Spontaneous Reporting - INRUD


Spontaneous Reporting - INRUD

Challenges in Causality

Assessment in Spontaneous

Reporting Systems

Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP

3 rd ICIUM, Antalya, Turkey

November 2011


• These are my personal views not

shared by the U.S. FDA or the U.S.


• I am not representing the FDA

• No conflict of interest to declare



Spontaneous Reporting Systems

– What

– Why

– Strengths/Limitations

• Evidence to Suggest Causal Relationship

• Approaches to Causality Assessment


– Naranjo

– Bradford Hill

• Case example

• Safety-related Drug Withdrawals

• Conclusions


What is Spontaneous Reporting?

• The process of reporting of all unsolicited reports

of adverse events from health care professionals

or consumers to the FDA (or any appropriate

authority) is called spontaneous reporting

-Ahmad SR, Goetsch RA, Marks NS. Spontaneous reporting in the United States. Chapter 9. In Strom’s

Pharmacoepidemiology, 2005 p. 135-159.


Why Spontaneous Reporting?

Limitations of Pre-marketing Clinical trials

• Too small --- 2,000-5,000

• Too short ---

Spontaneous Reporting



• Inexpensive/All patients/drugs

• Generation of hypothesis and signals

• Good for identifying rare, serious drug-induced events with low

background rate


• Passive surveillance

• Adverse event recognition

• Underreporting

• Duplicate reporting

• Report quality

Reporting biases


Factors to Consider in Causal


• Temporally associated with use of drug

• Biological plausible

• No other likely causes

– Underlying diseases or disease progression

– Concurrent meds

• Event abates after drug is stopped (+ dechallenge)

• Event recurs when drug is restarted (+ rechallenge)


Approaches to Causality

• Expert Judgement


– individual assessments

– no standardized tool

• Algorithms

– sets of specific questions with or without scores

• Probabilistic or Bayesian methods

– Is based on assigning i a prior probability bili to an event of


Agbabiaka bi TB, et al. Methods for causality assessment of ADRs. Drug Safety

2008;31: 21-37

Jones JK. Determining causation from case reports. In Pharmacoepidemiology,

Strom BL. 2000, p. 525-538.


WHO UMC Causality Categories

• Certain


• Possible

• Unlikely

• Conditional/Unclassified

• Unassessable/Unclassifiable


The Naranjo ADR Probability Scale

Questions Yes No Don’t


1) Are there previous conclusive reports on this


2) Did the ADR appear after the suspected drug was


+1 0 0

+2 -1 0

3) Did the ADR improve when the drug was discontinued? +1 0 0

4) Did the ADR appear with re-challenge? +2 -1 0

5) Are there alternative causes for the ADR? -1 +2 0

6) Did the reaction appear when placebo was given? -1 +1 0

7) Was the drug detected in blood at toxic levels? +1 0 0

8) Was the reaction more severe when the dose was

increased, or less severe when the dose was decreased?

9) Did the patient have a similar reaction to the same or

similar drug in any previous exposure?

+1 0 0

+1 0 0

10) Was the ADR confirmed by any objective evidence? +1 0 0


Bradford-Hill Criteria


• Consistency


• Temporality

• Biological gradient

• Plausibility


• Experimental evidence



Case Example -

Exenatide and Pancreatitis


A 64-year-old, nonalcoholic woman with NIDDM presented with a

1-month history of epigastric pain beginning 2 days after

starting exenatide. Serum lipase concentration was 2700 U/L

(reference range, 114–320 U/L), and serum amylase

concentration was 131 U/L (reference range, 30–110 U/L).

Liver function test results, lipid profile, and serum creatinine

concentration were normal. Abdominal computed tomography

(CT) showed changes consistent with pancreatitis, and the

gallbladder was absent. Exenatide was discontinued.

Conservative therapy resulted in rapid resolution of symptoms,

normal lipase concentration (151 U/L), and normal findings

from CT of the pancreas 90 days later.

Ayoub W., et al. Exenatide-induced Acute Pancreatitis. Endocrine Practice. 2010;16(1):80-83.


Case Example -

Exenatide and Pancreatitis i - 2

• A search in FDA’s AERS database to identify additional cases of AP in

association with exenatide and other antidiabetics

Reporting rate was compared with the RR of comparator antidiabetics

Reporting rates are typically based on case counts divided by some measure

of drug’s utilization

• If reporting rate of an event is > than background rate we can say that there

is a potential association between the drug & AE

Reporting rate for exenatide was higher compared to other

antidiabetics labeling change

-Ahmad SR, Swann J. N Engl J Med 2008;358:1971-2.

-Graham DJ, Ahmad SR, Piazza Hepp TD. Spontaneous Reporting – USA. Pp. 237-247. In: Mann R, Andrews E. (eds.). Pharmacovigilance. 2nd ed.


-Ahmad SR, Graham DJ. Exenatide and acute pancreatitis: Time to event analysis. Pharmacoepidemiol Drug Saf 2008;17:S132-3.

-Ahmad SR, Swann J. Reporting rates of hemorrhagic/necrotizing pancreatitis (HNP) in association with selected newer antidiabetics.

Pharmacoepidemiol Drug Saf 2009;18:S79-80.


Drug Withdrawals because of Safety Reasons

Drug Name Year Reason

Terfenadine (Seldane, Triludan) 1998 Drug interactions/Cardiac arrhythmias

Cisapride (Propulsid) 1999 Drug interactions/arrhythmias

Astemizole (Hismanal) 1999 Drug interactions/Cardiac arrhythmias

Troglitazone (Rezulin) 2000 Hepatotoxicity

Alosetron (Lotronex) 2000 Ischemic colitis; reintroduced 2002 on a restricted basis

Phenylpropanolamine yp p

2000 Hemorrhagic stroke

(Propagest, Dexatrim)

Cerivastatin (Baycol, Lipobay) 2001 Rhabdomyolysis

Lumiracoxib (Prexige) 2007 Hepatotoxicity

Rimonabant (Acomplia) 2008 Depression/suicide

Sibutramine (Reductil/Meridia) 2010 Cardiovascular outcome

Rosiglitazone (Avandia) 2010 Myocardial infarction/death. Still available in the U.S.



Spontaneous reporting systems are the most

common methodology used to generate and

detect new and rare signals

•In spite of challenges in causality

assessment, AE reports submitted to

spontaneous reporting systems have been

instrumental in most safety-related drug

withdrawals and labeling changes


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