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PPT - Zoledronic Acid: Development Overview PPT - Zoledronic Acid: Development Overview Presentation Transcript

  • Osteonecrosis of the Jaw (ONJ) and Bisphosphonates Oncologic Drugs Advisory Committee March 4, 2005 Novartis Pharmaceuticals
  • Novartis Presentation
    • ONJ Reported in Bisphosphonate-Treated Patients — An Overview
    • D. Young, MD Novartis Pharmaceuticals Corp
    • Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease
    • J. Berenson, MD Institute for Myeloma & Bone Cancer Research
  • External Advisors* * The views expressed by these individuals are their own and not necessarily those of Novartis Oncology. Chief, Division of Oral & Maxillofacial Surgery Long Island Jewish Medical Center Salvatore Ruggiero, DMD, MD Professor Emeritus Biostatistics Department University of Washington Lloyd Fisher, PhD Assistant Professor Department of Oral/Maxillofacial Surgery Columbia University Regina Landesberg, DMD, PhD Assistant Professor Department of Endocrinology University of Texas, MD Anderson Cancer Center Ana Hoff, MD Medical & Scientific Director Institute for Myeloma and Bone Cancer Research James Berenson, MD
  • Summary of Presentation (1)
    • Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma
    • Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002
      • ONJ remains poorly understood
      • Frequency estimates variable; however, ONJ appears to be an infrequent occurrence
      • Insufficient evidence to support difference between Zometa and Aredia
  • Summary of Presentation (2)
    • Novartis is committed to
      • Ensuring patient safety
      • Enhancing understanding of ONJ through additional clinical investigation
      • Continuing dissemination of evolving information and guidance to health-care providers and patients
    • Balance of benefit-risk for Zometa ® and Aredia ® remains favorable
  • Metastatic Bone Disease is an Important Clinical Problem in Cancer Patients 1. Jemal A, et al. CA Cancer J Clin. (2005) 2. Coleman RE. Cancer Treat Rev . (2001) 3. DeVita VT, et al. Cancer Principles & Practice of Oncology.  Lippincott Williams & Wilkins. NY (2005)  4. Shoup M, et al. J Am Coll Surg. (2003)   Annual estimate new cases - US, x1000 1 Incidence of bone metastases, % 2 Median survival, months 2-4 Myeloma 16 70 - 95 50 - 67 Renal 36 20 - 25 8 - 21 Melanoma 60 14 - 45 5 - 31 Bladder 63 40 9 - 20 Thyroid 26 60 49 Lung 173 30 - 40 17 - 33 Breast 213 65 - 75 18 - 24 Prostate 232 65 - 75 16 - 24
  • Zometa ® and Aredia ® in Metastatic Bone Disease
    • Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma
    • Zometa is effective in prostate cancer, whereas Aredia is not. Unlike Aredia, Zometa was tested and showed efficacy in other tumor types such as lung, renal, colorectal, and bladder cancer
    • Benefit-risk profile is well established, with known, manageable renal adverse events
    • Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions* , †
    * Hillner, et al. J Clin Oncol. 2003;21:4042-4057. † Berenson, et al. J Clin Oncol. 2002;20:3719-3736 .
  • Osteonecrosis (ON): Background
    • Etiology and pathogenesis not well understood
      • Impaired blood supply leading to ischemia proposed as pathologic process preceding ON *
    • Most commonly seen in hip †
    • Multiple risk factors suspected, including cancer and cancer treatments
    • Bisphosphonates used to treat ON with some success ‡
    (NS10-02) Zometa Core presentation ONJ (CO).ppt * Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis , AAOS, 105-116 † Assouline-Dayan et al (2002). Semin Arthritis Rheum ; 32:94-124. ‡ Agarwala S et al. Rheumatology (Oxford) . 2002.
