CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208745Orig1s000
`
`MEDICAL REVIEW(S)
`
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`

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`CLINICAL OUTCOME ASSESSMENT (COA) CONSULT REVIEW
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`
`COA CONSULT TRACKING NUMBER
`IND/NDA/BLA NUMBER
`REFERENCED IND FOR NDA/BLA
`LETTER DATE/SUBMISSION NUMBER
`PDUFA GOAL DATE
`DATE OF CONSULT REQUEST
`
`REVIEW DIVISION
`
` AT 2016-046
` NDA 208745
`IND 74883
`
`January 29, 2016/SDN 0
`
`January 29, 2017
`
` March 1, 2016
`
` Division of Gastroenterology and Inborn
`Errors Products (DGIEP)
` Lesley Hanes, M.D./Laurie Muldowney, M.D.
` Maureen Dewey
`
` Sarrit M. Kovacs, Ph.D.
`
`
` Elektra Papadopoulos, M.D., M.P.H.
`
` December 5, 2016
` Plecanatide/SP-304
` Synergy
` Patient-reported outcome (PRO)
` Stool frequency, stool consistency, and
`straining
` Single PRO sign/symptom items
` Treatment of chronic idiopathic constipation
`(CIC) in adult patients
` 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
` ☐Rare Disease/Orphan Designation
`☐Pediatric
`
`MEDICAL REVIEWER/TEAM LEADER
`REVIEW DIVISION PM
`
`PRIMARY COA REVIEWER
`COA TEAM LEADER
`ASSOCIATE DIRECTOR, COA STAFF
`(ACTING)
`REVIEW COMPLETION DATE
`ESTABLISHED NAME/TRADE NAME
`APPLICANT
`CLINICAL OUTCOME ASSESSMENT TYPE
`ENDPOINT(S) CONCEPT(S)
`
`COA NAME(S)
`INDICATION
`
`INTENDED POPULATION(S)
`
`PLEASE CHECK ALL THAT APPLY:
`
`Reference ID: 4017868
`
`

`

`Clinical Outcome Assessment Review
`
`Sarrit M. Kovacs, PhD.
`NDA 208745
`
`Plecanatide/SP—304
`
`Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining;
`PGA severity and change anchor scales
`
`A. EXECUTIVE SUMMARY
`
`This Clinical Outcome Assessment (COA) review is provided as a response to a request for
`consultation by the Division of Gastroenterology and Inbom Errors Products (DGIEP) regarding
`(b) (4)
`
`The applicant is currently post-phase 3 in their drug development program and awaiting an
`approval decision from the FDA. The proposed indication is treatment of chronic idiopathic
`constipation (CIC) in adult patients.
`
`The applicant proposed single patient-reported outcome (PRO) items in a daily bowel movement
`(BM) diary assessing for the measurement of completed spontaneous bowel movement (CSBM)
`and SBM stool frequency, stool consistency, and straining as pre—specified endpoints in two
`pivotal clinical trials in adult patients (18 and 80 years of age, inclusive) meeting the Rome HI
`functional constipation criteria as modified for this study for at least 3 months prior to the
`Screening visit.
`
`Although the applicant did not submit a full PRO evidence dossier, based on the all available
`evidence from the preliminary PRO evidence dossier from the IND phase and the end of phase 2
`study (Study 10) data, this review concludes that the PRO instruments used to assess CSBM
`stool frequency, SBM stool frequency, and stool consistency are fit—for-purpose to support the
`respective pre-specified secondary endpoints intended for inclusion in labeling claims (see
`Section C 1.4 [Labeling] for COA Stafi modification to applicant’s proposed labeling claims) in
`the context of use. However, the three daily symptom scores (abdominal pain, abdominal
`discomfort, and abdominal bloating) were not pre-specified in the endpoint testing hierarchy and
`were not Type I error controlled. This reviewer discussed this with the Clinical review team and
`these endpoints are not part of the CIC disease definition, therefore, the abdominal symptom
`instruments were not reviewed for their adequacy to support labeling claims.
`
`With regard to the straining PRO instrument, the applicant modified the response scale, from a 0-
`10 numeric rating scale to a 5-point verbal response scale, for the final straining scale used in the
`phase 3 studies. Although the applicant did not submit a full PRO evidence dossier for the final
`straining instrument, the qualitative patient data generally supported the relevance and
`meaningfulness of the straining concept and severity. The change from the 0-10 point scale to a
`5-point scale does not change the suitability of the straining item to support labeling claims.
`Based on this reviewer’s review of the same five response options used in the 5—point straining
`
`2
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`Reference ID: 401 7868
`
`

