The guiding philosophy of the National Guidelines for Stem Cell Research jointly prepared by the Indian Council of Medical Research (ICMR) and the Department of Biotechnology (DBT) is to promote scientific and ethical stem cell research while preventing premature commercialization and potential exploitation of vulnerable patients.
The new guidelines which will provide ethical and scientific directions to scientists and clinicians working in the field of stem cell research in the country, reiterate that the general principles of biomedical research involving human participants shall also be applicable to all human stem cell research. The guidelines have been prepared to ensure that research with human stem cells is conducted in a responsible and ethical manner and complies with all regulatory requirements pertaining to biomedical research in general and of stem cell research in particular.
These guidelines apply to all stakeholders including individual researchers, organizations, sponsors, oversight/regulatory committees and any others associated with both basic and clinical research on all types of human stem cells and their derivatives. However, these guidelines do not apply to research using non-human stem cells or tissues. Further, they do not regulate the use of haematopoietic stem cells for treatment of various haematological, immunological and metabolic disorders which has already been established as a standard of medical care.
As per the guidelines, research is prohibited in research related to human germ line gene therapy and reproductive cloning; in vitro culture of intact human embryos, regardless of the method of their derivation, beyond 14 days of fertilization or formation of primitive streak, whichever is earlier; clinical trials involving transfer of xenogeneic cells into a human host (any clinical research on Xenogeneic-Human hybrids is also prohibited); research involving implantation of human embryos (generated by any means) into uterus after in vitro manipulation, at any stage of development, in humans or primates; and breeding of animals in which any type of human stem cells have been introduced at any stage of development, and are likely to contribute to gonadal cells.
The guidelines on stem cell research, still in its nascent stage, is of utmost importance as some clinicians have started exploiting hapless patients by offering unproven stem cell treatments prematurely. Such fraudulent practices had to be stopped urgently, while ensuring that scientifically designed and responsible research on stem cells is not hindered. It was under this background that the ICMR and DBT jointly released Guidelines for Stem Cell Research and Therapy, way back in 2007, which has now been revised to reflect new scientific and clinical findings that have significantly changed the scope of stem cell research and possible translation.
The present guidelines have retained the earlier classification of stem cell research into three categories, namely Permitted, Restricted and Prohibited categories; an additional layer of oversight, besides the Institutional Ethics Committee (IEC), in the form of Institutional Committee for Stem Cell Research (IC-SCR) and National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) has been introduced. This mechanism of additional review has been accepted by the scientific community in the country and the required NAC-SCRT has become operational. The role and functioning of these committees is being streamlined.
Prohibits research in germ line gene therapy
The guidelines prohibit stem cell research in several areas including the research related to human germ line gene therapy and reproductive cloning; and clinical trials involving transfer of xenogeneic cells into a human host.
As per the guidelines, in the current state of scientific and technological understanding, research in stem cells is prohibited in areas related to human germ line gene therapy and reproductive cloning; in vitro culture of intact human embryos, regardless of the method of their derivation, beyond 14 days of fertilization or formation of primitive streak, whichever is earlier; and clinical trials involving transfer of xenogeneic cells into a human host.
Besides, any clinical research on xenogeneic-human hybrids is also prohibited. Other areas of prohibition include research involving implantation of human embryos (generated by any means) into uterus after in vitro manipulation, at any stage of development, in humans or primates; and breeding of animals in which any type of human stem cells have been introduced at any stage of development, and are likely to contribute to gonadal cells.
Apart from this, the guidelines have restricted research in several areas including creation of a human zygote by IVF, SCNT or any other method with the specific aim of deriving ES cell line for any purpose. This shall require several parameters such as that the proposed research cannot be carried out with existing ES cell lines, or those that can be derived from spare embryos; minimum numbers of embryos/blastocysts required for this research are clearly defined; and research teams involved have appropriate expertise and training in derivation, characterization and culture of ESCs.
Clinical trials using cells derived from the differentiation of human ES or iPS cells, or any stem cell after major manipulation shall require approval of DCGI after obtaining approval from NAC-SCRT through IC-SCR and IEC. Clinical trials sponsored by multinationals, employing cell products developed outside India, will also need prior approval from DCGI through IC-SCR and IEC.
Besides, international collaborative research projects should get clearance from the respective funding agencies as per their established procedure e.g. Health Ministry’s Screening Committee (HMSC). The imports of biological materials for research and development is regulated by Government of India vide their notification (No. L./950/53/97-H1 (Pt.) dated Nov 19, 1997.
