CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 2056130rig15000 SUMMARY REVIEW Deputy Division Director Review NBA 2056] 3 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Summary Review for Regulatory Action Date September 15, 2014 From Andrew E. Mulberg, MD, FAAP, CPI Subject Division Deputy Director Summary Review 205613 Supplement Applicant Name Salix Pharmaceuticals Date of Submission November 15, 2013 PDUFA Goal Date September 15, 2014 Proprietary Name Uceris Established (USAN) Name Dosage Forms Strength emulsion (aerosol foam) 2 mg budesonide per metered dose Proposed Indication(s) induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge (hm) Action/Recommended Action Tentative Approval for NME: Material Reviewed/ onsulted 0ND Action Package, including: Names of discipline reviewers Medical Officer Review Zana Marks, MD DTL Reviews Anil Rajpal, MD Clinical Pharmacology Review Dilara appar, Sue hih-Lee, CMC Tanm Mehta, Marie Kowblansky, Quality Micro Vinayak Pawar CDRH Reviews Branden Reid Bleta Vuniqi Quynerhu Nguyen 081 Susan Liebenhaut, MD Norrclinical (DGIEP) Dinesh Gautam, QT Review Team iang Liu Labeling Reviews Matthew Barlow Meeta Patel Morgan Walker Statistical Reviewer Shahla Farrar, Page 1 of17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 OND=Office 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 Scientific Investigations DRISK=Division of Risk Management CDTL=Cross-Discipline Team Leader Page 2 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Signatory Authority Review Template 1. Introduction Salix has proposed the following indication for Uceris (budesonide) 2 mg rectal foam: 1) Budesonide 2 mg rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge Budesonide 2 mg rectal foam (Uceris) contains a synthetic corticosteroid with topical antiinflammatory properties, weak mineralocorticoid activity, and undergoes substantial first-pass elimination. This extensive first-pass metabolism by the liver may ensure little systemic availability, which may result in less glucocorticoid (GCS)-related side effects compared to conventional systemically available steroids. The rectal formulation is provided as an emulsion which is filled into an aluminum can with an aerosol propellant. In this New Drug Application (NDA), the Applicant pursues the approval of budesonide with labeling for “…the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.” This is a 505(b)(2) application based onThis is a 505(b)(2) application. Entocort EC (NDA 21324) and Uceris (NDA 203634) are the reference drugs; it should be noted that NDA 203634 (Uceris) (owned by Salix) was a 505(b)(2) application that relied upon NDA 21324 (Entocort EC). Studies used to support registration have included BUCF 3001 and BUCF 3002 are replicate phase 3, multicenter, randomized ,double-blind, placebo-controlled studies designed to assess the efficacy and safety of budesonide 2 mg rectal foam (BID dosing for 2 weeks followed by QD dosing for 4 weeks) versus placebo in subjects with active mild to moderate UP or UPS. Both studies were planned and conducted as identical trials. They shared the same protocol design, were conducted concurrently in the US and Russia, and utilized the same data acquisition tools. In both Studies BUCF 3001 and BUCF 3002, the subjects were randomized to receive study treatment in a 1:1 ratio.; either 2 mg budesonide foam BID for 2 weeks followed by 2 mg QD for 4 weeks, or placebo foam BID for 2 weeks followed by placebo foam QD for 4 weeks. Figure 1 presents an overview of the study design for both studies: Page 3 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Figure 1: Study Flowchart for Pivotal trials Other studies used to support the registration of Uceris 2 mg recal foam are illustrated below in Table 1, Completed Studies: Page 4 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Table 1: Completed Studies The primary efficacy endpoint in BUCF3001 and BUCF3002 was the proportion of subjects who achieved remission with budesonide foam, as compared to an equivalent volume/regimen of placebo foam administered over 6 weeks (2 mg BID for 2 weeks followed by 2 mg QD for 4 weeks) in subjects with a diagnosis of active, mild-to-moderate UP or UPS. Remission was defined as an endoscopy score of ≤ 1(no friability observed), a rectal bleeding score of 0 (no bleeding observed), and improvement or no change from baseline in stool frequency subscales of the Modified Mayo Disease Activity Index (MMDAI) at the end of 6 weeks. This Summary review will discuss the sufficiency of evidence of clinical benefit supported by the data in this application to establish that Uceris 2 mg rectal foam is effective and safe for the treatment for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. My review will focus on the salient issues related to this risk/benefit assessment. 