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”