Import of ‘drugs’ (therapeutic products – including cells) requires license from the DCGI as per the regulations. Research involving introduction of human ES / iPS / SS cells into animals (including primates), at embryonic or foetal stages of development for studies on pattern of differentiation and integration of human cells into non-human animal tissues shall conform to the conditions that if there is a possibility that human stem cells could contribute in a major way to the development of brain or gonads of the recipient animal, the scientific justification for the experiments must be substantiated. Animals derived from these experiments shall not be allowed to breed; and such proposals would need approval of the NAC-SCRT for additional oversight and review through IAEC and IC-SCR.
Studies on chimeras where stem cells from two or more species are mixed at any stage of development viz embryonic, foetal or postnatal, for studies on pattern of development and differentiation would require prior approval of NAC-SCRT through IC-SCR and IAEC. Research in which the identity of the donors of blastocysts, gametes or somatic cells from which the human ES/iPS cells were derived is readily ascertainable or could become known to the investigator would also require prior approval of NAC-SCRT through IC-SCR and IEC.
Guidance document
The guidance document for regulatory approvals of stem cell and cell based products (SCCPs) issued by the Union health ministry will suggest a road map for regulation of stem cells and other cell based therapies being practised in the country. The rules and regulations in this document will apply to all organizations such as hospitals, private clinics, institutes, universities, tissue banks and companies who wish to obtain a license for the use of SCCPs for therapeutic purposes in India.
The ministry in June last year had formed an expert panel to suggest a road map for regulation of stem cells and other cell based therapies being practised in India. This guidance document is based on the recommendations of that committee and it is subsidiary to the amendments made in 2013 to the Drugs and Cosmetics Act (D&C Act), 1940 and the new rules proscribed thereunder.
This document describes the mandatory requirements to be administered by the government of India for development, manufacturing, and doing quality control of SCCPs for the purpose of their non-clinical and clinical usages. It addresses both autologous and allogeneic SCCPs. The document gives a detailed description of requirements related to non-clinical studies that are necessary to demonstrate proof of concept and define the pharmacological, safety and non-toxicological effects of SCCPs.
Descriptions on designing pharmacodynamic/pharmacokinetic studies i.e. dose finding clinical efficacy and safety studies are also available in which the pharmacovigilance aspects and the risk management plans have been given special consideration. The document will assist the DCGI/CDSCO in setting a road map to regulate the usage of SCCPs for regenerative medicine in India. It will also assist the stakeholders for regulatory submission.
This document will be in addition to other existing guidelines on SCCPs usage in India. The document is applicable only for the commercial usage of SCCPs in the prevention and treatment of human diseases and for doing clinical trials with SCCPs in India.
All institutions and investigators carrying out clinical trials and commercial usage of SCCPs, i.e. conducting a study in human subjects to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and/or efficacy of the said SCCP as per the amended provisions of the D&C Act, is required to obtain a license/ approval from the CDSCO.
The aim and scope of this document is to define the role of CDSCO in regulating the manufacturing, licensing and usage of SCCPs; to describe the various categories of licensing/approvals for facilities, clinical trials and protocols for SCCP usage for specific indications; to provide guidance to the applicants for isolation, characterization, culturing, processing, manufacturing, quality control, labelling and distribution of SCCPs; and to provide guidance for compliance, with all the regulatory requirements, to carry out clinical trials with SCCPs.
Experts omit 'Therapy' from guidelines
However the guidelines have omitted the word 'Therapy' from the title of the Guidelines to emphasize the fact that stem cells are still not a part of standard of care and hence there can be no guidelines for therapy until its efficacy is proven.
The drafting committee of the guidelines felt that the guidelines are intended to cover only stem cell research, both basic and translational, and not therapy. It has been made clear in these guidelines that any stem cell use in patients, other than that for hematopoietic stem cell reconstitution for approved indications, is investigational at present.
Accordingly, any stem cell use in patients must only be done within the purview of an approved and monitored clinical trial with the intent to advance science and medicine, and not offering it as therapy. In accordance with this stringent definition, every use of stem cells in patients outside an approved clinical trial shall be considered as malpractice.
The committee also felt that this clear definition will serve to curb the malpractice of stem cell “therapy” being offered as a new tool for curing untreatable diseases.
