WEBVTT Kind: captions Language: en 00:00:28.960 --> 00:00:35.840 Hello again. So, in today's lecture, we are going to look into some basics provisions 00:00:35.840 --> 00:00:43.120 related to Stem Cell Research in India. So, far we discussed what are the ethical consideration or 00:00:43.120 --> 00:00:49.440 challenges with respect to the embryonic stem cell research, a lot of ethical consideration whether 00:00:49.440 --> 00:00:55.920 you say when it is derived from the human embryo or when it is a induced pluripotent cell or even 00:00:55.920 --> 00:01:03.040 when it is a cloning procedure, where the somatic nuclear has been transfused to a oocyte. 00:01:04.080 --> 00:01:13.360 So, in India, the stem cells and the derivatives are categorized under the definition of the 'Drug' 00:01:13.360 --> 00:01:21.760 as per the Drugs and Cosmetic Act of 1940 and they are categorized as 'Investigational New Drug, IND' 00:01:21.760 --> 00:01:27.440 or 'Investigational New Entity or INE' when they are used for the clinical applications. 00:01:28.560 --> 00:01:33.920 Because we have already discussed the stem cell has a lot of potential because of its ability to 00:01:33.920 --> 00:01:40.480 differentiate into specific types of the cells or the tissue. So, these are popularly used for 00:01:41.600 --> 00:01:47.120 this regenerative therapy. But in India, so far the commercial use of the 00:01:47.120 --> 00:01:52.640 stem cells as the element of therapy is prohibited because it is more like a individual treatment 00:01:52.640 --> 00:01:59.280 depending on the persons need those cells are are programmed and accordingly, it develops 00:01:59.280 --> 00:02:08.320 and functions. So, it is emphasized that no stem cells administration to the human is permissible 00:02:08.320 --> 00:02:13.920 outside the purview of the clinical trial. So, in India, it is more an ongoing area of 00:02:13.920 --> 00:02:19.760 development. So, it is so far like a sort of a clinical trial process, 00:02:19.760 --> 00:02:30.320 where it is studied and being developed so far. So, as we have seen in the code of ethics or for 00:02:30.320 --> 00:02:35.440 the clinical trial regulation, so there are also principles of the bioethics and the regulations 00:02:35.440 --> 00:02:41.040 applicable to this kind of the stem cell research, even before initiating the clinical trials. 00:02:44.240 --> 00:02:51.680 So, if we see in India, the there are so like in 2007, we have the first guideline specific 00:02:51.680 --> 00:02:56.720 to the stem cell research and therapy. So, that is known as the guidelines for stem cell research 00:02:56.720 --> 00:03:03.600 and therapy and then, we have this national guidelines for stem cell research of 2013, 00:03:03.600 --> 00:03:10.800 which is again for revised in the year 2017. So, these guidelines are being developed by the 00:03:10.800 --> 00:03:16.240 department of biotechnology in collaboration with the Indian council of Medical Research. So, as an 00:03:17.200 --> 00:03:24.480 when we are progressing or developing with respect to the new standards of standards or process for 00:03:24.480 --> 00:03:31.440 the stem cell research and there has been changes in the guidelines as well. So, these are the 00:03:31.440 --> 00:03:37.200 current guidelines available in our country for the research purposes of the stem cells. 00:03:39.840 --> 00:03:44.000 So, as I mentioned the it is the stem cell products are 00:03:44.000 --> 00:03:49.680 considered as a kind of a drug under the Central Drug Standard Control Organization of the India. 00:03:50.480 --> 00:03:56.000 So, when a drug is being used by certain human, for human treatment it is used 00:03:56.720 --> 00:04:05.840 for or by the humans, so it has to be properly evaluated. So, in the year 2010, 00:04:05.840 --> 00:04:10.720 there was a committee named as the Cell Biology Based Therapeutic Drug Evaluation Committee, 00:04:10.720 --> 00:04:17.920 CBBTDEC which is basically responsible to review the cell therapy based clinical trials. 00:04:19.760 --> 00:04:26.240 So, after that, it was again evaluated by some technical committee and finally, the approval 00:04:26.240 --> 00:04:33.760 was given by the DCGI. But very recently the Apex Committee of the CDSCO has recommended that the 00:04:33.760 --> 00:04:39.520 Investigational New Drug proposals means the drugs under the drugs which are under investigation 00:04:39.520 --> 00:04:46.240 means under the clinical trials should be evaluated by this CB, this committee Cell Biology 00:04:46.240 --> 00:04:51.520 Based Therapeutic Drug Evaluation Committee. And it need not took place to the technical 00:04:51.520 --> 00:04:57.120 committee before or the further approval. It may be directly placed before the Apex committee, 00:04:57.120 --> 00:05:02.400 once it is reviewed by the appropriate Cell Based Therapeutic Drug Evaluation Committee. 00:05:04.480 --> 00:05:12.400 So, the as per the national guidelines for the stem cell research of 2013, it for the first 00:05:12.400 --> 00:05:18.480 time mandated that all the institutions which are carrying out research on the area of the human 00:05:18.480 --> 00:05:24.800 stem cells must constitute an institutional committee for the stem cell research. 