|Ahead of print publication
The National Guidelines for Stem Cell Research (2017): What academicians need to know?
Sandeep Lahiry1, Shouvik Choudhury1, Rajasree Sinha2, Suparna Chatterjee1
1 Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Pediatrics, Medical College and Hospital, Kolkata, West Bengal, India
Institute of Post-Graduate Medical Education and Research, 244 AJC Bose Road, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
| Abstract|| |
India recently updated its guidelines on stem cell research (SCR), the National Guidelines for Stem Cell Research 2017. It was drafted under a collaborative effort from the Indian Council of Medical Research and Department of Biotechnology. The new guidelines are a part of a continuous endeavor to tackle scientific, technical, as well as perceived challenges in the field of SCR. It seeks to facilitate safe, ethical, and regulated translational and clinical SCR by engaging all stakeholders proactively.
Keywords: Cellular therapy, clinical translation, clinical trials, India, stem cells
|How to cite this URL:|
Lahiry S, Choudhury S, Sinha R, Chatterjee S. The National Guidelines for Stem Cell Research (2017): What academicians need to know?. Perspect Clin Res [Epub ahead of print] [cited 2019 Sep 23]. Available from: http://www.picronline.org/preprintarticle.asp?id=257235
| Introduction|| |
India is one of the few countries to have formal guidelines on research involving stem-cell products and derivatives (SCPDs). While such efforts have been commended international community, significant concerns began to emerge from the mid-2000s over unproven stem-cell treatments being offered in clinics with apparently little by way of regulatory oversight. As a result, the requirements for carrying out stem cell research (SCR) were first outlined under the International Ethical Guidelines for Biomedical Research on Human Participants, published by the Indian Council of Medical Research (ICMR) in 2000 and later revised in 2006. However, their recommendations are nonbinding and controversial.
To ensure ethical and good-quality SCR, the ICMR released “draft guidelines for SCR/regulation” in 2002, which was elaborately worked upon along with the Department of Biotechnology (DBT), resulting in the formulation of “Guidelines for Stem Cell Research and Therapy (2007).” The 76-page document specified the ethical principles for SCR and recommended a process for formal committee approval of SCR activities and their periodic review/monitoring. It stipulated that the clinical use of stem cells was not permitted, and any use in clinical context (with the exception of already standardized use in autologous bone marrow transplantation and epithelial therapies for corneal disorders) must be the part of a clinical study, after due approval from the Institutional Committee for Stem Cell Research and Therapy (IC-SCRT), the relevant research ethics committee, and the Drugs Controller General of India (DCGI).
To encourage SCR, the Government of India focused on its policy on grants toward the infrastructure development and operational activities. In 2003, the Stem Cell Task Force was constituted, entrusted with the responsibility of evaluating project proposals, pushing the formulation of protocols, monitoring, and evaluating results. In fact, there was a proposal for “stem cell priority fund” with possibilities of including the ICMR, the Department of Science and Technology (DST), and the Defence Research and Development Organisation.
Consequently, in 2008, the Central Drugs Standard Control Organization (CDSCO) released a guidance document on submission requirements for new drug approvals for biotechnological/biological products, including SCPD. Later in 2010, the CDSCO constituted the Cellular Biology Based Therapeutic Drug Evaluation Committee to review cell therapy-based clinical trials in the country., Its formal recommendations were communicated in May 2011.
In 2012, the DCGI constituted a special division for stem cells in response to criticisms that it does not have any internal evaluation mechanism. The Government of India also set up a long-awaited National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT) to oversee and monitor activities in this field. Since the 2007 guidelines lacked statutory backing, many scholars had been recommending providing it legislative weight. Concerns/inputs from key stakeholders were invited and addressed, and the guidelines were updated as National Guidelines for Stem Cell Research (NGSCR) 2013. In 2014, the DCGI also announced that it would modify the Drugs and Cosmetics Act to treat “stem cells and cell-based products” as new drugs. In a nutshell, the 2013 guidelines were a landmark achievement, because, for the first time, it constituted the SCR in India as an object of governance. Moreover, it addressed complicated ethical, social, and legal issues involved SCR to a great extent.
