CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-301
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review
`
`
`
`From
`
`NDA/BLA #
`
`-
`
`Sun lement#
`A ulicant
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established
`SAN names
`
`Dosage forms / Strength
`
`Proposed Indication
`
`Recommended:
`
`
`
`1. Introduction
`
`October 29, 2008
`
`John E. H de, Ph.D., M.D., Clinical Team Leader, DGP
`Cross-Disciline Team Leader Review
`NDA 22-301
`
`N000, Original NDA
`Salix Pharmaceuticals, Inc.
`December 21, 2007; Received December 31, 2007
`October 31, 2008
`i
`
`APRISO
`Mesalamine
`
`Extended-release capsules for oral administration; each
`(33081116 contains 0.375 g mesalamine.
`'
`Maintenance of remission of ulcerative colitis in patients
`18 ear of a_e and older.
`Approval
`
`
`
`This application, received December 31, 2007, is an original NDA submission for a new oral
`formulation of mesalamine, also known as S-aminosalicylic acid, or 5-ASA. The prOduct is a
`gelatin capsule containing granules of mesalamine coated with excipients to give it both
`delayed-release and extended-release characteristics. Each capsule contains 0.375 g
`mesalamine.
`
`The proposed indication is “the maintenance of remission of ulcerative colitis in patients 18
`years of age and-older,” with proposed dosing of four capsules (1.5 g) once daily with or
`without food. The Applicant proposed labeling with a contraindication for hypersensitivity
`to salicylates, and with warnings about acute intolerance syndrome, renal toxicity, use in
`. hepatic impairment, use in patients with 1:,
`_,
`land use in patients with ,
`phenylketonuria.
`‘
`
`13(4)
`
`This application is not for a new molecular entity. Mesalamine was first approved in a rectal
`suppository for ulcerative colitis in 1987. Subsequently, several oral formulations of
`mesalamine have been approved for treating ulcerative colitis.
`
`Because the Applicant did not conduct all of the preclinical studies being relied upon, this
`was submitted as a 505B(2) application. The Applicant referenced preclinical information
`from studies conducted by Proctor & Gamble Pharmaceuticals for NDA 19-651 (Asacol) and
`by Axcan Scandipharm, Inc;, for NDA 21-252 (Canasa).
`
`

`

`Cross-Discipline Team Leader Review
`
`Apriso — NDA 22—301
`
`I 2. Background
`
`General Background
`
`Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology. Peak age of
`onset is in the early twenties, but age of onset can vary Widely. UC is more common in
`whites vs. non-whites and in women vs. men. The disease is manifest as mucosa] .
`
`inflammation and mucosal ulceration that occurs in the colon in a continuous segment
`beginning with the rectum. Extent of involvement varies, but it can include the entire colon.
`Involved areas classically show inflammatory changes that are limited to the mucosa, and,
`depending on severity, there may be extensive, broad-based ulceration. Clinically, UC
`presents as a chronic relapsing disease with variable-length bouts of bloody mucoid diarrhea
`and lower abdominal pain, but there may be long quiescent periods between attacks. There
`may also bersystemic manifestations of the disease, with involvement ofjoints, eyes, skin, or
`the hepatobiliary system. Potential serious complications include severe bleeding, toxic
`megacolon, and perforation. There is a very significant risk of colon cancer with
`longstanding disease, such that pancolitis of 10 years duration or longer has a 20- to 30—fold
`increased risk of cancer compared to the general population.
