1. Drug Safety Assessment using Dubai Real World Claims Database (DRWD) April 2016 Dr Sangameshwar B Mahagaonkar MBBS, MD, DNB Engagement Manager, Real World Evidence Solutions, IMS Health Middle East

2. 2 Contents IMS Health Confidential 1 3 2 5 4 7 6 Traditional Channels of Pharmacovigilance Four essential elements for Pharmacovigilance Emerging new channels for Pharmacovigilance Emerging Channels and Traditional Channels of Pharmacovigilance (PV): Complementary Value Can e-claims data be used to identify potential adverse events ? Conclusion & limitations of this research Pharmacovigilance Need for Pharmacovigilance and Safety Reporting for Drugs A Case study from Dubai Background

3. 3 Pharmacovigilance – Background Pharmacovigilance is an arm of patient care which heavily focus on adverse event reactions IMS Health Confidential 1.http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ 2.The safety of medicines in public health programmes: Pharmacovigilance an essential tool “Pharmacovigilance is the science and activity relating to the detection, assessment, understanding and prevention of adverse effects or any other possible medicine related problems” “An Adverse event is a response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function”

4. 4 Need for Pharmacovigilance and Safety Reporting for Drugs Pharmacovigilance is essential for the rational, safe and cost-effective use of medicines in all countries and consequently for public health IMS Health Confidential 1.http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ 2.Sahu et al. SpringerPlus 2014, 3:695 Improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions Detect problems related to the use of medicines and communicate the findings in a timely manner Contribute to the assessment of benefit, harm, effectiveness and risk of medicines, leading to the prevention of harm and maximization of benefit Encourage the safe, rational and more effective (including cost- effective) use of medicines Promote education and clinical training in pharmaco- vigilance and its effective communication to the public

5. 5 Traditional Channels of Pharmacovigilance Reporting of adverse drug reactions by various channels is highly important for the success or failure of any pharmacovigilance activity IMS Health Confidential 32145 Passive Surveillance Stimulated Reporting Active Surveillance Comparative Observational Studies Targeted Clinical Investigations Spontaneous Reports Case Series Product lawsuits Published literature Media reports Sentinel Sites Drug Event Monitoring Registries Cross-sectional Study (Survey) Case-control Study Cohort Study PHARMACOVIGILANCE METHODS 1.Sahu et al. SpringerPlus 2014, 3:695 2.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073107.pdf

6. 6 Four Essential Elements for Pharmacovigilance Identifiable patient and reporting physician, event and drug, are four required elements in pharmacovigilance activity IMS Health Confidential Identifiable Patient Identifiable Reporter (Physician) Adverse Event/ Reaction Suspect Drug Patients who suspect they have been affected by a reaction to a medicine are normally encouraged to inform their health professionals to enable them to report to the pharmacovigilance center Reports made by a health professional are an interpretation of information originally provided by a patient who has experienced the actual benefit or harm of a medicine taken Adverse reactions are a significant cause of morbidity and mortality and can affect adherence to treatment schedules and increase the risk of resistance and relapse of the disease On receipt of information from patients it is confirmed that that the adverse reaction occurred due to the new drugs and drugs of current issue

7. 7 Emerging New Channels for Pharmacovigilance Increasing number of patients are turned to new digital channels for sharing their experiences with drugs IMS Health Confidential 1.http://www.imi.europa.eu/webfm_send/912 2.http://www.who-umc.org/graphics/28202.pdf New strategies in pharmacovigilance activities are represented by the search of narrative description of adverse events in internet or digital media Digital media offers new opportunities for public health monitoring due to the availability of large amounts of data that is internet-based, patient- generated, unsolicited, and up-to-date

8. 8 Emerging New Channels for Pharmacovigilance (contd.) Structured web-based platforms serve as an information resource for both healthcare professionals and, especially, patients and carers IMS Health Confidential SMARTPHONES AND INTERNET Smartphones & tablets “APPLICATION” OF INTERNET Social media software based mobile applications SOCIAL MEDIA Digital media and Web 2.0 platforms such as Facebook and Twitter Specialist sites or and blogs such as Patients Like Me

9. 9 Emerging Channels and Traditional Channels of Pharmacovigilance (PV): Complementary Value The real promise of effective pharmacovigilance activity involves combination of patient-generated data on the internet with traditional pharmacovigilance data IMS Health Confidential TRADITIONAL CHANNELS Data mining of ADR in spontaneous reporting databases is the older methodology but makes it easier for physicians, patients and pharmacists to report suspected ADRs to the pharmacovigilance center Information on direct patient reports in pharmacovigilance differs in certain respects from information provided by health professionals, but has been found to be of complementary value EMERGING CHANNELS Good pharmacovigilance by emerging digital channels will identify the risk factors in the shortest possible time so that harm can be avoided or minimized Social media websites/apps are being piloted for spontaneous reporting of ADRs and provide opportunities to directly engage with and support patients Social data offers some advantages over traditional channels: Rapid, closer to real-time data and potentially richer sources than reports filtered through HCPs 1.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013443/ 2.http://www.who-umc.org/graphics/28202.pdf

