1. Challenges in Causality Assessment in Spontaneous Reporting Systems Syed Rizwanuddin Ahmad, MD, MPH, FISPE, FCP 3 rd ICIUM, Antalya, Turkey November 2011

2. 2 Disclaimer These are my personal views not shared by the U.S. FDA or the U.S. government I am not representing the FDA No conflict of interest to declare

3. 3 Outline Spontaneous Reporting Systems –What –Why –Strengths/Limitations Evidence to Suggest Causal Relationship Approaches to Causality Assessment –WHO-UMC –Naranjo –Bradford Hill Case example Safety-related Drug Withdrawals Conclusions

4. 4 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.

5. 5 Why Spontaneous Reporting? Limitations of Pre-marketing Clinical trials Too small --- 2,000-5,000 Too short --- <1 yr of exposure Too narrow --- restricted population

6. 6 Spontaneous Reporting – Strengths/Limitations Strengths Inexpensive/All patients/drugs Generation of hypothesis and signals Good for identifying rare, serious drug-induced events with low background rate Limitations Passive surveillance Adverse event recognition Underreporting Duplicate reporting Report quality Reporting biases

7. 7 Factors to Consider in Causal Assessment 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)

8. 8 Approaches to Causality Assessment Expert Judgement –individual assessments –no standardized tool Algorithms –sets of specific questions with or without scores Probabilistic or Bayesian methods –Is based on assigning a prior probability to an event of interest Agbabiaka 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.

9. 9 WHO UMC Causality Categories Certain Probable/Likely Possible Unlikely Conditional/Unclassified Unassessable/Unclassifiable

10. 10 The Naranjo ADR Probability Scale QuestionsYesNoDon’t Know 1) Are there previous conclusive reports on this reaction? +100 2) Did the ADR appear after the suspected drug was administered? +20 3) Did the ADR improve when the drug was discontinued?+100 4) Did the ADR appear with re-challenge?+20 5) Are there alternative causes for the ADR?+20 6) Did the reaction appear when placebo was given?+10 7) Was the drug detected in blood at toxic levels?+100 8) Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +100 9) Did the patient have a similar reaction to the same or similar drug in any previous exposure? +100 10) Was the ADR confirmed by any objective evidence?+100

11. 11 Bradford-Hill Criteria Strength Consistency Specificity Temporality Biological gradient Plausibility Coherence Experimental evidence Analogy

12. 12 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.

13. 13 Case Example - Exenatide and Pancreatitis - 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. 2007 -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.

14. 14 Drug Withdrawals because of Safety Reasons Drug NameYearReason TerfenadineTerfenadine (Seldane, Triludan)1998Drug interactions/Cardiac arrhythmias CisaprideCisapride (Propulsid)1999Drug interactions/arrhythmias AstemizoleAstemizole (Hismanal)1999Drug interactions/Cardiac arrhythmias TroglitazoneTroglitazone (Rezulin)2000Hepatotoxicity AlosetronAlosetron (Lotronex)2000Ischemic colitis; reintroduced 2002 on a restricted basis Phenylpropanolamine Phenylpropanolamine (Propagest, Dexatrim) 2000Hemorrhagic stroke CerivastatinCerivastatin (Baycol, Lipobay)2001Rhabdomyolysis LumiracoxibLumiracoxib (Prexige)2007Hepatotoxicity RimonabantRimonabant (Acomplia) 2008Depression/suicide SibutramineSibutramine (Reductil/Meridia)2010Cardiovascular outcome RosiglitazoneRosiglitazone (Avandia)2010Myocardial infarction/death. Still available in the U.S.

15. 15 Conclusions 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