2. Background Ulcerative proctitis (UP) is defined as a chronic inflammatory process limited to the rectum. The diagnosis of UP has been defined endoscopically as rectal mucosal inflammation extending up to, but not beyond, 15 cm proximal to the dentate line, normal-appearing mucosa proximal to the edge of inflammation, and histology compatible with idiopathic proctitis, including distorted crypt architecture or other features of chronicity, lamina propria Page 5 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 inflammation, crypt abscess, and neutrophils in the surface epithelium. The presence of a granuloma on rectal biopsy or perianal disease such as fissure or tags would suggest Crohn's disease and exclude a diagnosis of ulcerative proctitis. Appropriate stool cultures exclude identifiable enteric pathogens as a cause of symptoms. Grossly and histologically normal mucosa proximal to 15 cm from the dentate line is used to confirm a diagnosis of ulcerative proctitis as documented by flexible sigmoidoscopy or colonoscopy and biopsy.1 It is generally considered to represent one clinical variant of ulcerative colitis, and in studies of adults constitutes ≈20-35% of newly diagnosed cases of ulcerative colitis1. In contrast to more extensive ulcerative colitis, ulcerative proctitis is thought to follow a more benign course with less severe symptoms and a decreased propensity to develop cancer. Hyams has further noted that initially diagnosed UP often extends proximally and involves more medication as time progresses. This observation has been reported in studies of adults in that proximal extension with more significant colonic involvement may occur in 10-30% of subjects, and may occur either early or late after diagnosis. Topical medication with rectally administered 5aminosalicylic acid (5-ASA) and corticosteroid suppositories or enemas are considered effective treatment for most UP patients. The combination of topical 5-ASA and oral 5-ASA or topical steroids is considered for escalation of treatment. 5-ASA suppositories are suggested as first-line maintenance therapy if accepted by patients, although oral 5-ASA as maintenance therapy might prevent proximal extension of the disease. After re-assessment, chronically active patients refractory or intolerant to 5-ASAs and corticosteroids may require immunomodulators or biological therapy. Exceptional cases may require a proctocolectomy. The pathophysiology of UP is believed to be the same in adults and pediatric patients. The mechanism of action of products including mesalamines and steroids in UP is local and does not require systemic metabolism. The Modified Mayo Disease Activity Index used in these clinical trials referred to as the MMDAI is unique in several aspects of disease activity scores but does have the components characterized in the formal Mayo Score as well as variant forms like the Sutherland discussed below. These include endoscopic subscore, rectal bleeding, stool frequency and Physician Global assessment (PGA)-see Table 2 below. The modification made to the Mayo Index was the deletion of “friability” from an endoscopy score equal to 1. With this modification, the presence of friability was indicative of an endoscopy score of 2 or 3. In contrast to the UCDAI, for example, also referred to as the Sutherland Index, the UCDAI developed by Sutherland is a series of qualifiers about the symptoms of ulcerative colitis including stool frequency, rectal bleeding, the appearance of the lining of the colon, and a physician rating of disease activity2. Each of these items is given a number from 0 to 3, with 3 being the highest rating for disease activity. In 1 Hyams J, Davis P, Lerer T et al . Clinical Outcome of Ulcerative Proctitis in Children. J Pediatr Gastroenterol Nutr;1997;25:149-152 2 Sutherland LR, Martin F, Greer S et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987 Jun;92(6):1894-8. Page 6 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 clinical trials in adults, remission is often defined as a UCDAI score of 1 or less, and improvement is a reduction of 3 or more points from the score at the beginning of the trial.3 In the MMDAI it is very likely that the presence of friability in a higher subscore of endoscopy mandates a higher subscore for minimal disease. This issue will be