00:05:25.440 --> 00:05:29.920 Like we have this ethical committee for various animal research or the human research, 00:05:29.920 --> 00:05:35.680 so similarly, for the stem cell research also, there is a mandatory constitution of the committee 00:05:35.680 --> 00:05:41.200 which is known as the Institutional Committee for the Stem Cell Research. And it has to be 00:05:41.200 --> 00:05:46.000 registered with the National Apex Committee for the Stem Cell Research and the Therapy 00:05:46.560 --> 00:05:51.520 and this kind of registration or the constitution and the registration is 00:05:51.520 --> 00:05:56.480 mandatory for all the institutes, who are involved in stem cells research. 00:05:58.640 --> 00:06:05.760 So, now, as I said, we are in the process of developing or researching and more 00:06:05.760 --> 00:06:10.800 in the area of the stem cells. So, here I would like you to present briefly 00:06:10.800 --> 00:06:15.840 the scope and the purpose of this guideline and what are the important points the guidelines 00:06:16.560 --> 00:06:24.480 specifies. So, basically if you see the stem cell research guideline of 2017, this guideline 00:06:26.000 --> 00:06:32.560 is particularly for the human stem cells. So, this does not apply to the research using the 00:06:32.560 --> 00:06:37.520 non-human stem cells and their derivatives. It is particularly for the human stem cells. 00:06:38.640 --> 00:06:45.120 And further, this guideline also do not apply to the use of the hematopoietic stem cells, 00:06:45.120 --> 00:06:50.160 which are used generally for the treatment of the various hematological or immunological or 00:06:50.160 --> 00:06:55.840 metabolic disorders. Because already these kind of hematopoietic stem cells are well established 00:06:55.840 --> 00:07:00.320 in the standard medical care medical care practices across countries. 00:07:01.520 --> 00:07:08.000 There are some products which are kept outside the purview of this guideline 00:07:08.000 --> 00:07:14.240 are the protein rich plasma or the autologous chondrocytes or the osteocytes implantation. So, 00:07:14.240 --> 00:07:21.360 they are not covered under this guideline. And this guideline is particularly designed in a 00:07:21.360 --> 00:07:26.960 way that it has kept in mind the unique provision for the stem cells because the stem cells ability 00:07:26.960 --> 00:07:34.480 to proliferate unlimitedly and differentiate into different cells of the germline or different cells 00:07:34.480 --> 00:07:40.400 which might have oncogenic or the cancerous property or it may lead to the unrecognized 00:07:40.400 --> 00:07:46.720 toxicity or the safety issues and possibly, possible involvement with the implantation 00:07:46.720 --> 00:07:50.720 stages of the human development. So, we do not know much about 00:07:50.720 --> 00:07:55.120 the consequences of such kind of the research. So, the guidelines has been 00:07:55.120 --> 00:08:00.000 formulated in such a way that whether whenever a research with the stem cells is being carried out, 00:08:00.000 --> 00:08:05.680 it should take care of all the points which may be a point of concern at the later stage. 00:08:08.640 --> 00:08:16.240 So, basically the 2017 guideline focuses on the monitoring mechanism and the regulatory 00:08:16.240 --> 00:08:21.600 pathway for the basic clinical research and the product development based on the 00:08:21.600 --> 00:08:25.760 categories of the research and level of manipulation of the stem cells, which we 00:08:25.760 --> 00:08:33.120 will discuss little bit later in this class. And then, it also tries to identify and solve 00:08:33.120 --> 00:08:38.720 the issue related to the procurements of the gametes, embryos or the somatic cells for 00:08:38.720 --> 00:08:43.840 the derivation and the propagation of the stem cell lines, their banking procedures and their 00:08:44.400 --> 00:08:48.800 distribution. Because we have seen how there might be an ethical issue, while when you are 00:08:48.800 --> 00:08:53.840 procuring or when you are deriving the stem cells. So, all those points are also being covered here. 00:08:54.560 --> 00:09:00.240 The other important areas such as the international collaboration in the human stem cell 00:09:00.240 --> 00:09:06.720 research or the exchange of the cell lines or for the education or the advertisement purpose. So, 00:09:06.720 --> 00:09:13.040 all these issues are also being dealt with the in this current guideline of the 2017. 00:09:16.160 --> 00:09:22.000 One of the important part of this stem cell research is the guideline is the 00:09:22.000 --> 00:09:27.440 ethical consideration. So, we have seen starting from the Nuremberg code to other 00:09:28.480 --> 00:09:34.880 code of ethics for the human clinical trial, this needed a separate ethical consideration because 00:09:35.520 --> 00:09:40.560 the health or the safety of the rights of the donor, particularly in the stem cells 00:09:40.560 --> 00:09:44.640 is little bit different from the normal or other kind of the biomedical research. 