Earlier in the year 2007, the ICMR and the DBT had jointly released the draft 'Guidelines for Stem Cell Research and Therapy', which has now been revised by an expert drafting committee to reflect new scientific and clinical findings that have significantly changed the scope of stem cell research and possible translation. The committee has now dropped the word 'Therapy' as it felt that the stem cells are still not a part of standard of care and hence there can be no guidelines for therapy until its efficacy is proven.
However, the present guidelines have retained the earlier classification of stem cell research into three categories, namely Permitted, Restricted and Prohibited categories.
Functions of NAC-SCRT and IC-SCR listed
The guidelines have elaborated about the functions and composition of the National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) and the Institutional Committee for Stem Cell Research (IC-SCR).
According to the guidelines, the NAC-SCRT will be a multidisciplinary committee with a secretariat. It will have two main functions of general oversight of the field of stem cell research and therapy in India and formulation of policy related to it; and review of specific controversial or ethically sensitive research and proposals for therapeutic use of stem cells/differentiated derivatives.
There should be at least 15 members in the committee. The committee composition will include chairman, alternative chairman, member secretary, nominees from DBT, DST, CSIR, DSIR, ICMR, DCGI, DAE, MCI,
DGHS and biomedical experts drawn from appropriate disciplines such as haematology, pharmacology, immunology, cell biology, microbiology, genetics, developmental biology, clinical medicine and nursing. Other members would include a legal expert, social scientist, and women’s representative. In addition consultants/experts could be consulted / invited for specific topics and advice.
The committee has the responsibility to examine scientific, technical, ethical, legal and social issues in the area of stem cell or their derivatives based research and therapy. It has to maintain a register of all institutions involved in any type of stem cell research and therapy including details of their IC-SCR. Besides, it has to review annual reports of these IC-SCRs for compliance with national guidelines and ethical practices. Use of chimeric tissue for research shall be reviewed by it and will review and update the national guidelines for stem cell research and therapy periodically, considering scientific developments at the national or international levels.
The NAC-SCRT has to respond to queries/representations from all the stakeholders in the community (investigators, industry, R&D institutions, entrepreneurs, media, patient groups, govt agencies etc). It also has to respond to controversial issues raised /received from NGOs, patients, individuals etc., and diverted to NAC-SCRT by other agencies like ICMR, DBT, DST, MCI, DCGI, etc.
Moreover, the committee has to monitor any unethical practices related to stem cell research and/or therapy being followed at any organization or any individual and bring them to the notice of relevant authorities.
The IC-SCR will be a multidisciplinary body at the institutional level. Institutions involved in stem cell research are required to set-up a special review board to oversee research (basic science and clinical) in this field. It should be registered with the NAC-SCRT and should provide overview of all issues related to stem cell research at the institutional level.
The IC-SCR has to review and approve the scientific merit of research protocols and will function in compliance with all relevant regulations and guidelines. It should maintain a register of hES cell research conducted at the institution and hES cell lines derived or imported by institutional investigators and notify NAC-SCRT. It has to facilitate training of investigators involved in stem cell research and submit annual report to NAC-SCRT.
There should be at least seven members in the committee and it should include representatives of the public and persons with expertise in clinical medicine, developmental biology, stem cell research, molecular biology, assisted reproduction technology, and ethical and legal issues in stem cell research. It should have the resources to coordinate reviews of various protocols.
The chairman of the IC-SCR must have relevant medical/scientific background and be from outside the institute with no conflict of interest (COI). Members from law, ethics and social sciences must be from outside the institute and with no COI. Stem cell experts, if possible from outside the institute, can be the scientific/technical members. Member Secretary can be from the same institute and must not have any COI. Any member having COI with a particular proposal must abstain from the discussion and decision making process of that proposal.
IC-SCR members must be familiar with the current bioethical guidelines and guidelines for stem cell research.
What the future holds
According to experts, stem cell research holds great promise for improving human health by restoring cellular and organ function damaged by degeneration and various injuries. At the same time it also raises several scientific, ethical and social issues in the development of such applications. Apart from challenges of using the right kind of stem cells in the most appropriate way for a particular disease, there are also issues related to the use of human embryos to create human embryonic stem (hES) cell lines, potential for commoditization of human tissues and cells with inherent danger of exploitation of underprivileged people, and challenges related to prevention of human germ-line engineering and reproductive cloning.
There are also potential dangers of tumourigenicity with use of these cells keeping in view their potential for unlimited proliferation and possible introduction of genomic changes during in-vitro manipulations also limitations related to immunological tissue incompatibility between individuals. Research in this field, therefore, needs to be regulated with special attention to these issues.