Question 1

In which cases the extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible?

Accepted Answer

The extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible if following conditions are met:
Similarity with respect to quality has been proven to reference biologic
Similarity with respect to preclinical assessment has been proven to reference biologic
Clinical safety and efficacy is proven in one indication
Mechanism of action is same for other clinical indications
Involved receptor(s) are same for other clinical indications

New indication not mentioned by innovator will be covered by a separate application.

Question 2

What is the validity of clinical trial permission to initiate a clinical trial?

Accepted Answer

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.

Question 3

Whether registration of clinical trial in Indian Council of Medical Research- Indian Council of Medical Research (ICMR-CTRI) is mandatory?

Accepted Answer

Yes. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory.

Question 4

Which competent authorities are involved in the three-tier mechanism established for granting approval for research and development activities on recombinant DNA products and monitoring and evaluation of research activities involving recombinant DNA technology?

Accepted Answer

The three tier mechanism comprises the following authorities:
1.	Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site .
2.	Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks.
3.	Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms.

Question 5

Who can apply for grant of permission to conduct clinical trial study of biological products in human subjects?

Accepted Answer

Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial of a biological product can submit application for clinical trial.

Question 6

How to apply for grant of license to manufacture biological product for CT by State Licensing Authority (SLA)?

Accepted Answer

After obtaining permission in CT-11 or CT-14 or CT-15 as the case may be, the person, who intends to manufacture the biological product for CT, shall make an application for grant of license to manufacture the biological product by the respective State Licensing Authority (SLA) in accordance with the provisions of the Act and the Drugs and Cosmetics Rules, 1945.

Question 7

Whether Phase-I (first-in-human) study of a biological product discovered or developed outside India can be permitted to be conducted in India?

Accepted Answer

No. For biological product and 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 biological product.

Question 8

In India, genetically modified organisms (GMOs) and the products thereof are regulated under which act?

Accepted Answer

In India, genetically modified organisms (GMOs) and the products thereof are regulated under the “Rules for the manufacture, use, import, export & storage of hazardous microorganisms, genetically engineered organisms or cells, 1989” (referred to as Rules, 1989) notified under the Environment (Protection) Act, 1986.

Question 9

What is the labelling of a biological product manufactured under Form CT-11, CT-14 & CT-15?

Accepted Answer

Any biological product manufactured under Form CT-14 & Form CT-15 shall be kept in containers bearing labels, indicating the name of the biological product or code number, batch or lot number, wherever applicable, date of manufacture, use before date, storage conditions, name of the institution or organization or the center where the CT is proposed to be conducted, name and address of the manufacturer, and the purpose for which it has been manufactured.

Question 10

What is the validity period of permission granted in Form CT-11 /CT-14/CT-15 to manufacture a biological product or substance to conduct CT?

Accepted Answer

The permission granted in Form CT-11/CT-14/CT-15 to manufacture a biological product or substance to conduct CT shall remain valid for a period of 3 years from the date of its issue, unless suspended or cancelled by CLA. In exceptional circumstances the CLA may extend the period of the permission granted for a further period of 1year.

Question 11

What is the timeline for disposal of an application for clinical trial which is a part of discovery, research and manufacture of a biological product in India?

Accepted Answer

The application submitted to CLA for grant of permission to conduct clinical trial of a biological product discovered in India or research and development of the biological product are being done in India and also the drug is proposed to be manufactured and marketed in India, such application shall be disposed by way of grant of permission or rejection or processed by way of communication to rectify any deficiency of the application, as the case may be, as specified in rule 22, by the CLA within a period of 30 working days from the date of the receipt of the application. If no communication has been received from the CLA to the applicant within the said period, the permission to conduct clinical trial shall be deemed to have been granted.

Question 12

What are the key points to consider when selecting the reference biologic for the development of similar biologic?

Accepted Answer

The rationale for the choice of the reference biologic should be provided by the manufacturer of the similar biologic in the submissions to the DBT and CDSCO. The following factors should be considered for selection of the reference biologic:
The reference biologic should be licensed in India and should be innovator product. The reference biologic should be licensed based on a full safety, efficacy and quality data. Therefore another similar biologic cannot be considered as a choice for reference biologic.
In case the reference biologic is not marketed in India, the reference biologic should have been licensed and widely marketed for 4 years post approval in innovator jurisdiction in a country with well-established regulatory framework. In case no medicine or only palliative therapy is available or in national healthcare emergency, this period of 4 years may be reduced or waived off.
The same reference biologic should be used throughout the studies supporting the safety, efficacy and quality of the product (i.e. in the development programme for the similar biologic)
The dosage form, strength and route of administration of the similar biologic should be the same as that of the reference biologic.
The active substance (active ingredient) of the reference biologic and that of the similar biologic must be shown to be similar.

