1. Using the FDA’s Adverse Event Reporting System (AERS) in Postmarketing Surveillance Joyce P. Weaver, Pharm.D., BCPS Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research Food and Drug Administration Joyce P. Weaver, Pharm.D., BCPS Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research Food and Drug Administration Center for Drug Evaluation and Research

2. DSaRM Advisory Committee May 18, 2005 2OutlineOutline Description of postmarketing surveillance using AERS – Case reports, case series – Safety evaluator role Case studies – Terfenadine: QT/TdP – Salmeterol: Asthma exacerbation – Valdecoxib: SJS & CV events Summary Description of postmarketing surveillance using AERS – Case reports, case series – Safety evaluator role Case studies – Terfenadine: QT/TdP – Salmeterol: Asthma exacerbation – Valdecoxib: SJS & CV events Summary

3. DSaRM Advisory Committee May 18, 2005 3 Limitations of Premarketing Clinical Trials Size of the Patient Population Studied Narrow Population - often not providing for special groups: –Elderly, children, women, ethnicity, use in pregnancy, co-morbidities Narrow Indications Studied Short Duration –Not reflective of chronic use Size of the Patient Population Studied Narrow Population - often not providing for special groups: –Elderly, children, women, ethnicity, use in pregnancy, co-morbidities Narrow Indications Studied Short Duration –Not reflective of chronic use

4. DSaRM Advisory Committee May 18, 2005 4 Components of FDA’s Postmarketing Surveillance for Drugs Drug Utilization data: * Outpatient * Inpatient * Longitudinal External HC databases : *General popn *Special popn’s Passive Surveillance (AERS) Background Incidence Rates Active Surveillance

5. DSaRM Advisory Committee May 18, 2005 5 Adverse Event Reporting System (AERS) Voluntary, “spontaneous” reporting system – Sponsors required to report (21CFR314.80) Computerized database Origin 1969; > 3 million reports Contains human drug and “therapeutic” biologic reports exception = vaccines (VAERS) Adverse Event Reporting System (AERS) Voluntary, “spontaneous” reporting system – Sponsors required to report (21CFR314.80) Computerized database Origin 1969; > 3 million reports Contains human drug and “therapeutic” biologic reports exception = vaccines (VAERS) AERS

6. DSaRM Advisory Committee May 18, 2005 6 AERS Strengths Includes all U.S. marketed products Simple, inexpensive reporting system Detection of events not seen in clinical trials (“signal generation”) Especially good for events with rare background rate, short latency Case series evaluation: identification of trends, drug indication, population, and other clinically significant emerging safety concerns Includes all U.S. marketed products Simple, inexpensive reporting system Detection of events not seen in clinical trials (“signal generation”) Especially good for events with rare background rate, short latency Case series evaluation: identification of trends, drug indication, population, and other clinically significant emerging safety concerns

7. DSaRM Advisory Committee May 18, 2005 7 AERS Limitations Duplicate reporting occurs Extensive underreporting Quality of report is variable Reporting biases Actual numerator (# of events in pop) & denominator (# of exposed patients in pop) not known Difficult to attribute events with a high background rate, confounders, long latency Duplicate reporting occurs Extensive underreporting Quality of report is variable Reporting biases Actual numerator (# of events in pop) & denominator (# of exposed patients in pop) not known Difficult to attribute events with a high background rate, confounders, long latency

8. DSaRM Advisory Committee May 18, 2005 8 AERS cases unlike clinical trials Large Patient Population including: Elderly, children, women, ethnic groups, pregnancy, co-morbidities Wider indications than those studied Chronic use Complicated patients, complicated AERS cases Large Patient Population including: Elderly, children, women, ethnic groups, pregnancy, co-morbidities Wider indications than those studied Chronic use Complicated patients, complicated AERS cases

9. DSaRM Advisory Committee May 18, 2005 9 Safety Evaluator Daily “in-box” review of reports –all serious unlabeled; –serious direct; –some periodic; and –“enhanced pharmacovigilance” reports Periodic safety reports Main mission: identify and monitor “Safety Signals” Work with ODS epidemiologists, medical officers in OND Daily “in-box” review of reports –all serious unlabeled; –serious direct; –some periodic; and –“enhanced pharmacovigilance” reports Periodic safety reports Main mission: identify and monitor “Safety Signals” Work with ODS epidemiologists, medical officers in OND