Recently, on October 11, 2017, ICMR and DBT jointly updated the existing guidelines and released the NGSCR 2017. The underlying guiding philosophy of the document was to prevent the premature commercialization of unproven stem-cell therapies and generation of new knowledge based on the sound scientific rationale while addressing all ethical concerns. An important aspect of the new rule is that it clarifies the ambiguity over who has legal jurisdiction over the uses of stem cell.
[Table 1] provides an overview of the 2017 guidelines. Some major amendments in this guideline include mandatory registration of the Institutional Committee for Stem Cell Research and the Institutional Ethics Committee (IEC) with NAC-SCRT and CDSCO, respectively, undertaking clinical trials only at institutes with registered IC-SCR and IEC, conducting studies only at Good Manufacturing Practice (GMP)- and Good Laboratory Practice (GLP)-certified facilities and clinical research undertaken by medical professionals registered with the Medical Council of India (MCI) having an MCI-approved postgraduate qualification in the domain area of the specific trial. We further discuss some of the major provisions under the new rule.
| Ethical and Scientific Consideration|| |
Health, safety, and rights of the donor are of the utmost importance, and the following provisions in the new guidelines are committed to the same:
- Mandatory video consent (as per the CDSCO guidelines dated January 9, 2014 – Schedule Y)
- Screening for six major transmittable diseases (HIV-1 and 2, hepatitis B virus, hepatitis C virus, Treponema pallidum, human T-lymphotropic virus, and cytomegalovirus) or any other risk factors for genetic disorders
- Intellectual property rights of donated material will not vest with donor, but may be shared (to be mentioned in informed consent form). If commercialization brings any financial benefit, may be passed on to donor/community.
Key elaborations in manufacturing process and release criteria have been cited in the new guidelines, to ensure the safety and quality assurance:
- Cell processing and manufacturing stages to be compliant with requirements as per the Schedule M of Drugs and Cosmetics Act, 1940 and Rules, to ensure the rigor of quality control and quality assurance for product development
- SCPD can only be processed in a CDSCO-certified GLP and GMP facility (as per the Schedule L1 and M of Drugs and Cosmetics Act, 1940 and Rules, respectively)
- For preclinical studies on animals, all laboratories must obtain GLP certification from the DST. Institutes or laboratories must also obtain the National Accreditation Board for Testing and Calibration Laboratories accreditation, when processing SCPD for human use.
| Mechanism for Review and Oversight|| |
[Table 2] summarizes the regulatory framework under NGSCR 2017. Jurisdictional ambiguities over the governance of stem-cell therapy seem to have finally been resolved with the ICMR-DBT in the latest guidelines. Yet, even well-ordered statutory laws require mechanisms for enforcement. The process of reviewing and monitoring SCR will now be administered separately at institutional and national levels. The NAC-SCRT is to monitor research activities at the national level. The IC-SCR shall approve and monitor the SCR (basic and clinical) at the institutional level. It is mandatory for all the institutes and entities engaged in SCR to establish an IC-SCR and register the same with NAC-SCRT. The IC-SCR will provide periodic reports regarding the status of SCR to NAC-SCRT. The National Bioethics Committee has prepared the consent protocol for tissue collection for human SCR.
|Table 2: Regulatory framework as per the National Guidelines for Stem Cell Research 2017|
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| Categorization of Research Involving Stem Cells|| |
As per the new rule, SCR 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, which warrant additional review and monitoring as per the existing regulations, as follows:
- “ Permissible” – Research involving the establishment of new embryonic stem cell/induced pluripotent stem cell (iPSC) 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.