  • Osteonecrosis of the Jaw (ONJ)
    • Involves portion of jaw bone (maxilla or mandible)
      • No consensus on diagnostic criteria for ONJ
    • Incidence unknown
    • Pathogenesis not understood
      • Similar risk factors to ON suggested
    • Risk factors specific to jaw bones may play a role
      • Exposure to external environment through teeth
      • Risk of trauma from repeated dental procedures
    (NS3-19) July15,2004FDAONImeetingslides.doc
  • ONJ in Cancer Patients
    • Awareness was limited, now growing
    • ONJ incidence in cancer patients unknown
    • Few literature reports before 2003 1-3
      • Most often reported - osteoradionecrosis (ORN) following head and neck radiation
        • Reported incidence of 8.2% 4
    • Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002
    1. Winer et al. J Am Dent Assoc . (1972) 2. Schwartz. Head Neck Surg . ( 1982) 3. Sung et al. Spec Care Dent . (2002) 4. Reuther et al. Oral Max Surgery . (2003) (NS10-04) Zometa Core presentation ONJ (CO).ppt - Slide 4
  • Review of Available Data on ONJ
    • Clinical trials
    • Spontaneous reports to Novartis
    • Literature
    • MD Anderson Cancer Center study
  • Limitations in Existing Datasets Available Datasets
    • Controlled clinical trials
      • Most meaningful, quality assured, source verified, reliable
      • Lack of awareness of ONJ, follow-up to be updated
    • Spontaneous reports (Novartis database)
      • Incomplete case data
      • Diagnostic, selection, and reporting biases
    • Literature
      • Reports: anecdotal, completeness of data unknown
      • Web survey: uncontrolled, anonymous, selection bias, QA, and source verification
    • MDACC
      • Planned retrospective review
      • Ongoing, 25% completed
  • Review of Available Data on ONJ
    • Clinical trials
    • Spontaneous reports to Novartis
    • Literature
    • MD Anderson Cancer Center study
  • Screening for Potential ONJ Cases Novartis Databases Osteonecrosis Osteomyelitis Osteomyelitis drainage Osteomyelitis chronic Osteomyelitis acute Necrosis Bone infarction Aseptic necrosis bone Oral surgery Maxillofacial operation Mandibulectomy Jaw operation Jaw lesion excision Bone debridement
    • Screening results medically reviewed to identify ONJ
    Tertiary sequestrum Sequestrectomy Secondary sequestrum Primary sequestrum
    • Novartis used a wide net of 18 MedDRA terms:
    • No current MedDRA term
    • Lack of clear definition poses a challenge
  • Novartis Current “Case Definition”
    • Any case or report suggestive of the following to maxillofacial area was considered “ONJ”
      • Osteonecrosis
      • Osteomyelitis
      • Exposed bone
      • Bone necrosis
      • Sequestrum
      • Impaired healing post-dental procedure
  • Pivotal Trials: Study Design and Follow-up (1) 25 *Dose of Zometa ® is variable, Aredia ® dose 90 mg. N/A = Not available; Z = Zometa; A = Aredia. 90 1 51 A 90 1, H&N 8 1 47 Z 8 4 1 40 Z 4 HCM 037 90 1 52 A 90 8 1 51 Z 8 4 1 46 Z 4 HCM 036 N/A 10 75 A 90 1, MM N/A 40 30 Z/A* 1, MM 40 10 59 Z 4/8 20 10 62 Z 2/8 4 10 62 Z 0.4/8 MM and BC 007 0 10 197 Placebo 1440 13 185 A 90 BC-Chemotherapy P19 0 15 190 Placebo 1440 17 182 A 90 BC-hormonal P18 0 15 187 Placebo 1, MM 1485 18 205 A 90 MM P12 ONJ Cum dose Median, mg Follow-up Median, mo N Treatment, mg Patient population Trial