discussed below. Table 2: Modified Mayo Disease Activity Index (MMDAI) a. Each patient served as his or her own control to establish the degree of abnormality of the stool frequency. b. The daily bleeding score represented the most severe bleeding of the day. c. The physician’s global assessment acknowledged the 3 other criteria, the patient’s daily record of abdominal discomfort and general sense of well- being, and other observations, such as physical findings and the patient’s performance status. d. The modification made to the Mayo Index was the deletion of “friability” from an endoscopy score equal to 1. With this modification, the presence of friability was indicative of an endoscopy score of 2 or 3. (The table above is copied from Dr. Rajpal memorandum) 3. CMC The reader is referred to the CMC review of Tarun Mehta, Ph.D dated September 5, 2014 for complete information. The CMC Review noted certain issues that required clarification, specifically related to the Valve and Metering Head Materials of Construction, and Duration of Contact with Drug Product. CDRH has expressed some concern about potential leachables from the applicator. However, not only because there will be very short duration of exposure for the applicator to the drug while the drug is being administered, but also each applicator is for single use, the CMC reviewer did not find the leachable studies for the applicator necessary. Other issues related to the formulation content uniformity as the Delivered Dose Uniformity (b) (4) for Budesonide 2 mg Rectal Foam Lot Prepared as Directed in QCTP-278 As noted by 3 http://ibdcrohns.about.com/od/Glossary/g/Ulcerative-Colitis-Disease-Activity-Index-Ucdai htm Page 7 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Dr. Mehta, “The samples analyzed using in house method (QCTP 278) at , show the consistent results for all actuations except one outlier and meet the specification and USP <601> criteria. However, when the samples were analyzed using patient label instruction (USP (b) (4) <601>); the results were inconsistent and the mean assay value was law %), overall results did not meet the USP <601> requirement. These results were discussed within the review team for this application. Based on the discussion it was concluded that the applicant has to provide more data to (1) negate the doubt of inconsistent dosing when used by patients in real life and (2) the priming of the canister is needed or not because the first actuation result for 4 out of 5 canister showed the failure.) A meeting to discuss the conflicting results from the extra five canisters and consistent lower % label claim for the first actuation was discussed with the clinical team to provide their concern of efficacy and safety risk of the drug product (b) (b) (4) due to inconsistent dosing (range from (4) % to %). After the discussion it was decided that the same drug product was used in the clinical setting and had proven efficacious and safe. Therefore, no further action required to explain these data.” (b) (4) The CMC Reviewer recommends approval. 4. Nonclinical Pharmacology/Toxicology There are no new nonclinical issues raised with this application reviewed by Dinesh Gautam, Ph.D. The reviewers recommended changes to the Section 8.1 (Pregnancy) to conform to the format of the Proposed Pregnancy and Lactation Labeling Rule (PLLR) and to Section 13 Carcinogenicity. Please see Dr. Rajpal’s memorandum. 5. Clinical Pharmacology Dose ranging studies were performed to justify the current proposed dosing regimen of Budesonide 2 mg BID for 2 weeks followed by 2 mg QD for 4 weeks. Support for these recommendations is derived from appropriately performed Phase 2b and current Phase 3 Studies. Briefly, the Phase 2b dose finding study (BUF-5/UCA) in which 2 mg BID dosing regimen of budesonide rectal foam yielded more favorable treatment effect compared to that of placebo and 2 mg QD dosing (4 mg/day (BID)> 2 mg/day(QD) > placebo) . Supportive Phase 3 studies (BUF-9/UCA and BUF-6/UCA) have shown that majority of subjects experienced maximum treatment response after the first 2 weeks of treatment. Further details are discussed in Clinical Pharmacology review summary of Dr. Jippar. In terms of suppression of the hypothalamic-pituitary axis, commonly observed with Uceris 9 mg capsules and other steroid formulations, the issue is somewhat different for this Uceris formulation under review. As noted in Dr. Rajpal’s review, the percentages of patients with normal response to ACTH challenge by treatment group (combined data from the two trials) were as follows: The percentages of patients with normal response to ACTH challenge by treatment group (combined data from the two trials) were as follows: Page 8 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014   Budesonide group: Baseline: 83.5%; Wk 6: 68.5%; Difference (Baseline to Wk 6): 15.0% Placebo group: Baseline: 85.6%; Wk 6: 76.6% ; Difference (Baseline to Wk 6): 9.0% If one takes into account subjects who were discontinued prior to Week 6 due to reasons related to HPA axis suppression, a larger difference was seen between the two treatment groups; the percentages were as follows:  Budesonide group: Baseline: 83.5%; Wk 6: 62.7%; Difference (Baseline to Wk 6): 20.8%  Placebo group: Baseline: 85.6%; Wk 6: 75.9% ; Difference (Baseline to Wk 6): 9.7% These data support that Uceris 2 mg rectal formulation is also associated with short-term HPA suppression. The Clinical Pharmacology reviewer recommended Approval. 6. Clinical Microbiology Clinical microbiology considerations do not apply to this supplemental application because the product is not an antimicrobial product. 7. Clinical/Statistical-Efficacy The reader is referred to the Clinical review of Dr. Marks and the CDTL memorandum of Dr. Rajpal for further details. I will focus on specific issues relevant to the approval of this NDA. a. Assessment of Disease activity in Ulcerative proctitis and Ulcerative proctosigmoiditis and Definition of Remission: There are a number of different UC disease activity indices that have been approved for labeling of products for the management of UC including the Mayo Score of Disease activity, Sutherland Index and variant forms of each. In this NDA the clinical endpoint definition is described by the use of the Modified Mayo Disease Activity Index (MMDAI). The components of this score are delineated above in Table 2. Inclusion criteria for subjects in both pivotal trials, BUCF3001 and 3002 included baseline MMDAI score between 5 and 10, inclusive. Subjects must score ≥2 on the MMDAI rectal bleeding component and ≥2 on the MMDAI endoscopy or sigmoidoscopy component. The most important clinical characteristics in these presentations of Ulcerative colitis focus on rectal bleeding and endoscopic disease activity. Diarrhea is a prominent clinical sign as well in this disease. The remission definition for both trials included components of an endoscopy score of ≤ 1, a rectal bleeding score of 0, and an improvement or no change from baseline in stool frequency sub scales of the MMDAI at the end of 6 weeks of treatment or withdrawal. These are further described below in Table 3: Page 9 of 17 Reference ID: 3627629 Deputy Division Director Review NBA 2056] 3 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Table 3: Primary and Secondary Endpoints of Studies BUCF3001 and BUCF3002 Endpoint De?nition Proportion of subjects who achieve remission defmed as an endoscopy score of 1. a rectal bleeding score of 0. and an improvement or no change from baseline in stool frequency sub scales of the Modi?ed Mayo Disease Activity Index (MMDAI) at the end of 6 weeks of treatment or withdrawal. Ranked Proportion of subjects with a rectal bleeding MMDAI subscale score of at the end of Secondary: six weeks of treatment or withdrawal. 2nd Ranked Number of weeks subjects achieves a rectal bleeding MMD AI sub scale score of 0 Secondary: during the treatment phase (Weeks 1 through 6). 3rd Ranked Proportion of subjects who achieve an endoscopy MMD AI subscale score of 0 or 1 at Secondary: the end of six weeks of treatment or withdrawal. Primary: Table 4 below re?ects the results of the clinical trials noting several important features of remission characteristics and results. It is clear that there is bene?t in the responder groups who achieved clinical remission but a very large percentage of patients were nonresponders (74% and 62% in placebo and Budesonide Foam treatment groups). This lack of clinical remission was manifested in all three parameters of the remission de?nition with the lack of Table 4: Primary Endpoint: Remission* (Studies BUCF3001 and BUCF3002) (ITT Populations; LOCF Analysis) *Remission de?ned as an endoscopy score of 1. a rectal bleeding score of 0. and an improvement or no change ?om baseline in stool frequency sub scales of the Modi?ed Mayo Disease Activity Index Study BUCF3001 Study BUCF3002 Placebo Budesonide Placebo Budesonide E?'rcacy Foam p- p- Foam p- p- Endpoint 1 33 value'1 value 1 34 value? value Achieved Remissiont Responder 3245.8) 3) 0.0324 0.0322 4) O) <0.0001 <0.0001 Non- 98 82 14 75 responder (74.2) (61.7) (77.6) (56.0) (MMDAI) at