7 Key Points On Stem Cells and Cell Therapy: No Short Cuts Please
By : Professor Datuk Dr. A Rahman A Jamal
For the last few weeks I have been engrossed in a few issues relating to the ethics of stem cells and cell therapies. Our National Pharmaceutical Control Board has just completed the draft of the guidelines on cells and gene therapy products. While waiting for that important document, I would like to share my views on this promising area of therapy. The stem cell is a potent cell capable of self-renewal and also differentiating into many different types of tissues. It is so powerful in terms of its capacity for cell proliferation that it can also become cancerous. In this article, I would like to highlight these 7 points on stem cells and cell therapy which both the clinicians, scientists and the public should know. There are many in the internet too but please also visit the pages of the regulatory bodies such as the Federal Drug Authority (FDA) of USA, European Medicines Act (EMA) and the Therapeutic Goods Act (TGA of Australia, to get a feel and understanding about how this hugely potential therapy is regulated by each authority.
- There is a need to show that the stem cell works (efficacy) in animals first, preferably by the researchers themselves and their own lab. For the clinicians and scientists out there who want to be the saviour for the many patients with the various incurable illnesses, please remember that you have to prove efficacy in an animal model first. One cannot simple inject stem cells into patients with Alzheimer’s disease, Parkinson disease, kidney failure or heart failure without showing that it works. It amazes me that for pharmaceutical drugs, we doctors (and those sitting in ethic committees) probe extensively into the efficacy of the candidate drug and demand that the researcher show toxicity data, but somehow when it comes to stem cells, most clinicians and scientists are willing to forego many of those requirements. Remember, we need to show efficacy in an animal model of the disease in our own lab. If we have not done the pre-clinical experiments ourselves, then we should show the evidence that others have done it with reproducible results. But then the ethics committee must be wary of external data as for one animal study that show efficacy there are probably many unpublished studies which show the contrary. We need to do a proper and fair critical appraisal of the existing data, like we do on any investigational new drug.
- There is a need to show the mechanism of action and there no exception at all. At this very moment, many are echoing the paracrine effects of stem cells when they are injected into damaged or degenerative tissues. Yes, these are mediated via hundreds (or thousands) of molecules, growth factors and cytokines. But can we just accept this generic paracrine effect blindly to explain the mechanisms of repair (if it works at all) all just because these are stem cells? We often like to belittle the practitioners of alternative therapies or those using crude extracts of plants for treating many ailments for not being able to identify the active compound and also more so the mechanism of action. But somehow again, for stem cells many are willing to make an exception. How are we different than them if we cannot ask ourselves the same questions? How do we differentiate our allopathic medicine from theirs then? To those stem cell and cell therapy researchers out there, please do the appropriate research and show your evidence on the mechanism of action. Let us not hide behind the premise that there are no medical options left for the patients and there is nothing to lose by injecting them with stem cells. If we were to do this blindly, we are really regressing to the pre-Nuremberg era when human experimentation was performed without any scientific basis at all and based on pure trial and error approach.
- Stem cells are now being used for many unproven indications and doctors are the main culprits. The proven indications include bone marrow or stem cell transplantation for leukemias or genetic disorders like thalassaemia. Those unproven or experimental indications include for Alzheimer’s disease, Parkinson disease, kidney failure, heart failure, etc. This abuse and unregulated marketing of stem cells are not just happening in Malaysia but worldwide. This has even led to a medical business phenomenon called the stem cell tourism which is flourishing in China (where there is almost no regulation), Japan, Thailand and Mexico, just to name a few. Some of these stem cell clinics have even set up booths in USA and Europe (where there are much regulated) without shame or fear. I totally agree that there is a huge promise and potential for stem cells but like any potential pharmaceutical product, the clinical indication must be proven beyond doubt in a proper multi-centre clinical trial. At a national level meeting last November organized by the Ministry of Health Malaysia, a senior orthopaedic surgeon lamented the fact that stem cells are widely abused and are being used for many unproven indications in orthopaedics and the public are being duped into paying thousands of ringgit for therapies which conventional and current treatment have the same effects. Politicians, celebrities and our sportsmen are also using stem cells to treat ailments and injuries. For the ethic committees out there, please take note. Get one or two of the members to read and be familiar with the current regulation in stem cells and cell therapies. If you are not sure what to do, send the proposals to the national committee at the Ministry of Health for review (it is actually a must now). Do not just use logic or do not think that you are helping Malaysia to become the hub for stem cell therapies by endorsing unproven therapies or products for treatment and for clinical trials.
