Pharmacoepidemiology: Past, present and future

1. Pharmacoepidemiology: Past, present and future Kathleen Bennett, PhD Department of Pharmacology & Therapeutics, Trinity College Dublin bennettk@tcd.ie 3rd Sept 2009

2. ‘A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals’ William Osler,1891

3. What is pharmacoepidemiology? • Defined as the study of the utilization and effects of drugs in large numbers of people. • Pharmacoepidemiology borrows from both pharmacology and epidemiology, a bridge science spanning both pharmacology and epidemiology. • Pharmacoepidemiology can also be defined as the application of epidemiological methods to pharmacological issues.

4. Pharmacoepidemiology in practice • To quantify adverse events with medicines in the population • Patterns of drug utilisation, including adherence • Hypothesis generating

5. Pharmacoepidemiology – Observational studies • Without treatment allocation by chance, bias due to different baseline risks for disease in users and non-users of drugs cannot be ruled out completely - confounding by indication. • The potential for confounding is probably larger in observational studies assessing medications than in studies assessing lifestyle factors.

6. Pharmacovigilance • There are also some areas that are altogether unique to pharmacoepidemiology, e.g. pharmacovigilance. • Pharmacovigilance is a type of continual monitoring for unwanted effects and other safety-related aspects of drugs that are already on the market. • Pharmacovigilance refers almost exclusively to the spontaneous reporting systems which allow health care professionals and others to report adverse drug reactions to a central agency. • It relies heavily on reporting of safety events by health professionals.

7. Pharmacoeconomics • Pharmacoeconomics is that branch of health economics that focuses upon the costs and benefits of drug therapy. • Definition: The comparative analysis of alternative courses of action in terms of BOTH their costs and consequences.

8. Pharmacoeconomic Evaluation

9. Pharmaceutical Expenditure Under the Community Drug Schemes: 1991-2007 Source: Primary Care Reimbursement Service (PCRS) *Pharmaceutical expenditure includes payment to pharmacies for the cost of medicines, dispensing fees and payment to wholesalers under the High Tech Drug Scheme

10. Pharmacoeconomics & pharmacoepidemiology • Inter-related disciplines • Used by • Industry for marketing/price setting • HSE - reimbursement decisions • Public health - e.g. vaccination programmes • Can help identify whether particular sub-groups of patients will benefit most from a new drug and in which it is most cost-effective.

12. Historical background • US law, Pure Food and Drug Act, passed in 1906, followed by FD and cosmetic Act in 1938. • Preclinical toxicity testing and clinical data about drug safety required before drug marketed. • ‘Thalidomide disaster’ in 1961 led to establishment of committee of safety of medicines in 1968 in UK and changes elsewhere. • ‘Pharmacoepidemiology’ first appeared in medical literature (BMJ) in 1984.

14. Drug Toxicity • Thalidomide • Chloramphenicol and Grey Baby Syndrome • Gynaecological cancer in offspring of women receiving Diethyl Stilboestrol • Oculomucocutaneous syndrome with practolol • Liver disease from benoxaprofen • Valvular heart disease from Dexfenfluramine • Cardiac arrhythmias with terfenadine • Multiple drug interactions with mibefradil

15. What papers have shaped Pharmacoepidemiology?

19. Controversies

20. Pharmacoepidemiology in Ireland • Since 1968 Ireland has participated in the WHO International Drug Monitoring System and pharmacoepidemiology was mainly in the area of Adverse drug reaction (ADR) reporting. • The Yellow Card Scheme for ADR reporting has operated through the Irish Medicines Board since 1996 and the National Drugs Advisory Board (NDAB) before that. However, ADR reporting rates are low; <10% of all serious and 2-4% of non-serious ADRs reported.

21. The Pill Scare • In October 1995, the Committee of Safety of Medicines (CSM) issued a warning on the increased risk of thromboembolism associated with the third-generation oral contraceptive steroids. • This ‘Pill Scare’ led to some users stopping the oral contraceptive steroids mid-cycle and a rise subsequently in abortions and pregnancies was noted. • The Irish Medicines Board did not advise discontinuation of third -generation oral contraceptives , but advised further study and analysis of the previous studies to evaluate the impact of biases and confounders. • No regulatory action was taken.

25. Examples of pharmacoepidemiology databases • GPRD – GP research database in UK • MEMO – Scottish record linkage data • Saskatchewan Health Services - Canada • Kaiser Permanente – US • Odense database- Denmark • HSE-PCRS – prescribing data only Ireland

26. HSE-Primary Care Reimbursement Services (PCRS) • The PCRS is part of the HSE, and is responsible for making payments to healthcare professionals, e.g. doctors, dentists and pharmacists, for the free or reduced costs services they provide to the public. • It supports the delivery of primary healthcare by providing reimbursement services in their own community. • There are many schemes under the HSE-PCRS but for drug prescribing the three main ones are: GMS medical card scheme, Drug payment (DPS) and Long Term Illness (LTI) schemes.

