This document provides an introduction to pharmacoepidemiology. It defines pharmacoepidemiology as the study of drug use and effects in large populations. It discusses study designs used in pharmacoepidemiology including randomized trials, cohort studies, case-control studies, and case reports. Reasons for performing pharmacoepidemiology studies include fulfilling regulatory and legal obligations, assessing drug safety, and generating or testing hypotheses. Common data sources are spontaneous adverse event reporting, prescription databases, and medical records. Issues like adherence, molecular factors, ethics, and economics are also discussed.

1. AN INTRODUCTION TO PHARMACOEPIDEMIOLOGY Strom BL & Kimmel SE. Textbook of Pharmacoepidemiology. Dr. DivjyotKaur Jr –II Dept of Pharmacology

3. Study designs available for PE studies

4. Reasons to perform these studies

5. Sources of PE data

6. Molecular Pharmacoepidemiology

7. Bioethical issues

8. Pharmionics

9. Special applications of PE

12. (B) New types of information not available from premarketing studies (1) Discovery of previously undetected adverse and beneficial effects (a) Uncommon effects (b) Delayed effects (2) Patterns of drug utilization (3) The effects of drug overdoses (4) The economic implications of drug use

13. (C) General contributions of pharmacoepidemiology (1) Reassurances about drug safety (2) Fulfillment of ethical and legal obligations

14. Study designs available for PE studies In hierarchical order of progressively harder to perform but more convincing Randomized clinical trials Prospective cohort studies Retrospective cohort studies Case-control studies Analysis of secular trends Case series Case reports

16. First put forth by Sir Austin Bradford Hill in 1965Coherence with existing information (biological plausibility) Consistency of association Time sequence Specificity of association Strength of association Quantitative strength Dose-response relationship Study design

18. Analysis of secular trends and case-control studies- useful to explore these associations

20. (B) Marketing (1) To assist market penetration by documenting the safety of the drug (2) To increase name recognition (3) To assist in repositioning the drug (a) Different outcomes, e.g., quality-of-life and economic (b) Different types of patients, e.g., the elderly (c) New indications (d) Less restrictive labeling (4) To protect the drug from accusations about adverse effects (C) Legal (1) In anticipation of future product liability litigation

21. (D) Clinical (1) Hypothesis testing (a) Problem hypothesized on the basis of drug structure (b) Problem suspected on the basis of preclinical or premarketing human data (c) Problem suspected on the basis of spontaneous reports (d) Need to better quantitate the frequency of adverse reactions (2)Hypothesis generating—need depends on: (a) whether it is a new chemical entity (b) the safety profile of the class (c) the relative safety of the drug within its class (d) the formulation (e) the disease to be treated, including (i) its duration (ii) its prevalence (iii) its severity (iv) whether alternative therapies are available

22. Thus, the decision to conduct a PE study can be viewed as similar to the regulatory decision about whether to approve a drug for marketing or the clinical decision about whether to prescribe a drug. In both cases, decision making involves weighing the costs and risks of a therapy against its benefits.

24. Global Drug surveillance

25. Case- control surveillance

26. Prescription event monitoring

27. Automated databases

29. Very useful in HYPOTHESIS GENERATION, with need to explore possible explanations for the adverse event in question

31. Voluntary reporting by health care professionals or consumers

32. Mandatory reportingof AEs by manufacturers as required by law and regulation.

33. Individual spontaneous reports of ADRs, medication errors, & product quality problems, sent to FDA directly or indirectly, combined with data from formal clinical studies and from medical and scientific literature, comprise the primary data source upon which postmarketing surveillance depends.

35. Labeling change such as a ‘boxed warning’

36. Restricted use or distribution of the drug

37. Name or packaging changes

38. A “Dear Health Care Professional” letter

40. In 1984, FDA received reports of Hemorrhagic stroke (bleeding into brain or into tissue surrounding brain) in association with PPA.

44. The WHO Collaborating Centre for International Drug Monitoring in Uppsala (now known as the Uppsala Monitoring Centre, UMC)

46. harmonize the terms used to describe the adverse events and

47. to set criteria and definitions for at least the major serious types of reactions

48. to harmonize the way data are stored and communicated internationally

49. Main agencies involved in this are WHO, CIOMS, ICH and the EU.

50. The Medical Dictionary for Regulatory Activities (MedDRA) is being used more and more worldwide.

52. Drugs previously available on prescription being approved for OTC sales

53. In CCS, multiple case-control studies are conducted simultaneously in order to monitor the effects of prescription and OTC medications and dietary supplements (e.g. herbals) on risk of various illnesses.