`

`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.
`
`
`
`
`
`Reference ID: 4017868
`
`3
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`

`

`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
`
`
`Endpoint
`
`Concept
`Primary Endpoint
`Overall CSBM responder
`
`Secondary Endpoint
`CSBM frequency
`
`SBM frequency
`
`
`
`Assessment
`
`Based on patients’ response to the questions
`regarding number of BMs they experienced in 24
`hours, the time of each BM, the completeness of
`evacuation, and rescue medication use in the
`Daily BM Diary (see Appendix A).
`
`Based on patients’ response to the questions
`regarding number of BMs they experienced in 24
`hours, the time of each BM, the completeness of
`evacuation, and rescue medication use in the
`Daily BM Diary (see Appendix A).
`Based on patients’ response to the questions
`regarding number of BMs they experienced in 24
`hours, the time of each BM, and rescue
`medication use in the Daily BM Diary (see
`Appendix A).
`
`Proportion of patients who are
`overall CSBM responders during
`the 12-week Treatment Period.
`Patients who have ≥3 CSBMs per
`week and an increase from
`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.
`
`Change from baseline over the 12-
`week treatment period in CSBM
`frequency rate
`
`Change from baseline over the 12-
`week treatment period in SBM
`frequency rate
`
`
`
`Reference ID: 4017868
`
`4
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`

`

`Clinical Outcome Assessment Review
`
`Sarrit M. Kovacs, PhD.
`NDA 208745
`
`Plecanatide/SP—304
`
`Single PRO items assessing CSBM and SBM stool frequency, stool consistency, and straining;
`PGA severity and change anchor scales
`
`Stool consistency
`
`Change from baseline over the 12-
`week treatment period in stool
`consisten
`score
`
`Based on patients’ response to the stool
`consistency question in the Daily BM Diary (see
`‘
`I
`
`I a I dix A . Straining
`
`Change fi'om baseline over the 12-
`week treatment period in straining
`score
`
`Based on patients’ response to the straining
`question in the Daily BM Diary (see Appendix
`A .
`
`1.4 Labeling or promotional claim(s) based on the COA
`
`The applicant’s targeted labeling claim is:
`
`(hm)
`
`Reviewer ’s comments: Although the applicant did not submit afull PRO evidence dossier, based
`on the all available evidencefrom the preliminary PRO evidence dossierfrom the IND phase
`and the end ofphase 2 study (Study 10) data, this review concludes that the PRO instruments
`used to assess CSBM stoolfrequency, SBM stoolfrequency, and stool consistency arefit-for-
`purpose to support the respective pre-specified secondary endpoints intendedfor inclusion in
`labeling claims in the context ofuse. This reviewer also believes that thefour pre-specified
`secondary endpoints are suitablefor inclusion in the label based on the modest but consistent
`separation between treatment arms at the meaning‘ul responder thresholds across both studies.
`See Section 6 (Interpretation ofScores) and Appendices B-Hforfurther detail.
`
`The three daily Symptom scores (abdominalpain, abdominal discomfort, and abdominal
`bloating) were not pre-specified in the endpoint testing hierarchy and were not vae I error
`controlled;
`(m4) Ihis reviewer discussed this with
`
`the Clinical review team and these endpoints are notpart ofthe CIC disease definition,
`therefore, the abdominal symptom instruments were not reviewedfor their adequacy to support
`labeling claims.
`
`The COA Stafldefer to DGIEP regarding the review ofthe clinical data to support the pre—
`specified secondary endpoint labeling claims (i. e., review ofthe CDFplots showing separation
`between treatment arms at the rrreaning‘irl responder thresholds). Based on the meaningful
`anchor thresholds derivedfrom the end ofphase 2 study (Study 10), this reviewer has concluded
`thefollowing regarding thefirst three pre-specified secondary endpoints (see Appendices D-H
`[CDFplots] and Section 6 [Interpretation ofScores] forfurther detail). Thefollowingfindings
`have been reviewed in collaboration with, and verified by, the Oflice ofBiostatistics review
`team.
`
`Reference ID: 401 7868
`
`