Question 13

Who regulates the manufacture and import of biologicals in India?

Accepted Answer

CDSCO regulates the manufacture and import of biologicals in India. The organization is responsible for:
●	Approving clinical trials
●	Granting permission to import biologicals for local trials
●	Authorizing firms to export biologicals for biochemical and immunological analysis

Question 14

What is “clinical trial”?

Accepted Answer

A “clinical trial” in relation to a biological product means any systematic study of such biological products in human subjects to generate data for discovering or verifying its, 
clinical or; 
pharmacological including pharmacodynamics, pharmacokinetics or; 
adverse effects, with the objective of determining the safety, efficacy or tolerance of such new drug or investigational new drug

Question 15

In India, which regulatory framework is required for biosafety evaluation of biological products?

Accepted Answer

Prior to CDSCO, Genetically Modified Organisms (GMOs) and products thereof in research and application are required to ensure safety of the biological to the users as well as to the environment

Question 16

How can an application for grant of permission to conduct clinical trial of biological product be made?

Accepted Answer

An application for grant of permission to conduct clinical trial of biological product 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

Question 17

What are the criteria for the use of reference biologic not authorized in India?

Accepted Answer

The products, where the reference biologic is not authorized in India shall be considered on a case by case basis if such products have been granted marketing approval in countries with well-established regulatory systems such as US FDA, EMA etc. and have been in wider use for a minimum of four years.

Question 18

What are the timelines for disposal of application for conduct of clinical trial for biological products?

Accepted Answer

In general, the timeline for disposal of an application for conduct of clinical trial for biological products  is 90 working days from the date of receipt of application. However, if the biological product is discovered in India or research and development of the biological product are being done in India and also the biological product 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.

Question 19

Can I initiate a clinical trial straightway after deemed approval?

Accepted Answer

No. The information to initiate clinical trial of new drug or investigational new drug shall be made required to be submitted to CDSCO in Form CT-04A duly filled and signed before initiation of the clinical trial. As per the requirement, any sponsor or investigator shall before initiating the clinical trial is required to inform the CDSCO in Form CT-4A. On the basis of the said information the CDSCO shall take on record the Form CT-4A which shall become part of the official record and shall be called automatic approval of the CLA

Question 20

What is a “similar biologic”?

Accepted Answer

A “similar biologic” means a biological product which is similar in terms of quality, safety and efficacy to reference biological product licensed or approved in India, or any innovator product approved in International Council of Harmonization (ICH) member countries

Question 21

What is a “Biological Product

Accepted Answer

A Biological Product means a vaccine, r-DNA derived product, living modified organism, monoclonal antibody, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug.

Biological products, or biologics, are medical products made from a variety of natural sources (human, animal or microorganism) intended to treat diseases, prevent or diagnose diseases. Examples of biological products include vaccines, blood and blood products, human cells and tissues, gene therapies and cellular therapies.

Question 22

How to import a biological product for conducting clinical trial?

Accepted Answer

Any person or institution or organization who intends to import a biological product or substance for clinical trial shall make an application in Form CT-16 to the CLA. The application shall be accompanied by a fee specified in the Sixth Schedule and such other information and documents as specified in Form CT-16.

Question 23

What should I do if a biological product manufactured under Form CT-11/CT-14/CT-15 expires?

Accepted Answer

If the biological product manufactured for purposes of CT is left over or remains unused or gets damaged or its specified shelf life has expired or has been found to be of sub- standard quality, the same shall be destroyed and action taken in respect thereof shall be recorded.

Question 24

What are the toxicity study data required to be submitted for conduct of CT of biological product?

Accepted Answer

For Phase I Clinical Trials:
Systemic Toxicity studies: -
Single dose toxicity studies
Dose Ranging Studies
Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure.
Male fertility study:
In-vitro genotoxicity tests, –
Relevant local toxicity studies with proposed route of clinical application (duration depending on proposed length of clinical exposure).

Allergenicity or Hypersensitivity tests (when there is a cause for concern or for parenteral drugs, including dermal application).

Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related to an agent causing photosensitivity or the nature of action suggests such a potential).

For Phase II Clinical Trials:
Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I trial, with appropriate references.