`
`Approved therapies for UC include corticosteroids to “tide the patient over a critical period”
`of UC, and aminosalicylates, which are available in rectal formulations (Canasa and Rowasa
`[mesalamine]) and oral formulations (Azulfadine [sulfasalazine]; Asacol, Pentasa, and Lialda
`[mesalamine]; Dipentum [olsalazine]; and Colazal [balsalazide]) as limited-term therapy to
`treat mildly or moderately active UC. Azulfadine, Asacol, and Dipentum are also approved
`as chronic therapy to maintain remission in UC. The safety and effectiveness of oral
`mesalamine products for pediatric ulcerative colitis have not been established, although
`balsalazide (Colazal) is approved for pediatric use in patients 5 years and older. Also used,
`but unapproved, therapies for ulcerative colitis include azathioprine and 6—mercaptopurine,
`and, less commonly, cyclosporine. Use of any of the preceding has come to be considered
`part of “conventional therapy.” Remicade (infliximab), a TNF blocker, is approved for
`induction and maintenance of remission in moderately to severely active UC with inadequate
`response to conventional therapy.
`
`Mesalamine’s specific mechanism of action is unknown, but it is thought to act primarily
`topically in the colon by blocking cyclooxygenase and 5-lipoxygenase, thereby inhibiting
`production of arachidonic acid metabolites and diminishing inflammation. Mesalamine may
`also act as a reactive oxygen metabolite scavenger. Oral formulations of mesalamine are
`designed to have delayed~ and/or extended-release characteristics in an attempt to target
`delivery to the presumed site of action. Typically, a third or less of orally administered
`mesalamine products is systemically absorbed. Preclinical studies identified the kidney and
`GI tract as targets of toxicity when given in high doses.
`
`Approved oral mesalamine products contain a warning for an adverse reaction that can look
`like exacerbation of ulcerative colitis, and they also contain a warning for the potential to
`cause renal impairment. Postmarketing reports of renal injury have been uncommon, and it
`appears to be an idiopathic reaction to mesalamine when given to humans in the therapeutic
`dose range. The approved dose of oral mesalamine to treat active UC ranges from 2.4 to
`
`Page 2 of 16
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`Cross-Discipline Team Leader Review
`
`Apriso — NDA 22-301
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`4.8 g/day, in single or divided doses, depending on formulation. The approved dose for
`maintenance of remission (Asacol only) is 1.6 g/day divided into BID dosing.
`
`Presubmission Communications between FDA and the IND Sponsors
`
`The Applicant held a pre-IND meeting with the Division on August 20, 2003. At that
`meeting, the Applicant was advised that a 505B(2) application could be used'to support the
`new formulation, but that it should include comprehensive summaries of the referenced
`studies, and that additional preclinical studies would be needed for the excipient
`L
`.
`J The Applicant was also advised that it would be acceptable to pursue an
`application for maintenance of remission E
`j The IND
`submission was received on October 30, 2003, and studies were allowed to proceed.
`
`m4)
`
`An End-of—Phase-2 meeting was held on October 6, 2004. The Applicant proposed to
`conduct two identically designed, placebo-controlled, six-month studies of maintenance for
`remission in ulcerative colitis. Remission was defined as absence of blood in the stools and
`
`an endoscopy score of 1 or less based on the Sutherland Index endoscopy criteria. The
`Division agreed that the proposed studies should suffice for supporting the indication of
`maintenance, but the Division requested that the endoscopy criteria be modified so that
`remission required absence of friability; the Applicant agreed. The Division stated that the
`six-month study duration was adequate. The Applicant also had data on a similar
`formulation manufactured by Dr. Falk Pharma and inquired about the acceptability of using
`that data for the safety database. The Division respOnded that those data would be
`J considered only as supportive and stated that the safety would largely be dependent on data
`from patients treated with the Applicant’s formulation. The Division advised that about 100
`patients treated for one year with the to-be-marketed formulation would be needed. The
`Division remarked that a PK study in pediatric patients would not be sufficient to fulfill the
`pediatric requirement, and requested that a pediatric plan be included at the time of NDA
`submission. The Division requested that the Applicant conduct SegmentI and Segment III
`reproductive toxicity studies for T;
`g
`j in rats in addition to the their proposed six-
`month non-rodent oral toxicity studies and genotoxicity studies. The Applicant stated they
`did not believe Segment I and III studies were necessary and planned to provide FDA with
`additional information. The Division stated the studies to support clinical pharmacology and
`pharmacokinetics appeared acceptable.
