Flaws and errors in cardiac cell therapy reporting – Interview with Darrel Francis

by Alexey Bersenev on July 22, 2013 · 0 comments

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Darrel Francis – Professor of Cardiology at the Imperial College London. He is a senior author of the recent report, which challenges the validity of research and clinical trials in cardiac cell therapy, conducted by Bodo-Eckehard Strauer’s group. He kindly agreed to answer my questions.

1. Dr. Francis, What is your interest in cardiac cell therapy and how and when did you notice some errors in Strauer’s group reports? Did you discuss these errors with colleagues before compile the data in your recent publication? What was an opinion about Strauer’s work in your field?

I was at first very impressed by Dr Strauer’s Hotline Lecture at ESC 2010. On returning home to UK, two of my fellows, Dr Sukh Nijjer and Dr Graham Cole, realised that the paper was already published and that the “comparable” baseline Ejection Fractions were very far apart (P = 0.0000006). Cardiologist Dr Ceri Davies of the Royal London Hospital, a connoisseur of linguistic gymnastics, observed owlishly that “the word comparable could simply mean capable of comparison”.
This is a worldbeatingly amazing lecture, because every slide of results is mathematically incorrect. Please ask your readers to try to spot the impossible features in the online webcast and then consult the official list of contradictions. This a test of watchfulness, which we call “DOH”.
We wrote to the authors via the journal for an explanation. We also remarked that their patients seemed peculiar: enthusiastic to have endless invasive investigations for no benefit to them, yet unwilling to have stem cells. The letter of questions was published, but there was no answer. We had several communications with the journal by phone and letter, and the board finally informed us that there was nothing wrong.

2. Can you tell us more about multiple errors from Strauer’s studies in terms of data validity and potential impact on clinical trials results and meta-analysis reports? How soon, do you think, official University’s investigation can assess the severity of these errors?

Since the middle of 2012 (and perhaps before) the university seems to have been investigating the work of Dr Strauer. It must be a gargantuan task. With access to all the detailed records, perhaps they are cross checking them against original patient records, which explains the enormous time taken, as there seem to be many hundreds and perhaps several thousands of patients claimed to be treated (depending on which of Dr Strauer’s versions of reality you use). One of their studies alone is supposed to be of 702 patients (See Table 1 of DOI 10.1007/s00108-009-2359-1).
We are only ordinary people rather than expert investigators, so we only looked at information that Dr Strauer has made publically available. All our sources are given as clickable links in Table 4 of our paper for anyone to quickly check for themselves.
If the university investigation is stuck, perhaps they could start with the 200 impossible features in Tables 1 to 3 of our paper. This may help them reach a conclusion in a finite amount of time.

3. Journalist Larry Husten of Forbes noted, that your report was also criticized by professionals for (quote i) “overstates the prominence of Strauer and the impact of his work” and (quote ii) “it fails to sort out minor or trivial errors from major flaws”. What is your response to this critique?

I have been reading the work of Dr Strauer, which frequently reminds the reader of his pivotal role. See slide 7 of his presentation. I don’t know of anyone who has been so successful in absolutely every stem cell project he embarks on. This “Midas touch” is deserving of some prominence. When the Journal of the American College of Cardiology, a leading cardiac journal, wanted a “State of the Art” review in 2011, it was to him that they turned. Unfortunately the review was riddled with factual errors. One of my students named this the “net” paper, since the holes are bigger than the substance.
It is true that none of the errors have been “sorted out” (i.e. fixed) by the authors or journals, nor seemingly noticed by any of the thousands of readers who have read the articles carefully enough to cite them. Perhaps someone else amongst the tens of thousands of readers have noticed, but – like me – have been unable to communicate this through the journal. We will never know, because the journals won’t say. Bone marrow stem cell therapy with the Strauer method can convert a patient with the most severe heart failure into one whose mortality is half that of the general non-heart failure population. Indeed it seems that possibly dead patients have been returning to have followup tests and report their symptoms. These events may seem trivial to some unnamed professionals who presumably have this happening in their hospitals all the time – but I find it exciting.

4. As we noted from the last week news, posted by Forbes, you also have scrutinized a recent report about results of C-CURE trial, conducted by company Cardio3 Bio. How serious are errors from this report and what is your response to the company’s comment on a Forbes web-site?

