DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 207999 ACCELERATED APPROVAL Intercept Pharmaceuticals, Inc. Attention: Linda Robertson, Ph.D. Vice President, Regulatory Affairs and Quality Assurance 4760 Eastgate Mall San Diego, CA 92121 Dear Dr. Robertson: Please refer to your New Drug Application (NDA) dated June 27, 2015, received June 29, 2015, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for OCALIVA (obeticholic acid) tablets, 5 mg and 10 mg. We acknowledge receipt of your major amendment dated October 27, 2015, which extended the goal date by three months. This new drug application provides for the use of OCALIVA (obeticholic acid) tablets, 5 mg and 10 mg for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. APPROVAL & LABELING We have completed our review of this application, as amended. It is approved under the provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug product and related activities must adhere to the substance and procedures of the referenced accelerated approval regulations. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert). Information on submitting SPL files using eLIST may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. Reference ID: 3938353 NDA 207999 Page 2 The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and container labels that are identical to the enclosed carton and immediate container labels as soon as they are available, but no more than 30 days after they are printed. Please submit these labels electronically according to the guidance for industry titled “Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar material. For administrative purposes, designate this submission “Final Printed Carton and Container Labels for approved NDA 207999.” Approval of this submission by FDA is not required before the labeling is used. ACCELERATED APPROVAL REQUIREMENTS Products approved under the accelerated approval regulations, 21 CFR 314.510, require further adequate and well-controlled clinical trials to verify and describe clinical benefit. You are required to conduct such clinical trials with due diligence. If postmarketing clinical trials fail to verify clinical benefit or are not conducted with due diligence, we may, following a hearing in accordance with 21 CFR 314.530, withdraw this approval. We remind you of your postmarketing requirements specified in your submission dated April 27, 2016. These requirements, along with required completion dates, are listed below. 3057-1 A randomized, placebo-controlled clinical trial to evaluate the safety, efficacy and steady-state pharmacokinetics of OCALIVA (obeticholic acid) in patients with primary biliary cholangitis (PBC) with Child-Pugh Classes B and C hepatic impairment, including Child-Pugh Class C patients with varying levels of Model for End-Stage Liver Disease (MELD) scores. You may conduct this as a standalone trial or in a subset of patients in your confirmatory trial (PMR# 3057-3). Final Protocol Submission: Trial Completion: Final Report Submission: 3057-2 A randomized, placebo-controlled trial to evaluate the safety and efficacy of OCALIVA (obeticholic acid) used as monotherapy in patients with primary biliary cholangitis (PBC) who are intolerant of or non-responsive to ursodeoxycholic acid (UDCA). Enroll patients across all stages of PBC, by the Rotterdam criteria. You may conduct this as a stand-alone trial or in a sub-set of patients in your confirmatory trial (PMR # 3057-3). Final Protocol Submission: Reference ID: 3938353 12/16 12/22 04/23 12/16 NDA 207999 Page 3 Trial Completion: Final Report Submission: 3057-3 12/22 04/23 A randomized, double-blind, placebo-controlled trial to verify and describe that OCALIVA (obeticholic acid) induced reductions in alkaline phosphatase and/or total bilirubin are associated with improvements in the composite clinical endpoint of progression to cirrhosis, death, transplant, decompensation events and hepatocellular cancer. Your ongoing trial (747-302) should be revised to include patients across the spectrum of stages of primary biliary cholangitis (PBC), including patients with early, moderately advanced and advanced PBC by the Rotterdam criteria, and should be adequately powered to demonstrate benefit in each stage. Draft Amended Protocol Submission: Final Protocol Submission: Trial Completion: Final Report Submission: 09/16 12/16 12/22 04/23 Submit clinical protocols to your IND 063307 for this product. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each requirement in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. Submit final reports to this NDA as a supplemental application. For administrative purposes, all submissions relating to these postmarketing requirements must be clearly designated “Subpart H Postmarketing Requirement(s).” REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement. Reference ID: 3938353 NDA 207999 Page 4 POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS UNDER SECTION 506B We remind you of your postmarketing commitment (PMC): 3057-4 Develop a formulation that would allow once daily dosing of OCALIVA (obeticholic acid) for patients with hepatic impairment. Conduct a study in healthy subjects to characterize the bioavailability of the new formulation relative to an approved formulation. Submit your study protocol once you have a new formulation. The timetable you submitted on April 27, 2016, states that you will conduct this study according to the following schedule: Final Protocol Submission: Study/Trial Completion: Final Report Submission: 11/17 04/19 08/19 Submit clinical protocols to your IND 063307 for this product. Submit nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing final reports to this NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each commitment in your annual report to this NDA. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. All submissions, including supplements, relating to this postmarketing commitment should be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.” PROMOTIONAL MATERIALS Under 21 CFR 314.550, you are required to submit, during the application pre-approval review period, all promotional materials, including promotional labeling and advertisements, that you intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If you have not already met this requirement, you must immediately contact the Office of Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory project manager or the appropriate reviewer to discuss this issue. As further required by 21 CFR 314.550, submit all promotional materials that you intend to use after the 120 days following marketing approval (i.e., your post-launch materials) at least 30 days before the intended time of initial dissemination of labeling or initial publication of the advertisement. We ask that each submission include a detailed cover letter together with three copies each of the promotional materials, annotated references, and approved package insert (PI)/Medication Guide/patient PI (as applicable). Send each submission directly to: Reference ID: 3938353 NDA 207999 Page 5 OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotions (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266 Alternatively, you may submit promotional materials for accelerated approval products electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf ). REPORTING REQUIREMENTS We remind you that you must comply with the reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). MEDWATCH-TO-MANUFACTURER PROGRAM The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse event reports that are received directly by the FDA. New molecular entities and important new biologics qualify for inclusion for three years after approval. Your firm is eligible to receive copies of reports for this product. To participate in the program, please see the enrollment instructions and program description details at http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm. POST APPROVAL FEEDBACK MEETING New molecular entities and new biologics qualify for a post approval feedback meeting. Such meetings are used to discuss the quality of the application and to evaluate the communication process during drug development and marketing application review. The purpose is to learn from successful aspects of the review process and to identify areas that could benefit from improvement. If you would like to have such a meeting with us, call the Regulatory Project Manager for this application. PDUFA V APPLICANT INTERVIEW FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review. Reference ID: 3938353 NDA 207999 Page 6 ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments. FDA BENEFIT-RISK FRAMEWORK APPLICANT INTERVIEW FDA has also contracted with Eastern Research Group, Inc. (ERG) to conduct an assessment of FDA’s initial phase implementation of the Benefit-Risk Framework (BRF) in human drug review. A key element of this evaluation includes interviews with applicants following FDA approval of New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologic License Applications (BLAs). The purpose of the interview is to assess the extent to which the BRF provides applicants with a clear understanding of the reasoning behind FDA’s regulatory decisions for NME NDAs and original BLAs. ERG will contact you to schedule a BRF applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final reports. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to this evaluation.  If you have any questions, call CDR Anissa Davis-Williams, Senior Regulatory Project Manager, at (301) 796-5016. Sincerely, {See appended electronic signature page} Amy G. Egan, M.D., M.P.H. Deputy Director Office of Drug Evaluation III Center for Drug Evaluation and Research ENCLOSURE(S): Content of Labeling Carton and Immediate Container Labeling Reference ID: 3938353 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------AMY G EGAN 05/27/2016 ( Reference ID: 3938353