`
`A pre-NDA meeting was held October 29, 2007. The Division stated that the proposed
`safety database appeared adequate, but that its adequacy would be a review issue. The
`Agency asked that the submission clearly identify the formulation used in each PK study and
`recommended that the Applicant conduct a dissolution comparison of the Dr. Falk Pharma
`product to help assess the acceptability of data obtained using that product. The Division
`stated the toxicology package for E
`:1 appeared adequate. The Division did not
`agree that a pediatric waiver was appropriate, and the Division advised the Applicant to
`submit a plan or a request for deferral in the NDA submission.
`
`”(4}
`
`m4)
`
`Page3 of 16
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`

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`Cross-Discipline Team Leader Review
`
`Apriso — NDA 22-30]
`
`Submission and Review
`
`The NDA was dated December 21, 2007, and was received on December 31, 2007. It was
`given Standard review priority with an action date of October 31, 2008. The Application was
`submitted as paper copies. In the course of the filing review, problems were identified with
`the table of contents, indexing and tabbing ofjackets, and completeness of the safety data as
`it pertained to postmarketing experience with other mesalamine products. The Division and
`Applicant agreed on a plan to correct the deficiencies, and the application was filed with the
`Applicant’s commitment to provide additional safety information and new review jackets to
`resolve the organization problems.
`
`Shortly after submitting the application, the Applicant decided to withdraw the proposed
`trade name of ‘E
`J ' and replaced it with “APRISO.”
`
`M4)
`
`No Advisory Committee meeting was convened to discuss this application.
`
`The relevant review disciplines have all written review documents. The primary review
`documents relied upon are the following:
`
`Clinical Review by A. Peterson, dated 10/29/08.
`Statistical Review and Evaluation by S. Farr, dated 9/29/08.
`Office of Clinical Pharmacology Review by 1. Kim, dated 10/7/08.
`Phannacology/Toxicology Review and Evaluation by S. Chakder, dated 9/25/08.
`Chemistry Review by G. Holbert, dated 10/28/08.
`. Clinical Inspection Summary by K Malek, dated 8/28/08.
`Proprietary Name, Label and Labeling Review by M. Griffis, dated 10/9/08.
`DDMAC Labeling Comments by K. Klemm, dated 10/15/08.
`
`The following review OSE review documents were completed for other applications but have
`relevance to the current application and are referenced in the Clinical Review:
`
`Pericardial Effusion safety review for mesalamine by A. Mackey, dated 2/25/08,
`archived under NDAs 19-651, 19-618, 19-919, 20—049, 21-252, and 22-000.
`Renal Impairment safety review for mesalamine by A. Mackey, dated 3/19/08,
`archived under NDAs 19-651, 19-618, 19-919, 20—049, 21-252, and 22-000.
`
`The reviews should be consulted for more specific details of the application and review
`conclusions. This memorandum summarizes selected information from the primary review
`documents.
`
`Page 4 ofl6
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`

`Cross-Discipline Team Leader Review
`
`,
`
`Apriso — NDA 22—301
`
`3. me
`
`See the Chemistry Review by G. Holbert dated 10/28/08 for complete information.
`
`General product gualigg considerations
`The product consists of a polymer matrix mesalamine core granule with -- coatings
`designed to resist dissolution in the stomach but to dissolve at pH 2 6. The granules are
`filled into a hard gelatin capsule. Each capsule contains 0.375 g mesalamine. The drug
`substance is manufactured by E '
`jand the drug product is
`manufactured by Catalent Pharma in Winchester, KY.
`
`m4;
`
`The Chemistry Reviewer concluded that the NDA provided sufficient information to assure
`the identity, strength, purity, and quality of the product, and that there was adequate
`information on controls, process, specifications, and container/closure to support approval.
`Stability data'were provided to support expiration dating of 36 months.
`
`Facilities review/inspection
`The Establishment Evaluation Reports of the drug substance manufacturer, drug product
`manufacturer, finished dosage packers, and finished dosage stability tester were all
`acceptable. An overall recommendation of Acceptable was issued 8/4/08.
