Approved cell and gene therapy products fail commercialization….

Cell and stem cell technology, especially when genes are involved, are an exciting new field in medicine, which from a scientific point of view can improve quality of life of human beings considerably.

Christopher Bravery – a consultant on advanced biologicals, has opened “Cell Therapy Stream of the annual Bioprocessing Summit 2016” with a worrisome statement:

Half of approved cell and gene therapy products on European market eventually failed commercialization and were withdrawn.

Here are the details, why he comes to this conclusion.

Since introduction in 2007 of regulations for cell and gene therapy by the EMA in Europe as Advanced Therapy Medicinal Products (ATMP), the following seven (+1 to be) cell and gene therapy products were approved by EMA:

  1. Chondrocelect by Tigenix in 2009

  2. Glybera by uniQure in 2012  – Market price: 1.1 Million Euro

  3. MACI by Genzyme/ Sanofi/ Vericel in 2013

  4. Provenge by Dendreon in 2013

  5. Holoclar by Chiesi in 2015

  6. Imlygic by Amgen in 2015

  7. Strimvelis by GSK in 2016 – Market price: 594.000 € with money back guarantee in Italy!!

  8. Zalmoxis by MolMed in 2016 (not finally approved yet as of today)

Now, let’s look at their development in the market:

  1. MACI’s (3) authorization was suspended in 2014, just after being 1 year on the market.

  2. Provenge (4) was withdrawn in 2015, i.e. after  2 years being on the market.

  3. Chondrocelect, (1) withdrawal has been starting in 2016, after 7 years on the market.

So, 3 out of 4 (75 %) purely cell-based ATMPs or 3 out of 7 (43 %) of all approved ATMPs were withdrawn in the last 3 years! If we in this review exclude Zalmoxis, which yet has to be approved, the statistics will be even worse.

If we furthermore also exclude Glybera, a cell product which comes with a price tag of 1.4 Million US-Dollars per treatment, and which was administered only once in the three post-approval years and widely considered as a commercial flop, due to reimbursement problems, the above statistics will be much worse.

So, Christopher Bravery asked, is commercialization the solid case of failed ATMPs. Well, at this point, it apparently is! He, in his review was, however, emphasizing on “at this point”, because just only 7 approved products is not a big number for a statistical analysis besides, besides 4 products were only approved in the last one year and half – not long enough for a deep analysis of a market performance.

On the other hand 7 products approved in the last 10 years have also shown that the promise of advanced medical treatments with cell and stem cell therapy is not realizing as fast as it was thought by many.

Nevertheless, the question is “WHY is cell and stem cell treatment not being quickly applied in medical practice, and why commercialization of cell-based products is failing”? Christopher Bravery asked the audience: “Do we focus too much on regulatory approval, but not enough on commercialization?” Yet another question he asked: “Are we choosing the right indications?” Of course, it is important to analyze each case of failed commercialization and post-marketing adoption, but it does not explain alone why cell and stem cell treatment in Western Countries in spite of clear scientific advances and favorable safety reports is not applied in patients. All three mentioned withdrawals were initiated by the companies, manufacturing and marketing the product, but not by EMA according to Christopher Bravery. So, very clearly there is nothing wrong with the safety profile of these ATMPs, so much so more at the time of approval these ATMPs were deemed as “efficacious” in their intended applications.

However, the market is harsh. Sales were not as good as expected and companies were making business decisions. Were developers over-optimistic at the time of approval? Christopher Bravery think´s so and so do I. Didn’t they account for competitors, with favorable alternative technologies and reimbursement issues? Obviously not that deeply! In any case, as of today, it seems like, most of cell and gene therapies in Europe are not commercially viable. We have a lot of lessons to learn from these failures.

As I am also consulting in this field, I have asked myself often the questions “How can we bring new emerging cell and stem cell technology successfully to the market” especially in view of the cost of developing new medicinal products which had been skyrocketing in the last decade, to about 2.6 Billion US-Dollars per development and application, beside the long approval period of more than 10 years!  See also the link:  http://www.bioworld.com/content/tufts-study-cost-develop-new-drug-balloons-26b-0

I believe that Western Countries are too much focused on the “somewhat outdated model of regulatory approval for new cell and stem cell based medical products. The regulatory concept for the allopathy treatment model was and is still today adequate for approving medicinal products for human use. Technological advances, however, are giving us the tool to treat patients different, than just with mainstream medication, approved by regulatory.

The global increase in “Complementary and Alternative medicine / CAM” is indicating the dilemma physicians are facing. According to a recent MAYO clinic report about 40 % of patients are trying to find additional support with CAM therapies as mainstream medication does not improve their medical condition.

Cell and autologous Stem Cell treatment from my point of view is part of this so-called CAM therapies, which puts all involved into a difficult regulatory “Dark area”! I believe it is time to follow more strongly the philosophy of “medical treatment with investigational character ” in the responsibility of a physician than let regulatory and industry try to find a solution by modifying, basically  copied natural process, highly manipulated, to eventually provide physicians with a “treatment in a bottle “ which may fit a large treatment spectrum.