54. CCS relies on self-reports of medication and dietary supplement use

56. Potentially important confounders

57. Over-the-counter drugs

61. The limited contribution of spontaneous ADR reporting system in detecting hazards such as oculomucocutaneous syndrome with practolol, led Inmanto establish the system of PEM at the Drug Safety Research Unit (DSRU) at Southampton in 1981

62. It is one form of pharmacovigilance and is complementary to spontaneous reporting of suspected ADRs

68. Disease incidence data

69. Ad hoc case-control studies

70. Registry data

71. Pharmacy based postmarketing surveillance studies

74. Pharmacogenomics- Studies of genetic variability on drug exposure + encompasses approaches simultaneously considering data about thousands of genotypes in drug discovery and development, as well as responses in gene expression to existing medication (genome-wide approach)

75. Molecular PE- focuses on effects of genetics on clinical outcomes from medication use

77. Evaluating how these SNPs alter disease outcomes

78. Assessing impact of gene-drug and gene-gene interactions on disease risk

80. Cost-effectiveness of such approaches must be justifiable given the additional costs of genetic testing in clinical care

81. Ethical, legal and social implications of genetic testing must be considered and addressed

82. Another concern, that medicines will be developed only for the most common, commercially attractive genotypes, leading to ORPHAN GENOTYPES.

85. Cost of drugs is not limited to their purchase price

86. Includes the cost of preparation, administration, monitoring for and treating side effects,etc…

88. Economic data from Phase III studies are used to support initial pricing of new therapies and are used in professional educational activities by pharmaceutical firms

89. Post marketing economic studies are used to compare new therapies with existing ones and also to confirm the initial Phase III economic assessments of the product.

90. 3 types of economic analysis- cost-benefit - cost-effectiveness (mc used in medical care) - cost-identification

92. HRQOL has become an established outcome measure in clinical research

93. Encompasses - ability to function normally - to be free of pain - free of physical, psychological and social limitations or dysfunction - free from iatrogenic problems associated with treatment

97. Patient may commence taking the medicine but, execute the prescribed dose regimen poorly

98. They may discontinue taking the medicine altogether at anytimeThe high incidence of early discontinuation gave rise to the term “persistence” which is defined for each patient as the time between the first-taken and the last-taken doses

100. non-acceptance

101. poor execution

104. Essence of eMEM is to imbed into the drug package microcircuitry that is connected to one or more micro-switches which detect when the maneuvers occur that are needed to remove a dose of drug from the package

105. These maneuvers which vary from one type of package to another, are referred to as “medication events”.

107. To omit a single dose

108. Miss two sequential doses, miss 3 sequential doses, so on…

109. A prominent feature with patients’ dosing histories is – -the higher occurrence of dose omissions with evening doses than with morning doses -higher omissions on weekends than on weekdays -gradual ↑ in frequency of dose omissions as duration of t/t increases. -white coat compliance

110. There is a simple pragmatic reason for wanting to know what impact these deviations from the recommended dosing regimen have on the effectiveness and safety of the drug in question Case example: “How much adherence is enough?” Background- Doxycyclinehyclate 100mg , orally BD for 7 days, is generally accepted std of care for chlamydial infections of male urethra or lower genital tract of females. Question- How much does adherence alter responsiveness to doxycycline Approach- Study carried out by Public Health Dept of State of Alabama(USA) to examine the impact of poor compliance with prescribed dosing regimen of doxycycline on outcome of chlamydial treatment.

112. Outcomes of t/t appeared to be independent of adherence!

114. It is preferable from the consumers’ perspective, to make such a discovery early rather than late in a pharmaceutical product’s commercial lifetime

116. Early discontinuation of medications-

117. Halts the drug action, and thus the beneficial effects that the drug may have induced up to the point of discontinuation

118. Halts manufacturer’s revenue from sale of the product to patient

120. Evaluating and improving physician prescribing

121. Drug Utilization Review

122. Special methodologic issues in PE studies of Vaccine Study

123. PE studies of Devices

124. Studies of Drug-induced birth defects

125. PE and Risk management

126. Use of PE to study Medication Errors

128. The discipline of PE has been growing and will continue to grow within academia, industry and government

129. Methodologic advances in risk management and molecular PE

132. References Strom BL & Kimmel SE. Textbook of Pharmacoepidemiology.