`
`,
`Other issues
`This formulation has both delayed—release and extended-release characteristics. There is no
`FDA-accepted dosage form designation that includes both properties. In the labeling review,
`the Chemistry Reviewer recommended that the dosage form designation be‘ ‘extended-
`release capsules.”
`
`Because this also is a delayed—release formulation, which relies on pH—dependent dissolution
`to obtain its delayed—release property, the Chemistry Reviewer also recommended that
`labeling instruct that the product is not to be taken with antacids.
`
`The labels had adequate information as required.
`
`Conclusions and Recommendations
`The Chemistry Reviewer recommended the NDA for approval. He recommended labeling
`changes as described above. No Phase 4 commitments, agreements, or risk management
`steps were recommended.
`
`4. Nonclinical Pharmacology/Toxicology
`
`See the Pharmacology/Toxicology ReView and Evaluation by S. Chakder dated 9/25/08 for
`complete information.
`
`This application falls under Section 505B(2) of the FD&C Act because it relies on
`pharmacology and toxicology data for which the Applicant does not have right of reference.
`The Applicant made reference to a six-month repeat-dose rat study, a 12-month repeated-
`
`Page 5 of 16
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`Cross-Discipline Team Leader Review
`
`Apriso ~ NDA 22-301
`
`dose dog study, and mouse and rat carcinogenicity studies that were previously reviewed
`under NDA 19-651 (Asacol, Proctor & Gamble), and to a mouse lymphoma assay reviewed
`under NDA 21-252 (Canasa, Axcan Scandipharm, Inc.). The Applicant conducted and
`submitted four—week and 26-week oral toxicity studies with I;
`_
`I which is a
`component of the Applicant’s formulation. The Applicant also provided publications on the
`pharmacodynamics of mesalamine.
`
`N4)
`
`General nonclinical pharmacology/toxicology considerations.
`The kidney and GI tract were target organs of toxicity for mesalamine in acute studies in rats
`and mice. In repeat-dose studies in rats and dogs, the kidney was the target organ, with
`findings at high doses of regions of cortical and papillary necrosis and tubular changes.
`Other findings in chronic studies were stomach ulceration, gastric mucosal hemorrhage with
`mucosal/submucosal fibrosis, and urinary bladder inflammation in rats. Chronic nephritis
`was seen in chronic studies in dogs.
`
`1' up to 250 mg/kg/day, target
`_
`In a 26—week oral toxicity study in dogs using L
`organs were gall bladder, spleen, and urinary bladder. The 250 mg/day dose was a tolerated
`dose.
`
`11(4)
`
`Carcinogenicity
`Mesalamine was negative in genotoxicity assays. Mesalamine was not carcinogenic in rats at
`doses up to 480 mg/kg/day or in mice up to 2000 mg/kg/day.
`
`_
`Reproductive toxicology
`Mesalamine had no effect on fertility or reproduction in male and female rats at oral doses up
`to 480 mg/kg/day, and it was not teratogenic in rats and rabbits at oral doses up to 480
`mg/kg/day.
`
`Other issues
`
`The Reviewer recormnended changes to labeling sections 8.1 (Pregnancy),
`13.1 (Carcinogenesis), and 13.2 (Animal Toxicology) to insert or correct scaling factors
`relating the animal doses to the recommended human doses. See the Pharmacology/
`Toxicology review document for details.
`
`Conclusions and Recommendations
`
`The Pharmacology/Toxicology Reviewer recommended that the application was approvable
`with changes to the labeling. The Reviewer did not recommend any Phase 4 commitments.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`See the Office of Clinical Pharmacology Review by 1. Kim dated 10/7/08 for complete
`information.
`
`General clinical pharmacology/biopharmaceutics.
