1. Postmarketing Safety Assessment of Osteonecrosis of the Jaw Pamidronate & Zoledronic Acid Division of Drug Risk Evaluation Office of Drug Safety FDA Carol Pamer, R.Ph. Carolyn McCloskey, M.D., M.P.H. March 4, 2005

2. 2 Outline Overview of Adverse Event Reporting System (AERS) and safety signal review Summary of pamidronate & zoledronic acid cases of osteonecrosis of the jaw (ONJ) Issues concerning review of AERS reports Considerations for future studies of ONJ

3. 3 AERS (Adverse Event Reporting System) FDA has maintained a database of spontaneous reporting system case reports since 1969 Number of modifications made, including coding dictionary, search interface, and expanded database capacity

4. 4 Factors Affecting Reporting Nature of the adverse event Type of drug product and indication Length of time on market Media attention Extent and quality of manufacturer’s surveillance system Prescription or over-the-counter drug status Reporting regulations

5. 5 Evaluation of Cases General Approach Adverse event occurrence in expected time Absence of symptoms prior to exposure Positive dechallenge or rechallenge Consistent with pharmacological effects Consistent with known effects in the class Support from pre-clinical studies, clinical trials Absence of alternative explanations

6. 6 Limitations of Spontaneous Reports Passive surveillance –Underreporting occurs and is variable from drug to drug and over time Reporting bias exists Quality of the reports is variable and often incomplete Duplicate reporting occurs Can not reliably estimate incidence rates of events; numerator uncertain, denominator can only be projected

7. 7 Best Applications of AERS Safety signal generation and descriptive case series Events that are linked to specific diagnoses Events with a serious outcome that rarely occur in an untreated population Events with a short-to-moderate latency period following exposure

8. 8 Pamidronate & Zoledronic Acid

9. 9 Spontaneous Reports Pamidronate & Zoledronic Acid Case series of postmarketing spontaneous reports Drugs: Pamidronate, Zoledronic acid Database search terms related to diagnosis of osteonecrosis/osteomyelitis Cut-off date: January 13, 2005 Jaw involvement only, consistent w/ONJ

10. 10 Spontaneous Reports of ONJ General Characteristics

11. 11 Spontaneous Reports of ONJ (cont.) General Characteristics

12. 12 Difficulties in Assessing Cases Increased reporting likely due to DHP letter, publications, presentations, Confounding factors present in many Assessment of dechallenge, rechallenge confounded Determining time to onset of event

13. 13 Confounding Factors Most reports listed one or more of the following: –Drugs : corticosteroids, other bisphosphonates, thalidomide, cancer chemotherapy –Procedures: tooth extractions –Medical conditions: cancer Missing information in others

14. 14 Limitations of Dechallenge Assessment ONJ did not quickly resolve, regardless of therapies and drug dechallenge Most patients had continuing symptoms as of last follow-up obtained Multiple therapeutic interventions received by most patients Persistence of bisphosphonates in bone

15. 15 Determining Time to Onset Many patients developed symptoms after dental procedure (tooth extraction) w/lesion that did not heal Case series only included diagnosed ONJ, not symptoms alone (e.g., jaw pain, tooth loss) In many cases, information on early symptoms was missing

16. 16 Epidemiological Perspective

17. 17 Challenges of Studying ONJ ONJ rare event –Difficult to get background rates in general population; difficult to monitor trends Difficulty in identifying cases with ONJ in databases –No specific ICD-9 code Difficulty obtaining data on drug exposure Lack of suitable control/comparison groups

18. 18 Potential Study Data Sources Oncology Clinics –IV Bisphosphonate-Exposed Population Dentists & Oral Surgeons –Cases of ONJ Registry of all cases identified in different settings

19. 19 Considerations for Future Studies Limited utility of available data –Pharmacoepidemiological or postmarketing surveillance data Randomized, controlled trial data may be superior to data from these sources Use of registry to collect cases might be explored

20. 20 Conclusion Cases of ONJ reported in association with these drugs represent a highly plausible signal –Site specificity –Number of reports submitted to AERS –Temporal association –Serious outcome To identify contributing risk factors other studies are necessary

21. 21 Acknowledgements Mark Avigan, M.D., C.M. Jennie Chang, Pharm.D. Lanh Green, Pharm.D., M.P.H. Mary Willy, Ph.D.