the end of 6 weeks of treatment or withdrawal. ITT intent to treat: LOCF last observation carried forward. a. p-Values obtained from a logistic regression model with ?xed effects: treatment arm and b. p-Values obtained from the Cochran-Mantel-Haenszel (CMH) test adjusting for Table above modi?ed from tables in the Clinical Review. Source: Srunmary of Clinical Ef?cacy Page 79. achievement of a MIVIDAI Endoscopy score of 0 or 1, MMDAI Rectal Bleeding score of 0 and improvement of no change ??om baseline in MMDAI Bowel frequency score. From the data analysis in Table 3, it appears that the most dif?cult clinical component to remit is the rectal Page 10 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 bleeding, and endoscopy subscsores. This doesn’t make clinical sense in that bleeding should be reflected in the endoscopy subscore. From the additional analyses, concomitant oral 5-ASA use at baseline similar in both treatment groups in both studies: 59% in the UCERIS Rectal Foam group and 60% in the placebo group in Study BUCF3001 and 51% in both treatment groups in Study BUCF3002 (reference Table 7, Dr. Rajpal, and CDTL memorandum). In regards to other baseline disease characteristics, including extent of disease, normal number of stools per day (based on the question asked as part of the MMDAI assessment), type of disease (newly diagnosed vs. established), and duration of disease] were similar between the two arms of each of the two studies (see Table 5 below). Other Baseline Disease Characteristics are pictured below in Table 5 which apparently does not offer clear etiologies for the discrepancy in low remission rates between placebo and active treatment. Table 5: Baseline Characteristics in Pivotal Clinical Trials f Proctitis: disease limited to rectum (up to ~15 cm); Proctosigmoiditis: disease limited to rectum and sigmoid colon (up to ~40 cm) a The question asked was “Think back to a time when you were not suffering from your most recent flare of Proctitis/Proctosigmoiditis. What was the normal number of bowel movements you had in a 24-hour period?” For the normal bowel movement calculation (ie, when no UP/UPS symptoms were present), a bowel movement represented when stool was passed. Table is reproduced from CDTL memorandum Table 6 demonstrates that the disease severity does imply a potential relationship to efficacy remission as the moderate disease activity reflected by higher MMDAI scores trends higher to remission than the mild disease activity. These data are further supported by an analysis of the extent of disease classified as more proximal or extending more distal, as proctosigmoiditis or proctitis (Table 7, below). It is clear that the trend towards higher remission rates is correlated with extent of disease activity, with the extent of disease a characteristic that likely is clinically Page 11 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 20561 3 Uceris (budesonide) rectal foam 2 mg September 15, 2014 important. It is interesting to also note that the placebo responders are also higher in the more extensive disease category which remains unclear to this Signatory. Table 6: Analysis of the Primary Endpoint by Disease Severity Study Disease Severity Budesonide Placebo Difference nix (96) (BudesonideiPlacebo) (95% CI) Study 3001 Mild 36016 4-6) 4115 (26.7) 4.522 (18.2) 8.5% (-19.100. 36.1%) Moderate Score 471118 (30.8) 30.110 (27.3) 12.6% 24.70.11) Study 3002 \lild (MMDAI Score 4-6) 4:"13 (30.8) 22.4% 52.0%) Moderate (MMDAI Score 7-10) 541?] 19 (45.4) 33/135 21.1% 33.1%) Combined Mild (NIMDAT Score 4-6) 8/28 (28.6) 5.534 (14.7) 13.9% 34.4%) Studies Moderate (MMDAI Score 7-10) 101237 (42.6) 62.245 (25.3) 17.3% 25.6%) Soun?e Reviewer Reproduced from Statistical Review, Dr. Farrar Table 7: Analysis of the Primary Endpoint by Disease Severity Study UP vs.1?PS Budesonide Placebo Difference n/N un?N (Budesonide?Placebo) (95% Study 3001 Proctitis 13.137 (35.1) 8'43 (18.6) 16.5% 35.8%) Proctosigrnoiditis 37.195 (39.0) 25:88 (28.4) 10.5% 241%) Study 3002 Proctitis 9,535 (25.7) 5?38 (13.2) 12.6% (?5.59 o. 30.6%) Proctosiemoiditis 50:98 (51.0) 28109125.?) 25.3% 38.2%) Combined Proctitis 22.172 (30.6) 13"81 [16.1) 14.5% (120-6. 