Stem cell therapies and tissue engineering have opened up a new era of regenerative medicine, promising the replacement or regeneration of damaged cells or organs. Therefore, stem cells have emerged as one of the most enthralling areas of modern biology and medical research during the last decade. Today, cell/stem cell therapy has become the fourth pillar of healthcare industry along with pharmaceuticals, biologicals and medical devices.
The recent meeting of our Prime Minister Narendra Modi with Japanese stem cell pioneer and Nobel Laureate- Shinya Yamanaka at the centre for iPS Cell Research and Application (CiRA), Kyoto University has raised the curiosity among the Indian stem cell researchers about his interest and commitments towards stem cell science for incurable diseases. He has spurred the search for a cure for India’s major problem of sickle cell anaemia that afflicts mostly tribal population.
Several Asian countries are fast grabbing the opportunities to occupy the stem cell space and ready to implement new approaches for rapid development. These Asian countries are Israel, South Korea, Japan, China, Taiwan, Singapore, Thailand and India. However, leading companies who attracted the attention of global investors are majorly from Israel, Japan, South Korea and China.
For example, in Japan, they have given away their conservative regulatory approach to accommodate new regimen of stem cells therapy in the country. Upper house of Japan’s parliament has passed a legislation in 2013 which allows ‘conditional’ approval for stem cell therapies based on their strong safety profile in small clinical trials that can go to the market for treating patient without the usual requirement of efficacy. This most liberal and forward thinking decision of Japan to push the regenerative medicine in hope that the country can become a global leader in this area. This will not only attract both small and large business houses to this important area but also there will be a rapid turnaround time to produce marketable products in just one or two years, ultimately benefiting their ageing population.
More recently, Colorado state in USA passed a new law supported by the ultra-conservative Goldwater Institute, the so called right to try law. Inspired by the movie, The Dallas Buyer’s club, this law allows patients to try experimental, unproven, unapproved medical intervention that have completed at least phase-I clinical trial. Louisiana, Missouri and Arizona states are due to follow similar suit in next few months.
Globally, there are already more than dozen FDA approved stem cell products available in the market which was worth an estimated $ one billion in 2013. The US, South Korea and Canada are leading countries where these products have been approved for various indications like haematological diseases; bone grafting, osteoarthritis, myocardial infarction, diabetic foot ulcer, crohn’s disease and graft vs host disease (GVHD). There are several emerging stem cell products that may enter into the global market by 2014-15.
In India , DCGI has approved two autologous stem cell products, one for limbal insufficiency and other for acute myocardial infarction. However, their utility and demand is not known.
Indian stem cell industry is more or less 15 years old. However, stem cell industry in India has not grown the way it was expected and is rapidly losing great opportunities and global space. There are several reasons for this. Firstly, Indian companies does not have mind-set for developing new drugs or biologics and usually do not invest in entire cycle of drug discovery. They are largely dependant on western pharma companies to do all heavy lifting, when it comes to developing new drugs.
Secondly, severe constraints of government funds, lack of investors and talent pool are other road blocks in the growth of stem cell industry. Several stem cell companies mushroomed in India with the sole objective of earning a quick buck before they close the shop if any stricter regulation gets implemented. Another important reason was lethargic and chaotic regulatory process and delay in implementing national guidelines. The normal waiting period for getting a regulatory approval for conducting clinical trial in India is three years. No start-up company can survive so long and increase their massive burn rate. As a result, India could develop only one or two industrial players in stem cell therapeutic sector in the last 15 years.
Most worrying part of this technology is the failure of several stem cell drugs in the crucial global clinical trials at phase-II/III. A few of them also are Indian companies. This list of failed clinical trial is increasing rapidly and that raises the serious questions of efficacy of stem cell drug as therapeutics in several clinical indications. Unfortunately the hype and buzz created by several companies are distorting the reality and such hype will not revolutionize the medicine.
The major factors responsible for failure of clinical trials is large-scale manufacturing.