  • Pivotal Trials: Study Design and Follow-up (2) 25 Z = Zometa ® ; A = Aredia ® . 0 13 113 Placebo 52 13 114 Z 4 BC 1501 36 13 115 Open label phase 0 24 197 Placebo 1, PC 110 24 152 Z 8/4 54 16 49 Z 4 HRPC without bone metastases 704 0 10 208 Placebo 96 10 218 Z 8/4 58 13 214 Z 4 HRPC with bone metastases 039 0 5 247 Placebo 40 5 265 Z 8/4 24 6 254 Z 4 Lung cancer and other solid tumors (-BC/PC) 011 1,260 13 556 A 90 104 13 524 Z 8/4 1, MM 56 14 563 Z 4 BC and MM 010 ONJ Cum dose Median, mg Follow-up Median, mo N Treatment, mg Patient population Trial
  • Pivotal Trials: ONJ Cases* (NS4-13) Zometa Briefing Document January 2005.doc Table 4-4 * Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501 Aredia: P12, P18, P19 † Includes 1 patient who received Zometa 0.4 mg ×10 2730 Zometa ® (total) MM MM 2 † 1334 Aredia ® 90 mg 0 1347 Placebo PC MM 2 1227 8 + 4 mg H & N 1 219 8 mg MM 1 1284 4 mg Tumor type Number of ONJ cases Number of patients Treatment
  • ONJ Cases in Pivotal Trials (1) MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis 22 mo 14 mo 28 mo TTE Grade 2-3 Mandibular fracture Tooth abscess, HZV, Candida, steroids, chemo Z 0.4 A 90 ASN/Mandible 1999 1. MM Grade 2 Unknown Poor dentition, steroids, chemo A 90 OM/Jaw 1992 2. MM OM/Jaw 2001 Diagnosis/ site Year Grade 1 Continued CTC grade/ outcome Dental infection, chemo, steroids Risk factors 3. MM Case Z 4 Drug, mg
  • ONJ Cases in Pivotal Trials (2) MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer. OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis CTC grade/ outcome Risk factors TTE Drug, mg Diagnosis/ site Year Case 18 mo 27 mo 13 days OM/Mandible 1998 OM/Jaw 2002 ON/Maxilla 1999 Grade 2 - 3 R. mand. excision Grade 2 Unknown Grade 2 Continued Jaw infection, steroids, chemo Dental abscess, tooth extraction Chemo 6. MM 5. PC 4. H&N Z 8 Z 4/8 Z 8/4
  • ONJ Cases: Other Trials
    • Completed trials: no ONJ cases as of Jan 2005*
      • 23 trials in Zometa ® program (N = 3428)
          • Zometa 3217
          • Aredia 125
          • Placebo 86
      • 26 trials in Aredia ® program (N = 1401)
          • Aredia 1214
          • Placebo 187
    • Ongoing trials: 4 ONJ cases reported
      • > 10,000 patients enrolled
    *Except for 1 case of osteomyelitis of the jaw (OMJ) that existed prior to study entry.
  • ONJ Cases in Ongoing Zometa ® Trials* (NS4-13) Zometa Briefing Document January 2005.doc Table 4-4 † This study is not sponsored by Novartis. * All studies use Zometa 4 mg. ** Patient had pre-existing osteomyelitis of the jaw at study entry. 1 1 1** 1 ONJ cases, n Osteonecrosis Osteomyelitis Osteomyelitis Osteonecrosis Diagnosis MM BC PC BC Tumor type DE01 KR02 DE07 2408 † Zometa trial Spontaneous tooth loss, tooth extraction, dental abscess 15 101 Chronic dental infection 12 40 Pre-existing OM of jaw 9 309 Dental infection, extraction, chemo, steroids 4 1036 Risk factor Infusions prior to event, n Patients, N
  • Review of Available Data on ONJ
    • Clinical trials
    • Spontaneous reports to Novartis
    • Literature
    • MD Anderson Cancer Center study
  • Spontaneous Reports Of ONJ * Zometa ® or Aredia ® † (NS4-8) Zometa Briefing Document January 2005.doc Table 4-2 * Includes reportable cases from the literature. † The number of reported cases from generic pamidronate is unknown. ‡ 91% of patients diagnosed with ONJ and 28% diagnosed with osteomyelitis.
