India is a country which has a drug regulatory system operating at the Central Level as well as the State Level. At Central level, Central Drugs Standards Control Organization (CDSCO) is the organization which has been given the prime responsibility of approval of New Drugs, Clinical Trials in the country, laying down the standards for Drugs, control over the quality of imported Drugs, coordination of the activities of State Drug Control Organizations and providing expert advice with a view of bring about the uniformity in the enforcement of the Drugs and Cosmetics Act. In this article we shall be discussing about the New Drug approval process in India.

On 19th March, 2019 vide G.S.R. 227 (E), India has published new set of regulations which are applicable for all types of new drugs, investigational new drugs for human use, clinical trial, bioequivalence study, bioavailability study and Ethics Committee. These rules are known as New Drugs and Clinical Trial Rules, 2019.

Before moving ahead with understanding the approval process of new drugs in India, we shall first of all understand the definition of “Drug” and “New Drug” as per Indian laws.

As per Section 3 (b) of Drugs and Cosmetics Act, 1940, the drug includes:

(i) all medicines for internal or external use of human beings or animals and all substances intended to be used for or in the diagnosis, treatment, mitigation or prevention of any disease or disorder in human beings or animals, including preparations applied on human body for the purpose of repelling insects like mosquitoes;]

(ii) such substances (other than food) intended to affect the structure or any function of the human body or intended to be used for the destruction of [vermin] or insects which cause disease in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette;

(iii) all substances intended for use as components of a drug including empty gelatin capsules; and

(iv) devices intended for internal or external use in the diagnosis, treatment, mitigation or prevention of disease or disorder in human beings or animals, as may be specified from time to time by the Central Government by notification in the Official Gazette, after consultation with the Board.

As per Rule 2 (w) of New Drugs and Clinical Trial Rules, 2019, the 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 Licensing Authority with respect to its claims; or

(ii) a drug approved by the Central Licensing 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 Licensing 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 Licensing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs.

            In case the drug substance or drug product intended to be launched in India falls under the definition of New Drug as defined above, then the firm has to adopt various regulatory pathways as applicable. Regulatory pathways are dependent on following major factors:

  1. Nature of drug substance or drug product: The nature of drug product plays a crucial role in deciding the pathway of new drug approval. As per definition of new drug, 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 shall always deemed to be a new drug. Hence, every manufacturer who intends to launch any of these categories of drugs has to undergo extensive non-clinical and clinical trials as applicable to prove their safety and efficacy before considering for Marketing Authorization.
  2. Type of Formulation: Type of formulation also plays an important role in deciding the pathway of new drug approval. As per definition of new drug, modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licensing Authority shall always deemed to be a new drug. Hence, every manufacturer who intends to launch any of these categories of drugs has to undergo clinical trials and/or BA-BE studies as applicable before considering for Marketing Authorization.
  3. Drugs already approved in the country: As per the New Drugs and Clinical Trial Rules, 2019, a drug remains as a new drug for a period of four years from the date of their permission granted by the Central Licensing Authority. Hence, during this period, if a manufacturer wants to manufacture a new drug for sale and distribution, then he shall also apply for the new drug approval on CT-21. We shall be discussing about this category in detail as a prototype for new drug approval process.
  4. Investigational New Drug: These types of dugs require extensive research and trials both clinical and non-clinical. The clinical trials initiates from Phase I followed by Phase II and Phase III. The data generated shall be provided to regulatory authorities for their consideration of grant of Marketing Authorization.
  5. Orphan Drugs: In case of orphan drugs various requirements may be waived off on case to case basis, but the same requires approval from the Central Licensing Authority. In such cases, it is advisable to have a pre-submission meeting with CDSCO authorities, so that, the pathway can be discussed and mutually agreed upon.
  6. New Molecules, New Combinations, New Dosage Forms, New Indications, New Dosage, New route of administration: Every manufacturer who intends to launch any of these categories of drugs has to undergo clinical trials and/or BA-BE studies as applicable before considering for Marketing Authorization.

This is to be noted that the dossier requirements include Chemistry, Manufacture and Control (CMC), Non-Clinical information, Clinical data and Administrative information.

To understand the pathway of new drug approval process in India in details, we shall be taking a case of drug which has already been approved in India as a new drug but is still considered as a new drug as period of four years has not lapsed from the date of their permission granted by the Central Licensing Authority.

Case Study: A firm wants to manufacture a new drug which has been recently approved by Central Licensing Authority and four years has not lapsed from the date of their permission granted by the Central Licensing Authority. The pathway shall be as follows:

Step1: Apply for CT-11 or CT-14 as the case may be: CT-11 and CT-14 are permission to manufacture new drug or investigational new drug for the purpose of Clinical Trial, BA-BE or for examination, test and analysis. The major difference between CT-11 and CT-14 is the status of API approval. If API is procured from approved source, then permission shall be sought on CT-11 and if API is procured from unapproved source, then permission shall be sought on CT-14. The application for CT-11 and CT-14 is made to respective zonal offices of CDSCO through SUGAM portal.

Step2: Apply for Form 29: After receipt of CT-11 or CT-14 as applicable, the manufacturer then approaches it’s respective State Licensing Authority for grant of Form 29. Form 29 is a license to manufacture drugs for purpose of examination, test or analysis.

Step 3: Manufacturing of test batches and generation of data: After receipt of Form 29, a manufacturer shall procure API and other required material and manufacture the trial batches. All the CMC data and the data as required as per Second Schedule of New Drugs and Clinical Trial Rules, 2019 shall be generated.

Step 4: Clinical Research Organization: The manufacturer shall also come into an agreement with a Clinical Research Organization who shall conduct BA-BE studies as applicable on their behalf. They shall prepare the BA-BE study protocol and shall provide the protocol along with all related documents to the manufacturer.

Step 5: Application on CT-21: A manufacturer then files an application online to CDSCO. All the requisite information shall be uploaded and application shall be made after paying the requisite fees as per the Sixth Schedule of New Drugs and Clinical Trial Rules, 2019.

Step 6: BA-BE study NOC: If the regulatory authority on review found all the documents satisfactory, then they may issue CT-07 i.e. Permission to conduct BA-BE study of new drug. In case of any query, the same shall be resolved before grant of CT-07. After receipt of NOC, the CRO may initiate the BA-BE study.

Step 7: Sample testing at Indian Pharmacopoeia Commission, Ghaziabad: In parallel. The regulatory authority shall issue a letter, directing the manufacturer to get their drug sample tested at Indian Pharmacopoeia Commission, Ghaziabad. After receipt of this letter, the manufacturer shall send the drug sample for testing.

Step 8: Submission of additional data: The manufacturer after receipt of BA-BE study report, sample testing report shall upload the same on CDSCO portal alongwith the updated CMC data if any.

Step 9: Review of data and issuance of CT-23: In case the regulatory authority finds the entire data in order and satisfactory, then they may issue CT-23 i.e. permission to manufacture pharmaceutical formulation of new drug for sale or for distribution.

Step 10: License from SLA: After receipt of CT-23, the drug manufacturer has to then approach to State Licensing Authority for the grant of product permission on Form 25 or Form 28 as applicable.

A pictorial flowchart for New Drug Approval Process of Drug already approved in India

 

Note: The above pathway is a general overview and process flow for new drug approval process in India. Minor variations to this general pathway may happen on case-to-case basis.

To further understand the process of new drug approval in India or any support in filing of the application, please feel free to write to us on vaayath@gmail.com

REFERENCES:

  1. New Drugs and Clinical Trial Rules, 2019
  2. Drugs and Cosmetics Act, 1940