Cell and stem cell technology is a disruptive technology, which changes the treatment of diseases as we know dramatically, and like with all changes there are strong movements to find ways to maintain a “status quo”! The Result is, that in reality in the last ten years since FDA / EMA are regulating this new therapeutic field basically none of the products initiated by industry are really successful and that patients are finding ways to bypass this situation by engaging in medical tourism to places where they potentially find help to improve their condition.

I have seen good and less successful treatments, but in the end, with traditional approved medicinal products we have the same situation as clearly indicated by the government statistic in respect of adverse events of approved drugs.

From my point of view, we have to find a way where regulatory supports new technologies and its application without overregulating it, due to safety concerns in respect of potential treatments of patients. Unfortunately, the regulatory environment is becoming even more complex as regulators try to enter the domain of “medical procedure” with guidelines not being helpful for the further development of cell and stem cell related therapies. According to the FDA /EMA, guidelines are not binding, but on the other hand FDA / EMA can issue warning letters when guidelines may potentially be violated. This situation, intended to clarify the application of this new technology, unfortunately, has increased the uncertainty of treatment with cells and stem cells.

Until this is not changed, we will have medical tourism to countries supporting those new technologies where certified clinics and doctors, are advancing with new application of scientific knowhow, not yet approved by western regulatory agencies.

A good example is autologous stem cell treatments. Tens of thousands of patients had been treated globally already with autologous stem cells for various conditions. It is proven that there was no adverse event in any of the treated cases. FDA / EMA is not adjusting its regulation for those new technologies. Can there, will there be a problem with this kind of treatment, of course, there will, like with FDA / EMA approved medical products. Medical doctors are always trying to help patients in their medical need, but they are not always successful! Why are we pretending that mainstream medical treatment is different than investigational medical treatment in this respect?

As mentioned before, the way out is to be more open minded and to adjust the approval process by separating highly manipulated modern gene, biological and chemical based technologies from those easily performed at a physician as a medical procedure with own, autologous cell and stem cells.

In Europe, PRP treatment is considered not to be an advanced therapeutic medicinal product and can be used freely, whereas autologous stem cells are considered as ATMPs and therefore has to be following the clinical trial concept before used in human application.  This shows clearly that regulators do not understand the new technology as they rule old and new with the same regulation, blocking clearly scientific advances.

As long as the discussion “standardized medical treatment with industrial GMP processed patented products” versus “personalized treatment with autologous cell and stem cells as a bed side treatment by a physician as a medical but not product procedure” is not fully separated in the regulatory framework, medical treatment advance will be applied in countries where this concept is understood and regulated accordingly, like Japan , Australia, many other Asian countries, but also Panama, Mexico or the Bahama,  not following the somewhat outdated regulatory framework, but already adjusted it to support the new medical treatment technology.

The dilemma and poor result of R&D effort and its commercialization with regulated advanced medical products (ATMPs) is well documented by the review of approved ATMPs in Europe, by Christopher Bravery and a clear indication why we in Western Countries are facing a growing medical tourism, or even a kind of underground treatment activity, while the industry and sponsored scientific institutes claims, that doctors performing increasingly treatments with so-called unproven products and methods.

In our today’s globalized environment, patients have the possibility to find help in their “unmet medical need” by searching the digital information world available 24-7-365 times, and ONLY need to look for qualified clinics, as autologous cell and stem cell treatment had been proven all over the world to be safe and at least partially effective as documented in thousands of anecdotal studies and individual testimonies have shown.  

An anecdote is a story, and according the mainstream medicine not a study, as it refers to an individual’s experience with their disease or symptoms and the effort by a physician, often applying complementary and alternative medical treatments to treat a medical condition. People, but also modern, open minded physician, generally find anecdotes highly compelling, while regulatory agency and the allopathy trained scientists and doctors are deeply suspicious of anecdotes, claiming that they are not controlled studies, i.e. following the clinical trial route, and therefore cannot be considered as evidence based studies, like done with regulatory approved medicinal products.

Well, on 3 December 1967, South African doctor, Dr Christiaan (Chris) Barnard, performed the world’s first human to human heart transplant,  Dolly the sheep, on July 5, 1996,  was the first mammal to have been successfully cloned from an adult cell. If regulatory would have been involved, this never would have happened, besides it was anecdotal, and today it has opened up a huge new field of applied science, where heart transplant is after 50 years accepted as a medical option by mainstream medicine. Dolly was cloned by a team of Scottish  scientists at the Roslin Institute, part of the University of Edinburgh, Scotland, and Cloning a mammal defied the scientific dogma of its time. The success led to dire and fantastic predictions: Humans would be cloned. Diseases would be prevented. Lost children rebirthed, resulting that regulatory agencies all over the world started to define what maybe ethical cloning and what not. Today we can say that Cloning has had a bigger impact on science, but a smaller one on human life, than many expected. What will be considered as “normal” is time dependent and what will be in 20 or more years from now, who knows?

The only thing to add to this is, wherever you are, whatever your profession is, if you have not yet understood that everything has a life cycle, and changes are a continuous process of life and environment, please visit an open minded medical professional to  “Welcome you to the constantly changing 21st Century environment”!  

 

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