Pharmacoepidemiology
(Epidemiology 221b)
Instructor
Alec Walker Kresge 908 432-4565
Meetings
Kresge 201
Tuesdays and Thursdays 3:30 – 5:20
(No class December 17 and January 21 – HSPH Faculty Meeting)
Office hours Wednesdays 2:30 – 4:00 and by appointment
Purpose
The goal of this course is to introduce students to the most important issues of pharmacoepidemiology. To this end, we will emphasize the ways in which the observational study of drugs can draw on standard epidemiologic technique, and explore the ways in which drugs present unique research problems and opportunities.
Structure
Material will be taught through seminars, case studies, and group projects. Readings must be done in advance of the class.
Grading
There will be a term paper, to be done in teams. (60%)
Students will chosen in class to evaluate assigned papers for that class session. (10%)
Students will be expected to participate in class discussions. (30%)
Each activity is graded on a four-point scale, corresponding roughly to
1) work that would be fully acceptable from a professional colleague
2) work that shows evidence of a colleague-in-training
3) work that has some merit but would be insufficient for ordinary scientific interchange
4) unacceptable or incomplete work.
In the past, most students have performed at level 2 above. The grade for level 2 performance is a B+.
Term Papers
The term paper should be about 2000 words, and should cover some narrow topic in drug epidemiology. Students may co-author papers, in which case the expected length is 1500 words per author. Any class topic is acceptable for development into a term paper. A historical review of the development of evidence for an adverse effect of a drug or medical device is a very good topic. A straight current-evidence review would be acceptable if there is some interesting complication or uncertainty. If you can see applications of methodologic work that you are doing elsewhere, you may wish to consider a methods topic, but this must reflect a substantial adaptation of the methods and ideas to the special needs of pharmacoepidemiology. Each year one or two of the term papers makes its way into the published literature, and one or two become the basis of thesis proposal.
Staying in Touch
You can see some of the pharmacoepidemiology program's activities, and read some previous student papers at the Drugs and Devices Information Line website. You can get there by entering "Harvard Pharmacoepidemiology" on your web search engine, or by entering the following URL http://www.hsph.harvard.edu/Organizations/DDIL/ddilhpge.html . Papers are available under "Harvard Reviews in Pharmacoepidemiology." DDIL also provides links to the home pages of a number of regulatory authorities and research groups. You should make an effort to follow the links, so that you can get a sense of the "real" world of drug safety.
My e-mail address is amwalker@epi.harvard.edu .
Schedule
|
Date |
Topic |
|
November 10 |
Introduction: From Events to Epidemiology in Drug Safety |
|
12 |
Spontaneous Reports |
|
17 |
Population Case Series |
|
19 |
Bayesian and Recognition-Primed Causality Assessments |
|
24 |
Quantifying Risk and Benefit by National Surveillance. |
|
December 1 |
Follow-up studies. Confounding by Indication. |
|
3 |
Follow-up studies with sampling |
|
8 |
Case-Control Studies |
|
10 |
Determinants of Prescribing |
|
15 |
Duration of Therapy |
|
17 |
No Class |
|
January 5 |
Large linked data resources. Defining exposure |
|
7 |
Large linked data resources. Defining outcomes |
|
12 |
Roles for epidemiologists in the pharmaceutical industry |
|
14 |
The tension between clinical trialists and observational investigators |
|
19 |
Term papers due Denial: Some problems of institutional recognition of adverse drug effects in government and industry. |
|
21 |
No Class |
Class Synopsis
Introduction: From Events to Epidemiology in Drug Safety
November 10
Purpose
Provide an epidemiologist’s overview of the data and standard analyses in drug safety studies.
Readings
Feenstra J, van Drie-Pierik RJHM, Lacié CF, Stricker BHCh. Acute myocardial infarction associated with sildenafil. Lancet 1998;352:957-8
Assal F, Spahr L, Hadengue A, Rubbici-Brandt L, Burkhard PR. Tolcapone and fulminant hepatitis. Lancet 1998;352:958
Spontaneous Reports
November 12
Purpose
Spontaneous reports to regulatory authorities are the backbone of safety surveillance. We will review the structure and challenges of these programs.
Reading
Baum C, Kweder S, Anello C. The spontaneous reporting system in the United States. Chapter 10 of B. Strom, ed., Pharmacoepidemiology (Second Edition)
Wiholm BE, Olsson S, Moore N, Wood S. Spontaneous reporting systems outside the United States. Chapter 11 of Strom, op cit.
Lippman JS, Shangold GA. A review of post-marketing safety and surveillance data for oral contraceptives containing norgestimate and ethinyl estradiol. Int J Fertil 1997;42:230-239
Population Case Series
November 17
Purpose
Differentiate between selected and unselected case series. Review case-crossover design as a model for analysis of unselected case series.
Readings
Maclure M. The case-crossover design: A method for studying transient effects on the risk of acute events. Am J Epidemiol 1991;133:144-53
Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV. Valvular heart disease associated with fenfluramine-phenteramine. N Engl J Med 1997;337:581-8
Adams PC, Robinson A, Reid MM, Vishu MC, Livingston M. Blood dyscrasias and mianserin. Postgrad Med J 1983;59:31-3
Bayesian and Recognition-Primed Causality Assessment
November 19
Purpose
To understand Bayesian inference both as a technique for allocating cause in individual cases and as a paradigm for inference.
