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.