CENTER FOR DRUG EVALUATION AND
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`RESEARCH
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`APPLICA TION NUMBER:
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`22-301
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`SUMMARY REVIEW
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`Division Director Review
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`ulato Action
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`_ 0ctober31, 2008
`Donna-Griebel, MD
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`Proprietary Name /
`Established
`S ‘
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`Name
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`Dosage Forms / Strength
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`Pro osed Indication
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`Division Director Summary Review
`22-301
`Salix Pharmaceuticals
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`December 21, 2007
`October 31, 2008
`APRISO
`Mesalamine
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`0.375 g extended release capsule for oral
`administration
`' Maintenance of remission of ulcerative colitis
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`Approval
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`Material Reviewed/Consulted
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`'
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`0ND Action Package, including:
`Medical Officer Review
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`Pharmacolog Toxicolog Review
`CMC Review/OBP Rev1ew
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`Clinical Pharmacology Revrew
`DDMAC
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`CDTL Revrew
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`OSE/DMEPA
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`V
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`Names of disci line reviewers
`Aisha Peterson, MD/John Hyde, MD
`Shahla Farr, MS/Mike Welch, Ph.D.
`Sushanta Chakder, Ph.D.
`Gene Holbert, Ph.D.
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`Insook Kim, Ph.D.ISue-Chih Lee, Ph.D.
`Kathleen Kiemm, Pharm.D.
`Khairy Malek, MID/Constance Lewin, MD, MPH
`John H de, MD
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`Melina Griffis, R.Ph./Kellie Taylor, PharmD,
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`MPH/Carol Hol_uist, R.Ph.
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`OND=Offioe of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of seientific Investigations
`CDTL=Cross-Discipline Team Leader
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`Page 2 of 8
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`Appears This Way
`On Original
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`Division Director Review
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`1. Introduction
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`This NDA submission is a 505(b)(2) application. The applicant did not conduct all the
`nonclinical studies relied upon to support approval. The reference listed drugs are Canasa and
`Asacol. This review summarizes the salient findings of the FDA revieWers. Please refer to the
`Cross Disciplinary Team Leader review written by Dr. John Hyde for a comprehensive
`presentation of the issues identified during the review of this application, a description of the
`FDA reviewers’ analyses, and a discussion of the review team’s risk/benefit decision.
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`2. Background
`The regulatory history of this application is clearly summarized in Dr. John Hyde’s Cross
`Disciplinary Team Leader review. Although two major studies were submitted in this
`application to establish the efficacy of the mesalamine product Apriso, the biostatistical
`reviewer, Shahla Farr, MS, stated in her review that she believes that one of the studies can
`only be viewed as supportive evidence of efficacy. She expressed concern about the late
`changes in the statistical analysis plan of the study and the lack of statistically significant
`supportive evidence of efficacy in its secondary efficacy endpoints. Dr. Aisha Peterson, MD,
`the primary clinical reviewer, concluded, however, that both studies established the
`effectiveness of Apriso Dr. John Hyde addresses this variation in opinion among the
`reviewers regarding the strength of evidence of effectiveness demonstrated by the second
`studyin Section 11.0ther Relevant Regulatory Issues of his review.
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`3. CMC
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`I concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of 36 months. There are no outstanding
`issues.
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`
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`polymer matrix
`The manufacturing process involves application of
`mesalamine granule core. The coated granules are filled into gelatin capsules. The inner
`coating is designed to dissolve when exposed to pH 2 6, delivering mesalamine past the
`stomach. Although the formulation has both delayed- and extended—release characteristics,
`the chemistry reviewer recommended that the dosage form be designated “extended-release
`capsules. However, due to its delayed—release characteristics, the chemistry reviewer
`recommended that the product’s labeling include instructions that it should not be taken with
`antacids
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`[1(4)
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`4. Nonclinical Pharmacology/Toxicology
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`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharmacology/toxicology issues that preclude approval.
`I concur with the
`reviewer’s recommendations regarding product labeling.
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`5. Clinical PharmacOlogy/Biopharmaceutics
`I concur with the conclusions reached by the- clinical pharmacology/biopharmaceutics
`reviewer, Dr. Insook Kim, Ph.D., that there are no outstanding clinical pharmacology issues
`that preclude approval.
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`6. Clinical Microbiology
`Not applicable.