`

`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.”
`
`
`
`Reference ID: 4017868
`
`6
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`
`
`

`

`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:
`
`
`
`
`
`Reference ID: 4017868
`
`
`
`7
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`

`

`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
`
`
`
`•
`
`
`• See “Reviewer’s comments” in Section 4 (Content Validity) and 6 (Interpretation of
`Scores) for more information regarding the straining endpoint.
`If straining is accepted into the label, this reviewer recommends that the following
`language is used: “amount of straining with bowel movements (amount of time pushing
`or physical effort to pass stool).” This language is in line with the Linzess CIC labeling
`language for straining and is in line with the way patients (from the qualitative one-on-
`one interviews) interpreted severe straining (see Section 4 [Content Validity] for further
`detail).
`2 CONCEPT(S) OF INTEREST AND CONCEPTUAL FRAMEWORK
`
`The applicant did not provide a conceptual framework for the single-item sign and symptom
`scales.
`3 CLINICAL OUTCOME ASSESSMENTS
`
`The applicant had patients complete the constipation sign and symptom endpoint questions in the
`daily BM diary via electronic handheld device in both their phase 3 pivotal studies (Study 00 and
`Study 03). The questions were related to complete spontaneous bowel movement (CSBM),
`rescue medication use, SBM frequency, stool consistency, straining, and abdominal symptoms
`(Appendix A).
`
`The patients completed the daily BM diary at least once daily, following the Schedule of
`Assessments table below reproduced from the applicant’s Study 00 protocol:
`
`
`
`
`Reference ID: 4017868
`
`8
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`
`

`

`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
`
`
`
`
`
`
`The applicant did not submit a full PRO evidence dossier with the NDA and replied to the
`Agency’s request for a full evidence dossier by acknowledging their risk in opting not to provide
`one. The Agency’s request sent on March 16, 2016 was as follows:
`
`
`Submit a patient-reported outcome (PRO) evidence dossier supporting the PRO
`instruments that you included as key secondary endpoints proposed for inclusion in
`labeling (i.e., measuring “straining,”
`
`). The PRO evidence dossier should include the following: ·
`• Documentation of content validity of the PRO instruments, including a qualitative
`research report summarizing any literature reviews, expert interviews, research
`conducted with patients showing support that the core symptoms being measured
`are relevant and meaningful to CIC patients, that patients had defined the PRO
`items/questions and response options consistently (e.g., did the definitions of
`
`
`
`Reference ID: 4017868
`
`9
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`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
`
`
`
` overlap?), and that patients understood
`the items and response options in the way they were intended
`• Exact copies of the PRO instruments in the format that they were administered to
`patients in your phase 3 trials (e.g., paper versions, electronic screen shots), along
`with any user manuals and any training materials for the site, investigator, and
`patient
`• Psychometric analysis report including measurement properties of the PRO
`instruments (i.e., reliability, validity, ability to detect change) based on the
`longitudinal phase 3 data
`• PRO endpoint scoring algorithms
`• Clinically meaningful responder definitions for the PRO endpoints, including
`anchor-based analyses conducted with phase 3 data to establish clinically
`meaningful change from baseline for the PRO endpoints, using the two Patient
`Global Assessment (PGA) questions (change in constipation and constipation
`severity)
`• Cumulative distribution function (CDF) plots for the two PGA anchor scales that
`you plan to use to support the responder definitions you are proposing for the
`PRO endpoints
`
`
`Reviewer’s comments: This reviewer went back to the qualitative data submitted by the
`applicant during the IND 74883 phase and reviewed those preliminary data during the NDA
`review. With regard to the straining PRO instrument, the applicant modified the response scale,
`from a 0-10 numeric rating scale to a 5-point verbal response scale, for the final straining scale
`used in the phase 3 studies. Although the applicant did not submit a full PRO evidence dossier
`for the final straining instrument, the qualitative patient data generally supported the relevance
`and meaningfulness of the straining concept and severity. The change from the 0-10 point scale
`to a 5-point scale does not change the suitability of the straining item to support labeling claims.
`Based on this reviewer’s review of the same five response options used in the 5-point straining
`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.”
`
`With regard to scoring of the first four pre-specified endpoints (CSBM frequency, SBM
`frequency, stool consistency, and straining), the applicant stated the following reproduced from
`the Study 00 protocol:
`
`
`
`Reference ID: 4017868
`
`10
`
`
`
`
`
`(b) (4)
`
`