    • As of 22 Feb 2005, total reports = 875
    Total patients exposed Total 610 ‡ 1.9 million 1 million 218 125 267 Multiple myeloma Breast Other Indication 440 170 US Non-US Countries 119 248 243 Aredia Zometa Both Drug As of 07 Dec 04
  • Spontaneous Reports Of ONJ Reported Risk Factors † In 188 (31%) reports the patients had received both corticosteroids and chemotherapy. ‡ Broad criteria used, including all conditions and medications with potential impact on bone metabolism. Includes 3 patients with herpes virus infection of the maxillofacial area. (NS9-12) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc 450 (74) At least 1 risk factor in addition to cancer 263 (43) Other ‡ 57 (9) Transplant 89 (15) Thalidomide 89 (15) Anemia 28 (5) Radiotherapy to head and neck 63 (10) Hormonal therapy 315 (52) Chemotherapy † 230 (38) Corticosteroids † Reports, n (%) Reported risk factors
  • Spontaneous Reports Of ONJ Reported Dental Events
    • At least 50% of cases (n = 303) reported dental events preceding the diagnosis of ONJ
    (NS9-11) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc n (%) Dental events 9 (3) Denture trauma 16 (5)
      • Other (eg, tooth abscess, trauma)
    26 (9)
      • Dental problems, procedures (other than extraction)
    252 (83) Prior extraction
  • Spontaneous Reports Of ONJ Reported Outcomes ‡ 224/610 reports assessable for outcome analysis. § Also includes recovered with sequelae. 224 174 50 Total 55 46 9 Unknown 17 10 7 Deteriorated 107 86 21 No change 45 32 13 Recovered/Improved § Total ‡ Discontinued Continued Outcome Bisphosphonates
  • Spontaneous Reports: Time to Onset of ONJ
    • Direct comparison of time to onset between Zometa ® & Aredia ® is not feasible
      • No common definition of ONJ
      • Aredia available since 1991, Zometa since 2001
      • Utilization of Aredia has declined significantly since 2001 (including generic introduction)
      • Recent awareness could have accelerated diagnosis of ONJ
      • Concurrent therapy has changed significantly over time with contribution unknown
  • Review of Available Data on ONJ
    • Clinical trials
    • Spontaneous reports to Novartis
    • Literature
    • MD Anderson Cancer Center study
  • Literature Reports of ONJ (NS4-7) Zometa Briefing Document January 2005.doc Table 4-1 Letter to the editor case reports J Oral Maxillofac Surg , 2003 36 Marx Case reports J Oral Maxillofac Surg , 2004 63 Ruggiero et al. Clinical database review, abstract San Antonio Breast Cancer Symposium, 2004 6 Van Poznack Case reports, abstract Blood, 2004 14 Thakkar Abstract, anonymous Web-based survey Blood, 2004 62 Durie Case report, manuscript J Oral Pathol Med, 2004 10 Bagan Case report Rev Bras Oncologia Clinica (Brazil) , 2004 5 de Almeida, de Araujo, and Pire Methodology Journal ONJ patients reported, n Author
  • Literature Report of ONJ: Ruggiero et al. 2004 *
    • 63 cases between Feb 01- Nov 03
      • MM (28), BC (20), prostate (3), other (5), no cancer (7)
      • Pamidronate (57%), zoledronic acid (31%), oral BP (12%)
      • 71% female
      • Mandible (63%), maxilla (37%)
      • Typical presentation: pain, non-healing extraction socket, exposed bone
      • Other treatments: chemotherapy
      • Previous dental procedure: 86%
      • Majority required surgical removal of involved bone
    * Ruggiero SL, et al. J Oral Maxillofac Surg; 2004; 62 (5):527 - 534.
  • Literature Report of ONJ: Durie et al. 2004*
    • Web-based patient survey
    • Key issues
      • Data reliability/quality
        • Anonymous responders
        • Unable to assure data quality
    • Potential bias & analyses considerations
      • Patients with an event, more motivated to respond
      • Patients with more recent event, may be more likely to respond
    • Kaplan-Meier & logistic regression must be interpreted with caution
      • Not adjusted for time as confounding factor
      • Impact of approval / launch / usage time
        • Aredia ® approved since 1991 & Zometa ® since 2001
    * Durie et al. Blood 2004;104:Abstract 756.
