Stem cell therapy has the potential to change the face of human disease and alleviate suffering and is poised to be a major branch of medical treatment in the years to come. The Association of Biotechnology Led Entrepreneurs (ABLE) has been working closely with the government bodies to strengthen the regulatory environment of stem cells in India  It has now formed a dedicated six-member stem cell committee which has B.N. Manohar as its chairperson.

Stempeutics Research, a group company of Manipal Education & Medical Group is the only company in the country which has developed Stempeucel ,an investigational medicinal product which is undergoing  the last stage of phase 2 clinical trial for the indication of critical limb ischemia (CLI), osteoarthritis (OA) and liver cirrhosis (LC) and is expected to enter phase 3 trial by early 2013.  The company plans to launch Stempeucel in the Indian market by mid-2015.  

B. N. Manohar, Chairperson, ABLE Committee on Regenerative Medicine and CEO, Stempeutics gives an insight into the prospects of stem cell therapy to Nandita Vijay, Excerpts:

Could you give us a broad overview of the stem cell therapy scenario in India?
Stem cells hold great promise and potential for both basic sciences and medicine. Stem cells could be a major branch of medical treatment and eventually become a standard of care and practice in a few years. India has made great progress in stem cell research as evidenced by creation of human ES (Embryonic stem) cell lines as well as by publishing more than 100 scientific and clinical papers in various journals. As per GBI Research report, the stem cell market in India is estimated to touch $ 600 million by 2017.

The field of stem cell biology and regenerative medicine is rapidly moving towards translational research and eventually to clinical practice in India. For successful use of stem cells in clinical practice, there are several areas that need to be looked at. Firstly, it is  very important to determine the tissue source and the type of stem cells or differentiated cells that possess the greatest potential for curing a specific disease.

Secondly, robust preclinical models for determining efficacy, safety, toxicity, delivery routes and techniques should be tested to ensure that the cell type used is safe and efficacious to conduct human clinical trials. Thirdly, for allogeneic stem cell transplantation, immunological barriers must be overcome in order to sustain long-term engraftment. If these criteria are met with success,  it would be easier to obtain regulatory approvals that are required for effective translation of use of stem cells from ‘bench-to-bedside’.

Since stem cells have the potential to be differentiated into any type of cell, they offer promise for treatments for a wide range of disease conditions. These include damage to the brain, spinal cord, skeletal muscles and the heart. Stem cell therapy is still in clinical trial stage for most of these indications. Hopefully it should become a standard therapy in the near future.

Although stem cell therapy is still at the stage of clinical research, advances have been made in understanding on how to use these cells for treating various diseases. L.V. Prasad Eye Institute (LVPEI) has treated the largest number of patients (780) in the world for corneal blindness using cultured limbal stem cell therapy since the Institute started the procedure in 2001. The therapy is used to restore vision in cases of corneal damage due to burns or chemical injury. Some hospitals and stem cell companies are offering stem cell therapy for spinal cord Injury, Parkinson’s disease, stroke and cardiovascular indications.

What is the global scenario of stem cell therapy?
US FDA & EMEA have well defined guidelines for stem cell research and therapy, while it is evolving in South Asia /South East Asia countries. US FDA considers both allogeneic and autologous use of somatic cells as products and need to undergo product development life cycle. A few FDA approved stem cell products are making into the clinics in various parts of the world. Osiris Therapeutics recently announced the approval of its product Prochymal by Canadian regulators to treat children suffering from acute graft-versus-host disease (GVHD), a potentially deadly complication of allogeneic bone marrow transplantation. Osiris also got similar approval in New Zealand for Prochymal.

In 2011, the stem cells market witnessed high growth. More therapies are expected to be launched in the next five years. With the liberalization of stem cell research in the US, many more researchers are inventing in other avenues which could pave way for newer therapies. The stem cell therapy market in the US is projected to be $0.68 billion market in 2012 and $2.1 billion in 2017 growing at a CAGR of 25 per cent.