`The major metabolite of mesalamine is N-acetyl mesalamine (N-Ac-S-ASA), which is
`formed by N—acetyltransferase activity in the liver and intestinal mucosa. When Apriso is
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`Page 6 of 16
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`Cross—Discipline Team Leader Review
`
`Apriso — NDA 22-301
`
`administered under fasting conditions, about 32% i 11% (SD) of the mesalamine is '
`absorbed. With repeated dosing, the Tmax is 4 hours for mesalamine and 5 hours for
`N-Ac-S-ASA. The ty, is about 10 hours for mesalamine and 14 hours for N—Ac-S-ASA.
`
`Most of the drug is eliminated unabsorbed in the feces. Of the 32% that is absorbed, 2% is
`excreted in the urine as mesalamine, and 30% is excreted as N-Ac-S-ASA.-
`
`The food effect was evaluated using the mesalamine granules in a sachet (rather than in a
`gelatin capsule), a formulation that was demonstrated to be equivalent to the commercial
`product in an in vitro comparative dissolution study. The Clinical Pharmacology Reviewer
`noted that administration with food produced a lengthening of Tmax but similar Cmax
`compared to fasted administration. The Reviewer concluded that Apriso can be taken
`without regard to food.
`
`Drug-drug interactions
`From an in vitro study reviewed under a supplement to NDA 20-610 (Colazal [balsalazide]),
`mesalamine and, its N-acetyl metabolite were shown not to inhibit CYP1A2, CYPZCO,
`CYPZCl9, CYP2D6, and CYP3A4/5. Therefore, mesalamine is not expected to inhibit the
`metabolism of other drugs that are substrates of those CYP enzymes. No direct human in
`vivo drug-drug interaction studies were conducted with Apriso.
`
`Critical intrinsic factors potentially affecting elimination
`No investigations were conducted on the effect of intrinsic factors such as age, gender,
`hepatic insufficiency, or renal impairment on drug elimination.
`
`Demographic interactions/special populations
`No studies were done to evaluation the effects of demographic or special populations on the
`pharmacokinetics of Apriso.
`
`Thorough QT study or other QT assessment
`No thorough QT study or other QT assessment was performed. See comments under Other
`Relevant Regulatory Issues, below.
`
`Other issues
`
`The Applicant presented a scintographic study using radiolabeled mesalamine granules
`formulated by Dr. Falk Pharma and claimed that it showed approximately 80% of the orally
`administered dose was available in the colon. The Clinical Pharmacology Reviewer did not
`feel that the claim was substantiated, because the analysis could not distinguish between
`released and unreleased mesalamine and because the limited absorption at the target region in
`the intestine may not parallel availability in the target region.
`
`The Clinical Pharmacology Reviewer recommended that labeling include multiple-dose PK
`results, that PK results be presented in a tabular format, that fecal excretion results be
`deleted, and that the in vitro drug-interaction study results be included in the
`Pharmacokinetics section.
`
`Conclusions
`
`.
`
`The Clinical Pharmacology Reviewer found the information in the NDA acceptable provided
`agreement could be reached regarding the recommended labeling changes.
`
`Page 7 of 16
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`Cross-Discipline Team Leader Review
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`-
`
`Apriso — NDA 22—301
`
`6. Clinical Microbiology
`
`Clinical Microbiology considerations do not apply to this application because Apriso is not
`an antimicrobial agent.
`'
`
`7. Clinical/Statistical— Efficacy
`
`The reader is referred to the Clinical Review by A. Peterson dated 10/29/08 and the
`Statistical Review by S. Farr dated 9/29/08 for complete information.
`
`The substantial evidence for efficacy in this application came from the Applicant’s two
`pivotal studies of maintenance of remission in UC. They were essentially identical in design
`and are described together below.
`
`Phase 3 Studies — MPUCSOO3 and MPUCBOO4 (Study 3 and Study 4)
`
`Both of these Phase 3 studies were randomized, double—blind, placebo—controlled,
`multicenter studies in patients with UC in remission. The sites were in the US and Russia.
