2. The “Pharmaco” in Pharamcoepidemiology Alec Walker September 2013 1

3. Who Needs the “Pharmaco”? Epidemiology 221 is a course is for Epidemiologists in training New to drug safety research To explore recurring topics pharmacoepidemiology Through lectures and discussion, we will explore Examples of discovery of adverse drug effects Use of large databases Study designs for  Large data resources  Control for unmeasured confounding factors Institutional sensitivities Students will acquire Relevant vocabulary Key concepts Ability to pursue each of these topics in more depth 2

4. Epidemiology 221 Early Stories Discovery of Drug Effects Common Epidemiologic Designs Applied to Drugs Fall 2013 Alexander M. Walker MD, DrPH

5. Thomas Quasthoff  German bass-baritone  Born 1959  Recordings on Philips, EMI, BMG, Haenssler  1988 ARD International Music Competition in Munich  1996 Shostokovich Prize  1999 Tanglewood (Boston Symphony Orchestra) debut  1999 Exclusive Deutsche Grammophon contract  Profiled in Time, People, Esquire, 60 Minutes

6. Quasthoff’s Mother Took Thalidomide Many European women used thalidomide, an apparently safe sleeping medication, during pregnancy in the late 1950s and 1960. Quasthoff, like thousands of others, was born with phocomelia.

7. The FDA as Public Health Guardians 6

8. Thalidomide in 1960  Painkiller, sedative  Already in wide use around the world  Generally felt to be harmless  Over the counter in Germany since 1957 Richardson-Merrell submits application in US Hoping for approval by Christmas, when sedative sales generally peaked. 7

9. Frances Oldham Kelsey  Francis Kelsey Public health hero? Foot-dragging bureaucrat?  Spontaneous reports & pharmacovigilance 8

10. Delay in US Approval  Heavy pressure for approval  December reports of peripheral neuropathies in BMJ  Kelsey keeps asking for more data 9 Florence AL. BMJ 1960(2):1954

11. Meanwhile … 1959 – 1969  Phocomelia epidemic recognized but not understood 1961  November 16 Wedekund Lenz identifies half of phocomelia patients as having been exposed to thalidomide at a conference  December 2 (Lancet) UK Manufacturer notes rarity, lack of statistics, appeals for case reports, suspends sales  December 16 (Lancet) McBride notes 20% major malformation risk in thalidomide pregnancies 10 1962  Richardson-Merrell withdraws application

12. Phocomelia

13. Fêted as a Heroes  Distinguished Federal Civilian Service Award, August 7, 1962  Glowing write-up in Life 12

14. The Verdict of History 13 www.fda.gov/cder/pike/julyaug2001.htm

15. Induction into Women's Hall of Fame Frances O. Kelsey, Ph.D., M.D., was praised for her courage and influence at a special FDA reception to commemorate her induction last October into the National Women's Hall of Fame. Center Director Janet Woodcock, M.D., noted that Dr. Kelsey, a pharmacologist and physician, has long been honored for her role in blocking approval of the drug thalidomide. Dr. Kelsey's refusal to approve thalidomide for use in the United States earned her national recognition, and her work led to strengthened regulation of the pharmaceutical industry. Dr. Woodcock said that Dr. Kelsey has been an inspiration to many scientists in the Center who "stuck to their guns under great pressure.” 14 From “CDER News Along the Pike July & August 2001” www.fda.gov/cder/pike/julyaug2001.htm

16. The Recognition of Adverse Drug Reactions 15

17. It may be obvious: Toxicity is a simple matter of pharmacology

18. Some Paradigms for Discovery  Pattern 1: Unique story  Pattern 2: Distinct but delayed  Pattern 3: Quantitative

19. Pattern 1: A Unique Story Clinically Detectable Effects Very short time interval Prior hypothesis Known mechanism No alternative explanation Simple exposure

20. Clinical Recognition  A single observer  With a class of applicable hypotheses  Congruence between event and general rule  Lack of competing explanation  Pattern Recogn ition