  • Review of Available Data on ONJ
    • Clinical trials
    • Spontaneous reports to Novartis
    • Literature
    • MD Anderson Cancer Center study
  • MD Anderson Cancer Center Study Objectives and Methods
    • Principal Investigator: Ana Hoff, MD
    • Objectives †
      • Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency
      • Identify risk factors associated with ONJ
    • Methods
      • Retrospective chart review in past 10 yr
        • All IV BP users (N = 4032)
        • Identify patients with ONJ and ON of other sites
    • 963 charts reviewed by Jan 12, 2005
    • Issue: Non random chart review
      • Charts sorted by pharmacy records based on number of BP infusions (highest to lowest)
      • 7 charts reviewed out of sequence because ONJ was suspected
    † Amendment to expand the review to non-bisphosphonate users being considered. (NS10-11) Zometa Core presentation ONJ (CO).ppt
  • MD Anderson Cancer Center Study Interim Data: ONJ Cases by Tumor Type (NS4-16) Zometa Briefing Document January 2005.doc Table 4-7 * Thyroid cancer 18 – 1* – – – – 6 11 ONJ cases (n) 963 Total 15 Noncancer 89 Others 13 Lymphoma 17 Lung cancer 18 Prostate cancer 32 Renal cell carcinoma 148 Multiple myeloma 631 Breast cancer Patients (N) Tumor type
  • MD Anderson Cancer Center Interim Data: 18 Cases (NS4-18) Zometa Briefing Document January 2005.doc Table 4-8 * 4 months on Aredia. 57 months on Aredia followed by Zometa. Bisphosphonate received, n 30 (4 – 57)* Time from first BP to ONJ, mo Median (range) 10 Aredia then Zometa 1 Alendronate then Zometa 3 Zometa ® only 4 Aredia ® only
  • ONJ in Cancer Patients Treated With BPs Frequency Estimates Likely over-estimate 75 of 1203 (6.2%) of respondents reported ONJ Web-based survey (Durie) Review not complete 18 cases of 963 charts (1.9%) MDACC Follow-up needs to be updated 6 of 4056 pts (0.15%) Controlled clinical trials Likely under-estimate 875 of 2.9 million (0.03%) Spontaneous reports Assessment Frequency estimate Database
  • ONJ in Cancer Patients Treated With BPs: Open Questions
      • Natural history
      • Clear case definition
        • Diagnostic criteria
        • Staging system
        • Severity measures
      • Time to onset
      • Risk factors
      • Prevention measures
      • Treatment algorithm
      • Causality
    (NS3-19) July15,2004FDAONImeetingslides.doc
  • Novartis Initiatives
  • Novartis Initiatives—Completed Activities (NS21-5) 2002 2003 2004 2005 12/02 First ONJ report to Novartis 9/03 – 11/03 Zometa ® PI update/ Aredia ® PI update 12/03 Ad. board #1 (understand ONJ) 3/04 Ad. board #2 (generate guidelines; “white paper”) 1/03 Initiate f/u & data collection on cases 2Q-3Q Oncologist & dental surgeon visited to collect data 6/04 Distribution of the “white paper” at ASCO 9/04 Distribution of “Dear Doctor” letter 2/05 ASCO burst (FDA) 5/04 Patient initiative/Generation of education materials 4/04 initiate MDACC study 8/04 Zometa and Aredia labels revised 3/04 Updated PIs with additional ONJ info 4/04 IC changes made
  • Recommended Management of ONJ Advisory Panel – March 24, 2004 (1)
    • Diagnosis
      • Typical symptoms: pain, soft-tissue swelling and infection, loose teeth, and exposed bone
      • Imaging (eg, panoramic and tomographic), biopsy, and cultures may be helpful
    • Treatment
      • Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint
      • Antibiotics, antifungal and antiviral agents, oral rinses
      • Close follow-up, and cessation of BP therapy may be considered. Risk of SRE needs to be considered when stopping BP therapy
  • Recommended Management of ONJ Advisory Panel – March 24, 2004 (2)
    • Prevention
      • Avoid elective jaw procedures
      • Routine dental exams including panoramic radiograph
      • Tooth extraction prior to BP therapy if possible
      • Preventive dentistry prior to chemotherapy
      • Patient education regarding importance of good hygiene
      • Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit
      • Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy
  • Patient Outreach With Advocacy Groups
    • Meeting held May 2004
      • 9 patient advocacy groups attended representing multiple tumor types (breast, myeloma, prostate, lung, and kidney)
    • Additional follow-up with 14 groups (Dec 2004/early 2005)
