do we even need to be more certain? Will the study be able to provide the necessary information with acceptable certainty? Can the study be done in a timely manner? (what is that?) 37

38 Within an acceptable time frame? How long can we wait for the results? Is this time frame compatible with the ressources available? Seriousness of potential harm 38 Acceptable time

39 Required ressources for rapid evaluations A tailored dataset IN HOUSE Study group Have the required pharmacoepidemiological skills Enough but not too many people (and bureaucracy) Able to allocate TIME to the project ASAP 39

40 Conclusions RWD has the potential to qualify decision making through rapid evaluation of safety signals but is underused Not all safety signals are suited Requires data, skills and TIME Next step: Dedicated task forces with ready data for specific therapeutic areas 40

41 Maja Hellfritzsch Poulsen, MD Clinical Pharmacology and Pharmacy University of Southern Denmark 41

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43 What does it take? Designing and planning the study Analysis vs 1 Data tjek and validation of datamanagement Analysis vs 2 Interpretation and evaluation 43

44 Indicates suboptimal bioequivalence INR Warfarin Orion Marevan 5 mg Dose 44