| Levels of Manipulation Involving Stem Cell Research|| |
Before any clinical application/transplantation/translational research, the SCPDs may undergo variable degree of in vitro or ex vivo processing that carries the risk of contamination and may also lead to alteration in their properties, which may vary according to the degree and type of manipulation. Thus, different levels of manipulation used for SCR have been defined along with necessary approvals required for the same:
- “Minimal” – Where the processing neither alters the number nor the biological characteristics, and function of the cells (or tissue) relating to their utility for reconstruction, repair, or replacement, for example, use of bone marrow/peripheral blood/umbilical cord blood (UCB)-derived mononuclear cells/bone marrow concentrate using any device by intravenous route
- “Substantial” – Ex vivo alteration in the cell population (enhancement or depletion of specific subsets), expansion, cryopreservation, or cytokine-based activation, but one that is not expected to result in alteration of cell characteristics and function, for example, the adipose tissue may be more than minimally manipulated if the processing alters the original relevant characteristics of the tissue relating to its utility for reconstruction, repair, or replacement
- “Major” – Genetic and epigenetic modification of stem cells, transient or permanent, or of cells propagated in culture leading to alteration not only in their numbers but also in biological characteristics and function, for example, transdifferentiation, transduction/transfection by retro/lentiviruses, or other gene delivery vehicles to achieve specific selection and expansion of cells of interest.
| Basic Research Involving Stem Cells|| |
The guidelines for undertaking basic research involving stem cells include:
- In vitro studies (which largely fall under “permissible” category) require prior approval of IEC and IC-SCR. Exemption: the studies involving established human stem-cell lines registered with the IC-SCR
- In vitro studies on preimplantation human embryos must be carried out within 14 days of fertilization or formation of primitive streak, whichever is earlier
- Derivation of new human embryonic stem cells (hESCs) or iPSC lines from human embryonic or somatic cells, respectively, shall adhere to the conditions for gamete, embryo, and somatic cell donation, and with prior approval of IC-SCR and IEC
- Uterine implantation (human/animal) of manipulated cells with the intent of developing a whole organism is prohibited.
| Exclusions|| |
It must be noted that, in line with the previous guidelines, the 2017 guidelines also exclude the research involving non-human SCPD. Further, the guidelines also do not apply to hematopoietic SCR, indicated or approved in the treatment of various hematological, immunological, and metabolic disorders. Protein-rich plasma and autologous chondrocyte/osteocytes implantation also do not fall under the purview of these guidelines, as they are categorized as “other cell-based applications” and not stem-cell transplantation.
| Translational Research Including Clinical Trials Involving Stem Cells|| |
The preclinical studies and clinical trials using SCPD, for repair or regeneration of damaged tissues and organs as well as other clinical applications in conditions, where use of stem cells has not yet reached the standard of medical care, must abide the following norms:
- Requires prior approvals from IEC (humans), 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.
- Requires prior clearances from IC-SCR, IEC, and CDSCO and must be registered with CTRI. Any protocol amendments/deviations must have clearances from IC-SCR, IEC, and CDSCO
- Follow-up period of minimum 2 years is mandatory
- Establishing Data Safety Monitoring Board is mandatory
- All adverse events occurring during clinical trials must be reported to IEC, CDSCO, and NAC-SCRT through IC-SCR
- Trial records must be maintained for a minimum of 15 years.
| Banking of Involving Stem Cell Products and Derivatives|| |
The new guideline says that UCB is a rich source of CD34+ hematopoietic and mesenchymal (stromal) stem cells. The use of UCB-derived hematopoietic stem cells (HSCs) for the treatment of various hematological and immunological disorders is currently well established, particularly where a human leukocyte antigen-matched sibling is not available. However, there is a paucity of public-funded UCB banks in India. On the other hand, several private banks have come up, that engage themselves in promotional advertising, offering storage of cord blood with the promise of future therapeutic use. Such advertisements are often misleading for the public and lack comprehensive and accurate information.