00:09:45.520 --> 00:09:51.120 So, prior to the procurement of the biological material for the isolation of the stem cells, 00:09:51.120 --> 00:09:56.720 it is mandatory to obtain the informed consent from the voluntary donors. 00:09:56.720 --> 00:10:05.200 So, now inform consent means basically a process where the donor is made aware about the usage, 00:10:05.200 --> 00:10:10.960 the implications and other related aspect of the whole scientific research and whatever 00:10:10.960 --> 00:10:16.880 implication, it may have on his or her health. So, everything has to be properly explained to 00:10:16.880 --> 00:10:26.560 the donor and now, as per the revised guideline of 2014, the informed consent has to be in a 00:10:26.560 --> 00:10:33.600 video record. So, a video consent as per the guideline of the CDSCO should be recorded and 00:10:33.600 --> 00:10:38.960 it has not only the written consent; but it is a recorded consent, where it has to be properly 00:10:40.240 --> 00:10:45.680 conveyed to the donor that what are the issues or what implication, it may have on his health, on 00:10:45.680 --> 00:10:52.400 his social well-being or other related aspects. While the confidentiality and privacy are two 00:10:52.400 --> 00:11:00.400 important things related to any research, so the research ensures that the confidentiality 00:11:00.400 --> 00:11:05.360 and privacy of the donor as well as donor's identity has to be maintained 00:11:06.240 --> 00:11:14.320 all the way. And it also emphasizes the health and safety as well as the rights of the donor. 00:11:14.320 --> 00:11:22.800 So, like the donor must be made aware like what are the need of screening of the transmittable 00:11:22.800 --> 00:11:30.640 diseases and what kind of risk, he may be exposed to like during the collection process of the 00:11:30.640 --> 00:11:35.280 organs or the tissues or the cell, whether it is a ovum or a bone marrow etc. 00:11:35.280 --> 00:11:40.080 and what may be the other health risk associated with the local or the general anesthesia 00:11:41.360 --> 00:11:49.120 should be explained to the voluntary donor and it should be voluntary in nature. You cannot compel 00:11:49.120 --> 00:11:56.560 anyone to donate this kind of stem cells. And the donor should be informed under the 00:11:56.560 --> 00:12:05.200 exceptional exceptional circumstances that if required the donated material may be 00:12:05.200 --> 00:12:10.960 the cell lines or the products, they may be banked or shared with the other scientific 00:12:10.960 --> 00:12:16.240 groups for further studies and that consent must be taken prior. 00:12:17.920 --> 00:12:24.800 So, the cell lines and the products may also go genetic manipulation and like since they have 00:12:24.800 --> 00:12:29.680 the potential for the commercialization. So, the intellectual property right issues with respect 00:12:29.680 --> 00:12:36.800 to the biological material must be clarified and the once, it is donated generally the IPR 00:12:36.800 --> 00:12:45.440 does not vest with the donor. So, that issue that points must be made clear before it is donated or 00:12:45.440 --> 00:12:50.800 during the informed consent procedure. But again, if there are certain commercial benefit 00:12:50.800 --> 00:12:59.840 or a financial profit is achieved. So, again, the provision related to same whether or not 00:12:59.840 --> 00:13:06.880 the commercialization aspect or the profits should be shared with the community or the 00:13:06.880 --> 00:13:11.120 donor or possibility of that must also be discussed with the donor. 00:13:11.120 --> 00:13:18.080 So, these are because you know even though this does not sound important at that point 00:13:18.080 --> 00:13:22.320 when it is collected, but it might have a greater implication at the later stage. We 00:13:22.320 --> 00:13:26.480 will discuss more about that issue in the upcoming classes how the IPR issues or the 00:13:26.480 --> 00:13:33.840 benefit sharing issues might be a problem. So, that has to be taken care of at the earliest. 00:13:34.800 --> 00:13:40.160 So, the ethical consideration, rights of the donor that is one of the critical part of the 00:13:40.160 --> 00:13:45.360 regulation; other apart from that there are scientific consideration because you know the 00:13:45.360 --> 00:13:50.720 stem cells are very vulnerable to changes. They are the cells continuously dividing. So, when it 00:13:50.720 --> 00:13:56.480 is stored in an external condition or appropriate condition, sometimes there might be some changes. 00:13:56.480 --> 00:14:01.040 So, proper monitoring or identification of the proper cell line is also important. 