CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-301
`
`OTHER REVIEWg S)
`
`'
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE '
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`CLINICAL INSPECTION SUMMARY
`
`DATE:
`
`8/2 8/2008
`
`TO:
`
`FROM:
`
`THROUGH:
`
`'
`
`Heather Buck, Regulatory Project Manager
`Aisha Peterson, M.D., Medical Officer
`Division of Gastroenterology Products
`
`Khairy Malek, M.D.
`Good Clinical Practice Branch 1
`
`Division of Scientific Investigations
`
`Constance Lewin, M.D., M.P.H.
`Branch Chief
`Good Clinical Practice Branch 1
`
`Division of Scientific Investigations
`
`SUBJECT:
`
`Evaluation of Clinical Inspections
`
`NDA #
`
`22-30l
`
`APPLICANT:
`
`Salix Pharmaceuticals
`
`DRUG:
`
`—__ (mesalamine) Encapsulated Granules
`
`[1%
`
`NME:
`
`'
`
`No
`
`THERAPEUTIC CLASSIFICATION:
`
`Standard, 10 month
`
`INDICATIONS:
`
`'
`
`1. Maintenance of remission in mild to moderate ulcerative colitis.
`
`CONSULTATION REQUEST DATE: March 27, 2008
`
`DIVISION ACTION GOAL DATE: August 30, 2008
`
`PDUFA DATE:
`
`October 31, 2008
`
`

`

`
`
`
`
`I. BACKGROUND:
`
`Mesalamine is the agent commonly used to induce and maintain remission in mild to
`moderately active ulcerative colitis. Its action appears to be a topical effect, rather than
`systemic. The clinical efficacy of oral mesalamine compounds depends upon delivery of the
`intact molecule to the colonic mucosa without breakdown during digestion. This can be done
`I"
`_
`__
`J The study drug
`Mesalamine Pellets (MP) is a novel formulation of mesalamine which combines the
`
`advantages of both a delayed and extended release oral solid dosage form
`
`The inspected sites were chosen because of enrollment of large number of subjects. The
`Russian sites were also chosen because of suspicion of human subject protection violation as
`well as reported protocol violation.
`
`Two protocols were inspected:
`
`1. Protocol MPUC3003 entitled “A Multicenter, Randomized, Double-Blind, Placebo-
`Controlled, Trial To Evaluate The Use Of Mesalamine Pellet Formulation 1.5G QD To
`Maintain Remission From Mild To Moderate Ulcerative Colitis”
`
`2. Protocol MPUC3004: Same title as protocol MPUC3003
`
`11. RESULTS (by Site):
`
`Name of CI, Location
`
`Protocol # and #
`of Subjects
`
`Inspection Date
`
`Final
`Classification
`
`
`
`St. Petersburg, Russia
`Yuri Shvartz, M.D.
`Saratov, Russia
`Andrey Rebrov, MD.
`Saratov, Russia
`' Glenn Gordon, MD.
`Mexico, MO, USA
`
`30 Sub'ects
`MPUC3004
`30 Sub'ects
`MPUC3003
`19 subjects
`MPUC3003
`12 Subjects
`
`.
`
`June 26-30, 2008
`
`NAI
`
`June 24-27, 2008
`
`Salam Zakko, M.D.
`Bristol, CT, USA
`
`MPUC3004
`11 Subjects
`
`. K
`
`ey to Classifications
`NA] = No deviation from regulatiOns.
`VAl = Deviation(s) from regulations.
`OAI = Significant deviations from regulations. Data unreliable.
`Pending = Preliminary classification based on information in 483 or preliminary communication with the field;
`ElR has not been received from the field and complete review ofElR is pending.
`
`

