Sun Pharma submits proposal to CDSCO for manufacturing, marketing FDC to treat URTI; Details

New Delhi: Dilip Shanghvi led Sun Pharma recently submitted a proposal to seek permission from the national regulatory authority, Central Drugs Standard Control Organisation's (CDSCO) to manufacture and market Fixed dose combination of Cephalexin Extended-release and Clavulanate Potassium Tablets (375mg+125mg) and (750mg+125mg). However, the committee after detailed deliberation recommended for grant of permission to conduct the proposed In-vitro study as per the protocol presented.

The firm has further directed to submit their proposal along with the in-vitro study results for further consideration of approval of the said FDC. The committee also states that the Phase IV clinical trial protocol should be deliberated in the SEC once the proposal is considered for approval.

This comes following the firm's submission before the CDSCO to seek permission for the manufacturing and marketing of the drug indicated for the treatment of Upper Respiratory Tract Infections (URTI) and in treatment of uncomplicated skin and soft tissue infections.

Sun Pharma's strive to get a green flag for the said formulation from the Authority dates back to the year 2012. The firm has come a long way making attempts one after the other to get clearance for the same.

In 2012, the firm had conducted a non-comparative clinical trial of the said combination and the result of the study was placed before NDAC. However, the committee did not recommend for the FDC complying by the non-approval of the FDC in any country and further the inadequacy of the clinical trial data generated by the firm to support the efficacy of the formulation.

On the subsequent response of the applicant, the proposal was again deliberated in NDAC in the year 2013. This time the committee recommended that a comparative double-blind trial of Cephalexin+Clavulanate Potassium Vs Cephalexin should be conducted to show the superiority of the FDC. Protocol etc. should be submitted to the committee for examination.

The proposal was again deliberated in NDAC (Antimicrobial, Antiparasitic, Antifungal and Antiviral) in 2014, following the firm's response. The committee recommended for conducting the proposed trial.

"In terms of Risk/ Benefit, the committee opined that the FDC will have superiority over Cephalexin alone. Regarding unmet need and Innovation vis a vis current therapy, the committee opined that the proposed FDC will be useful in the said resistant patients. The committee also recommended including at least one site from North-East region of India," reads the committee recommendation.

However, the firm informed that experts during the NDAC meeting agreed that the comparative trial will not show any significant superiority of FDC over cephalexin alone on the basis of scientific explanation submitted by the firm. The proposal was also placed before the Technical committee in the same year. Accordingly, the firm was granted permission to conduct Phase III clinical trial with FDC of Cephalexin Extended Release (375 mg) and Clavulanate Potassium (125 mg) tablets with Cephalexin Extended-release (375 mg) tablets, a randomized Double-blind study. Subsequently, the firm has submitted the clinical report to the CDSCO committee and the clinical report was placed in SEC (Antimicrobial, Antiparasitic, Antifungal and Antiviral) meeting held in 2017.

Recommendations of SEC stated, "The firm presented the results of two phases III clinical trials of FDC of Cephalexin + Clavulanate Vs Cephalexin alone. The committee observed that there was no statistically significant difference of efficacy between the two groups. Hence based on these data, there is no justification for this combination".

On the subsequent response of the applicant, the proposal was again deliberated in SEC. Recommendations of SEC further mentioned, "The firm presented their justification for approval of the product based on clinical trial data generated. The Committee deliberated in detailed and reiterated its earlier stand that there was no statistically significant difference of efficacy between the two groups. Hence based on these data, there is no justification for this combination".

However, the firm did not agree with the recommendations of SEC and has requested to deliberate the proposal in Technical Committee for considering the application for grant of manufacturing and marketing permission of the FDC of Cephalexin Extended-release and Clavulanate Potassium Tablets (375mg+125mg) and (750mg+125mg).

The firm has mentioned that;

• The trial proposal was evaluated by the NDAC and approval was granted.


• The trial was not a superiority trial and hence showing statistical significant difference of FDC was not possible. The result of the clinical trials are comparable and in lines with the approved protocol with non-inferiority design.


• Various guidance documents of the United States Food and Drug Administration (USFDA) and the European Medicine Agency (EMA) recommend a non-inferiority design for conducting clinical trials with antimicrobials.


• Antimicrobials are also approved internationally based on a non-inferiority clinical trial.


• CDSCO guideline on FDC product also recommends non-inferiority clinical trial design in case of combination with clavulanic acid.


• An in-vitro study proved that the combinations show MIC >4 fold fall as compared to Cephalexin at MIC50 and MIC90 in both combination ratio 6:1 and 3:1 against Beta-Lactmase producing eighty-two strains of clinical isolates taken in the study. On the subsequent response of the applicant, the proposal was placed in 44th Technical Committee meeting held in 2018.

Recommendations of 44th Technical Committee read, "the firm presented the clinical data as well as some in vitro data in support of the efficacy of the FDC in a resistant strain of MSSA (Methicillin-Susceptible Staphylococcus aureus) before the committee. After detailed deliberation, the committee recommended that the firm should conduct an in vitro study to assess the efficacy of the FDC in a resistant strain of MSSA in community setup with statistically justified sample size. Accordingly, the firm should submit a protocol for the in-vitro study with statistical justification on sample size along with PhaseIV clinical trial protocol for review by the Technical Committee."

"If the results in-vitro study is found satisfactory, the FDC may be considered for approval subject to the Phase-IV clinical trial. As per the recommendation of the Technical Committee the applicant has now submitted In-vitro study protocol and Phase IV clinical trial protocol. The firm presented the In-vitro study protocol as well as a Phase IV clinical trial protocol before the committee," states the committee report.

The committee after detailed deliberation recommended for grant of permission to conduct the proposed In-vitro study as per the protocol presented. The firm should submit their proposal along with the in-vitro study results for further consideration of approval of the said FDC. The Phase IV clinical trial protocol should be deliberated in the SEC once the proposal is considered for approval.