1. Case reports of adverse drug reactions are important for recognizing newly identified reactions, generating hypotheses, and reminding clinicians. 2. Most reports describe drug-event pairs that are not between the eyes, requiring many reports for signal detection through quantitative methods. 3. While signals can be detected from accumulated case reports, clinical interpretation is still needed and hypotheses must be verified. The quality of reporting adverse drug reactions can be improved.

1. Adverse drug reactions: the role of case reports Jeff Aronson Reader in Clinical Pharmacology, Department of Primary Health Care, Oxford President, British Pharmacological Society Meyler’s Side Effects of Drugs Side Effects of Drugs Annuals Editor-in-Chief

3. Types of adverse drug reactions reports in the world literature

5. Reports of suspected adverse effects of mestranol and ethinylestradiol to the then Committee on Safety of Drugs 942 reports 88 PEs 854 others Inman, WH. “Don’t Tell the Patient”, 1999 63 441 Mestranol 25 413 Ethinylestradiol

6. Products containing considerable amounts of glycyrrhizinic acid Confectionery: Liquorice all sorts Torpedos Blackcurrant Pomfret (Pontefract) cakes Servez vous Sorbits chewing gum Stimorol chewing gum All types of liquorice root: Russian, Iranian, Chinese, Turkish, Afghan, and unknown origin Health products: Liquirizia naturale Liquorice flavoured diet gum Throat pearls Liquorice flavoured cough mixtures Herbal cough mixtures Antibron tablets Liquorice tea Chewing tobacco Alcoholic drinks: Belgian beers, pastis, anisettes–raki, ouzo, Pernod

8. Joseph Berkson (1899-1982) “ Scientist, statistical philosopher, innovator, and much loved curmudgeon” Logit (J Am Stat Assoc 1944; 39: 361) Berkson’s bias (Biometrics Bull 1946; 2: 47-53) Berkson [regression] error model (J Am Stat Assoc 1950; 45: 164-80) Interocular traumatic impact

9. Between-the-eyes adverse effects

10. Between-the-eyes adverse effects 1. Extrinsic or intrinsic tissue deposition of the drug or a metabolite Intrinsic: Deposition in nails, teeth Corneal microprecipitates Crystal-storing histiocytosis

11. Eiferman et al. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium. J Cataract Refract Surg 2001; 27(10): 1701-2

12. Between-the-eyes adverse effects 1. Extrinsic or intrinsic tissue deposition of the drug or a metabolite 2. A specific anatomical location or pattern of injury Cytotoxic drug extravasation Intrathecal administration Oral ulceration Oesophageal ulceration

13. Brazier et al. Ecstasy related periodontitis and mucosal ulceration—a case report. Br Dent J 2003; 194(4): 197-9

14. Between-the-eyes adverse effects 1. Extrinsic or intrinsic tissue deposition of the drug or a metabolite 2. A specific anatomical location or pattern of injury 3. Physiological dysfunction or direct tissue damage demonstrable by physicochemical testing Oligohidrosis Photosensitivity Taste disturbance Dry mouth

15. Between-the-eyes adverse effects 1. Extrinsic or intrinsic tissue deposition of the drug or a metabolite 2. A specific anatomical location or pattern of injury 3. Physiological dysfunction or direct tissue damage demonstrable by physicochemical testing 4. Infection, due either to the administration of an infective agent as the therapeutic substance or to demonstrable contamination BCG, mumps

16. Trevenzoli et al. Sepsis and granulomatous hepatitis after bacillus Calmette-Guérin intravesical installation. J Infect 2004; 48(4): 363-7

17. A crime scene analogy Distinctive outcome Recognizing a modus operandi Culprit’s fingerprints found at the scene of the crime Infection-related Culprit incriminated by recreating the crime scene Physicochemical dysfunction or tissue damage Culprit caught at the scene of the crime and seen committing it Specific anatomical location or pattern of injury Culprit caught at the scene of the crime Extracellular or intracellular tissue deposition Crime scene analogy Category

20. http://www.who-umc.org Database of 4.7 million case reports 94 countries 300,000 new records per year

23. Proportional Reporting Ratio (PRR) Produces a numerical “signal score” by which drug-event pairs can be ranked D C All adverse events reports in database B A Reports of the event of interest All other drugs in database Drug under review PRR = A / C B / D

24. Statistics in Medicine 2009; 28: 1774–92

39. Comprehensive reporting of suspected adverse effects Age Sex Weight Ethnicity Diagnoses Allergies Drug treatment (current/past) Family history Social history Severity Time-course Withdrawal Rechallenge Diagnostic tests Plasma concentrations Animal/in vtiro evidence Treatment Outcome Assessment of likelihood Drug Points in BMJ January 2001 to October 2002 (BMJ 2003; 326: 1346) 35 reports; 48 patients Of 19 desiderata: 9 (5-12) Of 14 yellow card items: 9 (4-12) Of 14 MedWatch items: 8 (3-11)

40. Aronson, BMJ 2003; 326: 1346; e-appendix

42. Discussion Likelihood of a true association Reasons for implicating the drug Why other drugs were not responsible Elimination of other possible causes Review of previous cases Methods of diagnosis Possible mechanisms Possible forms of management Implications for clinical practice Hypotheses generated

44. Conclusions Anecdotal reports of suspected adverse drug reactions make up a large propotion of the published literature A few drug-event pairs are interocular Most drug-event pairs are not and need large numbers of reports for signal detection Signals can be detected from accumulated anecdotes; they should then be interpreted clinically and verification attempted The quality of reporting is currently poor and should be improved; guidelines may help

45. Raymond Wolfinger: “ The plural of anecdote is data”