Trachea transplant

EU trachea transplant clinical trial TETRA “uncertain to take place”

The scandal of regenerative medicine researcher and surgeon Paolo Macchiarini and his deadly plastic tracheas repeatedly made world news. However, this human abuse, which started at the Nobel Prize-awarding Karolinska Institutet (KI) in Sweden and deaths of 8 patients (horrible as it was) was just a part of a much bigger horror story. The silent suffering and deaths of other trachea transplant patients of Macchiarini and his collaborators in UK and Italy, those who received a cadaveric decellurised trachea, is much less known. In fact, one of the 8 plastic trachea recipients, a young woman from England, was experimented upon while already on her death bed because of the cadaveric trachea transplant she received from Macchiarini and his partners from British university UCL in 2010. That young woman was one of 5 patients operated in this way at the Careggi University Hospital in Florence, Italy, and all 5 are dead. Just as another secret Macchiarini patient, operated illegally at the Barcelona hospital Institut Dexeus, outside of all oversight, is dead. A child patient operated in 2012 independently of Macchiarini, but with a similar technology at the Great Ormond Street Hospital in London, died just 2 weeks after the operation. We do not know how many victims of cadaveric trachea experimentation there really were, but there are just 3 known survivors, and two of them are still alive because their rotting cadaveric grafts were removed in time before suffocating them.

Because that part of Macchiarini horror trip remains in the dark (unlike his plastic trachea transplants), I focused my own reporting on it, by bringing back to memory all those dead patients which the hospitals in London, Florence and Barcelona pretend never existed. So far, the media narrative remained that cadaveric tracheas were actually all success stories, and this is why 62 patients were scheduled to be treated with those in two phase 1 clinical trials in UK and one EU-funded phase 2 clinical trial, all led by former Macchiarini partner, UCL laryngologist Martin Birchall. For the latter EU-wide trial with 48 patients, the Technical University Munich in Germany would be churning out cadaveric trachea grafts “regenerated” following a UCL recipe, which were to be then implanted into patients in UK, Italy, Poland and Austria.

All 3 clinical trials are now not going anywhere, also because the UK scientist Patricia Murray sounded alarm bells with British authorities and even the Parliament.

The European Commission now admits to me, through European Ombudsman, that their €6.8 mn phase 2 clinical trial TETRA with cadaveric tracheas, led by the UCL laryngologist Martin Birchall is unlikely to ever recruit any patients, because “the current delay to the INSPIRE project therefore makes the prospects for the commencement and completion of the TETRA project uncertain“.

INSPIRE is a phase 1 clinical trial in UK, suspended since December 2016, which was about to recruit 4 patients for trachea transplants using the technology of cadaveric tracheas Birchall developed together with his former partner, the scandal surgeon Paolo Macchiarini. The UK trial was suspended by UK authoritiesbecause of my reporting, its funding ran out and it is unlikely to be ever resumed. Even the official sponsor of both INSPIRE and TETRA, Cell & Gene Therapy Catapult, sulkily announced to change the status of the former trial from “active, not recruiting” to “suspended” at the website. And without INSPIRE (which EU Commission prefers to see as “delayed“, not as suspended) the phase 2 clinical trial TETRA becomes just a grave for tax money, but luckily not for patients. This is something however EU Commission sees no problem with, and these are their views declared to me in the nutshell, via a letter from European Ombudsman to whom I complained after my Freedom of Information request was rejected by EU Commission twice (here and here):

  • EU Commission refuses access to TETRA documentation because this could be “potentially causing reputational damage to the consortium and individuals linked to it“.
  • EU Commission sees no imminent “public health concerns or public benefits” because “the TETRA clinical trial is dependent on the successful completion of the INSPIRE project
  • The trial will not be terminated, and will simply trudge on until the end of its funding period on 31 December 2019.
  • EU Commission maintains that Macchiarini only transplanted plastic tracheas and had no contribution to the cadaveric trachea technology of INSPIRE and TETRA: “the scientific research involved in TETRA is pursuing a different method than the one developed by the doctor who has been subject to misconduct investigations
  • EU commission maintains that cadaveric trachea transplants, including those principal investigator Birchall was involved in, were either full successes (where patients survived) or they never happened (where patients died). The list of dead and mutilated patients who received cadaveric tracheas, which I specifically sent to EU Commission, was dismissed as not relevant for the current clinical trial

