Fixed Dose Combination

Fixed dose combinations (FDCs) are two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form.


GroupDiscussion

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.

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Frequently Asked Questions

What is an “orphan drug” as per the New Drugs and Clinical Trial Rules, 2019?

“Orphan drug” means a drug intended to treat a condition which affects not more than five lakh persons in India.

“New drug” means, (i) a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent, except in accordance with the provisions of the Act and the rules made thereunder, as per conditions specified in the labelling thereof and has not been approved as safe and efficacious by the Central Licencing Authority with respect to its claims; or (ii) a drug approved by the Central Licencing Authority for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form; or (iii) a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form; or (iv) a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licencing Authority; or (v) a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug; Explanation: The drugs, other than drugs referred to in sub-clauses (iv) and (v), shall continue to be new drugs for a period of four years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;

Yes. As per clause (w) of rule 2 of the New Drugs and Clinical Trials Rules, 2019 modified/sustained/prolonged/controlled release and NDDS of an approved drug are always considered as new drug and hence, require prior permission from CLA before obtaining the manufacturing license from the SLA for such products.

Any new drugs or investigational new drugs imported for the purpose of clinical trial shall be kept in containers bearing labels, indicating the name of the drug or code number, batch or lot number, wherever applicable, date of manufacture, use before date, storage conditions, name of the institution or organisation or the centre where the clinical trial is proposed to be conducted, name and address of the manufacturer, and the purpose for which it has been imported. Where a new drug or an investigational new drug is imported by the licencee on behalf of another person, the licencee shall indicate on the label of the container of the such drug, the name and address of the importer and the person to whom it is being supplied along with the scientific name of such drug, if known, or the reference which shall enable such drug to be identified and the purpose for which it is manufactured. No person or importer shall alter, obliterate or deface any inscription or mark made on the container, label or wrapper of any new drug imported without permission of the Central Licencing Authority.

A subsequent new drug means a drug approved by the Central Licencing Authority for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form. A subsequent new drug also includes a new drug already approved in the country.

Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial study of a new drug or an investigational new drug can submit application for clinical trial study

Yes. Any sponsor or investigator intended to initiate a clinical trial for new drug or investigational new drug shall obtain permission from CLA in Form CT-06. The applicant 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.

In general, the timeline for disposal of an application for conduct of clinical trial study is 90 working days from the date of receipt of application. However, if the drug is discovered in India or research and development of the drug are being done in India and also the drug is proposed to be manufactured and marketed in India then the timeline for disposal of an application for conduct of such clinical study is 30 working days from the date of receipt of application. In such case, if no response is issued by the CDSCO within 30 working days, the clinical trial will be considered to be deemed approved.

Minimum of seven members from medical, non-medical, scientific and non-scientific areas with at least, one lay person; one woman member; one legal expert; one independent member from any other related field such as social scientist or representative of non-governmental voluntary agency or philosopher or ethicist or theologian At least 50% of members not affiliated with the institute or organization in which EC is constituted Every member of the EC shall be required to undergo such training and development programs

An application for grant of permission to conduct clinical trial of new drug or investigational new drug shall be made in Form CT-04. The application should be accompanied by the necessary documents as specified under Second Schedule along with the fees as specified under Sixth Schedule of the NDs & CTs Rules, 2019. Order issued by CDSCO on 10th Apr 2019, Form CT-04 (and other Forms) can be manually completed and uploaded in SUGAM, till all the new Forms are integrated into the online submission portal.


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