10. DSaRM Advisory Committee May 18, 2005 10 Safety Signals New unlabeled adverse events (especially serious events) New interactions Increased severity or specificity of a labeled event Newly identified at-risk population New unlabeled adverse events (especially serious events) New interactions Increased severity or specificity of a labeled event Newly identified at-risk population

11. DSaRM Advisory Committee May 18, 2005 11 Use of Data Mining* Systematically “mine” AERS using mathematical tools to identify higher-than- expected frequency of product-event combinations Tool for hypothesis generation or support for further work on a hypothesis Supplement “in-box” review Does not replace expert clinical case review and interpretation *http://www.fda.gov/cder/guidance/6359OCC.htm Systematically “mine” AERS using mathematical tools to identify higher-than- expected frequency of product-event combinations Tool for hypothesis generation or support for further work on a hypothesis Supplement “in-box” review Does not replace expert clinical case review and interpretation *http://www.fda.gov/cder/guidance/6359OCC.htm

12. DSaRM Advisory Committee May 18, 2005 12 Exploring Possible Safety Signals in AERS A safety question is raised: –in-box report –data mining results –periodic safety report –study results –medical literature –NDA safety database –outside inquiry –Congressional inquiry –etc A safety question is raised: –in-box report –data mining results –periodic safety report –study results –medical literature –NDA safety database –outside inquiry –Congressional inquiry –etc

13. DSaRM Advisory Committee May 18, 2005 13 Exploring Possible Safety Signals in AERS Screen AERS for cases Analyze data mining Medical literature Evaluate cases Screen AERS for cases Analyze data mining Medical literature Evaluate cases

14. DSaRM Advisory Committee May 18, 2005 14 Case Search Strategy How focused should the search be? Search AERS @ MedDRA PT, HLT, HLGT, or SOC level Other case sources: literature, WHO, foreign regulators, studies Use Case Definition to refine series How focused should the search be? Search AERS @ MedDRA PT, HLT, HLGT, or SOC level Other case sources: literature, WHO, foreign regulators, studies Use Case Definition to refine series

15. DSaRM Advisory Committee May 18, 2005 15 Good Case Report* Description of event Suspected and concomitant products therapy details Patient characteristics (e.g., age, sex), baseline medical condition, co- morbid condition, family Hx, other risk factors Documentation of the diagnosis Dechallenge and rechallenge *http://www.fda.gov/cder/guidance/6359OCC.htm Description of event Suspected and concomitant products therapy details Patient characteristics (e.g., age, sex), baseline medical condition, co- morbid condition, family Hx, other risk factors Documentation of the diagnosis Dechallenge and rechallenge *http://www.fda.gov/cder/guidance/6359OCC.htm

16. DSaRM Advisory Committee May 18, 2005 16 Assessing Causality * For any individual case report, it is rarely possible to know whether the event was caused by a drug product Appropriate temporal relationship Relationship between disease, drug exposure, adverse event Concomitant drug use Medical, laboratory findings *http://www.fda.gov/cder/guidance/6359OCC.htm For any individual case report, it is rarely possible to know whether the event was caused by a drug product Appropriate temporal relationship Relationship between disease, drug exposure, adverse event Concomitant drug use Medical, laboratory findings *http://www.fda.gov/cder/guidance/6359OCC.htm

17. DSaRM Advisory Committee May 18, 2005 17 Assessing Causality (2) Dechallenge, rechallenge Plausibility Known drug class effects Support from pre-clinical studies, clinical trials Absence of alternative explanations Dechallenge, rechallenge Plausibility Known drug class effects Support from pre-clinical studies, clinical trials Absence of alternative explanations

18. DSaRM Advisory Committee May 18, 2005 18 Assessing Causality (3) Look for trends & patterns of events (age, sex, time to onset, dose, severity, outcome) Identify risk factors Evaluate strength of evidence for causal relationship Assess clinical significance Look for trends & patterns of events (age, sex, time to onset, dose, severity, outcome) Identify risk factors Evaluate strength of evidence for causal relationship Assess clinical significance

19. DSaRM Advisory Committee May 18, 2005 19 Challenges in Evaluating Case Reports Attribution difficult for events with high background rate Events with long latency may not be easily attributed to drug exposure (cancer) Cases often confounded by other possible etiologies Absence of complete diagnostic information Attribution difficult for events with high background rate Events with long latency may not be easily attributed to drug exposure (cancer) Cases often confounded by other possible etiologies Absence of complete diagnostic information