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`7. ClinicallStatistical-Efficacy
`Two major trials (Study 3003 and Study 3004) of similar design were submitted to support the
`effectiveness of encapsulated mesalamine granules (eMG) capsules (Apriso) in maintenance of
`remission of ulcerative colitis. The studies were randomized, double-blind, and placebo
`controlled. They enrolled patients with a history of ulcerative colitis (UC) whose disease had
`been in remission for at least 1 month and not more than 12 months. Remission was defined
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`as a revised Sutherland Disease Activity Index (DAI) rectal bleeding score of 0 and mucosal
`appearance score of 0 or 1. Patients were treated with 1.5 g of eMG or placebo x 1 dose daily
`for 6 months.
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`The primary endpoint cf the studies was the proportion of subjects relapse—free after 6 months
`of treatment. Relapse was defined, again using the modified Sutherland Disease Activity
`Index, as rectal bleeding. score 2 l and a mucosal appearance score 2 2. In the protocols’
`original analysis plans, patients who discontinued early were to be counted as relapses.
`However, late in the studies’ conduct, the analysis plans were amended to count early
`discontinuation as relapse only if the discontinuation was deemed related to lack of efficacy or
`to a UC—related adverse event.
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`In both studies, treatment with eMG resulted in a statistically significantly higher proportion of
`patients who were relapse-free at 6 months. (See the table below, which has been reproduced
`from biostatistical reviewer Shahla Farr’s review). The biostatistical reviewer, however,
`expressed concern about the robustness of the observed outcome in Study 3004, for the
`following reasons:
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`. 1) Study 3004 was stopped early. Although both studies started in December 2004,
`Study 3003 completed before Study 3004 in April of 2007 (with total N=305).
`Study 3004 was subsequently stopped by an amendment reducing its sample size,
`before completing its originally planned target enrollment ~ in August 2007 (with
`total N=257). When the reviewer performed a sensitivity analysis to explore the
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`impact of early stopping, assigning the observed placebo “success rate” in the study
`to the 43 subjects who would have been enrolled if the study had not been
`terminated early, the p value for the outcome comparison in Study 3004 shifted to
`p=0.06.
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`2) When the FDA reviewer applied the more conservative imputation strategy to
`account for missing data at 6 months (the original protocol plan of counting all
`patients who discontinued treatment early as having experienced a relapse), the p-
`value shifted in Study 3004 from the p< 0.001 observed in the applicant’s analysis,
`to p<0.046. The applicant’s analysis utilized a missing data imputation strategy for
`the primary efficacy analysis that counted only patients who were considered to
`have left the study early because of lack of efficacy or a UC-related adverse event
`as a relapse event. The results from these two analysis approaches are presented in
`the Table below with the more conservative strategy labeled “R__IT'I‘” (FDA
`Reviewer ITT analysis) and the less conservative strategy employed by the
`applicant as “A_ITT” (Applicant’s ITT analysis).
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`3)
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`In Study 3004, the hierarchical analysis of the secondary endpoints, which was
`prespecified only in a protocol amendment that occurred after study enrollment
`completed, stopped at the first secondary endpoint tested, rectal bleeding, because it
`failed statistical significance.
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`Pro I ortion of sub'ects rela se—free after 6 months of treatment
`Mesalamine
`Placebo
`3 95% CI for
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`Stud 3003
`No Relase (A ITT ** w65209—90
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`Difference
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`56/96=58% Wm), 32%)
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`P—Value
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`‘
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`J
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`<o.001
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`<0.001
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`—:_‘TT——Ti
`-_-_—_
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`as *
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`Ti—
`._. w ._. \ .... C\‘1?ooooo\
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`No Relapse
`117/164=71%
`55/93=59% I 12% (0%, 24.5%)
`3 0.046
`(R ITT ***
`!
`-
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`**Applicant’s ITT analysis (early dropouts as relapse only lack of efficacy or if UC—related
`AE occurred.
`'
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`No Relapse
`***
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`143/209=68%
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`49/96=51%
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`17% (5.5%, 29.2%)
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`‘
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`***FDA Reviewer’s ITT analysis, all early withdrawals as relapse
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`Although the biostatistical reviewer expressed concern about the robustness of the results of
`Study 3004, she still felt that this study was supportive of the findings of Study 3003. The
`clinical reviewers were persuaded that both of these major studies provided evidence that
`established that Apriso is effective in maintaining remission from ulcerative colitis. Dr. Hyde .
`pointed out in his Cross-Disciplinary Team Leader review that the outcome observed in Study
`3003 was itself highly statistically significant (even utilizing the more conservative FDA
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`analysis), and could provide strong evidence of effectiveness, even as a stand alone trial. I
`concur with Dr. Hyde’s conclusion.
`I also concur with the reviewers that the efficacy results
`presented in the product label should be those resulting from the analysis coding early
`discontinuations of any kind as a relapse. That analysis was the protocols’ original designated
`analysis.
