Role of Pharmacoepidemiology in Drug Evaluation

Role of Pharmacoepidemiology in Drug Evaluation Martin Wong MD, MPH School of Public Health and Primary Care Faculty of Medicine Chinese University of Hog Kong

Outline of Content Introduction: what is pharmacoepidemiology about? Research: Use of pharmacoepidemiology datasets Contributions & Roles of pharmacoepidemiology in various areas: Data supplementation in premarketing studies: Quantitation of the incidence of drug effects Discovery of undetected drug effects Analysis of cost-effectiveness of drugs Drug utilization patterns & adherence profiles Assess effects of drug overdoses & reassure drug safety Association between medication use and outcomes Future direction of development

What is pharmacoepidemiology about? the study of the use of and the effects of drugs in large numbers of people applies the methods of epidemiology to the content area of clinical pharmacology Epidemiology: methods of inquiry Clinical pharmacology: focus of inquiry Applies the methods of epidemiology to the content area of clinical pharmacology an effective tool to capture useful data for clinicians, researchers and policy-makers

Regulatory When should one perform pharmacoepidemiology studies? Earlier approval for marketing Response to question by regulatory agency Assist application for approval for marketing elsewhere Marketing To assist market penetration by documenting the safety of the drug To increase name recognition To assist in repositioning of the drug To protect the drug from accusations about adverse effects Legal Clinical Hypothesis testing/generating

Research: Use of pharmacoepidemiology Becoming more important to reflect real life clinical practice on pharmacological effects of medications and their utilization What happened to the RCTs? Are they not robust enough?

2007 Guidelines for the management of arterial Hypertension 1). the need to select higher risk patients 2). uncomplicated, younger and lower risk patients were under-represented 3). not representing real clinical practice 4). Prolonging the observation of patients after the end of trials might capture more real-life outcomes but these can only be done in an uncontrolled manner, the problem of selection bias still exist. The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) (2007). 2007 Guidelines for the management of arterial hypertension. European Heart Journal 28:1462-536.

Contributions & Roles of pharmacoepidemiology in various areas: 1). Data supplementation in premarketing studies Better quantitation of the incidence of known adverse and beneficial effects Higher precision In patients not studied prior to marketing e.g. the elderly, children, in pregnant women As modified by other drugs and other illnesses. Relative to other drugs used for the same medication.

Contributions & Roles of pharmacoepidemiology in various areas: 2). Quantitation of the disease incidence & drug effects

Gonzalez-Perez A et al. Breast cancer incidence and the use of antihypertensive medication in women. Pharmacoepi & Drug Saf 2004;13:581-585

Contributions & Roles of pharmacoepidemiology in various areas: 3). Discovery of undetected drug effects

Current Therapeutic Research 1997;58:555-563

4). Drug utilization patterns & adherence profiles

4). Drug utilization patterns & adherence profiles Li M et al. Utilization of Lipid-lowering Medications among adults in the United States 1999-2006. Atherosclerosis 2010;208:456-460

Contributions & Roles of pharmacoepidemiology in various areas: 5). Assess effects of drug overdoses & reassure drug safety Am J Cardiol 2010;106:1594-1601

Am J Cardiol 2010;106:1594-1601

Methods Data Source Electronic computerized system, Hospital Authority included a large population of Hong Kong ~ 1.3 million Robustness of database evaluated High completeness of demographic data (100%) & prescription details (99.98%)* *Wong MCS, Jiang Y, Tang JL, Lam A, Fung H, Mercer SW, Griffiths S. Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data. BMC Health Services Research 2008;8:138

K90 Stroke R96 Asthma K86 Uncomplicated hypertension Construction of a clinical research database ICPC: International Classification of Primary Care Drug prescription Clinical & epidemiological data Laboratory results T90 Diabetes Y85 Benign Prostatic Hyperplasia T93 Lipid disorders

Received > 1 anti-ht In 2004-2007 1,096,282 visit episodes (93,450 patients) (patients on anti-ht for unknown reasons) Total No K86 and no exclusion coding 36,409 Patients with > 1 coding (57,041 patients) 61.0% No K86 but with Exclusion Codes 10,182 All Patients with K86 coding (46,859 patients) 50.1% K86 coded + exclusion codes 16,155 Patients coded K86, AND without exclusion coding (30,704 patients) (425,324 anti-ht drug visit episodes) 32.9% of total *Wong MCS, Jiang Y, Tang JL, Lam A, Fung H, Mercer SW, Griffiths S. Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data. BMC Health Services Research 2008;8:138

Prescription Profiles of antihypertensive agents from 1.8 million prescriptions 60.00% 50.00% 40.00% 30.00% 20.00% CCB Beta-blocker Alfa-blocker ACEI Thiazide Diuretics Combination therapy Loop Diuretics ARBs K+-sparing diuretics/vasodilator/misc 10.00% 0.00% 2004 2005 2006 2007 *Wong MCS, Jiang Y, Tang JL, Lam A, Fung H, Mercer SW, Griffiths S. Health services research in the public healthcare system in Hong Kong: An analysis of over 1 million antihypertensive prescriptions between 2004-2007 as an example of the potential and pitfalls of using routinely collected electronic patient data. BMC Health Services Research 2008;8:138

Background International guidelines on management of arterial hypertension Thiazide diuretics a first-line agent JNC 7 th, NICE (ESC/ISH) Metabolic side effects of thiazide diuretics Includes Na + and K + Hospital admissions & even mortality Deters physicians from prescribing them