20. DSaRM Advisory Committee May 18, 2005 20 Developing a Case Series Using AERS & published literature Using knowledge of the clinical course of the disease Using defined case criteria Thorough database search strategies based on coding terminology using Medical Dictionary for Regulatory Activities (MedDRA) Using AERS & published literature Using knowledge of the clinical course of the disease Using defined case criteria Thorough database search strategies based on coding terminology using Medical Dictionary for Regulatory Activities (MedDRA)

21. DSaRM Advisory Committee May 18, 2005 21 Developing a Case Series (2) May use case definitions to facilitate the development of the case series to provide reasonable evidence of a product related adverse event Case definitions apply clinical features of event to AERS/MedDRA Incomplete info affects application of case definition May use case definitions to facilitate the development of the case series to provide reasonable evidence of a product related adverse event Case definitions apply clinical features of event to AERS/MedDRA Incomplete info affects application of case definition

22. DSaRM Advisory Committee May 18, 2005 22 Case Definition-Aplastic anemia* Clinical diagnosis of aplastic anemia; or The presence of two of the following criteria AND bone marrow biopsy shows severe hypocellularity, or moderate hypocellularity with <30% of residual hematopoietic cells.  WBC <3500/mm 3  Platelets <55,000/mm 3  Hemoglobin <10 g/dL with a reticulocyte count of <30,000/mm 3 (<30 x 10 9 /L) * Excerpt from ODS internal aplastic anemia case definition Clinical diagnosis of aplastic anemia; or The presence of two of the following criteria AND bone marrow biopsy shows severe hypocellularity, or moderate hypocellularity with <30% of residual hematopoietic cells.  WBC <3500/mm 3  Platelets <55,000/mm 3  Hemoglobin <10 g/dL with a reticulocyte count of <30,000/mm 3 (<30 x 10 9 /L) * Excerpt from ODS internal aplastic anemia case definition

23. DSaRM Advisory Committee May 18, 2005 23 Case Definition-Aplastic anemia* If a bone marrow biopsy has not been performed or a bone marrow aspiration only has been undertaken, any diagnosis of aplastic anemia should be regarded as presumed or unconfirmed. In these circumstances, it is better to report the bicytopenia or pancytopenia that is observed. * Excerpt from ODS internal aplastic anemia case definition

24. DSaRM Advisory Committee May 18, 2005 24 AERS Search-Aplastic anemia* Marrow depression and hypoplastic anemia (HLT) Additional MedDRA HLTs: –Blood counts NEC; –Bone marrow and immune tissue analyses; –Platelet analyses; –Red blood cell analyses; and –White blood cell analyses. HLT=Higher Level Term *Excerpt from ODS internal aplastic anemia case definition Marrow depression and hypoplastic anemia (HLT) Additional MedDRA HLTs: –Blood counts NEC; –Bone marrow and immune tissue analyses; –Platelet analyses; –Red blood cell analyses; and –White blood cell analyses. HLT=Higher Level Term *Excerpt from ODS internal aplastic anemia case definition

25. DSaRM Advisory Committee May 18, 2005 25 Safety Evaluator Role Cases submitted to FDA Cases searched for safety issues –Emerging role for data mining AERS searched for additional cases with the same safety issue –Broad search to find cases –Winnow using case definition –Look for “good” cases Case series (use case definition) Consult with epidemiologists Cases submitted to FDA Cases searched for safety issues –Emerging role for data mining AERS searched for additional cases with the same safety issue –Broad search to find cases –Winnow using case definition –Look for “good” cases Case series (use case definition) Consult with epidemiologists

26. DSaRM Advisory Committee May 18, 2005 26 AERS Case Studies Terfenadine-diagnosis, attribution Salmeterol-confounding by indication, incidence rates Valdecoxib-2 case studies – rare, easily diagnosed event – event with high background rate Terfenadine-diagnosis, attribution Salmeterol-confounding by indication, incidence rates Valdecoxib-2 case studies – rare, easily diagnosed event – event with high background rate

27. DSaRM Advisory Committee May 18, 2005 27 Terfenadine Case Study  Terfenadine  approved 1985  withdrawn 1998  QT/QTc/Torsades-most cases reported > 5 years after approval http://www.fda.gov/bbs/topics/ANSWERS/ANS00853.html http://www.fda.gov/medwatch/SAFETY/seldane.htm  Terfenadine  approved 1985  withdrawn 1998  QT/QTc/Torsades-most cases reported > 5 years after approval http://www.fda.gov/bbs/topics/ANSWERS/ANS00853.html http://www.fda.gov/medwatch/SAFETY/seldane.htm

