Christopher Bravery – a consultant on advanced biologicals, has opened Cell Therapy Stream of the annual Bioprocessing Summit with worrisome note: “Half of approved cell and gene therapy products on European market eventually failed commercialization and were withdrawn“. Let’s look at it in details.

Since introduction of regulation cell/ gene therapy as Advanced Therapy Medicinal Products (ATMP) in 2007, 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
  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
  8. Zalmoxis by MolMed in 2016 (not finally approved yet as of today)

Now, let’s look at withdrawal history:

  1. MACI’s authorization was suspended in 2014 (1 year on a market)
  2. Provenge was withdrawn in 2015 (2 years on a market)
  3. Chondrocelect withdrawal is starting in 2016 (7 years on a market)

So, 3/4 (75%) purely cell-based ATMPs or 3/7 (43%) of all approved ATMPs were withdrawn in the last 3 years! We can exclude Zalmoxis, which yet to be approved, and statistics will be even worse. We can also exclude Glybera, which was administered only once in 3 post-approval years and considered as commercial flop, and statistics will be much worse. So, is this the solid case of failed ATMPs commercialization? Yes, at this point it is. I’m emphasizing “at this point”, because (i) 7 approved products is not big number for statistical analysis and (ii) 4 products were approved in the last one year and half – not long enough for analysis of market performance.

The question is WHY? 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 right indications?”. Of course, it is important to analyze each case of failed commercialization and post-marketing adoption. As far as I know, all 3 mentioned withdrawals were initiated by companies-manufacturers, but not by EMA. So, nothing wrong was with safety of these ATMPs. Also, at time of approval these ATMPs were deemed as “efficacious” in 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? I think so. Didn’t they account for competitors and reimbursement issues? I think so. In any case, as of today seem like most of cell and gene therapies in Europe are not commercially viable. We have a lot of lessons to learn from these failures.

So, as of today regulatory approval in cell/ gene therapy doesn’t mean commercial viability. I’d like to encourage you to discuss reasons for commercial failures. Also, please post all links to failure analysis, posted somewhere on a web. We all have to learn.

PS 1: At the time of writing this post, by some reasons, all information, related to Chondrocelect was absent on EMA web-site.

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CAR T-cell therapy is disruptive technology on many levels. One of such levels is regulation. On the one hand regulators have not seen such impressive efficacy data for long time and it is very inspiring (FDA keeps awarding CAR T-cell developers with “Breakthrough Therapy” designation). On the other hand, high efficacy “comes with a high price” of toxicity. At this point, regulators are not sure how to deal with CAR T-cell therapy-related toxicities (FDA used to suspend every trial after every death case). As a response to uncertainties, brought by ” fast and furious CAR T-cell explosion”, FDA recently made a smart (and unusual) move – announced a pilot project for CAR T-cell database. You can watch FDA’s presentation on the project here (starts on 2h 38 min).

The main goal of the project is to (1) collect CAR T-cell trials data across all submitted INDs and (2) analyze and utilize data for benefit of sponsors and the agency. Cytokine release syndrome (CRS), as the most frequent toxic side effect of CAR T-cell therapies, was a driving reason behind creation of database. It was FDA’s response to uncertainty about toxicities, associates with new therapeutic agent. This uncertainty is totally understandable, because until now CART field did not come up with common grading system for CRS (so there is no consensus on what to do if… happen). It is purely practical project, based on integration of huge amount of safety data, accumulated by the agency.

Two big chunks of data will be collected: (1) all about toxicities and (2) all about manufacturing (information, provided by sponsors as CMC part of IND). FDA’s benefit here is to know (i) how to deal with toxicities and (ii) critical quality attributes of CAR T-cell products. It could potentially improve FDA’s review of CAR T-cell INDs, making it more rigorous and efficient. Sponsors will benefit by receiving advice/ suggestion from the agency on mitigation/ response to toxicities and on technical improvements in product development. Basically, FDA can leverage collective wisdom for approval of better CAR T-cell therapies.

The most important part of this project is information sharing. As authors of the project have claimed, participation of sponsors in the database will be totally voluntary. All sponsors with CAR T-cell therapy INDs will be asked to collaborate, and may decline. FDA highly emphasized that they will ensure data confidentiality and there will be no sharing of proprietary information. What is not very clear to me is whether sponsor, who did not wish to participate in this collaboration, would benefit from it anyway (I’d guess – yes). Here is one interesting Q&A piece about data sharing:

However, Mildred Cho, associate director of the Stanford Center for Biomedical Ethics, asked whether FDA would share or present their analyses or aggregate data from the pilot.
O’Leary responded that the agency hasn’t gotten that far in their planning yet, but said that sharing of high-level data would not be “unrealistic.”
Keith Wonnacott, director of regulatory affairs at Novartis, responded by asking how FDA would protect confidential information if the agency plans to share data from the pilot.
In response, Shultz said she imagines the data would represent trends or ranges of information rather than individual data points that could be tied back to the companies that provided them, thus protecting individual sponsors’ commercial interests.

It will be great to see some pieces of data on public domain to get some “inspiring ideas” about your future product, but sponsors will be afraid of any sort of public sharing. The sharing with FDA should be based on trust, first of all. With wild commercialization of CAR T-cell field, information sharing between developers became impossible, but this database could potentially provide an opportunity to individual developer to learn from experience of 100 other developers through the messenger – FDA. Isn’t it great?