As of now, there is no scientific basis for the preservation of cord blood for future self-use, and this practice therefore raises ethical and social concerns. Hence, under the new rule, banking of UCB or hESC/iPSC lines is only permitted in institutions currently licensed by CDSCO. Accordingly, commercial banking of all other biological materials is not permitted until further notification. Such institutions, if involved in SCR, must constitute the IC-SCR (and register it with NAC-SCRT) and have a standard operating procedures (SOPs) for banking and release. Moreover, the biological materials can only be released to institutes with registered IC-SCR and IEC.
| Procurement and Exchange of Stem Cells Products and Derivatives|| |
The procurement of SCPD is strictly regulated under the new guidelines, to prevent misuse and commercialization of unproven stem-cell therapy. The major provisions are:
- Import of any type of SCPD requires 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
- All international collaborations require approvals from the respective funding agencies followed by the approval from the Health Ministry's Screening Committee as per the Government of India guidelines
- In situation involving a conflict (scientific and/or ethical) between the collaborators, the existing Indian guidelines, acts, and regulations shall prevail for the work to be carried out in India
- Biological material can be procured only from the institutions that have IEC. The IEC must ensure that the SOPs are in compliance with the guidelines
- Only IEC and IC-SCR shall review and approve the process of procurement. If cells/tissues have been developed utilizing the IVF method, clearance from the NAC-SCR is mandatory
- For procurement of fetal or placental tissue as a source of stem cells, termination of pregnancy must comply with all obligations under the Medical Termination of Pregnancy Act, 1971
- Import of stem-cell lines for basic research will not require No Objection Certificate, but those required for clinical trials and originating oversees require 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.
| Publicity and Malpractice|| |
The advertising and publicity of probable benefits of stem-cell therapy through any mode by clinicians are not permitted as per the Chapter 6 of the Indian Medical Council (Professional Conduct, Etiquette and Ethics) Regulation. The MCI and medical councils of respective states have been directed to initiate action on the erring clinicians for the violation of code of ethics prescribed by it either taking suo motu cognizance or acting on any complaint received by them. Moreover, the Drugs and Magical Remedies (Objectionable Advertisements) Act, 1954 also prohibits the misleading advertisements relating to drugs and magical remedies and mandates the Directorate General of Health Services and relevant state authorities to take necessary action for violation of this act.
Advertisement of treatment of several diseases as listed in Schedule J of Drugs and Cosmetics Act, 1940 and Rules therein and any advertisement that violates the code for self-regulation in advertising, as adopted by the Advertising Standards Council of India, is not permissible. Hence, the publicity claiming available cure for conditions using SCPD is strictly prohibited.
| Concerns|| |
Recently, the ICMR has objected to amendments proposed by the Ministry of Health and Family Welfare to the Drugs and Cosmetics Rules, 1945, on the regulation of stem-cell procedures. The proposed amendments were notified on April 4, 2018, with 45 days until May 20, 2018, given for objections and comments. The ICMR submitted its objections on April 29, 2018.
The amendments seek to exclude “minimally” manipulated stem cells, from being defined as new drugs. Such an amendment contradicts the 2017 guidelines and bypasses approval needs for clinical trials (from NAC-SCRT) for establishing the efficacy and safety before receiving the market approval. If passed, these amendments may legitimize the use of unproven stem-cell therapies in India.
Moreover, many commercial entities involved in UCB have asserted that people should have the right to preserve their biological materials for the future and questioned the new guidelines restricting commercial banking of biological materials. For instance, LifeCell, a Chennai-based company, has argued that “banking is mere storage – not utilization statement.” If utilization was a concern, restrictions on the release of stored stem cells could easily have been prescribed, which has not even been considered.”
| Conclusion|| |
The vacuum around stem-cell activity in India – being a vacuum in governance or bioethical behavior – has always been more problematic than a simple failure to adequately enforce the guidelines through statutory or nonstatutory means. Thus, there is a requirement of more clarity about the implications of the new rule, to be sought from the regulatory authorities. Moreover, the guidelines concerning SCR are ever evolving, and better provisions will always be required as per changing international standards. As of now, the current guideline is a significant step in this regard. It has tried to encompass the major government regulations, institutional oversight, and communications enclosing basic and translational SCR, largely catering to the regulatory ambiguity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Subjects. Indian Council of Medical Research; 2006. Available from: http://www.icmr.nic.in/ethical_guidelines.pdf
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Guidance for Industry on Submission of Clinical Trial Application for Evaluating Safety and Efficacy. CDSCO Doc No. CT/71108, Version 1. 1; 2008. Available: Available from: http://www.cdsco.nic.in
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[Table 1], [Table 2]