Regulatory framework of

Regenerative medicinal products for review in India

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Presentation By:

Dr. V G Somani

Drugs Controller General (India)

Outline of Presentation

• Legal Provisions

• Guidance for Industry

• Licensing Procedure

• Clinical trial requirements

• Applications review system

• Screening committees

• MCI Code of Ethics regulation

• General undertanding under discussion.

Legal provisions • Regenerative medicinal products (RMPs) like stem

cell derived products, gene therapeutic products &Xenografts are regulated as Drugs under New Drugsand Clinical trail Rules 2019.

• Research on Regenerative medicinal productscomes under ICMR and researcher shall followNational Guideline for Stem Cell Research 2017.

• New Drugs means:- any drug which is not yetapproved by central licensing authority under Drugsand Cosmetics Act 1940.

New Drugs and Clinical trial Rules 2019:“new drug” means,

(i) a drug, including active pharmaceutical ingredient or phyto-pharmaceutical

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

(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;

Rules for requirement to import & manufacture of new drug in

India are specified under Chapter X of New Drugs and Clinical

Trial Rules 2019.

Rules for requirement to conduct Clinical trail in India are

specified under Chapter V Part A of New Drugs and Clinical trial

Rules 2019.

CMC data, pre-clinical, clinical trail data on safety & efficacy data

has to be submitted for approval of Regenerative Medicinal

Products.

Data is evaluated by Subject Expert committee.

Guidelines for Stem Cell Research has been published by ICMR

and DBT jointly as National Guideline for Stem Cell Research

2017. Aproved indications have been listed in Annexure-III i.e.

Guidance for Industry

Submission of clinical trial application for

Evaluating Safety and Efficacy.

Requirements for permission of New Drugs

Approval

Post Approval Change in biological products:

Quality safety and Efficacy Documents

Preparation of the Quality Information for Drugs

submission for New Drugs Approval.

Licensing Procedure

Indigenously manufacturers: The applicant is

required to obtain market authorization from

DCG (I) in Form CT-23 before obtaining

manufacturing license in Form 28 from State

Licensing Authority.

Importers: The applicant is required to obtain

market authorization from DCG (I) in CT-20

before obtaining Registration Certificate in Form

41 and import license in Form 10.

Pathway for indigenous manufacturersApplication for Manufacturing of Experimental test batches for test and Analysis (Form

30) to the SLA

Joint inspection by Expert/SLA/CDSCO Official

Permission for Manufacturing of Experimental batches of RMPs for Test and Analysis

(Form-29)

Pre -clinical studies as per New Drugs and Clinical trail Rules 2019

Application and protocol submission for conducting Phase I/II/III clinical study with the Experimental batches (CT-04)

(Pre - clinical data, Protocol for Clinical trial, CMC data as well as General Information as per CDSCO Guidance for Industry

-Review of Application in consultation with subject Experts

Submission of Clinical Study Report of Phase I/II/III of RMPs

Consultation with Subject Experts

Market Authorization Application in line with CTD format from manufacturer along with clinical trial report-

Permission issued in Form CT-23 followed by license in Form 28

CTD Module: -(Module-1: Administrative information) (Module-2: Overall Quality Summary) (Module-3: Chemistry Manufacture, Control (CMC)) (Module-4: Non –clinical data) (Module-5: Clinical Data)

Licensing procedure Contd….

Pathway for ImportersApplication to Import of finished formulation of RMPs for Test and

Analysis (Form CT-16)

Permission to Import of finished formulation of RMPs for Test and

Analysis (Form CT-17)

Application and protocol for conducting Phase III clinical study (Form CT-04)

(As specified in New Drugs and Clinical trail Rules 2019 i.e. Pre -clinical data, Protocol for Clinical trial, CMC data as well as General Information as per CDSCO Guidance for Industry)

Submission of Clinical Study Report of Phase III with Imported/manufactured product

Consultation with Subject Expert

Market Authorization Application as per CTD format from manufacturer along with clinical trial report

Permission issued in Form CT-20 followed by Registration Certificate in Form 41 & Import license in Form 10

CTD Module:

(Module-1: Administrative information)

(Module-2: Overall Quality Summary)

(Module-3: Chemistry Manufacture, Control)

(Module-4: Non – clinical data)

(Module-5: Clinical Data)

For New Drug products including biologicals discovered inIndia, clinical trial is required to be conducted right from Phase I. For New Drugs including biologicals approved outside India,Phase III studies need to be carried out to generate evidence ofefficacy and safety of the drug in Indian patients when used asrecommended in the prescribing information. Approval of new drugs is also considered based on clinicaltrial conducted in adequate number of Indian patients as a part ofglobal clinical trial and the drug is also approved in other countries. The Central Licencing Authority, with the approval of theCentral Government, may specify, by an order, the name of thecountries, from time to time, for considering waiver of local clinicaltrial for approval of new drugs under Chapter X and for grant ofpermission for conduct of clinical trial under Chapter V of NewDrugs and Clinical trial Rules 2019.

Clinical Trial requirement prior approval

Clinical Trial requirement relaxation As per New Drugs and Clinical trial Rules 2019: the local clinical trial may

not be required to be submitted along with the application if,

(i) the new drug is approved and marketed in countries specified by the

Central Licencing Authority under rule 101 and if no major unexpected

serious adverse events have been reported; or

(ii) the application is for import of a new drug for which the Central Licencing

Authority had already granted permission to conduct a global clinical trial

which is ongoing in India and in the meantime such new drug has been

approved for marketing in a country specified under rule 101; and

(iii) there is no probability or evidence, on the basis of existing knowledge, of

difference in Indian population of the enzymes or gene involved in the

metabolism of the new drug or any factor affecting pharmacokinetics and

pharmacodynamics, safety and efficacy of the new drug; and

(iv) the applicant has given an undertaking in writing to conduct

Phase IV clinical trial to establish safety and effectiveness of such

new drug as per design approved by the Central Licencing

Authority:

Provided that the Central Licencing Authority may relax this

condition, where the drug is indicated in life threatening or serious

diseases or diseases of special relevance to Indian health

scenario or for a condition which is unmet need in India such as

XDR tuberculosis, hepatitis C, H1N1, dengue, malaria, HIV, or for

the rare diseases for which drugs are not available or available at

a high cost or if it is an orphan drug.

