噻霉素Ⅲ期临床阳性结果

Cethromycin for CABP: Evaluation of Efficacy Christopher Kadoorie, Ph.D. Division of Biometrics IV Office of Biostatistics Anti-Infective Advisory Committee Meeting June 2, 2009 2 Brief History of Development • Cethromycin (ABT-773), a second generation ketolide, originally belonged to Abbott Labs • Nov. 27, 2000: Abbott/FDA meeting to discuss their Phase III developmental plan for cethromycin (CABP, AECB, ABS and T/P) • Feb. 9, 2005: Advanced Life Sciences, Inc. (ALS) licensed the product from Abbott (CABP only). • Dec. 12, 2005: ALS/FDA meeting, 2 adequate & well- controlled CABP studies were recommended • Dec. 17, 2007: ALS/FDA meeting, FDA requested NI study design justification • April 7, 2008: Pre-NDA meeting 3 Outline • Studies 05 & 06 • Sponsor’s NI Margin Assumptions • NI Margin Determination • FDA Reviewer Sensitivity Analyses • Patient Disposition • Clinical Cure Rates • Patient Distribution/Mortality by Age & PORT Score • Statistical Uncertainties • Conclusions 4 Studies 05 & 06: Design • Both Study-05 and Study-06: ¾ Enrolled patients with mild-to-moderate community-acquired bacterial pneumonia (CABP) ¾Were active-controlled, double-blind, parallel group, multi-center, NI studies with identical designs ¾ Randomized patients 1:1 to receive cethromycin (300 mg QD for 7 days) or clarithromycin (250 mg BID for 7 days) ¾Were sized for ~ 500 subjects assuming 10% NI margin, 90% PPc cure rate, 80% evaluability rate, 90% power at the 2α =0.05 level • Primary study design differences related to the geographical areas of selected study sites ¾ Study 05 conducted in US, Canada & South Africa (62 sites) ¾ Study 06 conducted Latin America, Europe & Israel (72 sites) 5 Studies 05 & 06: Inclusion Criteria • Studies 05 & 06 included adult patients with: ¾Recent onset of symptoms, and ¾A chest X-ray consistent with CABP, and ¾At least two of the following signs/symptoms: • Cough; • Fever ( >38°C or >100.4°F) , • Dyspnea or tachypnea (presence or absence) • Auscultatory findings of rales or evidence of pulmonary consolidation (dullness on percussion, bronchial breath sounds) • Elevated white blood cell count (WBC > 10,000/mm3) or 15% immature neutrophils or leukopenia (WBC < 4,500/mm3) • Patients were enrolled if considered suitable for oral antibiotic therapy 6 Studies 05 & 06: Visits Visit #1 #2 #3 #4 #5 Visit Name Baseline On Therapy Post Therapy Test of Cure* (TOC) Follow-up (telephone) Study Days -2 to 1 4 to 6 8 to 11 14 to 22 37 to 40 Timing within 48 hrs. of first dose 4-6 days after first dose 24-72 hrs. after last dose 7-14 days after last dose 30-33 days after last dose * Clinical response to therapy assessed by investigator at the TOC visit 7 Studies 05 & 06: Primary Endpoint • Primary efficacy endpoint: Clinical cure rate at TOC visit • Clinical cure at the TOC visit: ¾ Improvement/return to pre-infection state or no progression of pulmonary infiltrates consistent with pneumonia and ¾ Resolution of all baseline signs and symptoms of CAP • A clinical failure at the TOC: ¾ Persistence/worsening in signs/symptoms after 3-5 days of therapy or ¾ Requirement