00:14:01.040 --> 00:14:08.000 And so, the how these cells are being processed, how the enrichment 00:14:08.000 --> 00:14:14.320 or other in vitro expansion process are needed that has to be properly tested and evaluated 00:14:14.880 --> 00:14:18.640 and it is mandatory that the stem cells and their product 00:14:19.520 --> 00:14:25.360 are processed in a facility that is GMP certified, good Manufacturing Practices 00:14:25.360 --> 00:14:31.440 like it has been prescribed in our Drugs Act. Like what should be the GMP standard for in a 00:14:31.440 --> 00:14:37.520 premises, where the stem cell research can be carried out so and how where it is being stored, 00:14:37.520 --> 00:14:42.160 how where the experiments are being conducted. So, all the standards are 00:14:42.160 --> 00:14:46.800 already being provided in our Drugs Act. So, that has to be maintained properly. 00:14:49.280 --> 00:14:54.560 And when it comes to the pluripotent stem cell, it has further risk because again 00:14:54.560 --> 00:15:01.120 their inherent ability to differentiate into cells of all the three germs layer. So, they 00:15:01.120 --> 00:15:06.640 are more prone to the mutation if they are maintained for the prolonged period of the time 00:15:07.200 --> 00:15:15.280 and you know so, the human embryonic stem cell can grow into 200 different types of the cell. So, 00:15:15.280 --> 00:15:20.160 you can understand the processes, the the biological processes which might take place. 00:15:20.160 --> 00:15:26.080 So, the chances of mutation is very high there and it may 00:15:26.080 --> 00:15:29.840 grow and differentiate into inappropriate cellular phenotypes which is not required, 00:15:29.840 --> 00:15:35.760 if it is stored for a long period of the time and it may lead to ,malign or many malignant 00:15:36.880 --> 00:15:40.720 outgrowth or the cancerous outgrowth or it may sometimes fail to mature. 00:15:40.720 --> 00:15:46.320 So, there may be lot of issues when the stem cells are stored or preserved for a long period 00:15:46.320 --> 00:15:51.360 of the time. So, care must be take in to ensure that whatever the stem cells are being used, 00:15:51.360 --> 00:15:56.560 they are at the proper state so that later on their effectiveness can be properly evaluated. 00:15:59.040 --> 00:16:04.160 And for the cryopreserved or otherwise stored product, possible impact of the short or long 00:16:04.160 --> 00:16:08.560 term storage on the product viability and potency must be determined. And 00:16:10.080 --> 00:16:16.320 the quality control and quality assurance process for the stem cells are much more rigorous and 00:16:16.320 --> 00:16:23.600 again, the requirements of the Schedule M of the Drugs and Cosmetic Act must be maintained. And 00:16:23.600 --> 00:16:28.880 it is mandatory for all the clinical trials happening with respect to the stem cells. 00:16:30.400 --> 00:16:37.120 So, when the stem cells is received and then again, it is released? So it has to be tested 00:16:37.120 --> 00:16:43.040 with respect to certain criteria like the cell viability, what is the final cell population 00:16:43.040 --> 00:16:47.840 which can be determined by various marker process, stability and the other requirements. 00:16:47.840 --> 00:16:54.800 So, these are more of scientific requirement which needs to be tested and properly documented 00:16:54.800 --> 00:17:00.160 before the stem cells are being used. All the standard operating procedure must be 00:17:00.960 --> 00:17:07.520 properly maintained and desired standards of the identity, purity or the safety or traceability of 00:17:07.520 --> 00:17:14.480 the product must be maintained. So, that portion has also been emphasized in the guideline. 00:17:16.000 --> 00:17:22.800 And then, it also says something about the evidence based application, where like what 00:17:22.800 --> 00:17:27.200 is the clinical efficacy of the stem cells in a particular disease state and their use 00:17:29.920 --> 00:17:35.360 in appropriate indications? So, though the hematopoietic stem cells has been already been 00:17:35.360 --> 00:17:40.800 proven, for other it has been not it has not been proved at as yet. 00:17:40.800 --> 00:17:48.160 So, for every trial, the protocol must be designed carefully and it mentions that the 00:17:48.160 --> 00:17:52.880 follow up period for this kind of clinical trials must should be at least for 2 years; 00:17:53.520 --> 00:17:58.320 even it can be longer depending on the type or the source of the cell used 00:17:58.880 --> 00:18:01.680 or age and gender of the recipient. And 00:18:03.600 --> 00:18:09.040 it also says that the human participants enrolled for the clinical trial should not be charged and 00:18:09.040 --> 00:18:14.800 the procedure related to the trial including the hospital stay and other investigation process, 00:18:14.800 --> 00:18:19.200 laboratory investigation and the cost related to that should be borne by the 00:18:19.840 --> 00:18:25.040 investigator or the company who is carrying out those kind of research, but not the participant. 00:18:27.520 --> 00:18:33.520 Then, the intellectual property or the various IP whether you say patents or trademarks or other 00:18:33.520 --> 00:18:40.320 things, so the outcome of the research on the stem cells or stem cell lines or the application of the 00:18:40.320 --> 00:18:46.560 product and the derivatives might have commercial value and so, what would be the probable or best 00:18:46.560 --> 00:18:52.080 option for the sharing of such IPR should be in indicated in the informed consent form. 00:18:54.400 --> 00:18:58.480 So, apart from the scientific, ethical and safety concerns which are 00:18:59.760 --> 00:19:06.480 described in the guideline, there they also gives you a mechanism for the review and the oversight. 