`

`1. Boris Starostin, M.D.-Site # 572 '
`City Polyclinic # 38, Centre for Gastroenterology No 1
`26, Kavalergardskaya, 193015, St. Petersburg, Russia
`
`pa.
`
`What was inspected: The field investigator and I reviewed the records of all
`subjects in the study. There were no limitations to the inspection.
`
`General observations/commentary: We found 2 protocol violations:
`
`There were 3 flares in disease activity, for subjects # 8, 11 and 30, among the 30
`subjects’ records reviewed. The protocol specifies that a stool sample will be
`sent for analysis to rule out presence of Clostridium difficile, ova or parasites in
`case of a flare. In the 3 cases of flare, the clinical investigator (CI) did not send
`a stool sample for analysis. The CI defended his action, by stating that it was
`more important to treat the subjects’ symptoms immediately rather than to
`follow the unscheduled visit procedures and leave the flare subjects without
`treatment until the stool analysis results are back.
`
`The second protocol violation is that, for two subjects (#18 and 33), when the
`Cl received the hematology results and these were described by the lab as
`samples clotted or unsuitable for analysis, the C1 did not submit a second
`sample for analysis. In case of subject # 18, the affected hematology samples
`were for Visits 2 and 3. In case of subject # 33, the affeCted samples were for
`screening and Visit 1.
`‘
`
`C.
`
`Assessment of data integrity: These violations. would not affect the validity of the data.
`The data from this site can be used in support of the NDA.
`
`2. Yuri Shvartz M.D.-Site # 566
`
`Saratov State Medical University, Department of Hospital Therapy, Saratov Regional
`Clinical Hospital, 1 Smimovskoye Ravine, Saratov 410053, Russia
`
`a.
`
`What was inspected: We reviewed the records of all subjects in the study. There
`were no limitations to the inspection.
`
`General observations/commentary: The study was well conducted except that
`the first 6 subjects, at the beginning of the study, # 1-6, were given the
`preparatory medication (Fortrans) for sigmoidoscopy one day before these
`subjects signed informed consent documents.
`
`Assessment of data integrity: This violation would not affect the validity of the data.
`The data from this site can be used in support of the NDA.
`
`

`

`3. Andrey P. Rebrov, M.D.-Site # 565
`Saratov State Medical University, Department of Hospital Therapy, Saratov Regional
`Clinical Hospital, 1 Smimovskoye Ravine, Saratov 410053, Russia.
`
`a. What was inspected: we reviewed all the 19 subjects’ records at this site.
`There were no limitations to the inspection.
`
`. General observations/commentary: At this site we found one protocol violation,
`in that the CI enrolled one subject, # 9,
`in the study for two days before
`discontinuing the subject afier realizing that the subject’s lab result was positive
`for Hepatitis B.
`
`. Assessment of data integrity: Apart from the above protocol violation, the study was
`well conducted. This violation would not affect the validity of the data.
`The data from this site can be used in support of the NDA.
`
`4.
`
`Glenn Gordon, M.D.—Site # 618 _
`Center for Digestive and Liver Disease, Inc., 714 Medical Park Drive,
`Mexico, MO 65265-3726, USA
`
`a. What was inspected: The field investigator reviewed the records of all 12 subjects
`enrolled in the study, out of which 7 completed the study and 5 had early termination.
`There were no limitations to the inspection.
`
`b. General Observations: At this site the field investigator observed no violations.
`
`c. Assessment of data integrity: The data from this site are reliable and can be used in
`support of the NDA.
`
`5. Salam Zakko, M.D.-Site 419
`Connecticut Gastroenterology Institute, Brewster Road
`Bristol, CT, USA.
`
`a. What was inspected: At this site the field investigator inspected the records of all 11
`subjects randomized. Seven subjects completed the study and 4 had early termination,
`one discontinued due to an adverse event, and 3 discontinued due to lack of efficacy.
`There were no limitations due to the inspection
`
`. General Observations: At this site the field investigator observed no violations.
`
`. Assessment of data integrity: The data from this study can be used in support of the
`NDA.
`
`

`

`IV. OVERALL ASSESSMENT OF FINDINGS AND RECOMMENDATIONS
`
`The data from the 5 sites inspected are reliable and can be used in support of the NDA
`
`CONCURRENCE:
`
`Khairy Malek, M.O.
`Good Clinical Practice Branch I
`
`Division of Scientific Investigations
`
`{See appended electronic signature page}
`
`Branch Chief
`Good Clinical Practice Branch I
`
`Division of Scientific Investigations
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Constance Lewin
`8/29/2008 08:47:11 AM
`MEDICAL OFFICER
`
`Entered into DFS on behalf of Dr. Khairy Malek.
`
`