for additional antibiotics due to lack of improvement or ¾ Development of new pulmonary infection or extrapulmonary infection requiring other antimicrobial therapy or ¾ Progression of chest radiological abnormalities or ¾ Death due to pneumonia • Indeterminate at TOC: TOC evaluation was not possible 8 Studies 05 & 06: Analysis Populations • Intent-to-Treat (ITT) study patients: ¾ Received at least one dose of study medication ¾ Had clinical diagnosis of pneumonia supported by a positive pre- treatment chest X-ray and at least two appropriate clinical signs/symptoms • Clinical Per Protocol (PPc) patients also: ¾ Took 3 days of study medication (80% to be a clinical cure) and ¾ Had no other systemic antimicrobial agent administered from 1 week before therapy until TOC (unless failure or indeterminate) • Bacteriological Per Protocol (PPb) patients also: ¾ Had at least one qualifying pathogen isolated from baseline culture or identified via serology or antigen testing • mITT patients (defined in FDA analyses only) consisted of ITT patients with a qualifying baseline pathogen 9 Sponsor’s NI Margin Assumptions • ITT and PPc were the co-primary analysis populations • In each of the ITT and PPc, NI margins were determined by the higher of the two treatment group cure rates Higher Cure Rate: NI Margin: 90% ≤ Rate 10% 80% ≤ Rate < 90% 15% 70% ≤ Rate < 80% 20% • This implied NI margin determination of 15% ITT, 10% PPc • The Sponsor’s proposed NI margin based on 1992 “Points to Consider” document is no longer considered acceptable by FDA • In February 2001, the FDA posted a disclaimer to the above document stating the sliding-scale for selecting the NI margin was no longer in use. 10 NI Margin Determination: General Approach • “2007 Draft Guidance for Industry: Antibacterial Drug Products: Use of Non-inferiority Studies to Support Approval” recommends an adequately justified NI margin. • This margin should be based upon the active control treatment effect (M1) for an appropriate endpoint, discounted for statistical uncertainties such as: ¾Issues in data quality, study design and conduct, patient severity at baseline, variability in study sample sizes ¾Imbalances in prognostic factors • A substantial fraction of M1 (e.g. ≥50%) should be preserved to determine the NI margin (M2) such that any potential loss in efficacy is clinically acceptable. 1111 M1 15% (Control Effect) 0 30% 40%-10%-20% 20% Meta-analysis 50% Historical placebo-controlled studies Favors Control drug M2 P R E S E R V A T I O N (Point estimate, 95% CI) Discount for uncertainties 5% NI Margin Determination: Hypothetical Example 12 NI Margin Determination: Historical Evidence in CABP • NI margin for CABP has been previously discussed. • No data from placebo-controlled trials in CABP are available • Historical studies and clinical trials of antibacterial treatment of pneumonia provide evidence that antibacterial drugs reduced mortality in patients with pneumococcal or lobar pneumonia. • The effect of treatment on survival was consistently greater in older patients (older than 50 years) and in patients with bacteremia. 