10. 10 IMS Real World Claims, UAE (Dubai) – report Longitudinal databases may be used to identify and investigate adverse medication effects in cooperation with the DHA Patients Providers Payers Physician Time Period: Jan’14 – Jan’16 ** 2.9~ MM Patients (De-Identified) * 30 MM Claims & counting 70 MM Activities & counting Coverage: Dubai – Private ** Data gets added every month * Entire Dubai population to be covered by 2016 ~ Approximate 890+ Clinics 50+ Hospitals 690+ Pharmacies 80+ Optical De-identified Patient Data eClaims DHA Hub IMS Health Confidential

11. 11 Shortlist the most frequently prescribed medications Explore database for the most serious adverse events These adverse events should fulfill the 4 cardinal elements of adverse event reporting: –Adverse event –Suspected drug –Patient & –Physician Validate these findings through interviews with practicing physicians Conclude the suitability of claims database for investigating adverse drug events Hypothesis – Claims database can be used for investigating adverse drug events We tested this hypothesis through a systematic exercise IMS Health Confidential

12. 12 IMS Health Confidential Hypothesis – Claims database can be used for investigating adverse drug events We tested this hypothesis through a systematic exercise Period of data extraction 1 st January 2014 to 31 st January 2016 Key criteria: All statin & fibrate prescriptions; diagnosis of rhabdomyolysis & myositis starting after 1 week of medications Medication factors: Daily dose and duration of medication Patient factors: Age and gender wherever available

13. 13 Profile of physicians prescribing anti-cholesterol medications Anti-cholesterol medications are prescribed the most by cardiologists IMS Health Confidential Profile of physicians prescribing anti-cholesterol medications SpecialtyNumber of prescriptionsPercentage CARDIOLOGISTS173,21584.0 INTERNAL MEDICINE19,5889.5 FAMILY PHYSICIAN11,3415.5 NEPHROLOGISTS2,0491.0 Table 12. Distribution of physicians prescribing anti-cholesterol medications

14. 14 Analysis was done separately for statins monotherapy, fibrates monotherapy and combination therapy Rhabdomyolysis and myositis was evaluated in each arm IMS Health Confidential Title 2 Rhabdomyolysis = 22 Myositis = 2,238 Rhabdomyolysis = 73 Myositis = 315 Title 2 STATINS MONOTHERAPY FIBRATES MONOTHERAPY

15. 15 Majority of patients were on statins monotherapy Less than 10% of total prescriptions were statin-fibrate combination IMS Health Confidential Table 1. Distribution of the total patients on anti-cholesterol drugs during the period of 1 st January 2014 to 31 st January 2016 Anti-cholesterol treatment# of Patients Statins monotherapy 195,176 Fibrates monotherapy28,175 Statins & Fibrates combo therapy 17,158 Total patients206,193 STATIN MONORx

16. 16 Both rhabdomyolysis & myositis were reported among patients on statin monotherapy The incidence is consistent with published literature IMS Health Confidential Demographic attributesRhabdomyolysis (N = 73)Myositis (N = 2,238) Age (Mean ± SD)45.7±8.847.75±9.4 Gender Male34949 Female5275 LocationData unavailable Table 2. Age and gender distribution of patients affected by rhabdomyolysis and myositis among all patients on statins monotherapy (N =195,176) * Demographic information available only for 39 patients in rhabdomyolysis group & 1224 patients in myositis group STATIN MONORx

17. 17 Further analysis of rhabdomyolysis was done among patients on statin monotherapy Majority of patients were on atorvastatin followed by rosuvastatin IMS Health Confidential Drug-related Factors Rhabdomyolysis group (N = 73) Drug Name (n, %)Number of patientsAverage daily dose ATORVASTATIN4520 mg ROSUVASTATIN2215 mg SIMVASTATIN310 mg FLUVASTATIN180 mg PRAVASTATIN220 mg Table 3. Drug and average daily dose of statins in patients affected by rhabdomyolysis (N = 73) in the statin monotherapy group STATIN MONOTHERAPY RHABDOMYOLYSIS

18. 18 Most statin patients with rhabdomyolysis had similar duration of treatment Both dose and duration of treatment did not appear to be related to rhabdomyolysis IMS Health Confidential Drug-related Factors Rhabdomyolysis group (N = 73) Drug Name (n, %)Number of patients Average duration of treatment (in days) ATORVASTATIN45230 days ROSUVASTATIN22293 days SIMVASTATIN3300 days FLUVASTATIN164 days PRAVASTATIN2120 days Table 4. Drug and average duration of treatment with statins in patients affected by rhabdomyolysis (N = 73) in the statin monotherapy group STATIN MONOTHERAPY RHABDOMYOLYSIS