00:19:06.480 --> 00:19:13.120 So, already I have discussed in the initial slides that , there are two compulsory constitution of 00:19:13.120 --> 00:19:17.200 a body with the National Apex Committee on the Stem Cell Research and Therapy. 00:19:17.840 --> 00:19:23.520 So, that is the body by the CDSCO. So, this National Apex Committee on the Stem 00:19:23.520 --> 00:19:30.000 Cell Research and Therapy which is basically established as a body which will monitor and 00:19:30.000 --> 00:19:34.880 oversee the research activities at the national level and it lays down the basic guideline 00:19:34.880 --> 00:19:40.640 for the clinical and the basic research. And at the institutional level, so we have the 00:19:41.280 --> 00:19:46.320 Institutional Committee for the Stem Cell Research which basically approves and monitors the stem 00:19:46.320 --> 00:19:54.720 cell research at the institutional level. So, these committees basically ensure that the review, 00:19:54.720 --> 00:20:00.000 approval and the monitoring process for the research projects related to the stem cells 00:20:00.000 --> 00:20:06.720 should are being carried out with the compliance of the guidelines and 00:20:08.240 --> 00:20:13.440 the registration with the NAC SCRT is mandatory for the institutional committees. 00:20:13.440 --> 00:20:17.520 So, these are the two committees which basically review the whole process; then finally, 00:20:17.520 --> 00:20:22.720 we have the CDSCO or the Central Drug Standard Control Organization which gives the final 00:20:22.720 --> 00:20:31.040 approval for the clinical trial or related process for the stem cells. So, now, depending on the 00:20:31.040 --> 00:20:37.360 level of manipulation on the stem cells, the permissions or the approval process depends. 00:20:37.360 --> 00:20:40.480 So, there are different levels of manipulations. There may be minimal manipulation, 00:20:40.480 --> 00:20:45.600 there may be moderate manipulation or there may be severe manipulation. So, if there is minimal 00:20:45.600 --> 00:20:53.600 manipulation, though the clinical application of such cell requires the permission from the IC-SCR, 00:20:53.600 --> 00:20:58.880 Institutional Ethics Committee and the CDSCO approval and if it is meant for 00:20:58.880 --> 00:21:04.720 homologous use for unapproved indication, means in the same individual or the body. 00:21:05.440 --> 00:21:12.960 For example, the use of this bone marrow or the umbilical cord blood derived mononuclear cells 00:21:12.960 --> 00:21:17.280 or bone marrow concentration are using the device by the intravenous route for 00:21:17.280 --> 00:21:22.320 the clinical indication. So, it requires the permission from the Institutional Committee, 00:21:22.320 --> 00:21:24.800 Institutional Ethics Committee and the CDSCO. 00:21:27.280 --> 00:21:35.120 And if the minimally manipulated cells are used for the non-homologous purpose, approval from the 00:21:35.120 --> 00:21:40.880 CDSCO is mandatory apart from this institutional committee before even initiating the clinical 00:21:40.880 --> 00:21:49.040 application process. So, this is one example, where the use of the bone marrow or the peripheral 00:21:49.040 --> 00:21:56.560 blood or the umbilical cord blood derived mononuclear cells, if used by any device by any 00:21:56.560 --> 00:22:01.840 route of administration other than the intravenous or the neurological, musculoskeletal or 00:22:01.840 --> 00:22:10.240 cardiovascular for the cardiovascular diseases. So, if it is for homologous purpose, there is 00:22:10.240 --> 00:22:15.680 certain kind of permission requirement and if it is for the non homologous purposes, then also we 00:22:15.680 --> 00:22:22.320 need a different before the clinical application, we need the permission from the CDSCO. 00:22:24.000 --> 00:22:27.840 So, what may constitute a minimal manipulation, when the like 00:22:27.840 --> 00:22:33.280 cells are tissue cells or the tissues are removed and implanted into the same individual 00:22:33.280 --> 00:22:38.240 during the same surgical procedure within a single operation and you should not undergo 00:22:38.240 --> 00:22:42.960 the processing steps beyond centrifugation, rinsing, cleaning or the sizing. So, then it 00:22:42.960 --> 00:22:48.320 is considered as the minimal manipulation. And then, there is another process called 00:22:48.320 --> 00:22:54.720 the substantial manipulation, where the clinical trials using the cells that have gone 00:22:54.720 --> 00:23:00.880 more than minimal manipulation requires the approval from the CDSCO, only after obtaining 00:23:00.880 --> 00:23:04.400 the clearances from the Institutional Committee and the Ethics Committee. 