CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208745Orig1s000 MEDICAL REVIEW(S) CLINICAL OUTCOME ASSESSMENT (COA) CONSULT REVIEW COA CONSULT TRACKING NUMBER AT 2016-046 IND/NDA/BLA NUMBER NDA 208745 REFERENCED IND FOR NDA/BLA IND 74883 LETTER DATE/SUBMISSION NUMBER January 29, 2016/SDN 0 PDUFA GOAL DATE January 29, 2017 DATE OF CONSULT REQUEST March 1, 2016 REVIEW DIVISION Division of Gastroenterology and Inborn Errors Products (DGIEP) MEDICAL REVIEWER/TEAM LEADER Lesley Hanes, M.D./Laurie Muldowney, M.D. REVIEW DIVISION PM Maureen Dewey PRIMARY COA REVIEWER Sarrit M. Kovacs, Ph.D. COA TEAM LEADER ASSOCIATE DIRECTOR, COA STAFF Elektra Papadopoulos, M.D., M.P.H. (ACTING) REVIEW COMPLETION DATE December 5, 2016 ESTABLISHED NAME/TRADE NAME Plecanatide/SP-304 APPLICANT Synergy CLINICAL OUTCOME ASSESSMENT TYPE Patient-reported outcome (PRO) ENDPOINT(S) CONCEPT(S) Stool frequency, stool consistency, and straining COA NAME(S) Single PRO sign/symptom items INDICATION Treatment of chronic idiopathic constipation (CIC) in adult patients INTENDED POPULATION(S) Adult patients (18 and 80 years of age, inclusive) meeting the Rome III functional constipation criteria as modified for this study for at least 3 months prior to the Screening visit PLEASE CHECK ALL THAT APPLY: ☐Rare Disease/Orphan Designation ☐Pediatric Reference ID: 4017868 Clinical Outcome Assessment Review Sarrit M. Kovacs, Ph.D. NDA 208745 Plecanatide/SP-304 Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining; PGA severity and change anchor scales scale from other therapeutic areas and cognitively tested with patients concluding that the response options are generally well-understood and meaningful to patients, with the exception of the “very severe” response option, which some patients believed is redundant and not meaningfully different from “severe.” This reviewer has also reviewed the anchor-based responder definition methods for the pre- specified secondary endpoints. See Section 6 (Interpretation of Scores) below. The COA Staff defer to DGIEP regarding the review of the clinical data to support the pre-specified secondary endpoint labeling claims (i.e., review of the CDF plots showing separation between treatment arms at the meaningful responder thresholds). This reviewer believes that the four pre-specified secondary endpoints are suitable for inclusion in the label, based on the modest but consistent separation between treatment arms at the meaningful responder thresholds across both studies. See Sections C 1.4 (Labeling), 4 (Content Validity), and 6 (Interpretation of Scores) for further detail. B. BACKGROUND Materials reviewed: • Previous COA Reviews: o AT 2011-097; Miskala; finalized in DARRTS on January 13, 2012 o AT 2010-100; Miskala; finalized in DARRTS on December 29, 2010 • Preliminary PRO evidence dossier from the IND 74883 phase • End of phase 2 study (Study 10) protocol • Phase 3 study (Studies 00 and 03) protocols, report bodies, statistical analysis plans • Applicant’s reply to Agency information requests C. CLINICAL OUTCOME ASSESSMENT REVIEW 1 CONTEXT OF USE 1.1 Clinical Trial Population Adult patients (18 and 80 years of age, inclusive) meeting the Rome III functional constipation criteria as modified for this study for at least 3 months prior to the Screening visit. 3 Reference ID: 4017868 Clinical Outcome Assessment Review Sarrit M. Kovacs, Ph.D. NDA 208745 Plecanatide/SP-304 Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining; PGA severity and change anchor scales 1.2 Clinical Trial Design Pivotal phase 3 Studies 00 and 03 were both randomized, 12-week, double-blind, placebo- controlled studies to assess the safety and efficacy of plecanatide (3.0 and 6.0 mg) in patients with chronic idiopathic constipation. Both studies included patients from the United States and Canada. The study design of Studies 00 and 03 were identical: 1.3 Endpoint Hierarchy and Definition Concept Endpoint Assessment Primary Endpoint Overall CSBM responder Proportion of patients who are Based on patients’ response to the questions overall CSBM responders during regarding number of BMs they experienced in 24 the 12-week Treatment Period. hours, the time of each BM, the completeness of Patients who have ≥3 CSBMs per evacuation, and rescue medication use in the week and an increase from Daily BM Diary (see Appendix A). baseline of ≥1 CSBM for that week. An overall CSBM responder is a patient who is a weekly CSBM responder for at least 9 of the 12 treatment weeks, including at least 3 of the last 4 weeks. Secondary Endpoint CSBM frequency Change from baseline over the 12- Based on patients’ response to the questions week treatment period in CSBM regarding number of BMs they experienced in 24 frequency rate hours, the time of each BM, the completeness of evacuation, and rescue medication use in the Daily BM Diary (see Appendix A). SBM frequency Change from baseline over the 12- Based on patients’ response to the questions week treatment period in SBM regarding number of BMs they experienced in 24 frequency rate hours, the time of each BM, and rescue medication use in the Daily BM Diary (see Appendix A). 