Clinical Trials on Stem Cells as a Therapeutic Agent: An Analysis From Clinical Trials Registry-India (CTRI)

The stem cells have abundant potential for innovative therapeutic programs to replace or regenerate cells or tissues having functional impairment. Since the introduction of stem cell therapy using embryonic stem cells in 1998, the clinical use of the stem cells has increased. On the scientic ground, it is necessary to pass the clinical trials, otherwise, it may be recognised as an unproven therapy. The market of unproven stem cell therapy got attention when stem cell clinics started to advertise and claim to cure untreatable diseases. Indian Government has thus considered stem cell as a drug, and stem cells gone under clinical trials for market approval. In this study, we studied research trends related to clinical trials using stem cells as a therapeutic agent based on data obtained from the Clinical Trial Registry of India (CTRI). Our study showed that many clinical trials on the stem cells have been registered in the CTRI database, but only few of the clinical trials has been focusing on the actual stem cell drug development process. The greatest part of these trials were interventional and focused on bone marrow stem cells. On the other hand, only 2% of clinical trials actually focused on iPSCs. There is need to promote randomized clinical trials than single arm trials then our reliability on outcome from clinical trials may increases.


Introduction
Stem cells are the basic raw materials which has the potential to produce all other specially functionalized cell type or lineage. They have high capacity of self-replication and maintain itself as a niche. Stem cell therapy shows many promises as a treatment for previously untreatable and high-burden diseases. Ongoing research and clinical trials for the in treatments of spinal cord injury, heart failure, retinal and macular degeneration, and diabetes type 1 have proven that injecting stem cells at the target may help in reverting back to normal functioning (Menasche et al. 2015, Schwartz et al. 2015, Ilic and Ogilvie, 2017). The rst criterion to denote an 'unproven therapy' is the lack of scienti c rationale to suggest potential e cacy. According to Paul Knoep er (Leask 2019), "There's little evidence that adipose, bone marrow and amniotic stem cells can be used safely and effectively for a diverse array of conditions marketed by for-pro t clinics". While some studies have manifested that stem cell-based treatments can be safe but there is little clinical evidence at large that shows they are effective in human. (Iijima H et al. 2018).
The expectations are high from the stem cell therapy but the scienti c community argues about "unproven" stem cell therapy. The Indian government has taken it seriously on behalf of the Indian people due to continuous growth of "unproven" stem cell therapy which is considered as a drug in India.
Therefore, it must comply with rigorous clinical trials procedure. India recently updated its guidelines on stem cell research (SCR), the National Guidelines for Stem Cell Research 2017. The approach of a "drug" rstly introduced in National Guidelines of Stem Cell Research 2013, and it is now a "rule" mentioned in the "New Drugs and Clinical Trials Rule, 2019.
Clinical Trials Registry-India (CTRI) is the clinical trial registration database of India that provides information on the implementation status of clinical trials from all over India. Although CTRI.nic.in does not provide comprehensive results of clinical trials, it is a database of the plans for individual trials and provides information about target diseases, sponsors/principal investigators, planned schedule and protocols of the clinical trials and enrollment of the subjects. Furthermore, since the database provides comprehensive information on the details of the content of the planned clinical trial, one can perform various targeted analyses by extracting and tagging attribute data from each clinical study plan (Pillamarapu M, et al., 2019).
Manifold studies aiming on the trends in stem cell research and therapy have been conducted so far but using either ClinicalTrials.gov or multiple databases (Fung et

b. Content analysis of clinical trials
The clinical studies were normally classi ed as observational or interventional study types. This classi cation based on the de nition provided by the "ClinicalTrials.gov". So, we did not change the interpretation was provided by the CTRI. We, additionally include all those studies where the data is 'not provided' or 'not available' as a separate category for the analysis. All data are presented in percentage (and absolute numbers). Algorithm used for systematic CTRI database search on the clinical trials involving stem cells as a therapeutic agent is represented in Fig. 1.

a. Systematic search algorithm
One hundred thirty-ve clinical studies were identi ed using the prede ned criteria in the database search using "CTRI". Out of those 69 studies had to be excluded, because they did not use stem cells as a therapeutic agent.
b. Types of Clinical Trials