00:23:04.400 --> 00:23:11.600 In some cases, these cells are modified whatever they are minimally, 00:23:11.600 --> 00:23:17.600 they are more than minimally manipulated before the use of the same in the body. So, in that case, 00:23:17.600 --> 00:23:21.840 the nature of the permission or the sequence of the permission becomes little bit different. 00:23:24.480 --> 00:23:30.640 And major manipulation basically refers to the genetic and the epigenetic modification 00:23:30.640 --> 00:23:39.360 of the stem cells which may be a transient or the permanent manipulation and it leads 00:23:39.360 --> 00:23:44.320 to the alteration not only in their numbers, but also the biological character or the function. 00:23:45.520 --> 00:23:53.280 So, here like the process of regulating the lineage specific to different human embryonic 00:23:53.280 --> 00:24:00.000 stem cells or induced pluripotent stem cells for the desired cell type are coming under 00:24:00.000 --> 00:24:06.560 the purview of this major manipulation, where the trans differentiation or the 00:24:07.600 --> 00:24:12.800 use of various retro or lentiviruses or other gene delivery vehicles to achieve the selection 00:24:12.800 --> 00:24:16.880 and expansion of the cell of the interest. So, this is more complicated process. 00:24:16.880 --> 00:24:26.320 So, substantial manipulation, the level of permission is again like in each step, 00:24:26.320 --> 00:24:32.480 you need to have the permission and final CDSCOs approval is needed before this kind of 00:24:32.480 --> 00:24:35.200 applications can be carried out in the human subjects. 00:24:37.360 --> 00:24:43.600 So, if you see the total guideline, the guideline has divided the whole stem cell research into two 00:24:43.600 --> 00:24:52.560 criteria; first permissible area of the research and it has again in vitro studies using the stem 00:24:52.560 --> 00:24:58.400 cells isolated from the tissues, which can be done with the prior approval of the IC and the 00:24:58.400 --> 00:25:05.040 IC-SSR and the Institutional Ethics Committee. So, in the permissible area of the research, 00:25:07.840 --> 00:25:15.520 like you have to provide the appropriate plan or the design of the experiment and then only, it is 00:25:15.520 --> 00:25:21.920 allowed and you can carry out with the respective permissions from the respective committees. 00:25:22.720 --> 00:25:29.120 For example, the establishment of the new human embryonic stem cell lines from the spare embryos 00:25:29.120 --> 00:25:35.360 or the induced pluripotent cell embryo lines from the fetal or adult somatic cells or the 00:25:35.360 --> 00:25:41.200 somatic stem cells or from the fetal or adult tissues with prior approval of the Institutional 00:25:41.200 --> 00:25:47.920 Committee and can be done or provided appropriate informed consent is obtained from the donor 00:25:49.440 --> 00:25:53.360 and it should be registered in the NAC-SCRT committee through this 00:25:53.360 --> 00:25:57.360 Institutional Committee for the Stem Cell Research with appropriate documentation. 00:25:57.920 --> 00:26:01.840 And including the details regarding their derivation and the characterization means 00:26:01.840 --> 00:26:07.280 how the new human stem cells lines are being developed, all the scientific 00:26:08.000 --> 00:26:14.400 documentation has to be provided and then, the cell lines should be deposited or registered in 00:26:14.400 --> 00:26:20.320 the accredited cell banks for the potential used by the other investigators. Then, the pluripotent 00:26:20.320 --> 00:26:27.920 stem cells lines intended for the use in the clinical research need approval from the CDSCO 00:26:27.920 --> 00:26:33.200 after ensuring the clearance from the IC-SCR and the Institutional Ethic Ethics Committee. 00:26:34.000 --> 00:26:39.760 And then, the cell line should be provided with a particular reference unique identification number 00:26:39.760 --> 00:26:48.400 for the future reference. So, you have to maintain this process which is given in the guideline so 00:26:48.400 --> 00:26:54.080 that you can also carry out the establishment of the new human embryonic stem cell research. 00:26:54.080 --> 00:27:00.160 So, this falls under the permissible area of the research provided you meet this criteria. 00:27:00.160 --> 00:27:06.160 So, you may refer to the national guideline of 2017 first for broader understanding. I 00:27:06.160 --> 00:27:12.400 am just giving you the basics of or the basic points which are mentioned in the guidelines. 00:27:15.680 --> 00:27:20.000 Similarly, in vitro studies using the established cell lines can also be carried 00:27:20.000 --> 00:27:27.600 out with prior approval of this Institutional Committee. Then, but for the in vivo studies in 00:27:27.600 --> 00:27:33.040 experimental animals other than the primates, with established cell lines from any type of 00:27:33.040 --> 00:27:39.600 human pluripotent stem cells including their differential stems and human stem cells from 00:27:39.600 --> 00:27:44.320 any tissue are permitted with the prior approval of the Institutional Committee as well as the 00:27:44.320 --> 00:27:49.840 Institutional Animal Ethics Committee because it involves the usage of the experimental animals. 