In case of an application for directly starting a Phase II trial - complete details of the nonclinical safety data needed for obtaining the permission for Phase I trial, as per the list provided above must be submitted.

Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure.

In-vivo genotoxicity tests.
Segment II reproductive or developmental toxicity study (if female patients of child bearing age are going to be involved).

For Phase III Clinical Trials:
Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I and II trials, with appropriate references.
		In case of an application for directly initiating a Phase III trial – complete details of the non-clinical safety data needed for obtaining the permissions for Phase I and II trials, as per the list provided above must be provided.

Repeat-dose systemic toxicity studies of appropriate duration to support the duration of proposed human exposure.

Reproductive or developmental toxicity studies

Segment I (if female patients of child bearing age are going to be involved), and
Segment III (for drugs to be given to pregnant or nursing mothers or where there are indications of possible adverse effects on foetal development).

Carcinogenicity studies (when there is a cause for concern or when the drug is to be used for more than 6 months).

For Phase IV Clinical Trials:
Provide a summary of all the non-clinical safety data (listed above) already submitted while obtaining the permissions for Phase I, II and III trials, with appropriate references.
		In case an application is made for initiating the Phase IV trial, complete details of the non-clinical safety data needed for obtaining the permissions for Phase I, II and III trials, as per the list provided above must be submitted.

Application of Good Laboratory Practices (GLP) – The animal studies be conducted in an accredited laboratory. Where the safety pharmacology studies are part of toxicology studies, these studies should also be conducted in an accredited laboratory

Question 25

Can biological products be referred to as “investigational new drug”?

Accepted Answer

“Investigational new drug” means a new chemical or biological entity or substance that has not been approved for marketing as a drug in any country.

Question 26

Which mechanism has been established for granting approval for research and development activities on recombinant DNA products, and monitoring and evaluation of research activities involving recombinant DNA technology?

Accepted Answer

A three-tier mechanism has been established for granting approval for research and development activities on recombinant DNA products and monitoring and evaluation of research activities involving recombinant DNA technology.

Question 27

How to apply for permission to manufacture biological product for CT?

Accepted Answer

Any person who intends to manufacture a biological product as well as substance for CT shall submit application in CT-10 for obtaining permission from the CLA to manufacture such biological product.
Any person who intends to manufacture a formulation of a biological product after obtaining biological substance from an approved source for CT shall submit application in CT-10 for obtaining permission from the CLA in Form CT-11 to manufacture such biological product.
Any person who intends to manufacture a biological product after obtaining biological substance from an unapproved source for shall submit application in CT-12 for obtaining permission from the CLA in Form CT-14 to manufacture such biological product. In such case, the biological substance manufacturer is also required to submit application to CLA in Form CT-13 for obtaining permission in Form CT-15 to manufacture and supply the unapproved biological substance to the formulator for development of the biological product.
Any person who intends to manufacture an investigational biological product after obtaining the unapproved biological substance from another manufacturer for CT shall submit application in CT-12 for obtaining permission from the CLA in Form CT-14 to manufacture such investigational biological product. In such case the biological substance manufacturer is also required to submit application to CLA in Form CT-13 for obtaining permission in Form-CT15 to manufacture and supply the unapproved biological substance to the formulator for development of the investigational biological product.

Question 28

What is the timeline for disposal of application under Form CT-16?

Accepted Answer

After evaluating the Form CT-16 and documents, if satisfied, that the requirements of these rules have been complied with, grant the licence to import the biological product for CT in Form CT-17 within a period of 90 working days from the date of receipt of the application.

Question 29

Whether permission is required from the Central Licencing Authority  (CLA) for conduct of clinical trial in India?

Accepted Answer

Yes. Any sponsor or investigator intended to initiate a clinical trial for biological product 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.

Question 30

What is the validity period of license granted in Form CT-17?

Accepted Answer

The license granted in Form CT-17 shall remain valid for a period of 3 years from the date of its issue, unless suspended or cancelled by CLA. In exceptional circumstances the CLA may extend the period of the license granted under rule 68 for a further period of 1 year.

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Clinical trial review process for Biologicals/similar biologicals products in India

CDSCO regulates the manufacture and import of biologicals in India.

The organization is responsible for:

Approving clinical trials

Granting permission to import biologicals for local trials

Authorizing firms to export biologicals for biochemical and immunological analysis

Clinical Trial Steps

The clinical procedures for regulating biologics and biosimilars can be exhausting.