    • Planned activity: post ODAC briefing teleconference with patient advocacy groups
    (NS22-17) Patient Advocacy ONJ.ppt slide 1
  • Patient Brochure
    • Definition, signs, and symptoms of ONJ
    • Routine dental hygiene for patients with cancer
    • Dental care recommendations to patients with cancer
    • Urge patients to communicate with physicians and dentists regarding adverse events
    (NS21-1) “Taking Care of Yourself While Living With Cancer: Dental Health and Osteonecrosis of the Jaw” Novartis Patient Information Brochure. 2004. Taking Care of Yourself While Living With Cancer Dental Health and Osteonecrosis of the Jaw
  • Clinical Investigations – Actions Planned
    • Develop case definition and severity scale with expert panel
    • Obtain follow up data on patients from pivotal trials for ONJ
    • Develop CRF to capture data regarding ONJ in ongoing studies
    • Implement new studies that include prospective monitoring for ONJ
  • Clinical Investigation – New Studies
    • Retrospective chart review for ONJ in MM patients (initiate 2Q 2005)
    • Prospective studies to include ONJ assessment
      • Study 2352: MBC and MM (initiate 4Q 2005)
      • SWOG 0307: Adjuvant BC (under discussion)
    • Prospective registry for ONJ or ONJ natural history study (2H 2005)
  • Phase III Randomized Trial With Zometa ® Study 2352 Design Breast cancer/myeloma + bone metastasis Zometa pretreated: 12 mo N = 3513 Arm 1, n = 1,405 Zometa 4 mg q 3-4 wk Arm 2, n = 1,405 Zometa 4 mg q 3 mo Arm 3, n = 703 Placebo q 4 wk 13-month analysis for efficacy and safety* 0 * Primary efficacy endpoint: Time to first SRE Randomization 2:2:1 + Rescue: Zometa 4 mg q wk after first SRE + Rescue: Zometa 4 mg q wk after first SRE
  • SWOG 0307: Study Design
    • Randomized phase III trial; NSABP 34 replacement trial
    • Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000)
    R A N D O M I ZE Zometa ® * 4 mg IV q mo x 6 mos, q 3 mos x 2.5 yrs Clodronate* 1600 mg PO daily x 3 yrs Ibandronate* 50 mg PO daily x 3 yrs *Daily supplemental calcium (1000 to 1500 mg) and vitamin D (400 to 800 IU) (NS22-2) Leo’s SWOG slides.ppt slide 2
  • SWOG 0307: Osteonecrosis of the Jaw Surveillance Plan (NS22-3) Leo’s SWOG slides.ppt slide 3 - Patients are requested to a void dental procedures while on myelosuppressive chemotherapy - Patients are expected to undergo standard dental exam and care while on study - Osteonecrosis of the jaw was listed as one of the possible side effects of zoledronic acid in the S0307 Inform Consent Form Patient Information: - Completion of S0307 Dental Examination Form, Osteonecrotic Jaw Lesion Form, Treatment Summary Form, & Supplementary Follow-up Form - Consultation with S0307 Jaw/Dental Health Coordinator for any patient diagnosed with osteonecrosis of the jaw (Dr. Mark Shubert, DDS, MDS) Documentation: - Visual dental inspection and periodontal probing - X-rays only to assess degree of periodontal involvement and endodontic problems Required Exam: - Dental exams at baseline and end of study (completed by a dental health professional) - Standard dental exams and care while on study Schedule: Evaluation of risk factors for osteonecrosis of the jaw Objective:
  • ONJ Monitoring in Clinical Trials: Proposal
    • Physical examination of head & neck and oral cavity to
      • Rule out metastatic involvement
      • Detect
        • Breach of the oral mucosa
        • Exposed bone
    • Imaging
      • Panoramic radiograph
    • Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months)
    • Develop specific case report forms
      • Dental exam
      • ONJ assessment
  • Conclusions
  • Conclusions (1)
    • Zometa ® and Aredia ® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma
    • Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002
      • ONJ remains poorly understood
      • Frequency estimates variable; however, ONJ appears to be an infrequent occurrence
      • Insufficient evidence to support difference between Zometa and Aredia
  • Conclusions (2)
    • Novartis is committed to
      • Ensuring patient safety
      • Enhancing understanding of ONJ through additional clinical investigation
      • Continuing dissemination of evolving information and guidance to health-care providers and patients
    • Balance of benefit-risk for Zometa ® and Aredia ® remains favorable