`Study MPUC3003 (herein identified as “Study 3” for convenience) enrolled 305 patients and
`Study MPUC3004 (Study 4) enrolled 257. Patients were randomized to Apriso 1.5 g/day or
`placebo. The studies were designed to have a treatment period of six months. Patients who
`completed either study could be entered into the long—term, open-label study, MPUC3 005
`(Study 5).
`-
`
`Eligibility, treatment, and assessments
`To be eligible, patients needed to be adults with an historically confirmed diagnosis ofUCin
`remission for at least one month but with at least one flair1n the past 12 months. Current
`remission was defined as a rectal bleeding score of 0 (no bleeding) and an endoscopy score
`of 0 or 1 using the Sutherland Index criteria (but endoscopic criteria were modified so that
`presence of friability required assigning a score of at least 2). Patients were excluded for
`history of bowel surgery other than appendectomy, abnormally elevated creatinine, liver
`enzyme or bilirubin elevation more than twice normal, other disease of the GI tract,
`significant medical conditions, allergy to salicylates, or phenylketonuria. Patients could not
`have received immunosuppressants orcorticosteroids (oral, IV, or topical rectal) within 30
`' days of screening. See the Clinical Review for details of the eligibility criteria.
`
`In both studies, patients were randomized 2:1 to be treated with oral dosing of either Apriso
`1.5 g/day or placebo. Study drug was to be taken once daily in the morning for six months.
`In both studies, concomitant therapy could not include immunosuppressants, alternative UC
`therapy, systemic or topical corticosteroids, diarrhea preparations, or intestinal regulators.
`NSAIDs could not be used for longer than six weeks except for low—dose aspirin. Oral
`antibiotics were not allowed except for 7— to 10-day courses of metronidazole or
`ciprofloxacin.
`
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`Cross-Discipline Team Leader Review
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`Apriso — NDA 22~301
`
`In-office study visits were conducted at Month 1, Month 3 and Month 6. At these visits
`patients had a physical exam, routine blood tests, and urinalysis. Sutherland Index, excluding
`endoscopy score, was collected at the Month 1 and 3 visits. At Month 6, patients had a
`repeat endoscopy for assessment of remission status. Patients who presented with symptoms
`of UC relapse had stool cultures performed and were treated with antimicrobial therapy if
`positive. If cultures were negative, patients underwent endoscopy to determine relapse
`status. Patients who discontinued the study for any reason prior to Month 6 were to have all
`of the Month 6 assessments performed, including endoscopy.
`
`Endpoints
`The primary endpoint in both studies was maintenance of clinical remission through
`Month 6; with relapse from remission defined as a rectal bleeding score of .>_ 1 and an
`endoscopy score of 2 2 (note that this is not the complement of the remission criteria used to
`determine study eligibility). In the initial protocols, patients who discontinued were to be
`counted as relapses. Late in the studies, the analysis plans were amended to change this
`definition so that discontinuations were to be counted as relapses only if the discontinuations
`were for lack of efficacy or for a UC-related adverse event. See the Statistical Review and
`Evaluation for discussion of the details and timing of these amendments.
`
`Protocol-specified major secondary endpoints were: I) change in rectal bleeding score,
`2) change in mucosal appearance score, 3) change in physician’s rating of disease activity,
`.
`4) proportion with DAI S2 and with all components S 1 and no rectal bleeding, 5) mean
`change in DAI, 6) relapse-free duration, and 7) change in stool frequency score. Secondary
`endpoints were to be analyzed in the ITT population with LOCF imputation. To control for
`multiplicity, the endpoints were to be analyzed in sequence. If statistical significance was
`not achieved, all subsequent endpoint analyses were to be considered exploratory.
`
`
`Results
`
`A total of 305 patients from 42 centers participated in Study 3, and 257 patients from 37
`centers participated in Study 4. The median age was 46 years'in both studies, percent male
`was 48% and 47% (values are cited for Study 3 and Study 4, respectively), percent Caucasian
`was 90% and 96%, and percent from US. sites was 52% and 40%. The percent with
`baselineSutherland Index score of 0 was 34% and 43%; approximately 80% of all patients
`had baseline score 5 1 (using the modified endoscopy scoring).