27.8%) Studies Proctosigmoiditis 87/193 (45.1) 53197 (26.9) 18.2% 27.5%) Reproduced from Statistical Review, Dr. Farrar In toto, I agree with the reviews and recommendations of the Statistical reviewer, Dr. Farrar, and the DTL, Dr. Rajpal who recommend approval of this NDA based upon two statistically signi?cant trials demonstrating ef?cacy of Budesonide rectal foam 8. Safety Overall, the safety pro?le of Budesonide rectal foam supports an approval recommendation. The safety pro?le of the Uceris Rectal foam is akin to that observed with the Uceris oral formulation of budesonide. Budesonide and glucocorticosteroid products are generally associated with the following adverse reactions, Warnings and Precautions as identi?ed in the current labeling. Adverse reactions typical of systemic glucocorticosteroids include adrenal suppression, sleep and mood distru?bance, acne, striae, hirsutism, proximal myopathy, glucose intolerance, hypertension, narrow angle glaucoma, cataracts, bone loss, aseptic necrosis and reduced growth velocity. These adverse reactions are generally dependent on dose, treatment time, concomitant and previous glucocorticosteroid intake, and individual Page 12 of 17 Reference ID: 3627629 Deputy Division Director Review NBA 2056] 3 Uceris (budesonide) rectal foam 2 mg September 15, 2014 sensitivity. Other adverse reactions reported in clinical trials include dyspepsia, muscle cramps, tremor, palpitations, blrured vision, skin reactions, menstrual disorders, hypokalemia, and behavioral changes. From the review of safety, data associated Total AE's leading to Discontinuation and AE's Leading to Discontinuation in 1 Subject reported for patients in the primary analysis group are presented in Table 8 below: Table 8: RCT Population: Total AE's leading to Discontinuation and AE's Leading to Discontinuation in 1 Subject Placebo Budesonide Foam AE Leading to Discontinuation Total [11 12 26 AE's Leading to Discontinuation in 1 Subject: Blood cortisol decreased* 1 16 Adrenal insuf?ciency# 1 4 Ulcerative proctitis 4 Ulcerative colitis 3 0 Decreased blood cortisol was de?ned as a morning cortisol level of 5 mcg/dL. Adrenal insuf?ciency was de?ned as a cortisol level of 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH). Nrunbers of ABS in the table above are taken from Pages 108-111 of the Sunmrary of Clinical Safety. Data table reproduced from DTL Dr. Rajpal. Table 9 below re?ects on the commonly observed potential glucocorticoid related effects which do not re?ect any new adverse events associated with this molecule. Table 9: All Budesonide Population: Potential Glucocorticoid Related Effects Budesonide Foam Budesonide Enema Adverse Event Blood cortisol decreased* 58 Adrenal insuf?ciency? 13 0 Depression 3 0 Acne 4 0 Insomnia 3 0 Agitation 1 0 Sleep disorder 1 1 Decreased blood cortisol was de?ned as a morning cortisol level of 5 mcg/dL. Adrenal insuf?ciency was defmed as a cortisol level of 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic honnone (ACTH). Numbers of AE's in the table above are taken from Pages 119-120 of the Summary of Clinical Safety. Data table reproduced from DTL memorandum, Dr. Rajpal. For fruther review of the safety issues, the reader is referred to Dr. Marks? Clinical review. I agree with the approval based on review of the Safety of Uceris Budeosnide Rectal foam in this population. Page 13 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 9. Advisory Committee Meeting There was no Advisory Committee meeting for this application as there were no decisional issues that required input from the Advisory Committee during the review cycle. 10. Pediatrics This application concerns an orphan indication and therefore the Sponsor is not bound by PREA regulation.. The local action of the drug is expected to be the same in children as in adults. Although the treatment effectiveness of Uceris Rectal foam might be able to be extrapolated from the adult indication to the pediatric patients due to disease pathology being the same in both age groups and the same mechanism of action of the drug, one cannot extrapolate an effective pediatric dosage for a topically acting drug from adult studies. The rectal foam formulation is predominantly locally acting and systemic absorption is not needed for efficacy; nonetheless, a dose ranging trial evaluating smaller dosages stratified by age with drug-exposure information could have yielded useful prescribing information for patients, especially in the younger age cohort. Oral mesalamines are not approved for use in pediatric patients with inflammatory bowel disease. Both the oral and suppository mesalamines act by “local action.” It is likely that various dosages based on body size or age that account for systemic exposures would be important to understand the comparison to adult systemic exposure for understanding safety and tolerability with Uceris rectal formulation. Efficacy is determined by the impact on altering mucosal