28. DSaRM Advisory Committee May 18, 2005 28 Steps Required for Reporting Diagnosis of event Attribution of event to drug exposure Reporting of event  QT/QTc/Torsades w/ terfenadine- difficulty with diagnosis and attribution Diagnosis of event Attribution of event to drug exposure Reporting of event  QT/QTc/Torsades w/ terfenadine- difficulty with diagnosis and attribution

29. DSaRM Advisory Committee May 18, 2005 29 Salmeterol Case Study  approved 1994  early postmarketing reports of asthma exacerbation  cases confounded by indication  AERS data raise the question: is the incidence of asthma exacerbation greater with salmeterol? http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01192.html  approved 1994  early postmarketing reports of asthma exacerbation  cases confounded by indication  AERS data raise the question: is the incidence of asthma exacerbation greater with salmeterol? http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01192.html

30. DSaRM Advisory Committee May 18, 2005 30 Salmeterol Case Study  Salmeterol Multi-center Research Trial (SMART)  SMART stopped ~ 2 years ago after partially answering this question http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01248.html  Salmeterol Multi-center Research Trial (SMART)  SMART stopped ~ 2 years ago after partially answering this question http://www.fda.gov/bbs/topics/ANSWERS/2003/ANS01248.html

31. DSaRM Advisory Committee May 18, 2005 31 Valdecoxib Case Study 1 Valdecoxib, a COX-2 selective NSAID, marketed 2/2002 By 8/2002, 11 cases of SJS/TEN reported to AERS Information quickly incorporated into labeling http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html Valdecoxib, a COX-2 selective NSAID, marketed 2/2002 By 8/2002, 11 cases of SJS/TEN reported to AERS Information quickly incorporated into labeling http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html

32. DSaRM Advisory Committee May 18, 2005 32 Valdecoxib Case Study 1 Rare, easily diagnosed event Able to compare reporting rates between others in class at a similar point in marketing and to background rates Rare, easily diagnosed event Able to compare reporting rates between others in class at a similar point in marketing and to background rates

33. DSaRM Advisory Committee May 18, 2005 33 Valdecoxib Case Study 2 Thromboembolic events (TEEs) – Common events – TEEs listed in labeling from clinical trials – Some TEEs reported to AERS – AERS data not particularly helpful http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html Thromboembolic events (TEEs) – Common events – TEEs listed in labeling from clinical trials – Some TEEs reported to AERS – AERS data not particularly helpful http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01331.html

34. DSaRM Advisory Committee May 18, 2005 34 Summary: Using AERS for Postmarketing Surveillance Data from clinical practice Relies on diagnosis, attribution, reporting by healthcare providers Absence of complete diagnostic information Data from clinical practice Relies on diagnosis, attribution, reporting by healthcare providers Absence of complete diagnostic information

35. DSaRM Advisory Committee May 18, 2005 35 Summary: Using AERS for Postmarketing Surveillance (2) Especially useful for rare, easily diagnosed events Less useful for attribution of events: –with high background rates –confounded by indication –confounded by other etiologies –with long latency following drug exposure Cannot establish frequency of events Especially useful for rare, easily diagnosed events Less useful for attribution of events: –with high background rates –confounded by indication –confounded by other etiologies –with long latency following drug exposure Cannot establish frequency of events

36. DSaRM Advisory Committee May 18, 2005 36 DDRE Safety Evaluators –Janos Bacsanyi –Renan Bonnel –Jennie Chang –Evelyne Edwards –Evelyn Farinas –Charlene Flowers –Paula Gish –Lanh Green –Claudia Karwoski –Cindy Kortepeter –Hyon Kwon –Lauren Lee –Susan Lu –Janos Bacsanyi –Renan Bonnel –Jennie Chang –Evelyne Edwards –Evelyn Farinas –Charlene Flowers –Paula Gish –Lanh Green –Claudia Karwoski –Cindy Kortepeter –Hyon Kwon –Lauren Lee –Susan Lu –Ann Mackey –Carol Pamer –Kate Phelan –Marilyn Pitts –Martin Pollack –Robert Pratt –Adrienne Rothstein –Sonny Saini –Daniela Sanders –Mary Ross Southworth –Joslyn Swann –Melissa Truffa –Ron Wassel