INSPIRE expired

Thus, if my reporting did not prompt the NHS Health Research Authority to suspend INSPIRE already in December 2016, and if Liverpool regenerative medicine researcher Patricia Murray hasn’t raised the matter with the UK Parliament (here and here), with relevant UK authorities and with trial’s funder Innovate UK, then Birchall et al would have recruited and operated their 4 patients. They would then probably have issued yet another set of incorrect claims (as Birchall used to do before with past trachea transplants), all with full support of UCL who recently went to great lengths to whitewash their professor of all responsibilities in an external investigation, which then enthusiastically called for INSPIRE to be resumed. These proclaimed successes would have prompted EU regulators to swiftly issue an ethics approval for TETRA, and 48 patients in UK, Italy, Poland and likely also Austria would have received defrosted trachea grafts, which Birchall’s own research proved (both in vitro and in vivo, in a human patient) were liable to collapse inside patients and suffocate them.

But of course this is where TETRA participants and EU Commission expected stem cell magic to save the day and the lives of their prospective industrial resource, pardon, patients. The magic was supposed to be Made in Germany, at the clinic of TU Munich, which received from EU €900k to build a new trachea-regeneration facility. There, the grafts were namely to be decorated with patient’s own bone marrow cells, which will then become tracheal cartilage rings and magically let blood vessels sprout, something which even Birchall’s own UCL admitted already in 2015 was not supported by any scientific evidence.

The EU Commission simply has little luck with their regenerative medicine investments. They had to terminate Macchiarini’s own €5.5 Mn trachea transplant trial BIOtrachea in 2014 because, after a patent fight with UCL the Italian surgeon switched to using a different type of plastic which patent he owned, but which for the EU bureaucrats was not novel enough (read here). Recently EU Commission decided to invest €2.3 Mn into the business of a former Macchiarini associate, Suchitra Sumitran-Holgersson, after she and her surgeon partner were found guilty of misconduct and patient abuse for exactly same decellurised vein transplants the EU now wishes to see implanted in even more patients (read here, there was even an unethical trachea transplant). Yet another former Macchiarini associate from Germany coordinated a €5 Mn EU-funded clinical trial with overpriced decellurised heart valves (made by his own company) which were decreed to become alive and growing, all that without much actual scientific evidence (read here).

But those funding sums are actually peanuts. A HOPE consortium (now part of FET Flagship proposal Biofabrication for Regenerative Medicine) is very hopeful for EU Flagship funding worth of €1 Billion, their promise: “3D Biofabrication of functional & vascularized artificial living human organs” for transplantation, “thus eliminating transplantation waiting lists“. The consortium which some very eminent European stem cell researchers have joined, expects “an organ fabrication line” up and running by 2030 the latest, even “at the bedside” (read here). Knowing how EU Flagships evaluations work and how desperate EU Commission seems for at least some regmed miracles, 3D organ bioprinting might indeed get funded with a billion of Euro for 10 years.

This is probably why EU Commission will rather sink €9 Mn into Birchall’s TETRA and Sumitran-Holgersson’s VeriGraft and move on, rather than terminate those like BIOtrachea and admit being wrong about regenerative medicine once again.

EU Commission sets facts right

Because they cannot afford admitting a mistake, EU Commission and the European Ombudsman repeatedly educated me that Birchall’s research has nothing at all to do with Macchiarini’s, in fact they now declare the finger-pointing at TETRA as nothing else but a misguided obsession with the Macchiarini scandal:

“the Commission is aware of a particular interest from some individuals regarding the TETRA project, given a research fraud and misconduct scandal in the same field of research”

And this is why EU Commission, as the highest scientific authority, sees it as important to once again stress that

“the scientific research involved in TETRA is pursuing a different method than the one developed by the doctor who has been subject to misconduct investigations”.