4 Reference ID: 4017868 Clinical Outcome Assessment Review Sarrit M. Kovacs, Ph.D. NDA 208745 Plecanatide/SP-304 Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining; PGA severity and change anchor scales CSBM frequency: • There appears to be consistent separation between the 3mg treatment and placebo arm cumulative distribution function (CDF) curves at the meaningful threshold intersection with the x-axis (CSBM frequency endpoint change score) in both Studies 00 and 03. • Study 00 showed about a 19% separation between 3mg and placebo at the 1.8 CSBM threshold (2-point improvement in PGA constipation severity anchor from Study 10). • Study 03 showed about a 12% separation between 3mg and placebo at the 1.8 CSBM threshold (2-point improvement in PGA constipation severity anchor from Study 10). SBM frequency: • There appears to be consistent separation between the 3mg treatment and placebo arm CDF curves at the meaningful threshold intersection with the x-axis (SBM frequency endpoint change score) in both Studies 00 and 03. • Study 00 showed about a 30% separation between 3mg and placebo at the 2.8 SBM threshold (2-point improvement in PGA constipation severity anchor from Study 10). • Study 03 showed about a 13% separation between 3mg and placebo at the 2.8 SBM threshold (2-point improvement in PGA constipation severity anchor from Study 10). Stool consistency: • There appears to be consistent separation between the 3mg treatment and placebo arm CDF curves at the meaningful threshold intersection with the x-axis (stool consistency endpoint change score) in both Studies 00 and 03. • Study 00 showed about a 26% separation between 3mg and placebo at the 1.4 stool consistency threshold (2-point improvement in PGA constipation severity anchor from Study 10). • Study 03 showed about a 24% separation between 3mg and placebo at the 1.4 stool consistency threshold (2-point improvement in PGA constipation severity anchor from Study 10). With regard to straining, the fourth pre-specified secondary endpoint, this reviewer has concluded the following (see Appendices E-H [CDF plots]): Straining: • It is important to note that the applicant did not conduct cognitive interviews with CIC patients to support the 5-point straining item and response options that were used in the two phase 3 studies. However, the same five response options used in the 5-point straining scale have been used in other therapeutic areas and cognitively tested with patients concluding that the response options are generally well-understood and meaningful to patients, with the exception of the “very severe” response option, which some patients believe is redundant and not meaningfully different from “severe.” 6 Reference ID: 4017868 Clinical Outcome Assessment Review Sarrit M. Kovacs, Ph.D. NDA 208745 Plecanatide/SP-304 Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining; PGA severity and change anchor scales o The applicant did, however, conduct cognitive testing of a 0-10 point numeric rating straining scale and interviewed patients regarding their definition of severe straining. See Section 4 (Content Validity) for how patients, who reported experiencing severe or very severe straining, defined severe straining. • The 5-point straining scale was not included in the end of phase 2 Study 10 (an 11-point numeric rating scale [NRS] for straining was included, rather than the 5-point straining scale that was used in the phase 3 trials, Studies 00 and 03); therefore, the Study 10 anchor scales could not be used to establish a responder definition. o However, based on examining cross-validation anchor thresholds (obtained from one phase 3 study and applied to the other), it appears that the 2-point improvement in PGA constipation severity anchor is meaningful to patients and corresponded with about a 1-point improvement in straining score (i.e., matching up with a -1.1 point straining score change in Study 00 and a -0.9 point straining score change in Study 03 at the median score on the PGA constipation severity anchor scale): o The improvement threshold of a 1-point improvement in straining score showed a separation between 3mg treatment and placebo arms of about 15% in Study 00 and 13% in Study 03. • Based on qualitative research with patients in other disease areas, a one-point improvement from “very severe” to “severe” may not be a meaningful improvement for patients. That said, there were approximately 10% of patients in both studies in both the 3mg and placebo arms who reported that they were experiencing “very severe” straining at baseline. See applicant’s response below to FDA’s information request for the baseline severity of straining from both phase 3 studies: 7 Reference ID: 4017868 Clinical Outcome Assessment Review Sarrit M.