24. Pattern Key

25. Angioedema and ACE Inhibitors  Swelling of lips, mouth, throat  Within hours to days of 1 st Rx  1 in 200 patients  1 in 100 life-threatening  More common in blacks

26. Discovering Angioedema  Case reports  Short time  Rare in the absence of exposure  Distinctive characteristics  No alternative etiology  No reasonable doubt in after a case series

27. Pattern 2: Distinct but Delayed  Striking, usually rare event  Increased frequency leads to search  Essentially 100% of cases exposed

28. Phocomelia Lancet, Dec 16, 1961

29. Phocomelia and Thalidomide  Delayed  No precedent (read: no pre-existing hypothesis)  Distinctive pattern  Became evident after single clinicians themselves had seen multiple cases

30. Pattern 3: Quantitative  Known event  Increased frequency  Surveillance systems allow comparisons

31. Cerivastatin and Rhabdomyolysis  37 deaths reported in US 800,000 users  Many months of accumulating reports  Vs. 20 deaths in > 20 million users of other statins  Rhabdomyolysis relatively common in all statin users  For cerivastatin, principally in conjunction with gemfibrizil

32. Quantitative not Qualitative  Common enough to be well known  Infrequent enough that no one observer can quantify

33. Informal Inference: When it’s Easy …  Very short time interval  Prior hypothesis  Known mechanism  No alternative explanation  Simple exposure  Massive increase in frequency

34. Informal Inference: When it’s Difficult …  Delayed  Unanticipated  No known mechanism  Readily expected in absence of the drug  Multiple treatment modalities  Increased risk, but not overwhelmingly so

35. Crossing over from the Clinic to Population 34

36. How we evaluate causal connections 35 Theory Prediction Experiment Data

37. Theories for Drug Safety  Case Reports  Analogy  Animal Experience  Rumor

38. A Good Hypothesis  Content = Refutability  Refutability depends on predictions  Make a hypothesis better By forcing it to make refutable predictions Experiments (studies) are data collection organized in such a way as to test refutable predictions

39. Toxic Epidermal Necrolysis SCARS

40. Severe Cutaneous Adverse Reaction Syndrome SCARS Toxic Epidermal Necrolysis

41. Stevens Johnson Syndrome, Rash Severe Cutaneous Adverse Reaction Syndrome SCARS Toxic Epidermal Necrolysis

42. Case-Finding Examination of Other Reports Stevens Johnson Syndrome, Rash Severe Cutaneous Adverse Reaction Syndrome SCARS Toxic Epidermal Necrolysis

43. Roles of Epidemiology  Techniques for quantification Conceptual tools Mechanics  Repository of experience (of error) Confounded associations Distortions of information

44. Epidemiology’s Tools  Cohort studies  Case control studies  Correlational studies  Surveillance

45. Cohort Studies  A list of individuals at risk  The passage of time  The occurrence of events

46. Superinfection (1970s)

47. Case-Control Studies  Cohort studies with sampling  Captures covariates that would be difficult to ascertain Time-varying Resource intensive data collection

48. Case-Control Advantages  Relatively inexpensive  Relatively quick  Useful for rare outcomes

49. Case-Control Shortcomings  May not yield absolute risk  Focuses on a single outcome  Difficult to assure ascertainment  Difficult to verify suitable controls

50. MI and CCBs

51. Correlational Studies  Population frequency  Population exposure  Inference on association  The problem of common cause

52. Suicide v. CCBs in Sweden

53. Epidemiology as a Language for Evaluating Risk  Explicit definitions for concepts of risk  Measures for comparison  Vocabulary for describing multiple determinants  Nosology of induced and artificial associations  Experience of error

54. Wrapping Up  Epidemiology needs to formalize, not sterilize our innate ideas of causality  Epidemiology extends the vision beyond associations that are readily apparent  Epidemiologists can play a role in every stage of drug development

55. Thank You!