When I asked how that method is in fact different from Macchiarini’s (and in fact, also Birchall’s), I was referred to a statement from an EU Commission spokesperson I received already on 23 April 2016:

“In the TETRA trial, natural, decellularised and re-seeded donor-derived trachea scaffolds would be used, whereas in other projects referred to, synthetic scaffolds were developed and used. Compared to other trials with donor-derived tracheas, the approach that would be used in TETRA is more sophisticated, by using two investigational medicinal products (IMPs) and supporting techniques (adding muscle or other tissue flaps to provide a vascular base for the new trachea). In addition, the decellularisation procedure that would be applied to donor trachea is more standardised and advanced compared to methods used in earlier trials.”

First of all, the addition of “muscle or other tissue flaps” is totally useless to revive a piece of dead tissue, as trachea transplant expert Pierre Delaere once told me. It is not like there are any animal studies published by any of TETRA participants which can substantiate that authoritative claim of EU bureaucrats. Quite the opposite in fact: from the documents submitted in 2016 by TETRA coordinator to European Medicines Agency (EMA) we learn that there were indeed two trachea transplants performed, on two pigs:

“The first animal was to be recovered for 36 days; however it died spontaneously at 32 days post surgery, without predisposing symptoms or condition. The second animal was to be recovered for 28 days, however it was terminated at 12 days post surgery due to signs of respiratory compromise incompatible with life. The study was stopped on humane grounds”.

This basically means, TETRA technology has a 100% mortality rate. Cadaveric tracheas seem almost as effective as those made of plastic: in killing people, that is. That, and the fact that defrosted decellurised tracheas are very prone to collapse, something Birchall’s own research determined and which even Macchiarini knew and admitted, is apparently of no concern to EU Commission.

The best bit however is the schizophrenic state of bureaucratic denial by EU Commission who still maintain that Macchiarini never used cadaveric tracheas, only plastic. In reality, Macchiarini transplanted at least 9 patients with cadaveric tracheas, 6 are dead, two survived by getting their grafts removed. Birchall was involved with at least 3 of these patients, next to his own trachea transplant patients (see this list). In March 2010, the UCL laryngologist even on behalf of his UCL claimed credit for that secret and illegal trachea transplant operation Macchiarini performed in 2009 in Barcelona, on a 55 year-old female patient who later on died:

“Professor Macchiarini’s seminal work, together with the UCL team, has now saved the life of two adults and one child”.

Maybe these victims of Macchiarini’s and Birchall’s experimentation are what the EU Commission referred to as “other trials with donor-derived tracheas“. Thing is, one can safely bet that the same TETRA grant proposal I am not allowed to see presented those very patients as success stories, by misrepresenting their clinical evolution or their causes of death. In fact, EMA submission from TETRA coordinator does exactly this. This is probably the real reason why EU Commission refuses to release the TETRA documentation. No one should see what lies they fell for. Indeed, here is what TETRA still publicly announces to EU Commission, the tax-paying EU citizens and the world:

– Build on our successful compassionate use experience using autologous stem cell seeded scaffold-tracheal transplants in 48 patients
– Follow on from our Phase I 4 patient INSPIRE clinical trial which will improve on the clinical prototype used in compassionate use cases
– Conduct a 48 patient Phase II pivotal clinical trial to provide robust, quality data with validated GMP manufacturing processes to support an accelerated route to market for commercial exploitation in this orphan indication

It must be some obscure EU bureaucratic definition of “successful compassionate use experience“, because it has nothing to do with the reality of deaths and suffering those tracheas brought.

Thanks to my readers

It is only thanks to the activism and the contributions of my readers, which my reporting absolutely relies on, that patients are being spared dangerous trachea transplants and both INSPIRE and TETRA are now completely derailed, becoming nothing else but a huge research money waste. My special thanks go to already mentioned University of Liverpool professor Patricia Murray, and to Elizabeth Woeckner and her Citizens for Responsible Care & Research, Inc. (CIRCARE) in Philadelphia, USA. Many people owe their lives to them, without even knowing it.