inflammation and cannot be extrapolated by systemic exposure of the molecule and therefore requires a clinical efficacy endpoint. It should be noted though that adolescents would be a suitable first population akin to the adult population based on colonic length and potential for improvement. The study of younger children with UP and proctosigmoiditis could be done sequentially. The Sponsor has agreed to a PMC for a pediatric study which is described below 11. Other Relevant Regulatory Issues A. DSI audits For Study BUCF3001, Sites 857 and 520 were selected because each had a high percentage of the subjects in Study BUCF3001 relative to other sites. In Site 857, the reported proportion of patients that met the primary endpoint was 75% (6/8) in the budesonide rectal foam group and 0% (0/7) in the placebo group. In Site 520, the reported proportion of patients that met the primary endpoint was 40% (2/5) in the budesonide rectal foam group and 0% (0/5) in the placebo group. For Study BUCF3002, Site 0938 (in Russia) was initially selected because it had a high percentage of the subjects in Study BUCF3001 relative to other sites. In Site 0938, the reported proportion of patients that met the primary endpoint was 100% (15/15) in the budesonide rectal foam group and 0% (0/15) in the placebo group. The inspection of Site 0938 (in Russia) was denied. It should be noted that Site 0938 (in Russia) was inspected in 2009 by the Agency for another NDA (NDA 22554) and had been given a classification of No Page 14 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 Action Indicated (NAI) at that time. selected (see Dr. Marks’ summary). Another site (site 0198) in Study BUCF3002 was OSI concluded that the studies appear to have been conducted adequately, and the data generated by each of the three sites may be used in support of the respective indications. B. Financial disclosures No active issues C. 505(b)(2) Coordinating Committee Meeting This application was discussed at the 505(b)(2) Coordinating Committee Meeting on September 2, 2014. The outcome of that meeting was as follows: "This application is ~ cleared for a Tentative Approval (TA) action at best ~ from a 505(b)(2) perspective. The clearance for a TA action at best is because the applicant has submitted proof that NDA holder/patent owner were notified of the paragraph IV certification on August 18, 2014 and the NDA holder and/or patent owner have a window of 45 days in which to file a lawsuit. That window will close on October 2, 2014 which is after the PDUFA date." These issues therefore result in a tentative approval as discussed below in Section 13.1. D. Device Issues and CDRH Reviews For complete information, see CDRH Office of Device Evaluation Consult Review by Branden Reid, CDRH Office of Compliance Consult Review by Bleta Vuniqi, and CDRH Human Factors Consult Review by QuynhNhu Nguyen and the CDTL memorandum. All reviewers recommend approval of the sNDA and all issues are approvable. 12. Labeling Labeling reflects changes to the following sections of the label which the reader is referred to the approved labeling for further details. The specific issues are cited below as summarized by Dr. Rajpal:  Dosage and Administration (Section 2 of Label): A sub-section "Administration Instructions" was added with key instructions for patients, most notably the instruction to "Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use."  Warnings and Precautions (Section 5 of Label): A warning and precaution about the flammability of the contents was revised to include a statement that patients should discontinue use before initiation of bowel preparation for colonoscopy.  Adverse Reactions (Section 6 of Label): The following key revisions were made:  The Clinical Trials Experience sub-section was revised to include a separate summary table of potential glucocorticoid-related adverse reactions and discussion of those data. Page 15 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 20561 3 Uceris (budesonide) rectal foam 2 mg September 15, 2014 I The Post?Marketing Experience sub-section was revised to include adverse reactions reported from oral formulations of budesonide. Use in Speci?c Populations (Section 8 of Label): The following key revisions were made: I The Pregnancy sub-section was revised as recommended by the Nonclinical Pharmacology/Toxicology Reviewer (see Section 4.1 of this CDTL Review); in addition, a statement about possible hypoadrenalism in neonates exposed to glucocorticosteroids in utero was added (as recommended by the PMHS Maternal Health Reviewer). I The