27. HSE-PCRS pharmacy claims database • The number of GMS eligible persons by December 2007 was 1.28 million people ( ~ 30% of population). • Not fully representative - socially disadvantaged persons, children and the elderly are over-represented. • Accounts for approximately 70% of all prescribed medicines. • Limitations – no diagnosis or outcome data

28. Examples • Quality prescribing indicators • Elderly population exposed to potentially inappropriate medications; generic prescribing • European drug utilisation studies • Statins, PPIs, SSRIs, ACE/ARBs • Various disease areas including adherence to tamoxifen in breast cancer

29. Prevalence of potentially inappropriate medication use in those 65+ years The 1-year risk of receiving at least one PIM using the combination of Beers and McLeod criteria was 20.6% using the national prescribing data (2004)

30. % of prescriptions dispensed generically on the GMS in 2008

31. International Comparisons of Drug Utilisation Statistics Differences may reflect demographics and reimbursement issues

32. BMJ 2005

33. Aliment Pharm Therap 2009

34. On September 30, 2004, Merck and Co. voluntary withdrew rofecoxib (Vioxx) due to increased risk of CV events B J Clin Pharm 2007

35. Eur J Clin Pharm 2006

36. Hormone treatment in cancer • Hormone therapy is designed to alter hormone production in the body so that cancer cells stop growing or are killed completely. • Breast cancer hormone therapies often focus on reducing estrogen levels (a common drug for this is tamoxifen) and prostate cancer hormone therapies often focus on reducing testosterone levels. • In addition, some leukemia and lymphoma cases can be treated with the hormone cortisone.

37. Early Discontinuation of Tamoxifen T I Barron1 R M Connolly2 K Bennett1 M J Kennedy2 J Feely1 1Dept Pharmacology & Therapeutics, Trinity College Dublin. 2Academic Unit of Clinical & Molecular Oncology Trinity College Dublin & St. James’s Hospital. Email: barront@tcd.ie

38. Background • Adherence & Persistence • Definitions • Adherence (Synonym: Compliance) is the extent to which a patient takes medication in accordance with the prescribed interval and dose.1 • Persistence is the accumulation of time from initiation to discontinuation of therapy.1 • Significance? • Substantial worsening of disease and mortality. • Increased healthcare costs. • Healthy drug user effect. 1 ISPOR Medication Compliance & Persistence Special Interest Group. http://www.ispor.org/sigs/MCP_accomplishments.asp#definition

39. Background • Tamoxifen • 5 years of treatment reduces the relative breast cancer recurrence risk by 46% and the relative risk of death by 26%.1 • Comparisons of treatment durations indicate that women receiving less than 5 years of treatment have significantly higher breast cancer recurrence rates and mortality.1,2 1 Lancet 1998; 351: 1451-67; 2 Lancet 2005; 365: 1687-717

40. Aims • Aims • To evaluate persistence with tamoxifen therapy, in women aged 35 years or older, using prescription refill data from a national prescribing database. • Prescription refill data provide accurate and objective estimates of medication use in large populations over long periods of time. • This is the first study to evaluate tamoxifen persistence using this method.

41. Methods • HSE-PCRS 2000-2005 • All women over the age of 35 years , commenced on tamoxifen as initial hormonal therapy between January 2001 and January 2004. • Measurement of tamoxifen persistence • A period of 180 consecutive days of no tamoxifen supply. • Patients with no prescription for any item in the 12 months following non-persistence were reclassified as lost to follow up. • Patients starting alternative hormonal therapy before 180 days of no tamoxifen were reclassified as treatment switchers.

42. Methods • Potential determinants of non-persistence • Age at initiation of tamoxifen. • Co-morbidities. • Number of pharmacological agents received. • Use of antidepressant, antipsychotic, or anxiolytic/hypnotic agents. • Treatment for cognitive or functional impairment (Parkinson’s disease or dementia) • Cox proportional hazards model. • Stepwise selection with criteria for entry of p <0.1.

43. Results Study Cohort (n=2816)

44. Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004) Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004) Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004) 470 (16.7%) 470 (16.7%) 470 (16.7%) Lost to follow up Lost to follow up Lost to follow up 716 (25.4%) 716 (25.4%) 716 (25.4%) Stop tamoxifen & switch hormonal therapy before 180 days Stop tamoxifen & switch hormonal therapy before 180 days Stop tamoxifen & switch hormonal therapy before 180 days 34 (1.2%) 34 (1.2%) 34 (1.2%) Stop tamoxifen & switch hormonal therapy after 180 days Stop tamoxifen & switch hormonal therapy after 180 days Stop tamoxifen & switch hormonal therapy after 180 days Non-persistent Population 746 (26.5%) Non-persistent Population 746 (26.5%) Non-persistent Population 746 (26.5%) 143 (5.1%) 143 (5.1%) 143 (5.1%) Stop tamoxifen & restart tamoxifen after180 days Stop tamoxifen & restart tamoxifen after180 days Stop tamoxifen & restart tamoxifen after180 days 569 (20.2%) 569 (20.2%) 569 (20.2%) Stop tamoxifen & no subsequent hormonal therapy Stop tamoxifen & no subsequent hormonal therapy Stop tamoxifen & no subsequent hormonal therapy Persist with tamoxifen Persist with tamoxifen Persist with tamoxifen 884 (31.4%) 884 (31.4%) 884 (31.4%) Results -Tamoxifen non-persistence Fig 1: Outcomes for patients starting tamoxifen on the HSE-PCRS database (January 01 – January 04)

45. Results - Determinants of non-persistence

46. Discussion • Non-persistence with tamoxifen in clinical practice is higher than previously reported. • 35.2% of women discontinue tamoxifen by 3.5 years. • 22.1% discontinue tamoxifen by 1 year. • The determinants • Extremes of age, treatment with an antidepressant with non-persistence • Increasing numbers of prescribed medications associated with better tamoxifen persistence. • Conclusion • Persistence with tamoxifen cannot be assumed • Raises concerns about persistence with other oral hormonal therapies/anti-neoplastics in general

47. Pharmacoepidemiology – Methodological developments • Studies based on large health care utilization databases tend to use data collected for reasons unrelated to the research hypothesis thus lacking data on all important confounders. • To address unmeasured confounding and bias in database studies, several approaches have been proposed.

48. Some examples of methodological developments • STROBE and ISPE good practice guideline for conduct of PE studies • Propensity scores • Optimal selection of controls • Time dependency in cohort studies • Immortal time bias • Validation Studies • Case-crossover design