`

`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
`
`
`
`
`
`
`
`
`
`
`With regard to the applicant’s plans for handling missing data, the applicant stated the following
`reproduced from their statistical analysis plan for Study 00:
`
`
`
`Reference ID: 4017868
`
`11
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`
`
`

`

`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
`
`
`
`
`
`
`
`4 CONTENT VALIDITY
`
`The applicant conducted qualitative research with patients in the United States (see previous
`COA review: AT 2011-097; Miskala; finalized in DARRTS on January 13, 2012).
`• Phase 1 concept elicitation interviews were conducted in 20 patients with CIC (meeting
`either a two-seven of the Rome III Part C criteria) in 4 waves of individual one-on-one
`interviews with 5 patients each). Interviews lasted approximately 60 minutes. Cognitive
`interviews were conducted with an additional 15 patients with CIC (meeting either a
`four-seven of the Rome III Part C criteria) in 2 waves of interviews.
`• Phase 2 cognitive interviews were conducted in 15 patients with CIC (meeting either a
`four or five of the Rome III Part C criteria) completed at three clinical sites in the US.
`Interviews were completed in 3 waves of interviews.
`
`
`To date, the following information has been submitted (check all that apply):
`☒Literature review and/or publications
`☒Documentation of expert input
`
`
`
`Reference ID: 4017868
`
`12
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`
`
`
`

`

`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
`
`
`
`☒Qualitative study protocols and interview guides for focus group or patient interviews
`☒Chronology of events for item generation, modification, and finalization (item tracking
`matrix)
`☒Qualitative study summary with evidence to support item relevance, item stems and
`response options, and recall period
`☒Qualitative support for meaningful change
`☒Quantitative study summary with evidence to support item retention and scoring
`☐Transcripts (if available)
`
`
`The applicant concluded that the results from the concept elicitation and cognitive interviews
`supported the modification and finalization of the daily BM diary scales to include the severity
`of the most predominant, important, and bothersome symptoms of CIC, as well as the use of
`clear terminology for the items, response options, and recall periods for the daily BM diary and
`the patient global anchor scales.
`
`It is important to note that the 5-point straining scale that was used in the two phase 3 studies
`(Studies 00 and 03) was not cognitively debriefed with patients; only the 11-point numeric rating
`scale version of the straining item was tested with patients.
`
`Worthy of mention is the way the interviewed patients defined severe straining. Based on the
`patients’ quotes included in the applicant’s qualitative study reports submitted during the IND
`74883 phase, this reviewer had some concern that the patients might be defining severe straining
`in different ways. Therefore, the following information request was sent to the applicant on
`October 7, 2016:
`
`
`Using data from the CIC patients participating in the 50 qualitative interviews (phases 1 and 2 of
`the qualitative interviews during IND 74883), provide a table displaying the patients' interpretation
`of severity of straining. The table should include one row per patient with information included in
`four columns:
`a. An "X" in either Column 1 or Column 2, or another interpretation of severe straining in
`Column 3:
`i.
`Column 1: Patient defined severity of straining as amount of time or effort spent
`pushing/forcing a bowel movement
`Column 2: Patient defined severity of straining as straining that causes rectal
`pain, bleeding, tearing, or hemorrhoids
`Column 3: A description of another interpretation of severity of straining that does
`not fit into Column 1 or 2
`b. A description of how the patient describes his/her own current level of straining severity
`(e.g., none, mild, moderate, severe, very severe) in Column 4.
`
`ii.
`
`iii.
`
`
`The following clarification to the information request was sent to the applicant on October 27,
`2016:
`
`
`
`Reference ID: 4017868
`
`13
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`

