Fixed Dose Combination

Fixed Dose Combination

Grouping of Fixed Dose Combinations

Fixed dose combinations are divided into four groups and the data required for approval differs for each group.

Group 1 - FDC in which one or more of the active ingredients is a new drug

The first group of FDCs includes those in which one or more of the active ingredients is a new drug. For this group, the marketing data and clinical trial data to be submitted will be similar to data required for any new drug.

Group 2 – FDCs in which active ingredients are already approved or marketed individually

The second group comprises FDCs in which the active ingredients are already approved or marketed individually. Approval is required as the active ingredients may be combined for the first time for a particular claim and are thus likely to have significant interaction of a pharmacodynamic or pharmacokinetic nature. The data required for this group varies and is based on the following specifications:

For obtaining permission to carry out clinical trials with FDCs, a summary of available pharmacological, toxicological and clinical data of each of the active ingredients should be submitted. The rationale for combining the ingredients in the proposed ratio is also required. Apart from this, acute toxicity data (Lethal Dose 50 (LD 50)) and pharmacological data for the individual ingredients as well as for the proposed combination is required.

In case the clinical trials for the FDC are conducted in countries other than India, reports of such trials are required to be submitted. If the FDC is marketed abroad, the regulatory status in other countries should also be stated.

If the FDC combination is not marketed anywhere in the world but these drugs are already used concomitantly (individually) for the said claim, marketing permission may be granted based on chemical and pharmaceutical data. In this case, data showing the stability of the proposed dosage form has to be submitted.

Group 3 – Alterations in the ratio of active ingredients or proposal to make a new therapeutic claim

The third group of FDCs includes those which are already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim. The marketing permission for this group would require the submission of claims regarding the rationale for the combination which may include published reports. Permission for this category of FDCs is granted based on the nature of the claim and data submitted.

Group 4 – When ingredients are combined for convenience

The fourth group of FDCs includes those whose individual active ingredients (or drugs from the same class) have been widely used in a particular indications for years, their concomitant use is often necessary and no claim is proposed to be made other than convenience. It will have to be demonstrated that the proposed dosage form is stable and the ingredients are unlikely to have significant interaction of a pharmacodynamics or pharmacokinetic nature. No additional animal or human data are generally required for these Fixed Dose Combinations (FDCs), and marketing permission may be granted if the Fixed Dose Combination (FDC) has an acceptable rationale.

Form CT-04 - Application for grant of permission to conduct clinical trial of FDCs

Sponsors intended to initiate a clinical trial for FDCs shall submit application in Form CT-04 along with all other necessary documents specified under Second Schedule and fees as specified under Sixth Schedule of CT Rules 2019. Once satisfied with the submitted documents, the Central Licencing Authority (CLA) shall grant the permission to conduct clinical trial in Form CT-06.

For the review and approval of clinical trial (CT) applications, fixed timelines have been put down - 90 working days for global clinical trials and 30 working days for drugs being developed in India. To encourage research and development in India, a new provision of “automatic approvals” is introduced. If no response is received from the central licencing authority to the applicant within the said period (30 days), the permission to conduct clinical trial shall be deemed to have been granted by the central licencing authority. In such cases, before trial initiation the applicant is required to inform the central licencing authority in Form CT-4A; the central licencing authority on the basis of the said information, take on record the Form CT-4A which shall become part of the official record and shall be called “automatic approval”.

The permission to initiate clinical trial granted in Form CT-06 or automatic approval in Form CT 4A shall remain valid for a period of 2 years from the date of its issue, unless extended by the CLA. Clinical trial shall be initiated by enrolling the first subject within a period of 2 year from the date of grant of permission, failing which the sponsor should get prior permission from CLA before initiating the trial.

Phases of Clinical trial

Phase I - Human or Clinical pharmacology

The objective of phase I trial is the estimation of safety and tolerability with the initial administration of an investigational new drug into humans. Phase I trials are conducted in healthy subjects or certain types of patients (such as in cancer). Phase I may have one or a combination of the following objectives: -

• Measurement of maximum tolerated dose

• Measurement of pharmacokinetics and pharmacodynamics

• Early measurement of drug activity

Phase II - Therapeutic exploratory trials

Phase II trials are conducted to test the safety and effectiveness of a drug. Phase II trials are conducted for a particular indication or indications in patients with the target disease/condition. The study population for Phase II trials are selected by relatively narrow criteria, which leads to a relatively homogeneous population.

Apart from safety and efficacy parameters, Phase II studies are important for the following aspects:

• To determine the dose and regimen of the drug for Phase III trials

• Evaluation of potential study endpoints

• Evaluation of therapeutic regimens (including concomitant medications)

• Evaluation of target populations (e.g. mild versus severe disease) for further studies in Phase II or III

The above objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.

Phase III – Therapeutic confirmatory trials

The main purpose of Phase III trials is demonstration or confirmation of therapeutic benefits of the drug for use in the intended indication and recipient population. Phase III trials are designed to confirm the preliminary safety and efficiency evidence gathered in Phase II.

Phase III studies provide an adequate basis for marketing approval. Phase III studies also explore the dose-response relationships (relationships among dose, drug concentration in blood and clinical response), use of the drug in wider populations, in different stages of disease, or the safety and efficacy of the drug in combination with other drugs.

Trials involving extended exposure to the drug (for drugs meant to be used for long periods) are usually conducted in Phase III.

For new drugs approved abroad, Phase III studies may be required (if scientifically and ethically justified), to generate evidence of efficacy and safety of the drug in Indian patients when used as recommended in the prescribing information. Prior to conduct of Phase III studies in Indian subjects, Central Licencing Authority may require pharmacokinetic studies to be undertaken to verify that the data generated in Indian population is in conformity with the data already generated abroad.

In case a new drug is already approved and marketed in other country, where local clinical trial in India is waived off or not found scientifically justified for its approval for manufacturing first time in the country, the bioequivalence studies of such drug, as appropriate, is required.

Phase IV. Phase IV or post marketing studies (PMS) of new drugs are conducted after the approval of the drug. Phase IV trials or PMS explore nuances beyond the prior demonstration of the drug’s safety, efficacy and dose definition. Phase IV trials may include additional drug-drug interaction, dose response or safety studies and trials design to support use under the approved indication e.g. mortality or morbidity studies, epidemiological studies, etc.

CliniExperts provide full spectrum services for the following types of Drug Clinical Trials:

Local Clinical Trial - Phase I Trial,Phase II Trial,Phase III Trialand Phase IV Trial or Post Marketing Studies (PMS) (exclusively in India)

Global Clinical Trial - Phase I Trial,Phase II Trialand Phase III Trial

A snapshot of the Data to Be Submitted Along With the Application to Conduct Clinical Trials of FDCs

Phase I study

• Summary

• Specific Pharmacological effects

• General Pharmacological effects

• Pharmacokinetics, absorption, distribution, metabolism, excretion

• Pharmacodynamics / early measurement of drug activity

Phase II

• Summary

• Study report as given in Table 6 of Third Schedule

Phase III - Therapeutic confirmatory trials

• Summary

• Individual study reports with listing of sites and investigators.