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`Dr. John Hyde, the Cross-Discipline Team leader, noted in his review that although the
`duration of treatment for performing efficacy evaluation in both the major studies was 6
`months, substantial safety data were provided for product exposures beyond 6 months. Given
`that there was no safety issue-identified associated with exposures longer than 6 months that
`would preclude longer drug exposures, Dr. Hyde did not recommend that the label should limit
`the duration of treatment to the 6 month period evaluated in the two major clinical trials.
`I
`concur with this decision.
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`8. Safety
`Patients were randomized on a 2:] basis in the two major randomized, controlled clinical trials
`of 6 months duration that support this 505(b)(2) application, Study 3003 and Study 3004.
`Three hundred sixty seven of those patients were treated with at least one dose of Apriso and
`provided safety-data that could be compared to placebo control.
`In addition, there was an open
`label, single arm safety study that enrolled patients who had completed their participation in
`the two randomized, controlled trials, as well as patients who had not been previously exposed
`to Apriso. This extension study provides safety data on 190 additional patients exposed to
`Apriso in an open label setting. Of the total 557 patients that comprised the safety data base,
`352 had been exposed to drug for at least 6 months and 250 for at least a year.
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`Mesalamine is not a new molecular entity and there is extensive clinical experience associated
`with its use. OSE reviews that were performed for other mesalamine applications were
`reviewed for this application. Dr. Peterson also requested mesalamine postmarketing database
`reports for hepatic adverse events and found cases of worsening of pre-existing liver disease in
`patients who had taken mesalamine. Based on her postmarketing safety review of mesalamine
`products in general, she recommended that product labeling include in the Warnings and
`Precautions section a description of the observation of onset of liver failure in individuals With
`pre-existing liver disease and a statement that caution should be exercised when administering
`Apriso to patients with liver disease.
`I concur with the cliniCal reviewers’ recommendations
`for product labeling.
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`I concur with the reviewers’ decision to not require a thorough QT study for approval of this
`application given the extensive clinical experience with mesalamine, its limited absorption and
`the lack of nonclinical evidence that there is a risk of QT prolongation associated with
`mesalamine.
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`9. Advisory Committee Meeting
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`There was no advisory committee meeting to discuss this application. The product is not a
`new molecular entity and the reviewers had no scientific issues that required discussion in an
`advisory committee.
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`10.
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`Pediatrics
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`The application was presented to the PERC and the committee agreed with the reviewers’
`recommendation that the applicant be required to study at least two dosing regimens in
`children aged 5 years and older with ulcerative colitis in remission to assess pharmacokinetics,
`safety and effectiveness of this product. The PeRC concurred with a deferral of the
`submission of the study for this age range because the adult indication is otherwise ready to be
`approved. Because there are too few children below the age of 5 with ulcerative colitis to
`study, the PeRC concurred with a waiver of studies for that age group.
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`Other Relevant Regulatory Issues
`11.
`The Division of Scientific Investigations audited two US sites from each of the major
`efficacy studies, Studies 3003 and 3004, as well as three Russian sites. Sites were selected on
`the basis of their having enrolled large numbers of patients. After conducting the inspections,
`DSI recommended that the data from the sites could be used to support the NDA.
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`Dr. Peterson reviewed the financial disclosures for Studies 3003, 3004 and 3005. She
`identified only one investigator who had a disclosed equity interest. Because that investigator
`had only enrolled 4 of the 256 patients that participated in study 3004, and only 9 of 396 of the
`patients in Study 3005, she determined that the impact of the equity interest on the reported
`outcome of these studies was minimal.
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`LabeHng
`12.
`I concur with the labeling recommendations of the reviewers, which are thoroughly
`summarized in Section 12 Labeling of Dr. John Hyde’s Cross-Discipline Team Leader review.
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`13.
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`Decision/Action/Risk Benefit Assessment
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`0 Regulatory Action - I recommend approval of this 505(b)(2) application.
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`0 Risk Benefit Assessment — I concur with the risk and benefit assessment of the
`reviewers.
`I concur with Dr. John Hyde that the FDA’s review findings
`indicate that the risk and benefit characteristics of Apriso are similar to oral
`mesalamine products that are approved and marketed.
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`0 Recommendation for Postmarketing Risk Management Activities — I do not
`recommend a REMS.
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`0 Recommendation for other Postmarketing Study Commitments
`Pediatric studies should be required under PREA for patients aged 5 to 17
`years.
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`Page 8 of 8
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`Appears This Way
`On Original
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
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`/S/
`
`Donna Griebel
`10/31/2008 02:56:57 PM
`DIRECTOR
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`