Rejected: JnJ plea to waiver Phase IV trial for FDC drug containing Canagliflozin, Metformin

New Delhi: American multinational drug maker Johnson and Johnson's (JnJ) proposal for waiver of Phase IV clinical trial of its Fixed-Dose Combination (FDC) of Canagliflozin 50mg/ 150mg/ 50mg/ 150mg/ 50mg/ 150mg + Metformin 500mg/ 500mg/ 850mg/ 850mg/ 1000mg/ 1000mg film coated tablets was refused by the Central Drug Standard Control Organization (CDSCO) Technical Committee. JnJ was directed by the committee to conduct Phase IV clinical Trial for the said formulation.

The product is indicated in adults aged 18 years and older with type 2 diabetes mellitus as an adjunct and exercise to improve glycemic control:

• In patients not adequately controlled on their maximally tolerated doses of Metformin


• In patients on their maximally tolerated doses of Metformin along with other glucose-lowering medicinal products including insulin, when these do not provide adequate glycemic


• In patients already being treated with the combination of Canagliflozin and Metformin as separate

Last year, the firm presented the proposal to SEC Committee for the FDCs along with data of global clinical trial conducted in which Canagliflozin was used as add-on therapy in patients with Metformin and Índia was one of the participating countries. The firm also presented that Pharmacokinetics of both Canagliflozin and Metformin were bioequivalent when administered as fixed-dose combination or as individual components.

After detailed deliberation, the SEC committee recommended for approval of a grant of permission to import and market the FDC subject to the condition that the firm should conduct a Phase IV clinical trial. Accordingly, the protocol should be submitted before launching the product in the market, for review by the committee.

On the subsequent response of JnJ, the proposal was again deliberated in SEC (Endocrinology & Metabolism) held on 28.08.2018. Thereafter, the committee recommended that the firm should submit the Phase IV clinical trial protocol for review by the committee. However, the firm presented their request for Phase-IV CT waiver before the committee.

After detailed deliberation, the committee upheld its decision made in its meeting held earlier for the requirement of conducting the phase-IV clinical trial. The committee opined that this more imperative in view of the recent ADRs reported with such class of drugs.

Justification submitted by the firm reads;

1. The combination of Canagliflozin and Metformin has been approved globally in 54 countries including US, EU, etc., and is marketed since Aug 2014. the firm stated that they have already submitted report entitled Approval of FDCs by US FDA and with Vokanmet as a case study which captures regulations of approval of FDCs by US FDA and EMA and, the submissions and rationale submitted by Janssen to approve the


2. 1131 Indian patients have participated in total 9 Phase 2/Phase 3 studies that evaluated the administration of Canagliflozin 100mg Or 300mg in subjects with T2DM.of these patients, 839 patients were already on the background of Metformin.


3. Apart from rigorous data form phase 3 abundant data about the real-world experience has also been published. Use of Canagliflozin relative to the use of SGLT2i and found no statistically or clinically significant differences in any database in either flue on treatment or intent to treat analyses.


4. The safety concerns raised have been attributed! to the class effect of sodium-glucose cotransporter 2 inhibitors and are restricted to Canagliflozin alone, etc.

The firm's proposal was recently deliberated by the CDSCO Technical Committee and the committee agreed with the recommendation of the Subject Expert Committee (Endocrinology & Metabolism) and recommended that the firm should conduct Phase IV clinical trial with the drug as recommended by the SEC.

Also Read: Merck Ebola vaccine in demand rather than JnJ rival drug