委托协议书(职业健康体检类) title

Tysabri (natalizumab)Biogen Idec Inc.BLA 125104/15,Peripheral and Central Nervous System Drugs Advisory Committee Gaithersburg, MarylandMarch 7-8, 2006Alice Hughes, M.D.Division of Neurology Products,Center for Drug Evaluation and Research,2,Review of Non-PML Safety Issues,3,Outline,Infections other than PMLImmunogenicity and hypersensitivity reactionsCarcinogenicityPost-marketing reports of serious adverse eventsSummary of major safety concerns,4,Natalizumab- and placebo-treated patients had similar incidences of:infections overall: 73.7% vs. 73.9% (natalizumab vs. placebo)serious infections: 2.4% vs. 2.3%Natalizumab- and placebo-treated patients had similar incidences of:upper respiratory tract infections: 59.6% vs. 59.8%UTIs: 21.5% vs. 21.4%serious UTIs: 0.6% vs. 0.5%gastroenteritis: 9.1% vs. 9.0%,Infections other than PML:Placebo-controlled MS studies,5,Infections other than PML:MS studies,Incidences of specific infections in placebo-controlled studies:all lower respiratory tract infections: 13.3% vs. 12.2% (natalizumab vs. placebo)serious pneumonias: 0.4% vs. 0.2%vaginal infections: 7.5% vs. 6.2%all herpes infections: 7.0% vs. 6.1%gingival infections: 1.1% vs. 0.5%Atypical infectionscryptosporidial gastroenteritis with prolonged course (in monotherapy Study 1801)acute CMV infection with transaminitis (in open-label Study 1808),6,Infections other than PML:Placebo-controlled CD studies,Incidence of infections overall: 40.4% vs. 35.8% (natalizumab vs. placebo)Incidence of serious infections:2.5% vs. 2.6%Incidences of selected infections:URIs: 27% vs. 21% UTIs: 2.9% vs. 2.0% vaginal infections: 2.1% vs. 1.6%all herpes infections: 1.6% vs. 1.0%perianal abcesses: 1.1% vs. 0.6%serious viral meningitides: 0.2% (2) vs. 0serious UTIs: 0.2% (2) vs. 0One serious CMV infection (CMV colitis)Patient also receiving azathioprine,7,Infections other than PML:Long-term CD studies,Atypical InfectionsSix serious atypical lower respiratory tract infectionsPneumonia with lung abscessPulmonary aspergillosisPneumocystis carinii pneumoniaVaricella pneumoniaMycobacterium avium intracellulare complex pneumoniaBurkholderia cepacia infectionPossible tuberculosis infectionUnclear role of concomitant immunosuppressive/ immunomodulatory agents and intercurrent illnesses,8,Immunogenicity,Anti-natalizumab antibody formation assessed every 12 weeks in Phase 3 MS Studies and selected CD studies10% of patients had a positive antibody titer at least once4% of patients were transiently positive and 6% were persistently positive in MS StudiesIncidence of anti-natalizumab antibody formation was higher in Study 1802 (12%) than in 1801 (9%)Intermittent (irregular) infusions may lead to higher incidence of antibody formation,9,Immunogenicity,Anti-natalizumab antibody formation strongly associated with infusion reactions and hypersensitivity reactionsInfusion reactions occurred in 77% of persistently antibody-positive patients vs. 20% of antibody-negative patients in MS Studies 1801 and 1802Most frequent infusion reactions in antibody-positive patients: rigors, nausea, headache, urticaria, flushing, pruritus, dyspneaAnaphylactic/ anaphylactoid reactions occurred in 5.3% of antibody-positive patients vs. 0 antibody-negative patients in MS Studies 1801 and 1802Anaphylactic/ anaphylactoid reactions occurred in 1.3% of antibody-positive patients vs. 0 antibody-negative patients in selected CD studies,10,Immunogenicity,MS relapses reported more frequently as adverse events in antibody-positive patients (vs. transiently positive and antibody-negative patients)57% vs. 35% (antibody-positive vs. antibody-negative patients)Incidence of infections lower in antibody-positive patients (vs. transiently positive and antibody-negative patients)Overall infections in MS patients: 69% vs. 82% (antibody-positive vs. antibody-negative patients) Herpes infections in MS patients: 2.7% vs. 8.4%,11,Hypersensitivity reactions,Anaphylactic/ anaphylactoid reactionsMS placebo-controlled studies: 0.4% (6) vs. 0.2% (2) natalizumab vs. placeboCD placebo-controlled studies: 0.1% (1) vs. 0Long-term CD studies: 1 additional case of anaphylaxis (during first infusion in CD251; 300 days after receiving 4 infusions in prior CD study) Skin and subcutaneous tissue disorder infusion reactions in MS placebo-controlled studies: 4.6% vs. 1.9%Urticaria: 1.6% vs. 0.3%Delayed hypersensitivity eventsMost hypersensitivity events occurred during or immediately after second infusion; some occurred laterOne case of anaphylaxis associated with 13th infusion,12,Carcinogenicity:MS studies,Malignancies balanced in natalizumab- and placebo-treated patients in placebo-controlled studies (0.7% natalizumab vs. 1.3% placebo)Types of malignancies observed in natalizumab-treated patients in all MS studies: Breast CABasal cell CACervical CAColon CAMelanomaSquamous cell CAPituitary adenomaPapillary thyroid CA,13,Carcinogenicity:CD studies,Malignancies more frequently reported for natalizumab-treated patients in placebo-controlled studies (0.6% vs. 0.2%)Types of neoplasms observed in natalizumab-treated patients in all CD studies: Breast CALung CABladder CAColorectal CAMalignant melanomaUterine CABasal cell CASquamous cell CAUterine CARenal cell CA (clear cell)MeningiomaCraniopharyngioma (suspected)Lymphoma (B-cell),14,Carcinogenicity:Long-term CD studies,B-cell lymphoma (1)49 yo man who received 6 infusions of natalizumab in Studies 307 and 351 (9/04 2/05)History of infliximab therapy (8 doses ) Concomitant 6-mercaptopurine therapyHad submandibular lymphadenopathy during 9/04 screening examination; not apparent on subsequent examPresented with painful lymphadenopathy August, 2005 and was diagnosed (CT; biopsy) with B-cell lymphoma,15,Serious adverse events reported in post-marketing setting,DeathsInfectionsHerpes CNS infections Meningitis and encephalitisMalignanciesHypersensitivity reactions and other serious events,16,Summary of key safety issues:Non-PML infections,Types of infections suggest possible compromise in cell-mediated immunityHerpes infections, lower respiratory tract infections (especially those caused by atypical pathogens), and viral meningitides are of particular concernRole of concomitant medications and intercurrent illnesses in pathogenesis of infections is unclearRelative risks for infections similar in MS Studies 1801 (monotherapy) and 1802 (combination therapy)No clear association between increasing number of natalizumab infusions and risk for infections,17,Summary of key safety issues:Immunogenicity and hypersensitivity,Anti-natalizumab antibodies formed in approximately 10% of patientsPersistently positive anti-natalizumab antibodies associated with infusion reactions, hypersensitivity reactions, increased MS relapse/ CD exacerbations, decreased incidence of infectionsAnaphylactoid reactions occurred in 0.4% of natalizumab-treated MS patients overall and in 5% of antibody-positive patientsHypersensitivity reactions most common with second infusion but may occur much later,18,Summary of key safety issues:Carcinogenicity,No evident increase in risk for malignancies in MS studiesOne lymphoma (B-cell) in pat