Commercial therapeutic product incorporating stem cells as an active ingredient is a technological and scientific jump beyond conventional biological product where, cell culture is itself a product. They cannot be purified as it is possible in other biologicals. Stem cells are very sensitive to culture conditions and most unpredictable in nature. Other important factors that are affecting overall clinical outcome are donor variation, passage number, immunogenicity, type of stem cells and cryopreservation.
For example, results showed that minimally expanded mesenchymal stem cells (MSC) are more potent and retain therapeutic potential than MSC cultured for three logs for more expansion. Recently issued draft guideline by Central Drug Standard Control Organization (CDSCO) regarding stem cells and cell based products (SCCP) have permitted stem cells expansion for not more than six passages for autologous or allogeneic therapy before being administered to patients. Nobody knows on what basis CDSCO has permitted to culture the cells maximum up to six passages before being administered to patients.
There are no proven data that justify permitting CDSCO to approve maximum six passages for therapeutic purpose. Several global published data demonstrated the striking difference in clinical outcome between MSC expanded up to one or two passages and expanded up to six passages.
Clinical outcome is better in early passaged cells (one or two passages) than longer passaged cells (up to six passages). Stem cells passaged for long duration lose the therapeutic potential and they are no more effective for therapy. Such confused and baseless CDSCO guideline may mislead the start-up stem cell industry.
Stem cell isolation and manufacturing is a highly specialized technique. Lack of knowledge in stem cell culture, poor sterile technique, failure to adhere to follow good manufacturing standards, deficiencies in the processing of stem cells are the bigger concerns for the quality and clinically eligible stem cells. The poor manufacturing process and longer passaged cells may lead to therapies with dangerously high number of non-viable damaged cells that, in addition to potentially harming patients, could skew test results and jeopardize clinical data and ultimately failures. This may cause loss of precious time, efforts and money. Currently, India seriously lacks this expertise and it is the biggest hindrance in the success of stem cell industry. Due to this cost of good will be high and final product may be even costlier and unaffordable for common man.
It is most unfortunate that in India there are just handful of companies that are seriously focusing on stem cell therapeutics. Perhaps, only one or two who are seriously focusing on product development as per regulations. Other companies have no long-term vision and are just taking advantage of absence of a legal framework in the country and financially exploiting the patients. They may not even exist soon since bill to regulate stem cell practice is round the corner. Other stem cell companies are focusing on cord blood banking. Baring a few, all other cord blood stem cell banks are unregulated and operating unscrupulously.
Regulators are now amply clear that the stem cells are not a part of standard care and hence there can be no guidelines for the therapy until efficacy is proven. Accordingly, any stem cell use in patients must 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. At present every use of stem cells in patients outside an approved clinical trial shall be considered as malpractice. In this situation even stored umbilical cord blood stem cells cannot be used for any disease other than haematological condition.
During the last 15 years, our country , having two billion people could develop just one or two companies that are focussing on therapeutics compared to a smaller country like Israel which has 18 stem cell companies. Japan, South Korea, China, Taiwan have much more companies than India. We have yet to see any trial registered under CTRI for Phase-III, so commercial production is a long way to go. Until that , there will be untested, unproven stem cells leading to stem cell abuse.
Private equity holder or institutional investors or bigger pharma companies are not yet convinced that taking a risk on developing stem cell therapeutics is worthwhile since return on investment takes a longer time. Although the science is getting better, interesting and convincing, investors and promoters are wary and are not willing to understand this important area in the global arena and India is losing this space rapidly.
What India needs to do is to have a totally new approach as was implemented by Japan and some states of USA. More companies will be willing to enter this important area if a favourable environment is created. Then more stem cell therapeutics will be available in shorter turnaround time and will prevent patients from going for untested, unproven and unhygienic stem cell therapy. This will also create more specialized jobs in the country as more of our younger generation specializes in regenerative medicine. It is hoped that the recent interest shown by our prime minister in the stem cell research may change the outlook of Indian stem cell industry.
Ultimately, patients are the one who bear the burden of illness and not the policy- makers or medical agencies.
(The author is CEO, Kasiak Research Pvt Ltd, Mumbai)