Osteocel is an allograft containing mesenchymal stem cells and osteo-progenitors and it was developed by Osiris and sold to NuVasive Inc in 2008. Osteocel clocked up to $32 million revenues in 2009. In Korea, Pharmicell has successfully developed ‘Hearticellgram-AMI’ autologous product and received approval from the Korea Federal Drug Agency (KFDA) in July 1, 2011.

Hearticellgram-AMI uses autologous stem cells and is a personalized stem cell therapy product which overcomes immune rejection. Another Korean company, Medipost got approval for their product ‘Cartistem’ in January 2012 from the Korean FDA for the treatment of Osteoarthritis.

With stem cell products being rolled out in various parts of the world, the global stem cell market is poised to grow at a rate of 30 per cent from 2010 to 2012 and projected to be around $ 1.2 billion by 2012 and is expected to reach around $ 16 billion in 2017. North America is likely to post highest value by 2017.

For what disorders are the stem cells considered most useful?
Stem cells obtained from various tissue sources are currently being used in clinical research. They are three categories:  Adult Stem Cells,  Embryonic Stem Cells and Fetal Stem Cells. Based on method of delivery, stem cell therapies are classified as Autologous Stem Cell Therapy and Allogeneic Stem Cell Therapy.

The primary focus of stem cell therapy is for unmet medical needs. It is generally believed that adult stem cells are useful for  cardiovascular indications like congestive heart failure, myocardial infarction and limb ischemia.  Orthopedics indications like osteoarthritis and rheumatoid arthritis and other indications like Crohn’s disease and anal fistula. Embryonic stem cells and fetal stem cells are useful for nervous system diseases like spinal cord injury, stroke, Parkinson’s and Alzheimer’s diseases.

In autologous stem cells treatment , corneal blindness is treated in a big way.

What are the problems you feel are associated with stem cell treatment?
Stem cell therapies raise many concerns that are important and at times difficult to address. However, such is the case for any new therapies that are considered for human clinical use. The source of stem cell is a major ethical concern. The use of embryos is generally not agreed upon especially when fertilization is performed for the sole use of stem cell research and therapy. For those who believe that the human embryo, even at the one-cell stage, having absolute moral value, equal to that of a new born baby or/and adult, any embryo research is ethically unacceptable.

 However the use of surplus embryos obtained from in vitro fertilization (IVF) techniques is legally allowed for research use in many countries. The embryos used in these cases were created for infertility purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they are donated for research with the informed consent of the donor. There are no controversies on the usage of human adult stem cells for therapeutic purpose.

In terms of regulations, what are the standards available currently in India and how is it evolving?
It takes approximately a year to get Drugs Control General of India (DCGI) approval for conducting stem cell clinical trials in India. Regulatory approval process for conducting clinical trials for stem cell based products (or services) is evolving and the government bodies are engaged in publishing a new guideline for the use of human adult stem cells for therapy and product. This new guideline will address development, manufacturing and quality control as well as non-clinical and clinical development requirements for stem cell therapy & product. The proposed frame work will be complementary to existing regulations (Schedule Y of Drugs & Cosmetics Act). For large upscale of stem cells, Schedule M needs to be followed. Products’ specific requirements remain applicable for   drugs,  biologics (cellular based medicinal products) and medical devices.

The existing ICMR-DBT (Indian Council of Medical Research – Department of Biotechnology) Guidelines for Stem Cell Research and Therapy (2007) addresses ethical and scientific concerns to encourage responsible practices in the area of stem cell research and therapy. The guideline categorizes stem cell studies into three main groups, covering  permissible, restricted and prohibited research. It suggests a provision for two- tier of evaluation and monitoring. One is at  the institutional level called Institutional Committee for stem cell research and therapy (IC-SCRT) for permissible areas of research and the other at the national level called National Apex Committee for Stem Cell Research and therapy (NAC-SCRT) for restricted areas of research. All institutions and investigators carrying out research on human stem cells, existing and newly derived stem cell lines generated in India or in other countries should have prior approval and should be registered with NAC-SCRT through IC-SCRT.