Not ready to admit having made a mistake, the EU Commission (and European Ombudsman) still avoid acknowledging that INSPIRE was suspended without much hope to be ever resumed. They speak instead of the clinical trial being “delayed”, as if it is about to deliver its positive results at some point, with cured patients and their genius doctors beaming from newspaper photographs, inviting 48 more patients to enlist. Only in point 34 on page 9 does European Omdusman use the embarrassing s-word:

“It is uncertain even whether the TETRA clinical trial is going to take place. As the Commission has explained, and as is clear from publicly available information [referencing UK Parliament submissions by the INSPIRE funder Innovate UK and by INSPIRE sponsor Catapult, -LS] the TETRA project (a planned phase II clinical trial) relies on results to be obtained from a phase I clinical trial to be carried out under the INSPIRE project. The INSPIRE project was suspended in December 2016. So far no patients have been recruited for, or treated on, the INSPIRE trial. It is thus not currently possible for the participants in the TETRA project to request authorisation for the phase II clinical trial.”

Valley of death avoided

TETRA’s coordinator, the Liverpool-based company Videregen (where Birchall is paid advisor), received so far from the EU exactly €2,617,740.38. TETRA’s EU site might indicate how that amount was distributed among consortium partners (Medical University Vienna abandoned ship with only €2,500, while €65,500 were sunk into the recently dissolved project manager Euram Ltd). Videregen’s apparently pocketed over €1.5 Million, quite a lot for “a spin-out of technology developed at Northwick Park Institute for Medical Research (NPIMR)” which fought against bankruptcy until UCL and their trachea transplants came along, as Videregen’s CEO Steve Bloor declared:

“The ‘valley of death’ is very real. We might still be there if it wasn’t for our partnership with the Cell Therapy Catapult and UCL and the funding from Innovate UK. It was critical in persuading investors that we were a credible group of people, and helped us attract a further £1.2 million in private investment”

According to Bloor, “for the trachea transplants alone, we estimate the market value across Europe and the US could be up to £300 million” and this is maybe why his Videregen totally forgot to inform its investors and the UK Social Stock Exchange that INSPIRE clinical trial (which the money shower depends on) has been suspended. Bloor’s Videregen did announce that they expect “initial positive clinical data” from phase I trial INSPIRE by 2019 and TETRA starting right after.

While Videregen is the official sponsor of TETRA, their partner Cell & Gene Therapy Catapult is the sponsor of INSPIRE. Just like EU Commission and Videregen, Catapult was also very reluctant to admit that the phase 1 clinical trial is suspended (though they had no alternative in their submission to UK Parliament’s Science and Technology Committee, prompted by Murray’s critical letter). Keith Thompson, CEO of Catapult, reiterated on March 14th the EU philosophy that Macchiarini solely and exclusively “undertook a number of tracheal replacements with synthetic tracheal grafts“, never a cadaveric one, and that “the technology of these synthetic tracheal grafts bears little relation to that of the INSPIRE trial“. Thompson then explained why in his view INSPIRE should remain listed as “ongoing, and participants are receiving an intervention or being examined” despite being utterly voluntarily “stopped early” in December 2016:

“because the trial had not started patient recruitment, no patients have been treated and there have been no site initiation visits, the trial status on the database was changed to reflect that it was active but not recruiting rather than suspended because it was felt this reflected better that trial hadn’t initiated rather than being stopped early”.

In that email, Thompson sounded very sure that UK Medical Health products Regulatory Agency (MHRA) will soon greenlight INSPIRE at their upcoming meeting. Indeed, MHRA and Birchall go way back. Birchall et al thanked “the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA), especially Ian Rees, who gave timely and free advice on regulatory aspects of this case” in their not entirely honest paper Elliott et al Lancet 2012, about a 2010 trachea transplant. The advice went both ways: Birchall is in fact a self-declared “Technology Advisor to MHRA”, one wonders on which technology exactly. No wonder MHRA regularly told myself and others to bugger off when asked about Birchall’s clinical trials.

What a surprise the Catapult CEO must have had despite such previous smooth partnership with MHRA, as he wrote 4 days later:

“We met with the MHRA on 15th March 2018 to discuss our assessment of risk, during which we informed them that we are formally suspending the trial (and will amend the relevant Clinical trial registries to reflect this) while we gather further information on the product”.

The status of INSPIRE on is was changed to suspended on March 29th 2018. With this, TETRA is as good as over. No patients were harmed in the making of this travesty.

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Leonid Schneider
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One thought on “EU trachea transplant clinical trial TETRA “uncertain to take place””

  1. I am student of clinical research. I found your article very helpful for my project research. It has cleared my doubts about this topic and I am obliged for this informative post. Keep sharing.