As per Sixth Schedule : No fee shall be chargeable in respect of

application for conduct of clinical trial for orphan drugs as defined

in clause (x) of rule 2.

Clinical Trial requirement relaxation

As per second Schedule of New Drug and Clinical trial 2019, For

new drug substances discovered or developed in countries other

than India, Phase I data should be submitted along with the

application. After submission of Phase I data generated outside

India to the Central Licensing Authority, permission may be

granted to repeat Phase I trials or to conduct Phase II trials and

subsequently Phase III trial concurrently with other global trials for

that drug. For a drug going to be introduced for the first time in the

country, Phase III trial may be required to be conducted in India

before permission to market the drug is granted unless otherwise

exempted.

Clinical Trial requirement relaxation

Accelerated approval process may be allowed to a new drug for a

disease or condition, taking into account its severity, rarity, or

prevalence and the availability or lack of alternative treatments,

provided that there is a prima facie case of the product being of

meaningful therapeutic benefit over the existing treatment.

If the remarkable efficacy is observed with a defined dose in the

Phase II clinical trial of investigational new drug for the unmet

medical needs of serious and life threatening diseases in the country,

it may be considered for grant of marketing approval by the Central

Licencing Authority based on Phase II clinical trial data. In such

cases, additional post licensure studies may be required to be

conducted after approval to generate the data on larger population to

further verify and describe the clinical benefits, as per the protocol

approved by the Central Licencing Authority.

Accelerated Approval process

Technical Review andForward the file toConcerned DI’s

for validation

Manufacturers/importer

application

Submission of application

in CRU after acceptance

by Pre screening officers

Review of applications:

Pre-screening 1. Check administrative

2. Check legal document

3. Check fees

1st Level

Review

Central Registry

Unit

DDC (I)/ JDC (I)

ADC (I)Summary Basis of

approval

DI’s

ADI

DCG(I)

File signed and

send back to

concerned officer for

issue the letter

Issuance of

letters by CRU 2nd Level

Review

On Site Evaluation

CMC Evaluation

SEC,

Zonal

2 Hard and 1 Soft

copies

Various Screening Committees involved in

Approval of RMPs in India

For Import / Marketing Authorization of the Stemcell Products in India:

1. Subject Expert Committee

2. Technical Committee for appeal

To Conduct Research in India:

1. ICMR.

2. National Apex Committee for Stem Cell Research and Therapy (NAC/

SCRT) – To oversee the activities in the field of stem cell research in India.

3. As per National Guidelines for Stem Cell Research 2017, approved

indications for Hematopoietic stem cell transplantation (HCT) are mentioned

under Annexure3 of the guidelines for adult as well as pediatric which does

not require any prior approval.

MCI code of ethics regulation

To prevent any misuse of RMPs, the code of ethics regulation laid down by MCI

shall be followed by the Physician as under:-

Clause 2.3: The physician should neither exaggerate nor minimize the

gravity of a patient’s condition.

Clause 3.7.1 : A physician shall clearly display his fees and other charges

on the board of his chamber and/or the hospitals he is visiting. Prescription

should also make clear if the Physician himself dispensed any medicine

Clause 6.1: A physician shall not make use of him / her (or his / her name)

as subject of any form or manner of advertising or publicity through any

mode either alone or in conjunction with others which is of such a character

as to invite attention to him or to his professional position, skill, qualification,

achievements, attainments, specialities, appointments, associations,

affiliations or honours and/or of such character as would ordinarily result in

his self aggrandizement.

Clause 8.4: Decision on complaint against delinquent physician shall be

taken within a time limit of 6 months.

All the minimal manipulations performed by the physicians which are not

Draft Rule for Stem Cell and Cell Based Products in India.

General understanding about -Stem Cell derived Products means

a drug which has been derived from processed cells including

cell or tissue which has been processed by means of

substantial or more than minimal manipulation

with the objective of propagation and / or differentiation of a cell

or tissue,' cell activation, and production of a cell-line,

which includes pharmaceutical or chemical or enzymatic

treatment, altering a biological characteristic,

combining with a non-cellular component,

manipulation by genetic engineering including gene editing &

gene modification.

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Draft Rule for Stem Cell and Cell Based Products in India.- For the purpose above understanding –

(i) Substantial or more than minimal manipulation means ex-vivo alteration

in the cell population (T-Cell depletion, cancer cell depletion), expansion,

which is expected to result in alteration of function.

(ii) The isolation of tissue, washing, centrifugation, suspension in

acceptable medium, cutting, grinding, shaping, overnight culturing without

biological and chemical treatment, disintegration of tissue, separation of

cells, isolation of a specific cell, treatment with antibiotics, sterilization by

washing or gamma irradiation, freezing, thawing and such similar

procedures, regarded as minimal manipulations and are not considered as

processing by means of substantial or more than minimal manipulation.

(iii) Human cells or tissues removed from an individual for implantation of

such cells or tissues only into the same individual for use during the same

surgical procedure should not undergo processing steps beyond rinsing,

cleaning or sizing and these steps shall not be considered as processing.

This is still under development.

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Thank you