`
`The tables below present the principal efficacy results for maintenance of relapse-free status
`for Studies 3 and 4. The first table presents results of the Applicant’s primary analysis
`according the statistical plan in the final protocol amendments. (By that analysis, early
`discontinuations without endoscopy are counted as relapses only if the discontinuation was
`for lack of efficacy Or for a UC-related adverse reaction.) The second table presents the
`results counting all early discontinuations as relapses.
`
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`Cross-Discipline Team Leader Review
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`Apriso — NDA 22-301
`
`Percentage of Patients Relapse-Free through 6 Months in Maintenance Studies
`Applicant’s Primary Analysis*
`
`-
`
`1.5 g/day
`Placebo
`Difference
`% (# no relapse/N)
`.% (# no relapse/N)
`(95% CI.
`
`APRISO
`
`P-value
`
`79% (165/209)
`
`58% (56/96)
`
`21% (9.5%, 32%)
`
`
`
`
`
`
`
`
`Study4
`
`80% (131/164)
`
`
`68% (63/93)
`12% (1.1%, 24%)
`
`
`
`* Early dropouts counted as relapse only if lack of efficacy or if UC~related adverse event occurred.
`
`0.029
`
`Percentage of Patients Relapse—Free through 6 Months in Maintenance Studies
`All Dropouts Counted as Relapse
`
`
`
`APRISO
`
`
`
`Placebo
`1.5 g/day
`% (# no relapse/N) % (# no relapse/N)
`
`,
`
`Difference
`(95% CI.)
`
`P-Value
`
`Study 3
`
`68% (143/209)
`
`51% (49/96)
`
`17% (5.5%, 29.2%)
`
`<0.001
`
`Study 4
`
`71% (117/164)
`
`59% (55/93)
`
`12% (0%, 24.5%)
`
`0.046
`
`
`
`
`
`
`Subgroup analyses of the primary outcomes in the pooled studies were conducted by country,
`gender, age group, race, baseline disease severity, and baseline remission duration. There
`were too few non-whites and too few patients over 65 years to provide meaningful
`conclusions about those groups, although the estimated treatment effect was at least as large
`in non-whites, but little effect was seen in patients over 65. For the other subgroup analyses,
`the observed treatment effects were generally in the same range as the overall effect, and
`nominal statistical significance for each Subgroup was seen in the pooled analysis. See the
`Statistical and Clinical Reviews for details.
`
`‘
`
`Secondary endpoints analyses found a greater increase from baseline in rectal bleeding for
`placebo in Study 3 compared to Apriso (p=0.01), but there was not a statistically significant
`difference for the second secondary endpoint of change in mucosal appearance (p=0.4l). By
`the hierarchical analysis plan, none of the other secondary endpoints in Study 3 were deemed
`to show statistically significant differences. In Study 4 the change in rectal bleeding score
`did not Show a statistically significant difference (p=0.38), so that none of the differences in
`secondary endpoints in that study were deemed statistically significant.
`
`The Statistical Reviewer noted that the imputation strategy for the primary endpoint and the
`hierarchical testing order for the secondary endpoints were changed in late—stage protocol
`amendments after study completion. The Statistical Reviewer also noted that the sample size
`for Study 4 was revised downward from 300 to 250 in an amendment dated 8/9/07, which is
`one day after the stated Study 4 completion date. The Applicant stated the amendment
`occurred prior to breaking the study blind.
`
`Page 10 ofl6
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`Cross-Discipline Team Leader Review
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`‘
`
`Apriso — NDA 22-301
`
`Conclusions and Recommendations
`
`The Statistical Reviewer concluded that the results reported in the submission supported the
`conclusion that Apriso is efficacious for maintenance of remission of UC. She felt that the
`evidence fiom Study 3 was clearer ,and that Study 4 should only be considered as supportive
`due to the late-stage study design changes and lack of secondary endpoint efficacy.
