Recombinant DNA Products

Recombinant DNA technology is playing a vital role in medical research and developing novel therapeutics. Recombinant DNA technologies (genetic, protein, and metabolic engineering) allow the production of a wide range of peptides, proteins, and biochemicals from naturally non-producing cells. The production of synthetic human insulin and erythropoietin by genetically modified bacteria and production of new types of experimental mutant mice for research studies are some well-known examples of recombinant DNA technology.


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Recombinant DNA Products

Recombinant DNA technology involves modifying genetic material outside an organism to obtain improved and desired characteristics in living organisms or as their products. The technology involves the insertion of DNA fragments from a variety of sources, having a desirable gene sequence via appropriate vector. Manipulation in organism's genome is carried out either by inserting one or more new genes and regulatory factors or by decreasing or blocking the expression of endogenous genes through recombining genes and elements.

In India, recombinant DNA products are considered to be new products as per the New Drugs & Clinical Trial Rules, 2019 and therefore require the permission of the Central licensing authority for both import and production for marketing purposes. As per the Biosafety Guidelines, the research work related to recombinant technology is overseen by the Department of Biotechnology through Institutional Biosafety Committees (IBSC) and Review Committee on Genetic Manipulation (RCGM) whereas, the commercial/large scale applications are dealt with by the Genetic Engineering Approval Committee (GEAC) of the Ministry of Environment & Forests.

Recombinant DNA products must be validated by detailed clinical trials that prove their safety and efficacy in treating the indicated disease. The New Drugs & Clinical Trial Rules, 2019 establishes the procedure for Clinical Trial.

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. The mechanism comprises of following competent authorities:

  • Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site

  • Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks

  • Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms

After getting approval from the above competent authority, the application is made to Central licensing authority for clinical trial and/or marketing of recombinant DNA products in India.

Any sponsor or investigator intended to initiate a clinical trial for recombinant DNA products shall obtain permission from Central Licensing Authority 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 New Drugs and Clinical Trial Rules 2019. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory.

In general, the timeline for disposal of an application for conduct of clinical trial for recombinant DNA products is 90 working days from the date of receipt of application. However, if the product is discovered in India or research and development of the product is done in India and also the 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 Central Licensing Authority within 30 working days, the clinical trial will be considered to be deemed approved.

For recombinant DNA products 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.

Toxicity study data required to be submitted for conduct of clinical trials of recombinant DNA products are as follows:

For Phase I Clinical Trials:

1. Systemic toxicity studies

2. Male fertility study

  • In-vitro genotoxicity tests

  • Relevant local toxicity studies with proposed route of clinical application

  • Allergenicity or Hypersensitivity tests

  • Photo-allergy or dermal photo-toxicity test

For Phase II Clinical Trials:

  • Summary of all the non-clinical safety data (as specified in phase I)

  • 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

For Phase III Clinical Trials:

  • Summary of all the non-clinical safety data submitted while obtaining the permissions for Phase I and II trials.

  • 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

  • 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:

  • A summary of all the non-clinical safety data 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)

CliniExperts can be your partner to develop strategic, flexible approaches to maximize safety and efficiency and make data-driven decisions for every study. Our functional and therapeutic expertise spans a broad range of indications. CliniExperts provide full spectrum services for the following local and global clinical trials:

  • Phase I Trial

  • Phase II Trial

  • Phase III Trial

  • Phase IV Trial or Post Marketing Studies (PMS) (exclusively in India)

Summary

  • In India, recombinant DNA products are considered to be new products as per the New Drugs & Clinical Trial Rules, 2019 and therefore require the permission of the Central licensing authority for both import and production for marketing purposes.

  • As per the Biosafety Guidelines, the research work related to recombinant technology is overseen by the Department of Biotechnology through Institutional Biosafety Committees (IBSC) and Review Committee on Genetic Manipulation (RCGM).

References

  • New Drugs and Clinical Trials Rules, 2019, Ministry of Health & Fam. Welfare, Notification, G.S.R. 227(E), (March 19, 2019).

  • Khan S, Ullah MW, Siddique R, et al.Role of Recombinant DNA Technology to Improve Life. Int J Genomics. 2016;2016:2405954.



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Frequently Asked Questions

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?

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.

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.

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

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.

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.

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.

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.

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.

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.

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.


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