00:27:50.560 --> 00:27:57.360 And there are also certain consideration that the the animals where the in vivo studies are 00:27:57.360 --> 00:28:03.040 being carried out, these animals shall not be allowed to breed if the stem cells are likely 00:28:03.040 --> 00:28:09.440 to be incorporated in the gonads or the relevant tissues or the organs of the sacrificed animals 00:28:09.440 --> 00:28:15.680 should be preserved for the validation of the claims made by the investigator in the future. 00:28:15.680 --> 00:28:21.440 So, these animals must not be allowed to reproduce as well as the relevant tissues 00:28:21.440 --> 00:28:27.920 must be properly placed so that if any issues arise, so it has to be properly validated. Yes, 00:28:27.920 --> 00:28:32.800 it has used in a proper manner so that evidence has to be preserved. 00:28:34.560 --> 00:28:40.880 There are restrictive areas of the research. So, under the restrictive areas of the research 00:28:42.000 --> 00:28:47.920 like creation of the human pre implantation embryos by in vitro fertilization, 00:28:47.920 --> 00:28:52.320 intracytoplasmic sperm injection, somatic cell nuclear transfer 00:28:52.320 --> 00:28:58.080 process or any other method with the specific aim of deriving the embryonic stem cell lines 00:28:58.080 --> 00:29:03.920 for any purpose is a restrictive area. So, if you want to carry out any of this 00:29:04.800 --> 00:29:11.360 process as mentioned there, you need to provide the reasonable or reasoning 00:29:11.360 --> 00:29:18.080 for taking out such kind of the study. For example, you have to propose that the proposed 00:29:18.080 --> 00:29:23.520 research cannot be carried out without the exist with the existing embryonic cell lines. 00:29:23.520 --> 00:29:32.400 So, it needs new embryonic stem lines for carrying out this research and you have to provide the 00:29:33.200 --> 00:29:38.240 reasoning that how much how minimally you are using this embryo or the blastocysts, 00:29:39.120 --> 00:29:44.000 you have to properly define in your research plan. And also the research team should have 00:29:44.000 --> 00:29:49.360 appropriate expertise and training for the derivation, characterization and culture of the 00:29:49.360 --> 00:29:55.360 embryonic stem cells. So, this process has like if you want to carry out any of the restrictive 00:29:55.360 --> 00:30:00.880 areas of the research, proper validation of the research plan is one of the essential criteria. 00:30:02.880 --> 00:30:08.400 And then, regarding the international collaboration or sponsor research, 00:30:08.400 --> 00:30:12.000 so the clinical trials sponsored by the multinational companies or 00:30:12.880 --> 00:30:19.520 which are developed cell lines which are developed outside the India should get the clearance from 00:30:19.520 --> 00:30:26.160 the regulatory authorities from the respective country as well as it needs prior approval from 00:30:26.160 --> 00:30:32.000 the CDSCO following the clearance from both the Institutional Committee on the Stem Cells 00:30:32.000 --> 00:30:36.240 Research as well as the Institutional Ethics Committee of the trial site. 00:30:37.840 --> 00:30:42.640 And the all the international collaboration requires approvals from the respective funding 00:30:42.640 --> 00:30:47.600 agencies, followed by the approval of the ministry screening committee as per the government of 00:30:47.600 --> 00:30:54.000 India's guideline. And import of any type of the stem cells or their products or the derivatives 00:30:54.000 --> 00:31:01.600 of their things requires the license of the CDSCO as per the established regulation and only 00:31:02.240 --> 00:31:05.760 if they have a prior prior clearance from the regulatory authorities of the 00:31:05.760 --> 00:31:09.200 country of the origin, then only these processes are initiated. 00:31:11.440 --> 00:31:19.520 And so, if there are research which involves the introduction of the human embryonic stem 00:31:19.520 --> 00:31:24.720 cells or induced pluripotent stem cells or somatic stem cells into the animals 00:31:24.720 --> 00:31:31.840 including the primates at the embryonic or fetal or the any other developmental state, then, 00:31:35.520 --> 00:31:41.280 it has to be again supplemented with certain information because it is again a development 00:31:41.280 --> 00:31:44.960 of the chimera, where you are trying to incorporate the human stem cells into 00:31:44.960 --> 00:31:49.280 the animal may be to understand the pattern of differentiation and the integration. 