13 FDA Reviewer Sensitivity Analyses • To examine patient populations more comparable to historical populations, Reviewer analyses included study patients meeting the following criteria: ¾ PORT Scores ≥ 2, and ¾ No Prior antibiotic therapy (just prior to start of treatment) and ¾ No atypical sole pathogens (e.g. L. pneumophila, M. pneumoniae, C. pneumoniae); • Each of these criteria is often critical for assessing the effect due to treatment in CABP patients • A few exceptions were identified by the FDA reviewers: ¾ Two ITT patients with prior antibiotic therapy were not excluded on that basis (Prior topical Abx unlikely to affect course of CABP infection) ¾ Six ITT patients with atypical pathogens were not excluded on that basis (evidence of bacterial infection from sputum results) ¾ Only three of these ITT patients were included in FDA analyses. 14 Patient Disposition: Randomized Patients • Study 05 randomized 584 patients (292 to each study arm) ¾2 patients (1 in each arm) failed to receive study drug ¾67 patients (30 Cethromycin, 37 Clari) had inadequate radiographic evidence or a confounding disease, ¾515 ITT patients (261 Cethromycin, 254 Clari) ¾231 ITT patients (110 Cethro, 121 Clari) met Reviewer analysis criteria • Study 06 randomized 522 patients (261 to each study arm): ¾1 Clari patient failed to receive study drug ¾11 patients (4 Cethro, 7 Clari) had inadequate radiographic evidence or a confounding disease, ¾ 510 ITT patients (257 to Cethro, 253 to Clari) ¾218 ITT patients (113 Cethro, 105 Clari) met Reviewer analysis criteria 15 Study 05 (n=515) Study 06 (n=510) Population Cethromycin (n=261) n (%) Clari (n=254) n (%) Total N (%) Cethromycin (n=257) n (%) Clari (n=253) n (%) Total N (%) Sponsor Analysis Criteria Met: ITT 261 (100) 254 (100) 515 (100) 257 (100) 253 (100) 510 (100) PPc 218 (84) 208 (82) 426 (83) 224 (87) 221 (87) 445 (87) mITT 81 (31) 85 (33) 166 (32) 76 (30) 72 (28) 148 (29) Reviewer Analysis Criteria Met: ITT 110 (42) 121 (48) 231 (45) 113 (44) 105 (42) 218 (43) PPc 89 (34) 93 (37) 182 (35) 98 (38) 92 (36) 190 (37) mITT 33 (13) 34 (13) 67 (13) 21 (8) 22 (9) 43 (8) Patient Disposition: Key Analysis Populations 16 Clinical Cure Rates: Primary Analysis Study 05 Study 06 Analysis Pop. Cethromycin n/N (%) Clari n/N (%) Difference 95% CI Cethromycin n/N (%) Clari n/N (%) Difference 95% CI Sponsor Analysis Criteria Met ITT 217/261 (83.1) 206/254 (81.1) 2.0 (-5.0, 9.0) 213/257 (82.9) 224/253 (88.5) -5.7 (-12.1, 0.8) PPc 205/218 (94.0) 195/208 (93.8) 0.3 (-4.7, 5.3) 205/224 (91.5) 212/221 (95.9) -4.4 (-9.3, 0.5) mITT 73/81 (90.1) 72/85 (84.7) 5.4 (-5.8, 16.7) 62/76 (81.6) 63/72 (87.5) -5.9 (-18.9, 7.0) PPb 70/73 (95.9) 67/69 (97.1) -1.2 (-8.7, 6.2) 57/64 (89.1) 61/63 (96.8) -7.8 (-18.1, 2.6) Reviewer Analysis Criteria Met ITT 89/110 (80.9) 95/121 (78.5) 2.4 (-8.8, 13.6) 86/113 (76.1) 90/105 (85.7) -9.6 (-20.9, 1.6) PPc 84/89 (94.4) 89/93 (95.7) -1.3 (-8.7, 6.1) 85/98 (86.7) 86/92 (93.5) -6.7 (-16.2, 2.7) mITT 29/33 (87.9) 27/34 (79.4) 8.5 (-10.4, 27.3) 12/21 (57.1) 17/22 (77.3) -20.1 (-47.0, 8.8) PPb 26/27 (96.3) 24/25 (96.0) 0.3 (-15.1, 17.6) 12/17 (70.6) 17/19 (89.5) -18.9 (-46.4, 8.6) 17 Clinical Cure Rates: by PORT Scores (I ,II vs. III, IV) Study 05 Study 06 PORT Scores Cethromycin n/N (%) Clari n/N (%) Cethromycin – Clari Diff; 95% CI Cethromycin n/N (%) Clari n/N (%) Cethromycin – Clari Diff, 95% CI ITT Subjects I, II 202/237 ( 85.2) 185/227 (81.5) 3.7 (-3.5, 10.9) 191/225 (84.9) 199/223 (89.2) -4.3 ( -11.0, 2.3) III, IV 15/24 (62.5) 21/27 (77.8) -15.3 (-44.1, 13.6) 22/32 (68.8) 25/30 (83.3) -14.6 (-38.7, 9.5) PPc Subjects I, II 190/200 (95.0) 175/186 (94.1) 0.9 (-4.1, 6.0) 183/196 (93.4) 189/197 (95.9) -2.6 (-7.5, 2.4) III, IV 15/18 (83.3) 20/22 (90.9) -7.6 (-33.9, 15.0) 22/28 (78.6) 23/24 (95.8) -17.3 (-37.2, 2.6) mITT Subjects I, II 66/73 (90.4) 69/81 (85.2) 5.2 (-6.3, 16.8) 57/67 (85.1) 58/65 (89.2) -4.2 (-17.1, 8.7) III, IV 7/8 (87.5) 3/4 (75.0) 12.5 5/9 (55.6) 5/7 (71.4) -15.9 18 Clinical Cure Rates: by Age (< 50 vs. ≥ 50) Study 05 Study 06 Age Cethromycin n/N (%) Clari n/N (%) Cethromycin – Clari Diff; 95% CI Cethromycin n/N (%) Clari n/N (%) Cethromycin – Clari Diff, 95% CI ITT Subjects < 50 124/149 (83.2) 97/114 (85.1) -1.9 (-11.5,7.8) 120/134 (89.6) 124/136 (91.2) -1.6 (-9.4, 6.2) ≥ 50 93/112 (83.0) 109/140 (77.9) 5.2 (-5.4, 15.8) 93/123 (75.6) 100/117 (85.5) -9.9 (-20.6, 0.9) PPc Subjects < 50 117/125 (93.6) 93/100 (93) 0.6 (-6.9, 8.1) 114/119 (95.8) 117/120 (97.5) -1.7 (-7.1, 3.7) ≥ 50 88/93 (94.6) 102/108 (94.4) 0.2 (-7.1, 7.5) 91/105 (86.7) 95/101 (94.1) -7.4 (-16.3, 1.5) mITT Subjects < 50 40/45 (88.9) 39/43 (90.7) -1.8 (-6.7,13.1) 45/51 (88.2) 41/44 (93.2) -4.9 (-18.6, 8.7) ≥ 50 33/36 (91.7) 33/42 (78.6) 13.1 (-4.8, 31) 17/25 (68.0) 22/28 (78.6) -10.6 (-38.1,17.0) 19 Clinical Cure Rates by Target Pathogens Study 05 Study 06 Studies 05 & 06 Clinical Cure Rates by Population Target Pathogen Cethromycin n/N (%) Clari n/N (%) Cethromycin n/N (%) Clari n/N (%) Cethromycin n/N (%) Clari n/N (%) Sponsor Analysis Criteria Met mITT H.influenzae 33/36 (92) 23/26 (88) 24/33 (73) 21/22 (95) 57/69 (83) 44/48 (92) S .pneumoniae 10/12 (83) 17/22 (77) 15/19 (79) 7/11 (64) 25/31 (81) 24/33 (73) M.catarrhalis 3/3 (100) 6/6 (100) 2/4 (50) 3/4 (75) 5/7 (71) 9/10 (90) S.aureus 10/14 (71) 13/14 (93) 7/8 (88) 9/11 (82) 17/22 (77) 22/25 (88) PPb H.influenzae 33/35 (94) 20/20 (100) 23/27 (85) 21/22 (95) 56/62 (90) 41/42 (98) S.pneumoniae 9/9 (100) 15/18 (83) 15/17 (88) 7/9 (78) 24/26 (92) 22/27 (81) M.catarrhalis 2/2 (100) 6/6 (100) 2/3 (67) 3/4 (75) 4/5 (80) 9/10 (90) S.aureus 9/10 (90) 13/13 (100) 6/7 (86) 9/9 (100) 15/17 (88) 22/22 (100) Reviewer Analysis Criteria Met mITT H influenzae 14/16 (88) 14/16 (88) 7/13 (54) 12/13 (93) 21/29 (72) 26/29 (90) S.pneumoniae 8/9 (89) 11/14 (79) 6/9 (67) 4/8 (50) 14/18 (78) 15/22 (68) M.catarrhalis 3/3 (100) 5/5 (100) 1/3 (33) 3/4 (75) 4/6 (67) 8/9 (89) S.aureus 4/5 (80) 6/7 (86) 1/2 (50) 1/2 (50) 5/7 (71) 7/9 (78) PPb H influenzae 14/15 (93) 11/11 (100) 7/11 (64) 12/13 (93) 21/26 (81) 24/25 (96) S pneumoniae 7/7 (100) 10/11 (91) 6/7 (86) 4/6 (67) 13/14 (92) 14/17 (82) M.catarrhalis 2/2 (100) 5/5 (100) 1/2 (50) 3/4 (75) 3/4 (75) 8/9 (89) S.aureus 3/3 (100) 6/6 (100) 1/2 (50) 