Adverse drug reactions: the role of
case reportsJeff AronsonReader in Clinical Pharmacology, Department of Primary Health Care,
Oxford
President,British
PharmacologicalSociety
Meyler’s Side Effects of Drugs
Side Effects of Drugs Annuals
Editor-in-Chief
Types of adverse drug reactions reports in the world literature
Reasons for publishing anecdotes of adverse drug
reactionsReason Examples
Newly recognized ADR Oculomucocutaneous syndrome (practolol)
Generate hypotheses Teratogenicity (antihistamines)
Test hypotheses Loading dose in renal insufficiency (digoxin)
Diagnostic tests Lung damage (KL6) (amiodarone)
Elucidate mechanisms Torsade de pointes/QT (antiarrhythmics)
Methods of management Self-poisoning (verapamil)
Systematic review Thromboembolism (mestranol)
Remind and educate Hypokalaemia (liquorice)
Reports of suspected adverse effects of mestranol and ethinylestradiol to the then Committee on Safety of
Drugs
942 reports
88 PEs 854 others
63 441Mestranol
25 413Ethinylestradiol
Inman, WH. “Don’t Tell the Patient”, 1999
Products containing considerable amounts of glycyrrhizinic acidConfectionery:
Liquorice all sorts Torpedos Blackcurrant Pomfret (Pontefract) cakes Servez vous Sorbits chewing gum Stimorol chewing gumAll 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 teaChewing tobaccoAlcoholic drinks: Belgian beers,
pastis, anisettes–raki, ouzo, Pernod
Reasons for publishing anecdotes of adverse drug
reactionsReason Examples
Newly recognized ADR Oculomucocutaneous syndrome (practolol)
Generate hypotheses Teratogenicity (antihistamines)
Test hypotheses Loading dose in renal insufficiency (digoxin)
Diagnostic tests Lung damage (KL6) (amiodarone)
Elucidate mechanisms Torsade de pointes/QT (antiarrhythmics)
Methods of management Self-poisoning (verapamil)
Systematic review Thromboembolism (mestranol)
Remind and educate Hypokalaemia (liquorice)
Proof
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
Between-the-eyes adverse effects
Between-the-eyes adverse effects1. Extrinsic or intrinsic tissue
deposition of the drug or a metabolite
Intrinsic: Deposition in nails, teethCorneal microprecipitatesCrystal-storing histiocytosis
Eiferman et al. Ciprofloxacin microprecipitates and macroprecipitates in the human corneal epithelium.J Cataract Refract Surg 2001; 27(10): 1701-2
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 extravasationIntrathecal administrationOral ulcerationOesophageal ulceration
Brazier et al. Ecstasy related periodontitis and mucosal ulceration—a case report. Br Dent J
2003; 194(4): 197-9
Between-the-eyes adverse effects1. 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
OligohidrosisPhotosensitivityTaste disturbanceDry mouth
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
Trevenzoli et al. Sepsis and granulomatous hepatitis after bacillus Calmette-Guérin intravesical installation.
J Infect 2004; 48(4): 363-7
A crime scene analogy
Category Crime scene analogy
Extracellular or intracellular tissue deposition
Culprit caught at the scene of the crime
Specific anatomical location or pattern of injury
Culprit caught at the scene of the crime and seen committing it
Physicochemical dysfunction or tissue damage
Culprit incriminated by recreating the crime scene
Infection-related Culprit’s fingerprints found at the scene of the crime
Distinctive outcome Recognizing a modus operandi
Comprehensiveness and adverse effects of amiodarone
Meta-analysis(n = 4153)
1.801.201.000.960.490.470.470.35
Anecdotes(n = 357)
0.110.441.000.460.260.020.100.26
UMC(n = 7043)
0.441.701.000.890.770.490.201.04
Site of ADR
HeartThyroidRespiratoryNervous
systemLiverGastrointestinalEyesSkin
Loke, Derry, AronsonBr J Clin Pharmacol; 2004: 57: 616-21
http://www.who-umc.org
Database of 4.7 million case reports94 countries300,000 new records per year
Quantitative & automated numerator-based statistical methods producing relative reporting rates
In principle these methods aim to answer the question: Are adverse events reported with the drug at a disproportionately high rate?
A disproportionately high reporting rate of a drug-event pair does not necessarily betoken a causal relation
Therefore these methods need to be accompanied by clinical evaluation and subsequent verification
Proportional Reporting Ratio (PRR)
Drug under review
All other drugs in database
Reports of the event of interest A B
All adverse events reports in database
C D
PRR =A / C
B / D
Produces a numerical “signal score” by which drug-event pairs can be ranked
Statistics in Medicine 2009; 28: 1774–92
Comprehensive reporting of suspected adverse effects
AgeSexWeightEthnicityDiagnosesAllergiesDrug treatment (current/past)Family historySocial historySeverityTime-courseWithdrawalRechallengeDiagnostic testsPlasma concentrationsAnimal/in vtiro evidenceTreatmentOutcomeAssessment of likelihood
Drug Points in BMJJanuary 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)
Aronson, BMJ 2003; 326: 1346; e-appendix
TitleStructured summaryIntroductionThe case report
Demographic informationDiagnosesDrug therapyOther relevant history
The adverse eventTreatmentDiscussion
Discussion
Likelihood of a true associationReasons for implicating the drugWhy other drugs were not responsibleElimination of other possible causesReview of previous casesMethods of diagnosisPossible mechanismsPossible forms of managementImplications for clinical practiceHypotheses generated
Conclusions
Anecdotal reports of suspected adverse drug reactions make up a large propotion of the published literatureA few drug-event pairs are interocularMost drug-event pairs are not and need large numbers of reports for signal detectionSignals can be detected from accumulated anecdotes; they should then be interpreted clinically and verification attemptedThe quality of reporting is currently poor and should be improved; guidelines may help
Raymond Wolfinger: “The plural of anecdote is data”