`

`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
`
`
`
`Submit an updated table that does not treat Columns 1 and 2 as mutually exclusive. Place an "X"
`in both Columns 1 and 2 if patients defined straining in both ways during their interviews.
`
`
`The applicant’s response to the information requests resulted in the following calculations by this
`reviewer:
`• Of the 32 patients (of the 50 interviewed) who defined severe straining during their
`interviews:
`o 60% (n=19/32) defined severe straining as amount of time or effort spent
`pushing/forcing a bowel movement
`o 40% (n=14/32) defined severe straining as straining that causes rectal pain,
`bleeding, tearing, or hemorrhoids
`
`• Of the 18 CIC patients that reported that they are currently experiencing severe straining
`(i.e., at least reporting a 6 on the 0-10 point straining scale or reporting “severe” or “very
`severe” straining):
`o 83% (n=15/18) defined severe straining as amount of time or effort spent
`pushing/forcing a bowel movement
`o 61% (n-11/18) defined severe straining as straining that causes rectal pain,
`bleeding, tearing, or hemorrhoids
` Of those 11 patients, 73% (n=8/11) also defined straining as amount of
`time or effort spent pushing/forcing a bowel movement.
`
`
`Therefore, it appears that most of the patients defined severe straining as amount of time or effort
`spent pushing/forcing a bowel movement, regardless of whether or not they also defined it as
`causing rectal pain, bleeding, tearing, or hemorrhoids.
`
`See Section 6 (Interpretation of Scores) for further detail on patients’ impressions regarding the
`patient global anchor scales.
`
`Reviewer’s comments: The applicant opted not to provide a full PRO evidence dossier with their
`NDA submission in response to FDA’s information request for the full dossier sent on March 16,
`2016; the applicant also acknowledged that they were aware of the risk in not providing a full
`dossier for Agency review. Nonetheless, the applicant did provide a preliminary PRO evidence
`dossier during the IND 74883 phase (including patient qualitative interview reports and item
`tracking matrices). The qualitative work conducted did include cognitive testing of the exact
`scales used for the first three secondary endpoints (CSBM frequency, SBM frequency, and stool
`consistency). However, all patient qualitative work was done with an 11-point NRS straining
`instrument, not the 5-point straining scale that was used in the phase 3 trials. The applicant
`modified the response scale, from a 0-10 numeric rating scale to a 5-point verbal response scale,
`for the final straining scale used in the phase 3 studies. Although the applicant did not submit a
`full PRO evidence dossier for the final straining instrument, the qualitative patient data
`
`
`
`Reference ID: 4017868
`
`14
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`

`

`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
`
`
`generally supported the relevance and meaningfulness of the straining concept and severity. The
`change from the 0-10 point scale to a 5-point scale does not change the suitability of the
`straining item to support labeling claims. Based on this reviewer’s review of the same five
`response options used in the 5-point straining 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.”
`5 OTHER MEASUREMENT PROPERTIES (RELIABILITY, CONSTRUCT
`VALIDITY, ABILITY TO DETECT CHANGE)
`
`
`This reviewer could not find results from any psychometric properties and performance analyses
`that might have been conducted by the applicant. The applicant opted not to submit a full PRO
`evidence dossier to support the reliability, validity, and ability to detect change for the pre-
`specified endpoints.
`6 INTERPRETATION OF SCORES
`
`The applicant tested a number of different improvement/change anchor scales within their patient
`cognitive debriefing one-on-one interviews. This reviewer has included a brief summary below
`of the relevant findings concerning the two anchor scales that were used to interpret the
`meaningfulness of the statistically significant improvement findings in the endpoint scores from
`the patients’ perspective. The applicant did not submit patient interview transcripts; therefore,
`the information below is based on the applicant’s cognitive interview reports that included some
`patient quotes.
`
`Patient Global Assessment (PGA) Constipation Severity (Appendix B)
`• The PGA Constipation Severity item is a current state anchor scale) with no risk of recall
`error.
`• This item was used by this reviewer as the primary anchor scale to establish the
`meaningfulness of improvement in patient scores over time (week 12 score minus
`baseline score.
`• The applicant did not ask patients what would be meaningful to them regarding a one-,
`two-, or three-category change in response options over time for this item.
`Reviewer’s comments: Given that more than one patient (phase 1, wave 2) implied that a
`change from “very severe” to “severe” might not be a meaningful improvement (one
`patient quote was: “severe and very severe to me would be pretty much the same), this
`reviewer considered a two-category change as a meaningful improvement anchor.
`
`
`
`15
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`
`
`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
`
`
`Patient Global Assessment (PGA) Constipation Change (Appendix C)
`• The PGA Constipation Change item required patient recall from the start of study
`medication 12 weeks earlier; some patients expressed being unable to recall back that
`far; risk of recall error
`o Some patients (phase 2, waves 1 and 3) expressed having difficulty remembering
`signs and symptoms even from three days earlier (some patient quotes regarding
`being able to remember back three days were: “tha