1/1 (100) 4/5 (80) 7/7 (100) 20 PORT Scores Study 05 Study 06 Cethromycin (n=261) Clarithromycin (n=254) Cethromycin (n=257) Clarithromycin (n=253) < 50 n=147 ≥ 50 n=114 < 50 n=114 ≥ 50 n=140 < 50 n=134 ≥ 50 n=123 < 50 n=136 ≥ 50 n=117 I 136 (93) - 110 (96) - 125 (93) 1 132 (97) - II 11 (8) 90 (79) 3 (3) 114 (81) 9 (7) 90 (73) 4(3) 87 (74) III - 16 (14) 1 (1) 23 (16) - 23 (19) - 24 (21) IV - 8 (7) - 3(2) - 9 (7) - 6 (5) V - - - - - - - - Patient Distribution: by Age & PORT Score (ITT) 21 Mortality: by Age & PORT Score PORT Scores Studies 05 & 06 (Safety) N=1103 Cethromycin (n=552) Clarithromycin (n=551) < 50 n=427 ≥ 50 n=125 < 50 n=428 ≥ 50 n=123 I 0/277 - 0/258 - II 0/125 2/93 (2.2%) (deaths 2 and14 days after last dose) 0/138 3/91, (3.3%) (2, 3 & 53 days after last dose) III 0/17 0/23 0/27 1/25 (4.0%) (15 days after last dose) IV 0/8 0/9 0/5 0/7 V - - - - Patients with deaths 14, 53 & 15 days after last dose were not included in the ITT population (Safety only). Three Study 05 patients included who met ITT requirements but were excluded from Safety population 22 Statistical Uncertainties: Active Control Effect • Evidence based on the current data may not provide a similar active control effect compared to historical data. • Study 05 & 06 populations differed substantially from historical ones in patient disease severity. In historical populations ¾ Baseline mortality risk was higher ¾ Observed mortality rates were higher • Study 05 & 06 disease etiologies differed from historical ones ¾ Study subjects most commonly infected with H. influezae ¾ Historical study subjects most commonly infected with S. pneumoniae • Study 05 & 06 evaluated clinical response whereas historical evidence was based on mortality. Statistical Uncertainties: More Concerns • Study 05 & Study 06 did not provide consistent estimates of treatment differences (Study 06 results less favorable) • Study 05 & 06 PORT III/IV patients comprised only 10% &13% of ITT ¾ Analyses in these subjects were limited ¾ Influence of these patients on overall results were limited • Study 05 & Study 06 treatment differences sensitive to PORT class consideration (higher PORT scores tended to favor clarithromycin) • Studies 05 & 06 results could be influenced by attenuation of treatment effect due to lessening disease severity. Since this factor is difficult to quantify or adjust for, appropriate NI margins may be unclear. • Studies 05 & 06 had limited clinical/micro data for a CABP indication: ¾ 45% & 43% of ITT patients included in reviewer ITT analysis ¾ 13% & 8% of ITT patients included in reviewer mITT analysis ¾ Only 9 cethromycin patients in each study with S.pneumoniae in reviewer analysis Conclusions • Overall evidence suggests that Study 05 & 06 patients may have lower disease severity compared to historical study patients ¾ Baseline mortality risk was lower than in historical trials ¾ Observed mortality rates were lower than in historical trials • Thus the active control effect & NI margin may be unclear ¾ Lack of comparability with historical studies ¾ Potential attenuation of active control effect from lower