Stem Cells and Cell-Based Products

Stem cells are undifferentiated cells of the human body that are able to differentiate into any cell of an organism and have the ability of self-renewal. Based on the cell type/tissue of origin, stem cells are classified as Somatic Stem Cells and Pluripotent Stem Cells.


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Stem Cells and Cell-Based Products

Categorization of Research Involving Stem Cells

Stem cell research is broadly categorized in three major areas, based on the ethical and/or safety concerns regarding the source of stem cells and levels of manipulation:

  • Permissible

    – Research involving the establishment of new embryonic stem cell/induced pluripotent stem cell lines

  • Restrictive

    – Research involving human preimplantation embryos processed by in vitro fertilization (IVF)/intracytoplasmic sperm injection/somatic cell nuclear transfer to derive ESC lines

  • Prohibited

    – Research involving human germline gene therapy and reproductive cloning, in vitro studies of human embryos beyond 14 days of fertilization or formation of primitive streak, studies involving xenogeneic cells or hybrids, genome-modified embryos for developmental propagation, implantation of any type of processed human cells/embryos into uterus of humans/primates, or the development of chimeric gonadal cells.

In 2017, the Department of Biotechnology and the Indian Council of Medical Research released the National Guidelines for Stem Cell Research (NGSCR). As per the NGSCR, all clinical use of stem cells and their products needs to be supported by clinical trials to prove safety and efficacy, and require licenses for manufacture and sale.

For research involving stem cells, two levels of monitoring mechanism have been established: one at the national level focussing primarily on policy – the National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) and the other, the Institutional Committee of Stem Cell Research (IC-SCR) is a more self-regulatory system of review at the institutional level. It is mandatory for the IC-SCR to register with NAC-SCRT and submit periodic report on their scientific activities for effective functioning.

Clinical Trials Involving Stem Cells

Clinical trials undertaken with Stem Cell and Cell based Product come under the ambit of Central Drugs Standard Control Organisation (CDSCO). All sponsors /clinics/hospitals who intend to develop and utilise stem cells therapies have to meet the rigorous standards prescribed for clinical trials.

Like all new drugs, stem cell products should go through preclinical testing and clinical trials – Phase I- IV.

Preclinical testing

Preclinical testing would require prior approvals from IEC, Institutional Animal Ethics Committee (small animals), and Committee for the Purpose of Control and Supervision of Experiments on Animals (large/nonhuman primates).

Product testing must include safety, biodistribution (local and systemic), and immune rejection studies. Single- and repeated-dose toxicity studies should be performed in relevant animal models. The risk for tumorigenicity, genotoxicity, and developmental toxicity must be assessed on the intended clinical use.

Clinical Trials

for Stem Cell Products

Clinical trial for stem cell products requires prior clearances from IC-SCR, IEC, and CDSCO. The trial needs to be registered with the Clinical Trials Registry- India (CTRI). Any protocol amendments/deviations must have clearances from Institutional Committee for Stem Cell Research (ICSCR), Institutional Ethics Committee (IEC) and CDSCO. Any stem cell based product already approved and marketed outside India (or for concurrent clinical trial in India) will require approval of CDSCO after clearance from IC-SCR and IEC.

Sponsors intended to initiate a clinical trial for stem cell products shall submit application in Form CT-04 along with all other necessary documents to the Central Licencing Authority. Once satisfied with the submitted documents, the Central Licencing Authority shall grant the permission to conduct clinical trial in Form CT-06. For the review and approval of clinical trial applications, fixed timelines have been put down - 90 working days for global clinical trials and 30 working days for drugs being developed in India.

Follow-up of trial participants is required depending on nature of the experimental stem cell-based intervention and the persistence potential of cellular products. For each indication, a minimum of two years of post-trial follow-up is mandatory with respect to the safety data. Follow-up can be extended by one year or more depending on the type/source of the cells and the degree of their manipulation.

A separate Data Safety Monitoring Board (DSMB) should be established for clinical trial involving stem cells. All adverse events occurring during clinical trials must be reported to IEC, CDSCO, and NAC-SCRT through IC-SCR.

CliniExperts provide full spectrum services for the following types of Drug Clinical Trials:

  • Local Clinical Trial - Phase I Trial, Phase II Trial, Phase III Trial and Phase IV Trial or Post Marketing Studies (PMS) (exclusively in India)

  • Global Clinical Trial - Phase I Trial, Phase II Trial and Phase III Trial

Dealing with stem cells products can be daunting due to the numerous rules and strict regulatory pathways – Make Cliniexperts your partners to ease the process.

Procurement and Exchange of Stem Cells Products and Derivatives

The procurement of Stem Cells Products is strictly regulated to prevent misuse and commercialization of unproven stem-cell therapy. The major provisions related to procurement of Stem Cells Products are as follows:

  • Import of any type of Stem Cells Products mandates license from CDSCO as per the established regulations.

  • Clinical trials sponsored by multinationals, employing the cell products developed outside India, should have clearances from the regulatory authorities of the country of the origin and shall need prior approval from the CDSCO following clearance from both IC-SCR and IEC of the trial site.

  • Import of stem-cell lines for clinical trials and originating oversees requires import clearance from the CDSCO. For export of indigenously developed cell lines, IEC and IC-SCR clearances must be obtained and submitted along with the Material Transfer Agreement during the review of such research proposals.

Summary

  • All clinical use of stem cells and their products needs to be supported by clinical trials to prove safety and efficacy, and require licenses for manufacture and sale.

  • Like all new drugs, stem cell products should go through preclinical testing and clinical trials – Phase I- IV.

  • Clinical trial for stem cell products requires prior clearances from IC-SCR, IEC, and CDSCO. The trial needs to be registered with CTRI.

References

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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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