As per ICMR-DBT guideline there is no approved indication for stem cell therapy as a part of routine medical practice, other than bone marrow transplantation and corneal limbal cell treatments. Accordingly all stem cell therapy other than BMT and corneal epithelial treatment shall be treated experimentally. It should be conducted only as clinical trial after obtaining approval from DCGI. This applies to both autologous & allogeneic clinical trials.

Any organization planning to market stem cell therapy/product need to submit Form 44 (or other forms) to DCGI with proper documentation. DCGI generally refers the proposal to ICMR for their recommendations. ICMR has formed an expert stem cell committee to review all the proposals and this committee meets at periodic intervals. A proposal may go through expert committee review process multiple times before being approved for clinical trials. ICMR sends their recommendation to DCGI who  ultimately gives the consent  letter based on further review done at his  office. After getting the DCGI approval,  it is mandatory for the organization to register the clinical trials detail in CTRI (Clinical Trials Registry of India) before starting the study.

In order to expedite the approval process and bring out more clarity on stem cell therapy/clinical trials DCGI has recently formed Cellular Biology Based Therapeutic Drug Evaluation Committee (CBBTDEC). This committee is controlled by DCGI and the Director General of ICMR has been nominated as its  Chairman.  In future all clinical trials and probably all queries related to stem cell therapy will be addressed by this committee.

What is the ABLE’s action plan  to strengthen the regulatory environment?
ABLE has recently formed a committee to focus on Regenerative Medicine (ABLE-RM) to ensure  how India can leverage its intellectual talent and become a global leader in this field. ABLE-RM roles and responsibilities include bringing all stem cell and regenerative medicine companies under one roof and voice the issues together to the government and to the public and articulate latest developments happening in the industry.

To strengthen the regulatory environment and to form a robust guideline for stem cell therapy in India, ABLE-RM is focusing on :

Tax benefits and duty exemptions for stem cell companies.  Consider certain stem cell products as ‘orphan’ drug status,  on similar lines that of USFDA  procedures in the US  to ensure  trials are  on fast track approval mode.

Give necessary inputs to the regulatory bodies to build  a robust guideline for stem cell therapy in India by taking  relevant inputs from US FDA and EMEA guidelines.

Build India as a destination for stem cell research, clinical research and contract manufacturing apart from seeking other fiscal incentives such as subsidy (for plant and machinery for biotechnology and industries) and power concession.

What is the future of this novel therapy?
Stem cells will be available as off-the-shelf product in the near future for treating various unmet medical needs. Majority of these products will be based on adult stem cells. Preclinical disease models will be developed to test the ability of these cells to protect at-risk cells and replace cells lost to injury or disease. Human mesenchymal stem cells, isolated from various post natal and adult human tissues, will become an attractive tool for their potential in cell therapy and will hit the market in the near future. New up-scaling technologies will emerge for mass production of stem cells without losing their inherent ‘stemness’ properties,  there by making stem cell products affordable.

The potential of mesenchymal and other stem cells will certainly attract pharma companies to expand their horizons to stem cell field to develop stem cell as a drug. Big pharma companies have already started investing in stem cell companies i.e. Pfizer has tied up with Athersys, Genzyme with Osiris, Teva with Gamida Cell, Cephalon with Mesoblast and in India, Cipla has tied up with Stempeutics. Pharma companies will invest billions of dollars in stem cell research in the next decade.

Even though off-the-shelf allogeneic products will be available in the market in the near future, there will be a good scope for autologous product for certain indications,  in particular for cosmetic applications. Autologous therapy using adult stem cells will move from a lab service model to a medical device model. Development of point-of-care medical devices will gain momentum,  where stem cells can be isolated in minutes from patient’s own bone marrow or adipose tissue followed by their administration to the target disease tissue. Millions of dollars will be spent in developing efficient, cost effective medical devices for autologous therapy.

Also in the next decade, generation of induced pluripotent stem cell (iPSC) lines and their differentiated derivatives will promote patient specific & disease specific drug development. The major concerns of teratoma formation by these cells have to be overcome before their clinical application. Due to their pluripotent nature, iPSCs might change the entire scenario in drug development and will open avenues for personalized medicine using stem cells.