disease severity ¾ Difficulty quantifying or adjusting for attenuation in the treatment effect • Although Reviewer analyses could examine subgroups at higher risk, clinical and especially micro data were limited • Treatment differences were also inconsistent across PORT classes ¾ For PORT III & IV patients, differences in Cure rates favored Clarithromycin by ~ 15% in each study ¾ For PORT I & II patients, differences were smaller but may be unclear due to potential attenuation from lack of disease severity. Acknowledgements • Thamban Valappil, Ph.D. • John Alexander, M.D., M.P.H Integrated Analyses by PORT Score (All Other Reviewer Analysis Criteria Met) Study CL05 & CL06 (Combined) PORT Score Cethromycin n/N (%) Clarithromycin n/N (%) Treatment Difference: Cethromycin – Clarithromycin (95% CI) Cethromycin n/N (%) Clarithromycin n/N (%) Treatment Difference: Cethromycin – Clarithromycin (95% CI) ITT (N=833) mITT (N=203) = 1 173/201 (86.1) 162/183 (88.5) -2.5 (-9.6, 4.7) 44/51 (86.3) 38/42 (90.5) -4.2 (-19.3, 10.9) = 2 143/173 (82.7) 146/177 (82.5) 0.2 (-8.3, 8.7) 31/39(79.5) 36/45 (80.0) -0.5 (-20.1,19.1) = 3 23/34 (67.6) 33/41 (80.5) -12.8 (-35.4, 9.7) 8/11 (72.7) 8/10 (80.0) -7.3 (-45.1, 32.5) = 4 9/16 (56.3) 6/8 (75.0) -18.8 - 2/4 (50.0) 0/1 (0.0) -50.0 - ≥ 1 348/424 (82.1) 347/409 (84.8) -2.8 (-8.0, 2.5) 85/105 (81.0) 82/98 (83.7) -2.7 (-14.2, 8.8) ≥ 2 175/223 (78.5) 185/226 (81.9) -3.4 (-11.2, 4.4) 41/54 (75.9) 44/56 (78.6) -2.6 (-20.1, 14.8) ≥ 3 32/50 (64.0) 39/49 (79.6) -15.6 (-35.1, 3.9) 10/15 (66.7) 8/11 (72.7) -6.1 (-41.9, 32.3) PPc (N=705) PPb (N=171) = 1 164/172 (95.3) 154/161 (957) -0.3 (-5.4, 4.8) 43/45 (95.6) 37/38 (97.4) -1.8 (-12.1, 8.5) = 2 137/146 (93.8) 138/146 (94.5) -0.7 (-6.7, 5.4) 28/30 (93.3) 33/36 (91.7) 1.7 (-14.4, 16.9) = 3 23/28 (82.1) 32/33 (97.0) -14.8 (-34.1, 0.9) 8/11 (72.7) 8/8 (100) -27.3 = 4 9/13 (69.2) 5/6 (83.3) -14.1 - 2/3 (66.7) 0/0 (- ) - - ≥ 1 333/359 (92.8) 329/346 (95.1) -2.3 (-6.1, 1.5) 81/89 (91.0) 78/82 (95.1) -4.1 (-12.8, 4.6) ≥ 2 169/187 (90.4) 175/185 (94.6) -4.2 (-10.1, 1.7) 38/44 (86.4) 41/44 (93.2) -6.8 (-21.7, 6.9) ≥ 3 32/41 (78.0) 37/39 (94.9) -16.8 (-33.0, -1.7) 10/14 (71.4) 8/8 (100) -28.6 - �Cethromycin for CABP:�Evaluation of Efficacy� Brief History of Development Outline � Studies 05 & 06: Design Studies 05 & 06: Inclusion Criteria Studies 05 & 06: Visits Studies 05 & 06: Primary Endpoint Studies 05 & 06: Analysis Populations Sponsor’s NI Margin Assumptions NI Margin Determination: General Approach Slide Number 11 NI Margin Determination: Historical Evidence in CABP FDA Reviewer Sensitivity Analyses � Patient Disposition: Randomized Patients Patient Disposition: Key Analysis Populations Clinical Cure Rates: Primary Analysis Clinical Cure Rates: by PORT Scores (I ,II vs. III, IV) Clinical Cure Rates: by Age (< 50 vs. ≥ 50) Clinical Cure Rates by Target Pathogens Patient Distribution: by Age & PORT Score (ITT) Mortality: by Age & PORT Score Statistical Uncertainties: Active Control Effect Statistical Uncertainties: More Concerns Conclusions Acknowledgements Integrated Analyses by PORT Score (All Other Reviewer Analys