To examine more naturalistic approaches to causality assessment.
Readings
Lane, DA. Causality assessment for unintended drug effects. Chapter 6 in A.G. Hartzema, M.S. Porta and H.H. Tilson (Eds.) Pharmacoepidemiology: An Introduction Harvey Whitney Books Cincinnati 1991
Klein G. The Power of Intuition. From Sources of Power: How People Make Decisions. The MIT Press, Cambridge, 1998, pp. 31-44
Quantifying Risk and Benefit by Means of National Surveillance
November 24
Purpose
A few drug effects that can be assessed and quantified by national surveillance. There are however many pitfalls.
Readings
Coulter DM, Edwards IR. Mianserin and agranulocytosis in New Zealand. Lancet 1990; 336:785-7
Lindberg G, Bingegfors K, Ranstam J, Råstam L, Melander A. Use of calcium channel blockers and risk of suicide: ecological findings confirmed in population based cohort study. BMJ 1998;316:741-5
Follow-up Studies. Confounding by Indication.
December 1
Purpose
The association between cimetidine and gastric cancer has been the object of a long-standing discussion, one that has only recently been resolved.
Readings
Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP. Cimetidine and gastric cancer: preliminary report from post-marketing surveillance study. Brit Med J 1982;285:1311-1313
Colin-Jones DG, Langman MJS, Lawson DH, Vessey MP. Postmarketing surveillance of the safety of cimetidine: mortality during the second third and fourth years of follow up. Brit Med J 1985;291:1084-88
Johnson AG, Jick SS, Perera DR, Jick H. Histamine-2 receptor antagonists and gastric cancer. epidemiology 1996;7:434-436
Walker AM. Confounding by indication. Epidemiology 1996;7:335-336
Follow-up Studies with Sampling
December 3
Purpose
In order to define confounding factors and time-varying factors in a cohort study it may be necessary to sample the population.
Readings
Jick H, Vasalakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A population-based study of appetite suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998;339:719-24
Baird IM. Risks of heart-valve abnormalities with appetite suppressants. Lancet 1998;353:1403-4
Case-Control Studies
December 8
Purpose
To appreciate the role of definition of study subjects in the assessment of causal associations in non-randomized investigations
Readings
WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effects of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-1588
Walker AM. Newer oral contraceptives and the risk of venous thromboembolism. Contraception 1998;57:169-181
Determinants of Prescribing
December 10
Purpose
Examine the ways in which prescribing practices may affect the population composition of users, and the methods for assessing the impact of these on observational studies.
Readings
Dunn N, White I, Freemantle S, Mann R. The role of prescribing and referral bias in studies of the association between third generation oral contraceptives and increased risk of thromboembolism. Pharmacoepidemiol Drug Safety 1998;7:3-14
Lidegaard Ø. The influence of thrombotic risk factors when oral contraceptives are prescribed. Acta Obstet Gynecol Scand 1997;76:252-260
Duration of Therapy
December 15
Purpose
Risks in a cohort defined by current use of a drug may change with increasing duration of use. These changes could be etiologic, or they may reflect changing cohort composition.
Readings
Lewis MA, Heinemann LAJ, MacRae KD, Bruppacher R, Spitzer WO. The increased risk of venous thromboembolism and the use of third generation progestagens: Role of bias in observational research. Contraception 1996;54:5-13
Weiss NS. Bias in studies of venous thromboembolism in relation to the use of new formulations of oral contraceptives. (letter) Contraception 1997;55:189-190
Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997;56:141-146
Large Linked Data Resources
January 5 and 7
Purpose
Learn the mechanics and organization of large linked databases
Review the breadth of study options in these resources
Readings
Lanza LL, Walker AM, Bortnichak EA, Dreyer NA. Peptic ulcer and gastrointestinal hemorrhage associated with nonsteroidal anti-inflammatory drug use in patients younger than 65 years. Arch Intern Med 1995;155:1371-1377
Lanza LL, Dreyer NA, Schultz NJ, Walker AM. Use of insurance claims in epidemiologic research: Identification of peptic ulcers, GI bleeding, pancreatitis, hepatitis and renal disease. Pharmacoepidemiology Drug Safety 1995;4:239-248
Roles for Epidemiologists in the Pharmaceutical Industry
January 12
Purpose
Review functions of drug development from the viewpoint of an epidemiologist’s contribution.
Reading
None. Note that term papers are due in one week, on January 19.
The Tension between Clinical Trialists and Observational Investigators
January 14
Purpose
The attitude toward what constitutes a valid basis for causal inference is long-standing point of friction between epidemiologists and clinical experimenters. At the heart of the controversy are issues of psychology as much as logic.
Readings
None
Denial: Some problems of institutional recognition of adverse drug effects in government and industry
January 19
Purpose
More psychology. What seems to be true is commonly a function of how closely you identify with the history and outcomes of a question.
Reading
And the Band Played On. Randy Shilts. Excerpts.