Qualifying notice for Ocaliva

Dossier ID : e186967

[name of employee removed]
[title of employee removed]
Intercept Pharmaceuticals, Inc.
4760 Eastgate Mall
San Diego, CA
92121 USA

Dear [name of employee removed]:

This Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada Guidance Document: Notice of Compliance with Conditions (NOC/c), is to advise you that information submitted in support of the New Drug Submission for Ocaliva (obeticholic acid), Control Number 198418, for the indication of 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, qualifies to be considered for authorization in accordance with the NOC/c Guidance. In keeping with the provisions outlined in the NOC/c Guidance, the following additional information is requested to complete the assessment:

1. A letter, signed by the Chief Executive Officer or designated signing authority of Intercept Pharmaceuticals, Inc., indicating that you agree to have this submission considered under the NOC/c Guidance. Please be reminded that in agreeing to accept an NOC under the NOC/c Guidance, Intercept Pharmaceuticals, Inc. consents to the posting of the NOC/c-QN on Health Canada's website.

2. A draft Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Intercept Pharmaceuticals, Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to supply the following:

a. Final report of the pivotal study number 747-302, a randomised, double-blind, placebo-controlled multicentre study evaluating the effect of Ocaliva on clinical outcomes (time to cirrhosis, death, transplant, decompensation events and hepatocellular cancer) in subjects with PBC should be submitted as confirmatory data. Sufficient number of subjects with different stages of PBC progression according to Rotterdam criteria should be included in the study which would allow demonstrating the efficacy of Ocaliva at each stage of the disease. Sufficient number of elderly subjects (over 65 years of age) should be included to allow demonstrating the efficacy of Ocaliva in this age group. Sufficient number of subjects with BMI≥30kg/m2 should be included to demonstrate the efficacy in this subgroup. Please indicate the earliest availability of the data.

b. Final report of Study 747-401, a randomised, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of Ocaliva in patients with PBC and moderate to severe hepatic impairment should be submitted at the earliest availability.

c. Final study report of a randomised, placebo-controlled trial evaluating the safety and efficacy of Ocaliva used as monotherapy in patients with PBC who are intolerant of or non-responsive to UDCA should be submitted as confirmatory data. Sufficient number of elderly subjects (over 65 years of age) should be included to allow demonstrating the efficacy of Ocaliva in this age group.

d. Biopharmaceutics:

The data provided to support the bench top stability (24 hours at ambient temperature) and freeze-thaw stability (five cycles from -70°C) of obeticholic acid (6-ECDCA) in human K2EDTA plasma were not considered to be acceptable since the percent relative error values for the QCBL (bench top stability) and QCFL (freeze-thaw stability) samples were greater than 15%. The rationale of spiking error was not considered to be acceptable given that evidence to support the conclusion was not provided.

Please provide an amendment to the method validation report to include the following stability experiments conducted with multiple (minimum three) replicates at each of the low QC and high QC concentrations in the appropriate matrix (including the same anticoagulant used in the comparative bioavailability studies) as per the October 8, 2015 Notice to Industry: Clarification of bioanalytical method validation procedures. In addition, the stability studies should be conducted such that the stressed samples should be compared to the same samples at time zero (freshly spiked control samples) rather than a comparison to the nominal value.

  1. Freeze-thaw stability data for the number of cycles that is considered to be reflective of the number of cycles experienced by subject samples from the study (frozen at the temperature used in the study and thawed at room temperature) in spiked plasma.
  2. Bench top stability data in spiked plasma over a length of storage that is considered to be reflective of the processing period of the batches of the subject samples from the study.
  3. Please provide a copy of the revised analytical method validation standard operating procedure (SOP) that reflects the changes to the manner by which the stability assays are conducted.

e. Post Market Safety Monitoring Studies:

  1. Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada should be forwarded within 15 days to the Marketed Health Products Directorate, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.
  2. Annual safety summary reports should be provided to the Therapeutic Products Directorate in a manner deemed consistent with the current Guidance Document: Notice of Compliance with Conditions (NOC/c).

3. A draft of the Patient Medication Information section of the Product Monograph outlining the potential risks, benefits and side effects of Ocaliva for the indication of 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.

4. A draft of the Product Monograph that is consistent with the requirements outlined in section 5.2.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that, if applicable, a boxed text should appear on the cover page, at the beginning of each major section of the Product Monograph (Parts I and II), and on the first page of the Patient Medication Information section, disclosing the nature of the authorization granted for Ocaliva for the indication of 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.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance documents on the Management of Drug Submissions and Notice of Compliance with Conditions. Sponsors are instructed to submit a complete response [refer to "Guidance Document: Notice of Compliance with Conditions (NOC/c)] with the requested information within 30 calendar days of the date of this letter.

In order to facilitate and to ensure proper processing, please include a revised Submission Certificate with your response, quote the product name and control number, and address all correspondence to the Office of Submissions and Intellectual Property.

Yours sincerely,

Marion Law
Director General
ML/jb

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