Regulatory Decision Summary for Mar-Phytonadione

The information provided with the initial submission was determined not to have met the requirements for a Submission Relying on Third Party Data (SRTD). In particular, a systematic literature review relevant to the proposed indication was not provided and the literature references that were provided were considered inadequate. A Notice of Deficiency (NOD) was therefore issued on April 22, 2020.

The additional literature references filed by the sponsor in Response to the NOD were not considered adequate to allow Health Canada to reach a conclusion regarding the overall benefit-harm-uncertainty profile for Mar-Phytonadione. The sponsor also did not provide a critical appraisal of the submitted literature references or describe any relevant Cochrane-style review/meta-analysis, despite this being the topic of the single major objection in the NOD. A NOD-Withdrawal (NOD-W) was then recommended. 

The following additional deficiencies were identified and included in the NOD-W:

• Inadequate data to confirm bioequivalence (BE) of the formulations used in the pivotal literature references to the formulation proposed for marketing

Criteria no. 3 of Health Canada’s SRTD guidance document (2015) states that in accordance with requirement C.08.002(2)(m) of the Food and Drug Regulations, an SRTD requires submission of evidence, based on comparative pharmaceutical and/or comparative bioavailability data, to establish that the product used in studies reported in the literature is representative of the proposed commercial product. The SRTD Guidance document also clearly states that clinical studies reported in the literature and included in the submission will not be considered sufficient to establish the clinical safety and efficacy required by the Regulations unless it is demonstrated that the proposed commercial product will have the same in vivo performance as the product used in the studies reported in the literature. The data submitted by the sponsor were not adequate to confirm that the reference product administered in the pivotal BE studies (that is [i.e.] Mephyton 5 milligram (mg) tablets [Valeant Pharmaceuticals North America LLC]) is the same as the products administered in the submitted pivotal literature references. Furthermore, the data submitted were not adequate to confirm that the Mephyton 5 mg tablets (Valeant Pharmaceuticals North America LLC) administered in the pivotal BE studies and the products administered in the pivotal literature references are the same as the current United States reference product (Mephyton 5 mg tablets that is manufactured by Bausch Health Companies Inc. and distributed by Bausch Health US, LLC).

• Lack of valid bioequivalence (BE) studies conducted under fed conditions

The sponsor recommended that Mar-Phytonadione be taken with food to maximize bioavailability. As a result, the comparative bioavailability studies conducted under fed conditions were considered pivotal in order to demonstrate BE. However, there were significant concerns regarding the integrity of the data from the submitted fed studies, given that the analytical portion of Study 714/14 and the clinical and analytical portions of Study PCLPL-048-18 were conducted at a site that is under investigation for violation of Good Clinical Practices (GCP). The data integrity concerns regarding the site invalidates any conclusion of BE between the Mar-Phytonadione 5 mg tablets and the foreign reference product, Mephyton 5 mg tablets (Valeant Pharmaceuticals North America LLC).

• Lack of food-effect comparative bioavailability study

The sponsor suggested that there is a clinically significant food-effect with respect to bioavailability of both Mar-Phytonadione 5 mg tablets and the United States reference product (Mephyton 5 mg tablets, Valeant Pharmaceuticals North America LLC) based on cross-study comparisons between Study 605/15 (BE study conducted under fasting conditions) and Studies 714/14 and PCLPL-048-18 (BE studies conducted under fed conditions). As a result, the sponsor recommended that Mar-Phytonadione 5 mg tablets should be taken with food. However, the sponsor’s conclusions regarding the effect of food on the bioavailability of Mar-Phytonadione are based on cross-study comparisons rather than data from a food-effect study, and the available food-effect data were conducted at a site that currently is under investigation for GCP compliance and data integrity concerns, as described above.

Notwithstanding the absence of adequate bridging data between the different reference products, as described above, the labelling for the Mephyton 5 mg tablets (Valeant Pharmaceuticals North America LLC) administered in the submitted pivotal BE studies does not include any information regarding the effect of food on the Mephyton 5 mg tablets or a recommendation regarding the timing of administration of the product relative to food intake. Information regarding the effect of food on the bioavailability of the product administered in the pivotal literature references was also not submitted. Food effect data are therefore still required and should be based on either data from the literature regarding an appropriate reference product or a new, properly designed, comparative bioavailability study conducted and analysed at a reliable International Council on Harmonisation (ICH) GCP compliant site, with no known data integrity issues and using an appropriate reference product

Quality
There were also issues identified based on preliminary review of the chemistry and manufacturing component of the submission, and these were recommended for inclusion in the NOD-W.