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![Page 1: Postmarketing Safety Assessment of Osteonecrosis of the Jaw Pamidronate & Zoledronic Acid Division of Drug Risk Evaluation Office of Drug Safety FDA Carol.](https://reader035.fdocuments.net/reader035/viewer/2022081421/56649e7f5503460f94b82b9b/html5/thumbnails/1.jpg)
Postmarketing Safety Assessment of Osteonecrosis of the Jaw Pamidronate & Zoledronic Acid
Division of Drug Risk Evaluation Office of Drug Safety
FDACarol Pamer, R.Ph.
Carolyn McCloskey, M.D., M.P.H.March 4, 2005
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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
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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
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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
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Evaluation of CasesGeneral 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
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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
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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
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Pamidronate & Zoledronic Acid
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Spontaneous ReportsPamidronate & 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
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Spontaneous Reports of ONJ General Characteristics
Drug(s), as mentioned in reports (n = 654 reports) Percentage of TotalPamidronate only (n=136) 21 %Pamidronate and Zoledronic Acid, sequential use (n = 187) 28 %Zoledronic acid only (n = 318) 49 %Pamidronate, Zoledronic acid and/or hx otherbisphosphonate mentioned (n =13)
2 %
TOTAL 100%
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Spontaneous Reports of ONJ (cont.) General Characteristics
Primary Indication(s) for use Percentage of TotalMultiple Myeloma (n=214) 33%--MM and hx of other cancer (n = 9) 1%Breast Cancer (n = 169) 26%--BC and hx of other cancer (n = 2) < 1%Prostate Cancer (n = 43) 6%--PC and hx of other cancer (n =2) < 1%Cancer, unspecified or other type (n =107) 16%Osteoporosis, osteopenia, “osteolysis” (n = 7) 1%Unknown or other (n = 101) 15%TOTAL 100%
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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
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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
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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
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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
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Epidemiological Perspective
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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
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Potential Study Data Sources
• Oncology Clinics
– IV Bisphosphonate-Exposed Population
• Dentists & Oral Surgeons– Cases of ONJ
• Registry of all cases identified in different settings
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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
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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
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Acknowledgements
• Mark Avigan, M.D., C.M.
• Jennie Chang, Pharm.D.
• Lanh Green, Pharm.D., M.P.H.
• Mary Willy, Ph.D.