We haven’t scrutinised anything. We just noticed that in this non-Strauer enterprise, the numbers did not match, the percentages were wrong, and the clinical trials registration number pointed to a what seems to me to be a different trial sharing only the same company. I was briefly overwhelmed by déjà vu.
The good news is that the journal, which was not able to relay our questions on 3 previous stem cell papers that did not add up (link 1, link 2, link 3) is agreeable to doing so on this paper. The authors are composing a resolution which I imagine will be published alongside the questions in the journal.

5. Did you look at other cell therapy reports? If so, what is results of your analysis? Will you continue to watch cardiac cell therapy field precisely in the future?

We have learnt that JACC requires notification of discrepancies to arrive within 3 weeks, composed into the form of a letter and uploaded onto the website. Our university is too small to maintain this in the long term. I am looking for other institutions to help us in a rota system. If any reader is interested in joining our rota, please let me know. Perhaps they could take one month per year as the guardian of arithmetic.

6. One of conclusions, that we can make from your report is a problem with pre-publication peer review. What is your experience in communication with journal editors about errors in the papers before and after publication acceptance? Why do you think editors are not willing to respond to these issues rapidly? Do you think, will any retractions follow, based on your data?

I have spoken to the senior editors of both journals and the associate editor of one, about the questions raised in Int J Cardiol. All were cordial and thanked me for my efforts, but I came away with the impression that their processes seem complex and weighted in favour of not reporting discrepancies in papers.
We should not blame the journals or reviewers for accepting incorrect papers. We should only blame them for not making the discrepancies, once known, accessible to the readers of the paper.
We should also not blame peer reviewers. When I am peer reviewing an article, I think of myself as the author’s friend whispering in their ear, to prevent them from publishing something stupid. I try to be helpful. But I don’t have the raw data and I can’t see everything neatly like it is in the final paper, and I am not looking for discrepancies generally.
Finally it is possible that Retraction Watch is having an unintended consequence, even though I am a big fan. Journals can’t quietly retract an article giving vague reasons any more. Perhaps it would be better if someone set up an “Unretracted Watch” where obviously incorrect papers could be discussed. Appearance in that forum would give a journal a reason to move to the more respectable “Retraction Watch”.

7. One of the most discussed issues in cardiac cell therapy field is using left ventricle ejection fraction and other functional characteristics as an endpoint for clinical trials. Some professionals consider, that mortality and morbidity should be the most important endpoints in overall conclusion about efficacy. What do you think? How to choose endpoints wisely in cardiac cell therapy?

It sounds like they are having the wrong discussion. What is important is that the trials should be randomized and blinded. Non-randomized trials give no information at all, since volunteers generally do much better than non-volunteers (Clark AL, Lammiman MJ, Goode K, Cleland JG. Is taking part in clinical trials good for your health? A cohort study. Eur J Heart Fail 2009;11:1078 –1083.).
Unblinded trials are unwise because clinicians generally nudge values to fit in with expectations, since they know that individual measurements are unreliable. Differential care can also affect event outcomes. We have discussed (here and here) the crisis arising from using for scientific purposes measurements whose quality is so poor that they are only suitable for clinical practice. Similarly clinical practice relies on behaviours which if carried out in scientific environments would be considered misconduct.

Before embarking on the necessary very large (many-thousand patient) randomized controlled trial for a morbidity/mortality trial, we should first do reliable studies with physiological endpoints, to develop and refine the intervention methods. This requires setting aside clinical bad habits which can be painful to recognise. When I say this I am unpopular in the clinical world. But not liking a fact does not make it untrue.

8. Finally, what is your perspective on cell and stem cell therapy in cardiology? Will it revolutionize the field? What the field is missing to deliver a promise? What is the most promising cell type? Any hope for autologous bone marrow cells – whole and separated?

There are many types of stem cell therapy, and autologous bone marrow cells is only one of them. I am just a guy with a calculator, who has for a while been observing human behaviour in clinical research. I really know very little about the basic science of bone marrow stem cell therapy. In my optimistic moments I look to the wisdom of Dr Clarke’s words on http://stemcellheartcure.wordpress.com.

Thank you very much for your time Dr. Francis!

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