19. 19 Further analysis of patients affected with myositis was done Atorvastatin was the commonest prescription followed by rosuvastatin IMS Health Confidential Table 5. Drug and average daily dose of statins in patients affected by myositis (N = 2,238) in the statin monotherapy group Drug-related Factors Myositis group (N = 2,238) Drug Name (n, %)Number of patientsAverage daily dose ATORVASTATIN1,57615 mg ROSUVASTATIN53710 mg SIMVASTATIN8612.5 mg FLUVASTATIN2680 mg PRAVASTATIN1325 mg STATIN MONOTHERAPY MYOSITIS

20. 20 Patients affected with myositis and on statin monotherapy had similar duration of treatment Here again, medication dose and treatment duration were not related to myositis IMS Health Confidential Drug-related Factors Myositis group (N = 2,238) Drug Name (n, %)Number of patients Average duration of treatment (in days) ATORVASTATIN1,576256 days ROSUVASTATIN537267 days SIMVASTATIN86260 days FLUVASTATIN26270 days PRAVASTATIN13250 days Table 6. Drug and average duration of treatment with statins in patients affected by (N = 2,238) in the statin monotherapy group STATIN MONOTHERAPY MYOSITIS

21. 21 The incidence of adverse events was consistent with published literature IMS Health Confidential Demographic attributesRhabdomyolysis (N = 22)Myositis (N = 315) Age (Mean ± SD)44±9.346.7±8.9 Gender Male1022 Female0155 LocationData unavailable Table 7. Age and gender distribution of patients affected by rhabdomyolysis and myositis among all patients on fibrates monotherapy (N =28,175) Both rhabdomyolysis & myositis were reported among patients on fibrates monotherapy * Information available only for 10 patients in rhabdomyolysis group & 177 patients in myositis group FIBRATES MONOTHERAPY

22. 22 Most patients with rhabdomyolysis and on fibrate monotherapy were on fenofibrate taking lower dose Fenofibrate was the most frequently prescribed fibrate IMS Health Confidential Drug-related Factors Rhabdomyolysis group (N = 22) Drug Name (n, %)Number of patientsAverage daily dose FENOFIBRATE20315 mg GEMFIBROZIL2600 mg Table 8. Drug and average daily dose of fibrates in patients affected by rhabdomyolysis (N = 22) in the fibrates monotherapy group FIBRATES MONOTHERAPY RHABDOMYOLYSIS

23. 23 Patients affected with rhabdomyolysis took fenofibrate for shorter time than gemfibrozil Treatment duration for gemfibrozil is higher than fenofibrate IMS Health Confidential Drug-related Factors Rhabdomyolysis group (N = 22) Drug Name (n, %)Number of patients Average duration of treatment (in days) FENOFIBRATE20198 days GEMFIBROZIL2254 days Table 9. Drug and average duration of treatment with fibrates in patients affected by rhabdomyolysis (N = 22) in the fibrates monotherapy group FIBRATES MONOTHERAPY RHABDOMYOLYSIS

24. 24 Patients affected with myositis took lower dose of fenofibrate than gemfibrozil Treatment duration and dose were unrelated to adverse events IMS Health Confidential Drug-related Factors Myositis group (N = 315) Drug Name (n, %)Number of patientsAverage daily dose FENOFIBRATE254300 mg GEMFIBROZIL61650 mg Table 10. Drug and average daily dose of fibrates in patients affected by myositis (N = 315) in the fibrates monotherapy group FIBRATES MONOTHERAPY MYOSITIS

25. 25 Again, duration of treatment does not appear to be related to myositis IMS Health Confidential Patients affected with myositis took fenofibrate & gemfibrozil for almost the same duration Drug-related Factors Myositis group (N = 315) Drug Name (n, %)Number of patients Average duration of treatment (in days) FENOFIBRATE254256 days GEMFIBROZIL61267 days Table 11. Drug and average duration of treatment with fibrates in patients affected by myositis (N = 315) in the fibrates monotherapy group FIBRATES MONOTHERAPY MYOSITIS

26. 26 Survey among practicing physicians revealed lesser rates of serious adverse events than discovered in database Could this be a reporter bias? IMS Health Confidential Myalgia 100% Myalgia & myositis 100% Rhabdomyolysis 15% Most common adverse events of statin monotherapy Most common adverse events of fibrates monotherapy Ever seen rhabdomyolysis with statin / fibrate therapy Yes, especially simvastatin 100% Are these dose and duration dependent adverse events Avoid routine prescription 60% Are statins & fibrates safe?

27. 27 Claims database while serves a proxy to medical records is not a complete reflection of the same Corroborating lab values for adverse events could not be studied Additional demographic attributes and co-existing morbidities could not be evaluated Causality between medication and adverse event cannot be established (this was not the objective of the study)! Adverse events may be under-reported in real world practice Longitudinal e-claims database however can be used to identify medication related serious adverse event BUT Such events identified need additional investigations to establish causality Despite the limitations, this research did achieve its objective Serious adverse events can be identified using claims database but need additional corroboration IMS Health Confidential

28. Thank you