Discussion
In this study, we analyzed current scenario of clinical trials on stem cell as a therapeutic agent in India using the CTRI database. Worldwide, the stem cell treatment considered as a cell-based therapy or simply "stem cell therapy" but in India, it considered as a "drug". Therefore, the notion of treatment has changed from "therapy" to "drug". After considering as a drug, the regulatory requirement has also been changed (Qiu et al, 2020).
Using the database of clinical trials several studies have been published on the stem cell therapy using different perspectives. All these studies were conducted using ClinicalTrials.gov and also gathering the . Although these studies showed clinical trials conducted in India but scenario of Indian context was limited. Another most important thing is that these all studies used prime source was ClinicalTrials.gov not CTRI database. Our study is solely dependent on the CTRI database with the acceptance of some limitations of this database. Pillamarapu et al, 2019 have described these limitations and many information is not seen or missing on the CTRI database. Similar situation is also found in a study done by Negoro et al, 2018 using ClinicalTrials.gov.
Our study is based on the clinical trials on stem cells registered in CTRI database, the priority being given to interventional types (70%) of trials (Fig. 1). The single armed trials (43%) were mostly used for conducting a trial instead of randomised clinical trials (RCTs) (33%) (Fig. 2). The RCTs have important value in the eld of clinical trial eld. The study showed Phase 1 clinical trials (43%) and Phase 3, only 9% of the total trials. When focusing on the recruitment status of clinical trials, we found that, majority of clinical trials were in the open to recruitment status (26%). The patient recruitment was completed in only 14% of the trials. The autologous stem cell sources (55%) were slightly higher than the allogenic stem cell sources utilised. That is, the autologous stem cells is more preferred than the allogenic stem cells used during the stem cell therapy (Fig. 5). Among the scrutinised data, we found that, bone marrow was the most favoured stem cell source in this eld (Fig. 6).
The Stempeucel® is a product have market authorisation approval. The Stempeutics have gotten the market authorization for Critical Limb Ischemia due to Buerger's Disease and Critical Limb Ischemia due to Peripheral Arterial Disease from the CDSCO (Stempeutics, 2021). The Stempeucel® is currently under clinical trials for Knee Arthritis, which is now in the Phase 3 (CTRI/2018/09/015785). This drug also applying for the Diabetic Foot Ulcer, which is also in the Phase 3 (CTRI/2019/12/022351). In woman, Asherman syndrome is a rare disease of uterus. This draft shows promise for development and promotion of future medicine. The Indian government aims to promote the stem cell research and therapy through clinical trials then in future, India will be a real and an affordable destination for the "stem cell tourism".

Conclusions
Our study shows that many clinical trials on the stem cells have been registered in the CTRI database, but only few these clinical trials is been focussing on the actual stem cell drug development process. The greatest part of these interventional trials is focusing on the use of bone marrow stem cells and only 2% of clinical trials on iPSCs. Hence, more attention on the iPSCs is needed for the future use. There is need to promote randomised clinical trials than single arm trials so that reliability on outcome from clinical trials may be enhanced.

Declarations Ethical Approval
The manuscript is based on systematic review analysis, does not require any ethical approval.
-Consent to Participate The manuscript is based on systematic review analysis, does not involve any participation of indiduals or a clinical study.

-Consent to Publish
The manuscript is based on systematic review analysis, does not require any ethical approval.

-Authors Contributions
Suman Ray provided the concept of the study and preparation of the manuscript. Chandrashekhar did the systematic review analysis and involved in the preparation of the manuscript.

-Funding
No funding support.

-Competing Interests
The Authors have no competing or con ict of interest.
-Availability of data and materials The data is given in the manuscript and if any furthaher clari cation required, the dtata will be made available by contacting the authors individually. Figure 1 Flowchart for searching the clinical trials on stem cells as a therapeutic agent registered in the CTRI database.   Analysis of the clinical trials on stem cells as a therapeutic agent registered in the CTRI database based on Disease category (in percentage).