`

`REGULATORY PROJECT MANAGER LABELING REVIEW
`
`(PHYSICIAN LABELING RULE)
`
`Division of Gastroenterology Products
`
`Application Number: 22-301
`
`Name of Drug: __.... (mesalamine) Encapsulated Granules
`
`11(4)
`
`Applicant: Salix Pharmaceuticals, Inc
`
`Material Reviewed:
`
`Submission Date(s): December 21, 2007
`
`Receipt Date(s): December 31, 2007
`
`Submission Date of Structure Product Labeling (SPL): December 21, 2007
`
`Type of Labeling Reviewed: Word
`
`Background and Summag
`
`We received NDA 22-301 from Salix Pharmaceuticals, Inc. on December 31, 2007. The
`proposed indication for this NDA is maintenance of remission of ulcerative colitis in patients 18
`years of age and older. The proposed prescribing information in Structured Product Labeling
`(SPL) format, and the proposed package insert in Physician’s Labeling Rule (PLR) format was
`submitted with the original NDA. We have not yet received the color carton and container labels
`but expect them in June, 2008.
`
`This review provides a list of revisions for the proposed labeling that should be conveyed to the
`applicant. These comments are based on Title 21 of the Code of Federal Regulations (201.56 and
`201.57), the preamble to the Final Rule, Guidance(s), and FDA recommendations to provide for
`labeling quality and consistency across review divisions. When a reference is not cited, consider
`these comments as recommendations only.
`
`

`

`The following issues/deficiencies have been identified in your proposed labeling.
`
`R_evie_w
`
`1. Highlights
`a Revise the “Initial U.S. Approval” statement to read “Initial U.S. Approval: 1987”
`o The labeling should reflect. . .”The verbatim statement “Initial U.S. Approval”
`followed by the four-year digit year in which FDA initially approved a new molecular
`entity, new biological product, or new combination of active ingredients”. [Best
`Practices]. The active ingredient mesalamine was first approved as Rowasa NDA
`19-618 on December 24, 19871.
`b Change font size from 10 point type to 8 point type, and adjust margins to 1/2 inch on all
`sides. Note that these adjustments will likely reduce the section to one-half page as is
`required.
`
`0 Highlights, excluding the boxed warning, must be limited in length to one-half page
`(e.g., would fit on one-half page if printed on 8.5” x 11 paper, single spaced, 8 point
`type with 1/2 inch margins on all sides, in a two-column fonnat). [Best Practices].
`c Revision Date for a new NDA should be left blank at the time of submission and will be
`edited to the month/year of the application or supplement approval. Date should read:
`“Revised: month/year”. [Best Practices].
`
`2. Table of Contents
`
`0 Change 13.2 subsection title from "Animal Toxicology” to “Animal Toxicology and/or
`' Pharmacology”. [Best Practices].
`0 Create subsection headings that identify the content. Avoid using the word
`“General”. See subsection 5.1 under the Warnings and Precautions. [Best Practices].
`
`3. Full Prescribing Information
`’
`0 Remove bold from body systems in subsection 6.1. All headings and subheadings must
`be highlighted by bold type that prominently distinguishes the headings and
`subheadings from other labeling information. Therefore, for other labeling
`information, use bold type sparingly; and use another method for emphasis such as
`italics or underline.
`[Best Practices}.
`
`0
`
`In subsection 6.1 Clinical Studies Experience, include the following statement (or
`appropriate modification) preceding presentation of adverse reactions from clinical
`trials: 1"
`
`
`
`
`
`
`1h :/’iwwaccessdatafda. ov’scri)ts/cder/ob/docs/obdetail.cfrn9A l No=019618&TABLE1=OB Rx
`
`13(4). .
`
`

`

`Recommendations
`Please address the identified deficiencies/issues and re-submit labeling by August 1, 2008. This
`updated version of labeling will be used for fimher labeling discussions.
`
`Heather Buck
`
`Regulatory Project Manager
`Division of Gastroenterology Products
`
`Supervisory Comment/Concurrence:
`
`Brian Strongin, R.Ph., M.B.A.
`Chief, Project Management Staff
`Division of Gastroenterology Products
`
`Drafted: HB 3/26/08
`Revised/Initialed: BS 3/26/08
`Finalized: 3/27/08
`Filename:
`
`RPM LABELING REVIEW
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Heather G Buck
`3/27/2008 08:23:55 AM
`CSO
`
`Brian Strongin
`3/27/2008 09:57:48 AM
`CSO
`
`