The manufacturing part of database at this point is much less clear than safety part. FDA got a lot of questions from RAC members about how agency will ensure the quality and comparability of such data. Let’s say if they will collect data on T-cell phenotype from incoming apheresis collection, how these data will be comparable across INDs if different antibodies, flow cytometers and parameters were used? How much data will be enough for statistical rigor (to draw the trend and find commonalities)? Will it be even possible? The same questions could be applied to whole manufacturing process – all developers use different cell culture media, processing devices, analytical methods and so on.

At this point, it is unclear whether pilot FDA”s CAR T-cell project will succeed. But, I think, idea is great! It looks to me like regulatory disruption, which could be applied (if successful) to other cell therapies in the future. Finally, I’d give a couple of advises to commercial CAR T-cell developers – (1) collaborate and (2) hire Kimberly Schultz after she will be done with her fellowship at FDA.

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The recent report, published in Acta Neuropathologica, describes 2 cases of spinal tissue mass formation after local transplantation of autologous olfactory mucosa in patients with spinal cord injury. Both patients underwent cell translplantation 7- and 5 years ago in Portugal as part of clinical trial. Patients were evaluated at University of Michigan Medical Center for progressive neurological symptoms and were diagnosed with spinal cord mass. Surgical findings revealed “multiloculated mass with mucinous, septated compartments”. Histologic examination and immunofluorescence showed presence of olfactory epithelium-like, respiratory epithelium-like excessive tissues and immature neural cells. Stem cells were detected by positive staining for p63 and keratin 5 markers.

This is not the first case of spinal cord tissue mass formation at the site of local olfactory mucosa transplantation. Very similar case was reported in 2014. Mucus-producing epithelium and respiratory epithelium was found in excised masses in all 3 cases. In all cases, cells were freshly isolated, but not propagated in culture. These studies demonstrated that autologous olfactory mucosa-derived stem/ progenitor cells are persist for long time (5-8 years), proliferate and differentiate in the site of spinal cord injury. The presence of respiratory epithelium may indicate to metaplasia of olfactory mucosa-derived cells.

Olfactory mucosa contains neural stem/ progenitor cells and olfactory ensheathing cells, which are proved to be “therapeutically useful” in experimental models of spinal cord injury. The efficacy of olfactory mucosa-derived cell transplantation remain unclear, since no results of Phase 2/3 well designed controlled trials were reported to-date. As per my personal communication with the author of report, there was no clinical improvement observed after cell transplantation in both patients. Absence of any clinical benefit was also described in patient from 2014 report.

Excessive tissue formation is becoming quite common, but still rare complication of regenerative cell therapy. Since complication manifest many years after procedure, these patients should be followed-up for 5-15 years.

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Brain tumor after infusion of fetal liver-derived cells in patient with diabetes

January 24, 2016

I’m continuing to document of all clinical cases reports on complications of cell therapy with focus on regenerative medicine. I’m trying to capture all published autopsy or pathology reports. I believe, such database will equip professionals with a knowledge and allow to avoid mistakes in future translation of cell therapies. Today, I’m going to highlight […]

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On conditional approval of cell therapy products

December 20, 2015

As you may know, about 2 years ago Japan has passed a new law for regulation of Regenerative Medicine. Under this law, the regulatory pathway for commercial cellular products is significantly accelerated by skipping of typical “Phase 3 trial” and allowance of marketing authorization after demonstration of safety and some (minimal) signs of efficacy (Phases […]

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Results of regenerative medicine clinical studies from 2014

March 1, 2015

Starting from 2014, I was trying to capture results of clinical studies in cell therapy. Today, I’d like to share some results of this attempt. I decided to narrow down my analysis to regenerative medicine, since most of cell-based therapies with published results belong to this category. Inclusion criteria and definitions Clinical study defined as […]

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Trends in cell therapy clinical trials 2011 – 2014

February 14, 2015

Post updated on Feb. 17, 2015 Today I’m sharing some of my data for the last 4 years. This is a snapshot of trends in cell therapy trials from 2011 to 2014. This year, I’m planning to make few posts on cell therapy trends. I’d like to analyze some trends in mesenchymal stromal cells, adipose […]

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Cell therapy clinical trials – 2014 Report

January 22, 2015

This is 2014 report of registered cell therapy clinical trials. Every year I give a snapshot of some tracked data, captured from international clinical trials databases. You can see previous annual reports here. Definitions and criteria I tracked clinical trials which fall in definition of cell therapy: administration of living cells in human with therapeutic […]

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Embryonic stem cells in cerebral palsy – results of clinical study from India

January 11, 2015

One clinical study, which was released 2 weeks before Christmas holidays captured my attention (but not attention of mass media). One of the most scandalous Indian “stem cell tourism” clinic Nutech Mediworld published(!) results of the study, which evaluates embryonic stem cell transplantation in children with cerebral palsy. Yes, you’re reading it correctly – embryonic […]

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Cell therapy clinical trials failures in 2014

January 4, 2015

Today, I’d like to highlight the most interesting, in my opinion, clinical trials failures, reported in 2014. As field is moving to efficacy (Phase 2) trials, we are starting to see more failures. In this overview, I’m going to focus on efficacy results. I hope we can learn a lot from these failures and avoid […]

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