Postmarketing Safety Assessment of Osteonecrosis of the Jaw Pamidronate

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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

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