00:31:49.840 --> 00:31:57.440 So, what exactly you want to study? The expected outcome of the study and possibility that 00:31:57.440 --> 00:32:05.040 the stem cells can contribute majorly for the development of the brain or any other 00:32:05.040 --> 00:32:09.760 germ line cells of the recipient animals and the scientific justification of the such 00:32:09.760 --> 00:32:16.720 experiment must be substantiated with the data. And animals derived by such experiments should 00:32:16.720 --> 00:32:22.320 not be allowed to breed as well as it needs the approval for the from the NAC, 00:32:24.560 --> 00:32:27.840 the National Apex Committee on the Stem Cell Research and Therapy and 00:32:28.560 --> 00:32:34.320 also, it needs the in house clearance by the Ethics Committee and the internal 00:32:35.040 --> 00:32:41.040 Internal Committee on the stem cell research. So, the more complicated the research, 00:32:41.040 --> 00:32:49.120 you need more and more detailed plan and proof of evidence of a validated plan so that it 00:32:49.120 --> 00:32:55.440 ensures that the research are not carried out for any purpose which is not good 00:32:55.440 --> 00:33:00.240 for the society or which will not give a result, where it is not that beneficial. 00:33:04.480 --> 00:33:09.440 So, again, studies on the chimeras also need a special permission. So, these are the various 00:33:09.440 --> 00:33:15.520 aspects which are mentioned in the guideline. And also if you are trying to carry out certain genome 00:33:15.520 --> 00:33:20.000 modification, may be using the available gene editing technology, maybe the CRISPR 00:33:20.000 --> 00:33:26.240 technology or the other any other technology, it requires the review by all the committees like 00:33:26.800 --> 00:33:31.440 Institutional Committee, Ethics Committee as well as the Institutional Bio Safety Committee 00:33:31.440 --> 00:33:36.000 and finally, it has to be reviewed by the Review Committee on the Genetic Manipulation. 00:33:36.000 --> 00:33:38.960 These are the committee developed by the department of biotechnology. 00:33:39.680 --> 00:33:42.400 When we go to next module, we will read more about this committee, 00:33:42.400 --> 00:33:49.360 what are the functions of this committee. So, here these permissions are required and 00:33:49.360 --> 00:33:55.760 the expertise of the research team is also very utmost importance in carrying out such things. 00:33:58.720 --> 00:34:03.760 Also, the guideline interestingly mentions certain prohibited areas of the research. 00:34:04.400 --> 00:34:11.760 So, the stem cell research are prohibited in some particular areas. First like the research 00:34:11.760 --> 00:34:17.040 related to the human germ line gene therapy and reproductive cloning is prohibited in India. 00:34:17.920 --> 00:34:24.160 And in vitro culture of the intact human embryo regardless of the method of their derivation 00:34:24.160 --> 00:34:30.000 beyond 14 days of the fertilization or formation of the primitive streak, whichever is earlier 00:34:30.000 --> 00:34:36.800 is prohibited in India. Clinical trials involving the Xenogeneic cells are prohibited. 00:34:37.520 --> 00:34:42.480 Forth, any clinical research on the Xenogeneic and human hybrids are also prohibited. 00:34:43.360 --> 00:34:47.280 Use of the genome modified human embryos germ line, 00:34:47.280 --> 00:34:52.880 stem cells or gametes for the developmental propagation are also prohibited in India. The 00:34:52.880 --> 00:34:59.840 research involving the implantation of the human embryos by in vitro manipulation at any stage 00:34:59.840 --> 00:35:05.280 of the development into the uterus of the human or the primates are also prohibited in India. 00:35:06.000 --> 00:35:10.240 Breeding of the animals in which any type of the human stem cells has been 00:35:10.240 --> 00:35:16.480 introduced in any stage of the development and which may contribute to the chimeric gonadal 00:35:16.480 --> 00:35:22.160 cells are also prohibited in India. So, these are the few restrictive areas or the prohibited 00:35:22.160 --> 00:35:30.880 areas where research is totally prohibited. So, any company or any organization interested 00:35:30.880 --> 00:35:36.640 in the stem cell research must adhere to this guideline and adhere to the standards 00:35:36.640 --> 00:35:43.040 prescribed in the guidelines before they carry out any stem cell research in India while 00:35:43.760 --> 00:35:51.120 there are few linical trial candidates in other countries in India, we are also progressing. 00:35:51.120 --> 00:36:02.160 But again, it is yet to develop comparative standards like we are not that developed 00:36:02.160 --> 00:36:07.520 like the other countries like US particularly in United States, where already some of the 00:36:07.520 --> 00:36:11.840 products are also in the market. Here it is only restricted to the clinical research. 00:36:12.640 --> 00:36:18.000 So, this is briefly about the Indian regulation on the stem cell research. 00:36:19.360 --> 00:36:24.480 Going forward, we will discuss more about the regulatory aspects of the other biomedical 00:36:24.480 --> 00:36:30.880 products India and in other countries as well. So, these are the few references. Also, 00:36:30.880 --> 00:36:35.680 you may find the guidelines in the DBT websites for the stem cell research; you 00:36:35.680 --> 00:36:41.040 may go through it for a detailed understanding. So, thank you very much for attending the session. 00:36:41.760 --> 00:36:46.400 Looking forward for the other sessions. Thank you.