Nursing Mothers and Pediatric Use sub-sections were revised (as recommended by the PMHS Maternal Health Reviewer). I The Hepatic Impairment sub-section was revised to include the Child-Pugh Class corresponding to the severity of hepatic impairment; also, a statement was added that dosage adjustment is not needed for mild (C hild-Pugh Class A) hepatic impairment. Nonclinical Toxicology (Section 13 of Label): This section was revised as recommended by the Nonclinical Pharmacology/Toxicology Reviewer (see Section 4.1 of this CDTL Review). Clinical Studies (Section 14 of Label):The following revisions were made: I All results were presented separately for each study (5) (0 I The results for the second secondary endpoint were not included because the sponsor did not conduct the analysis of this endpoint as pre-speci?ed in the Statistical Analysis Plan (see Section 7.3 of this DTL Review). I The results for the third secondary endpoint were presented descriptively because the second secondary endpoint was not met (see Section 7.3 of this DTL Review). Stool frequency data were presented for patients that met the primary endpoint because the primary endpoint (as de?ned) could be met even if the stool frequency subscore did not decrease. 13. Decision/Action/Risk Benefit Assessment 13.1 Regulatory Action: All of the review divisions recommended an Approval for which gained concurrence from the Clinical reviewer and CDTL. I agree with the recommendations from these disciplines for Tentative Approval for Uceris (Budesonide) rectal foam for the indication proposed for The listed drug upon which your application relies is subject to a period of patent protection and therefore fmal approval of your application lurder section 505(c)(made effective rurtil the period has expired. Your application contains certi?cations to patents under section 505(b)(2)(A)(iv) of the Act stating that the patents are invalid, rmenforceable, or will not be infringed by yoru? manufacture, use, or sale of, this drug product under this application (?Paragraph IV certi?cations?). It is tentatively approved under 21 CFR 314.105 for use as recormnended in the agreed-upon enclosed labeling (text for the package insert, text for the patient package insert, carton and immediate container labels). This determination is based upon information Page 16 of 17 Reference ID: 3627629 Deputy Division Director Review NDA 205613 Uceris (budesonide) rectal foam 2 mg September 15, 2014 available to the Agency at this time, [i.e., information in your application and the status of current good manufacturing practices (cGMPs) of the facilities used in the manufacture and testing of the drug product]. This determination is subject to change on the basis of any new information that may come to our attention. Section 505(c)(3)(C) of the Act provides that approval of a new drug application submitted pursuant to section 505(b)(2) of the Act shall be made effective immediately, unless an action is brought for infringement of one or more of the patents that were the subject of the paragraph IV certifications. This action must be taken prior to the expiration of 45 days from the date the notice provided under section 505(b)(3) is received by the patent owner/approved application holder. You notified us that you complied with the requirements of section 505(b)(3) of the Act. However, because the 45-day period described in section 505(c)(3)(C) of the Act has not yet expired, final approval cannot be granted. 13.2 Risk Benefit Assessment: I have concluded that the data in these submissions do reflect a risk and benefit supporting the proposed use of Uceris for management in adults. Recommendation for Postmarketing Risk Evaluation and Mitigation Strategies: There are no requirements for postmarketing risk evaluation and mitigation strategies. Recommendation for other Postmarketing Requirements and Commitments: 1) A 6-week randomized, double blind, placebo-controlled trial in children 5 to 17 years of age with active, mild to moderate distal ulcerative colitis (extending up to 40 cm from the anal verge). The trial will evaluate pharmacokinetics (PK), efficacy for induction of remission, and safety of at least 2 doses of Uceris (budesonide) Rectal Foam. The effects of 6 weeks of Uceris (budesonide) Rectal Foam on the HPA axis will be assessed. Final Protocol Submission: 4/2015 Trial Completion: 1/2018 Final Report Submission: 4/2018 Page 17 of 17 Reference ID: 3627629 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ANDREW E MULBERG 09/15/2014 Deputy Director Summary review Reference ID: 3627629