Background The majority of reports on anti-ht & electrolytes were conducted in Caucasian countries alone electrolyte profiles among Chinese hypertensive patients on thiazides have been scarce and were small scale Ethnicity is associated with different pharmacological outcomes of antihypertensive agents even small ethnic differences may bear substantial health resource implications

Inclusion criteria: Participants Patients who newly attended the public primary care practice & prescribed a single antihypertensive agent as the first-ever antihypertensive pharmacotherapy in the public sector during January 2004 to June 2007 coded by physicians with ICPC K86 (uncomplicated hypertension) had their plasma Na + and K + levels checked 4 16 weeks after the prescription Exclusion criteria: subjects having concomitant cardiovascular factors or clinical conditions that could confound antihypertensive prescription choice Discontinued or switched their drug prescription or received Na + or K + supplements before electrolyte measurements

Conditions for Exclusion

Antihypertensive drug classes Each patient was classified into one drug group according to the prescription BB: β-blockers, TD: Thiazide diuretics, CCB: Calcium channel blockers, RAS: drugs acting on the renin angiotensin system, and Others(including α-blockers, potassium-sparing and other diuretics, vasodilators, and combination therapy). Evaluated the dosage of each prescription qualitatively as low, medium, or high according to standard drug formulary.

Outcome variables (1). the mean plasma Na + /K + levels (2). the proportions of patients having low (Na <135 meq/l; K <3.4 meq/l), normal (Na 136 147 meq/l; K 3.5 5.1 meq/l), and high (Na >148 meq/l; K >5.2 meq/l) levels among the various drug classes. Independent predictors and covariates include patients age, gender, payment status (fee waivers vs. payers; each consultation costs US$5.77), district of residence, estimated GFR (in tertiles), and the antihypertensive drug classes prescribed

Statistical Analysis Two multivariate regression analyses Binary outcome variables: Na + and K + significant differences between districts with respect to antihypertensive prescribing, conducted sensitivity analyses where district of residence was included and then excluded as an independent variable, respectively, to avoid overcontrolling of covariates

Results 2,759 eligible patients; mean age = 63.6 years (95% C.I. 63.4, 64.5)

Major Findings (1). Thiazide diuretics had the lowest levels of Na + ; CCBs and thiazide diuretics had the lowest levels of K when compared to other drug classes the absolute magnitude of differences were minimal. (2). Factors positively associated with Na + from multivariate regression analysis advanced age, male gender, and thiazide user (3). RAS and BBs were less likely to present with K + when compared with CCB.

Interpretations (1). Elderly women could have expanded fluid volume after increased fluid intake but decreased ability to excrete free water, which might explain the higher risks of Na + among the elderly. (2). Male patients with advanced age should have their sodium levels monitored more closely. (3). Physicians should not be deterred from prescribing thiazide. (4). some caution is needed in prescribing thiazide and CCBs because the prevalence of K + (11.8 and 12.8%, respectively) is still not negligible

Limitations 1). Could the sample size be larger? 2). Baseline electrolyte: absent 3). Ethnicity: generalizability to other races? 4). risk association: not cause-and-effect relationship 5). Dietary diary & other confounders: not available

Contributions & Roles of pharmacoepidemiology in various areas: 6). Association between medication use and clinical outcomes

JHH 2009; 23: 735-742

JHH 2009; 23: 735-742 All-cause mortality & anti-hts

JHH 2009; 23: 735-742

Contributions & Roles of pharmacoepidemiology in various areas: 7). Analysis of cost-effectiveness of drugs

Pharmacotherapy 1991; 11: 50-5

Future direction of development 1). Rapid development & increased interests globally Annual international conference on pharmacoepidemiology: attendance 50 (1980) 900 (2004) ISPE: 800 members from 37 countries; guidelines (2004) Academic Journals: Clin Pharmacol Ther. (IF: 6.961, 11/237); J Clin Epidemiol; Pharmacoepidemiol & Drug Saf. Actively solicit pharmaco-epi studies number of summer programmes on pharmaco-epidemiology Michigan SPH (10%), McGill, Erasmus U. Rotterdam, Johns Hopkins Initiatives from pharmaceutical companies Forming their own pharmaco-epidemiology units

Future direction of development 2). The academics Methodologic advances Expanded use of neural networks, propensity scores, sensitivity analyses, time-varying exposures & confounder control, data mining Involvement of pharmacoepidemiologists into policy questions Emergence of pharmacogenetic studies New content areas of interest E.g. drug utilization, prescription profiles Logistical advances Funding Personnel

2). The academics Future direction of development Training in statistical techniques Confounding management Use of propensity scores Better use of large-scale datasets Coding rate of HT (ICPC-2 K86)/ DM (ICPC-2 T90) Coding rate is increasing

Future direction of development 3). The Industry role of pharmacoepi expanding Contribute to identify problems & document drug safety Develop & evaluate risk management programme prophylactic studies by manufacturers Post-marketing studies for all newly marketed drugs for chronic diseases Protect major investment made in developing a new drug Reduce legal liability Pharmaceutical companies: investment in external pharmacoepidemiologic data resources Need adequately trained researchers with statistical skills & robust dataset

Future direction of development 4). The Regulatory Agencies Also expanding Postmarketing pharmaco-epi studies replacing pre-marketing phase III studies (e.g. zidovudine) Use of therapeutic risk management approaches change regulation Increase attention to drug safety (COX-2 inhibitors; NSAIDs)

5). The law Future direction of development No. of lawsuits related to adverse drug effects Awareness of the legal system s ability to obtain substantial remuneration for those suffered from adverse effects Financial payments: put entire drug company at risk

Brian L. Strom. Pharmaco-epidemiology (4 th edition), Wiley References

Future direction of development Let s join our hands Thank you