- In Malaysia, the only way to take action is for the patient or the doctor to make a report. There are enough Acts around to take action against doctors or practitioners who are using stem cells unethically. The Private Health Care Facility Act is one of them. Under this act, all private hospitals and clinics are supposed to submit an application for any new therapies which they are introducing at their premises. But somehow, this has not happened when it comes to stem cells. In one local big private hospital, one clinician has been injecting stem cells into patients with many different diseases and charging them directly. This is done not through the hospital billing system, hence it goes undetected. I knew about this because this doctor presented his case series at a conference in the same symposium in which I presented about the ethics of stem cell research and therapies. I was both angered and embarassed. There were also a couple of international speakers who were bewildered that this could happen in Malaysia. I promptly made a call to the medical director of the hospital shortly after and he has duly advised this particular doctor to stop offering the therapy until it is proven. I also reported to the MOH about this. Many of those clinical indications are unproven and should be done in a clinical trial setting. For the public, consumers and patients, please take note. If it is a clinical trial, the patients or study subjects should not pay for the treatment. Don’t waste your money or savings on treatments which are unproven.
- Beware of international companies who want to partner with Malaysian companies or researchers in stem cell therapy. My usual first question to the CEO or chief scientist of these international companies is why their therapies or products are not approved in their own country or why they did not set up their practice in their own country. Many of these companies have failed to get registration of their products in their own countries. There is a company which is marketing an off-the-shelf product that can be used in an allogenic manner for the treatment of osteoarthritis and is still waiting for registration from the Australian authorities for the past 3 years. Last year, the company came to Malaysia to try and obtain registration and with the support of the biotechnology fraternity and also some local orthopaedic surgeons. Many of these companies see the loophole in regulation locally (The guidelines by our own National Pharmaceutical Control Board will be ready soon but at the moment we have the guidelines issued by the Ministry of Health. The NPCB guidelines will be similar to the one from the European Medicines Act, so to all IEBs and IRBs you can just google for the EMA document. Even if we don’t have guidelines, it does not mean that anything goes and this is a free-for-all phenomenon) and assumed that our institutional ethics board are naive about stem cells and cell therapies. To my colleagues sitting in the respective IEBs and IRBs, to the hospital directors and heads of departments, please be aware of such companies and also of our clinicians and scientists being duped into collaborating without proper and extensive due diligence.
- One common principle guiding the regulations from different countries is the concept of minimal manipulation. If you harvest bone marrow and peripheral blood stem cells and enrich them using standard separation methods before transplanting into the recipients, then it is minimal manipulation. This is allowed and considered standard therapy for diseases like leukemia. If you harvest stem cells and expand them in cell culture (to get a higher cell numbers like for mesenchymal stem cells) that is considered substantial manipulation. If you add growth factors or cytokines to activate the cells, that is also considered significant manipulation. The biology and the phenotype of the cells may have changed with the manipulation hence there are more stringent requirements before these cells can be injected into patients.
- Finally, I want to end with the concept of unproven indications. Our allopathic medicine has always been driven by the evidence-based approach. The questions ‘where is the evidence’, ‘was it a randomized clinical trial’ and ‘was there enough samples and study power’ are questions that we doctors ask other doctors when we discuss new therapies. But somehow for stem cells, we seemed to be drawn in by the big promise and potential that we seldom pose those questions. Let me explain further. Stem cell transplantation for leukaemias or as a rescue for high dose therapy for cancers are considered proven therapies. The cells are minimally manipulated after harvesting and they are for homologous use. For unproven indications like for stroke, myocardial infarction or Alzheimer’s, the therapy is still experimental hence must be done in a clinical trial setting. There are many ongoing clinical trials all over the world at this very moment and we like others who are not performing similar trials, must wait for their conclusions. If any one of us wants to do clinical trials then we must follow the standard practices and the regulations just like for an investigational new drug. One cannot just open up a practice, start advertising, and begin injecting desperate patients with the stem cells.
I am being brutally honest here and I know many would not be happy with the way I write this. But these are the realities and we as doctors and researchers should able to know when a treatment is proven and when it is not. Even if we want to offer something to our patients (who have no options left), first and foremost we should do no harm. There are patients who have died and also who have developed cancers because they were given stem cells for unproven therapies. I agree that Malaysia should not be left behind in stem cell research and therapy, but there are no short cuts. We have to go back to basics and understand comprehensive the biology of stem cells in the laboratory first. When we have shown how it works in a mouse or a primate model and prove that there are no short-term and long-term toxicities then we can start doing the first-in-man clinical study. Even if we are using the autologous approach (cells harvested from and given back to the same patient) and with minimal manipulation, we still need to show efficacy. Otherwise, we might as well inject distilled water into the patients, obtain a good placebo effect and get rich quickly. At least the distilled water does no harm to the patients.