`
`The Clinical Reviewer concluded that both pivotal studies demonstrated Apriso is effective
`in maintenance of remission from ulcerative colitis, and that the efficacy profile was the
`same between genders and nationalities. She felt that the limited enrollment of non-whites
`and patients over 65 made conclusions about those subgroups difficult, but that it was
`appropriate to extrapolate efficacy to them. The Clinical Reviewer recommended that the
`information in the application supported approval for the maintenance of remission of
`ulcerative colitis in patients 18 years of age and older.
`
`8. Safety
`
`In addition to the two six-month efficacy studies described above, the Applicant conducted
`an open-label extension study, Study 5. The study accepted patients who completed Study 3
`or Study 4, provided they were in remission, had not'withdrawn for a drug—related adverse
`reaction, and had acceptable compliance with taking study medication. Study 5 also
`accepted additional patients in remission from UC who had not participated in the Phase 3
`efficacy trials; eligibility criteria were similar to those of the efficacy studies. Patients were
`treated with Apriso 1.5 g/day once daily in the morning. Treatment duration could be up to
`two years. Monitoring Visits that included vital signs and laboratory testing occurred every
`three months after starting treatment, and there was an additional visit at Month 1. There was
`also telephone contact at Months 2, 4, and 5. At the time of the NDA submission, 365
`patients had enrolled; the number increased to 387 by the time of the cutoff for the 120-day
`safety update.
`
`The safety data base used for labeling was comprised of 557 patients treated with Apriso, of
`whom 354 had been exposed for at least six months and 250 for at least a year. A total of
`367 patients came from the two placebo-controlled studies and an additional 190 from the
`open-label extension study. In addition, the Applicant provided safety information for
`studies conducted using a mesalamine formulation made by Dr. Falk Pharma. That product
`is similarto Apriso but is manufactured at a different site (in Europe). Although dissolution
`profiles of the two products are similar, there has not been adequate evaluation to determine
`if they can be considered bioequivalent. While the safety data from the Dr. Falk Pharma
`product were evaluated during the NDA review, the review team considered them as
`secondary safety data . {‘55
`
`.4
`
`51(4)
`
`There were no deaths in the clinical studies with Apriso. (However the safety update report
`for Dr. Falk Pharma mesalamine formulations covering the period of January 2002 to
`February 2008 described three deaths, one of which involved anaphylactic shock and was
`considered possibly related to the product.) Serious adverse events occurred at an overall
`rate 0f 1.4% in the Apriso randomized controlled studies. Four serious adverse events were
`
`Page 11 of16
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`Cross-Discipline Team Leader Review
`
`Apriso — NDA 22-301
`
`seen with Apriso: distal esophagitis, UC flare, pancreatitis, and second degree AV block with
`worsening LV function. None of these led to study medication discontinuation directly,
`although the patient with UC flare had already discontinued due to preceding symptoms. Of
`the non-serious adverse reactions, most were mild or moderate. Severe reactions occurred at
`a rate of 6% for Apriso and 5% for placebo. Discontinuations due to adverse reactions were
`11% for Apriso and 17% for placebo; these were mostly recurrence of UC symptoms. The
`Clinical Reviewer provided recommendations for a table of common adverse reactions to
`include in labeling, as well as recommendations for adverse reactions to be included in the
`listing of less common events of significance.
`'
`
`Mesalarnine products have been the subject of recent reviews of postmarketing data by OSE.
`The Clinical Reviewer also requested selected reports from the postmarketing database
`regarding hepatic adverse reaction. The Clinical Reviewer examined postmarketing adverse
`event reports for mesalamine products and found several cases of worsening of pre—existing
`liver disease associated with mesalamine use. She recommended that the labeling include a
`warning cautioning about use with patients with liver disease. See Section 7.1.17 of the
`Clinical Review for further information.
`
`Conclusions
`The Clinical Reviewer concluded that, overall, Apriso appears to have a safety profile
`comparable to other mesalamine products when used at the recommen