Module 8: New Drug Application: Fixed dose combination of two or more drugs

Approval of New Drugs in India

8.5 A fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage, dosage form (including sustained release dosage form) and route of administration.

General Consideration:

A clear justification with a valid therapeutic rationale of the particular combination of active substances proposed will be the basis of approval. It is not always necessary to generate new (original) data. Evidence may be obtained from the scientific literature, subject to its being of adequate quality.

In case of FDC where all the active ingredients are approved individually, if a Clinical Trial (CT) is required, confirmatory studies to prove efficacy, preferably by parallel group comparisons in which the FDC is compared to its individual substances may be considered. When feasible, a placebo arm may be incorporated. Comparative CTs of the FDC with reference treatment may be necessary, especially when the therapeutic justification talks more on the FDCs superiority over a reference treatment.

Treasury Challan: of INR 15,000 if all active ingredients are approved in India for more than one year, or INR 50,000 in case any of the active ingredients is unapproved or approved for less than one year. However, a Challan of only INR 15,000 is required, in case the applicant has already submitted an application along with a Challan of INR 50,000 towards any of the single active ingredient approval, which is less than 1 year old.

Any test batch/trial batch of new drugs for test and analysis purpose should be manufactured after obtaining licence in Form 29 from the concerned State Licensing Authority and copy of the licence should be submitted along with the application on form 44 for seeking permission to manufacture and market the new drug.

Summary of available pharmacological, toxicological and clinical data on the individual ingredients should be submitted along with any published data. Bio-availability/Bioequivalence (BA/BE) studies and Clinical trial in Indian subjects should be carried for FDCs wherever applicable. BA/BE study report and Clinical Study Report conducted in Indian population as per Appendix II of Schedule Y. The study report should be certified by each of the participating investigator(s) in the study and the certification should acknowledge the contents of the report, the accurate presentation of the study as-undertaken, and express agreement with the conclusions. In case of injectable formulation, sub-acute toxicity data conducted with the applicants’ product has to be provided.

A FDC application should have data on source of bulk drugs /raw materials, complete chemical and pharmaceutical information, proposed Package Insert (generic name of all active ingredients; composition; dosage form/s, indications; dose and method of administration; use in special populations; contraindications; warnings; precautions; drug interactions; undesirable effects; overdose; pharmacodynamic and pharmacokinetic properties; incompatibilities; shelf-life; packaging information; storage and handling instructions) and draft Label / Carton etc.

FDCs can be divided into the following groups and data required for approval for marketing is described below:

1. FDC – Not marketed in India & one or more active ingredient(s) is a new drug not approved in India.

Such type of FDCs can be further classified into two categories as follows:

a) One of the ingredients of the combination is an Investigational New Drug (IND): Complete Data required as for new drug application with rationale for combining them in the proposed ratio and therapeutic justification along with supporting literature.

b) One or more of the ingredients of the combination is a New Drug not approved individually in the country however the same is approved in other country: If such FDC is marketed abroad Phase III clinical trials are required to be conducted in India. In case, such a combination is not marketed anywhere in the world, clinical trials right from Phase I as appropriate are required to be conducted in the country. (In case of injectable formulation, sub-acute toxicity data conducted with the applicants’ product has to be provided)

2. FDC – Not marketed in India but the active ingredients are approved/ marketed individually & it is likely to have significant PK/PD interactions
This group of FDCs includes those in which active ingredients already approved /marketed individually are combined for the first time (for marketing in India), for a particular claim and where the ingredients are likely to have significant interaction of a pharmacokinetic or pharmacodynamic (PK/PD) nature. This can be further classified in to following,

a) FDC – Marketed abroad: This group of FDCs is being marketed abroad with an established safety and efficacy in humans. Application should be filed along with summary of Drug-Drug-Interactions (known and/or expected) among the active ingredients present in the FDC, along with its implications. This should be prepared and signed by a competent person on behalf of applicant. Clinical trials data showing safety and efficacy of the FDC in the same strength (that has been carried out in other countries) including published data.

b) FDC – Not marketed anywhere but individual components used concomitantly: Clinical data showing safety and efficacy of the FDC /Concomitant use of the ingredients, in the same strength, including published data. If enough supportive literatures are not available, then ‘adequate evidence’ on safe and effective concomitant use of the ingredients should be provided.

c) FDC – Not marketed and individual components are not used concomitantly: In case the FDC is not marketed anywhere in the world and the individual components are not concomitantly used in routine clinical practice and the ingredients are likely to have significant PK/PD interaction, clinical trials/Bioequivalence Studies may be required

3. FDC – Marketed in India but some changes are sought: Permission will be granted depending upon the nature of the claim and data submitted. A clinical trial/ BABE study may be required if the justification provided for the new claim(s) is not satisfactory.

4. FDC – Only for convenience: This group of FDC includes those whose individual active ingredient (or drugs from the same class) have been widely used in a particular indication(s) for years, their concomitant use is often necessary and no claim is proposed to be made other than convenience and should have demonstrated stability with no significant PK/PD interaction among the ingredients. Data showing safety, efficacy and convenience in use of the FDC has to be provided. If enough supportive literatures are not available, then ‘adequate evidence’ on its convenience to users has to be demonstrated. No additional animal or human data are generally required

5. FDC – Subsequent approvals after the approval of primary applicant’s FDC: FDCs which are of same strength/ratio, formulation and indication(s) of the already approved FDC of a primary applicant. Bioavailability/Bioequivalence as required. The guideline does not require conduct of BE study with the applicant’s original formulation. Based on same principle, if an FDC is approved in India for first time, for subsequent approval applicant is required to submit chemical and pharmaceutical for the FDC. However, if any of the individual ingredients are approved for less than 4 years in India and a BE study is required for the single ingredient formulation, a BE study is required to be conducted with the proposed FDC also.

Dr. Manoj Karwa

Auriga Research Ltd.
Email: [email protected]


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