The NIH acted with “an abundance of caution to ensure the study continues to meet the highest standards for participant safety and scientific integrity.”
After years of journal article retractions and fraud investigations related to “false and/or fabricated data” coming out of the laboratory of former Harvard researcher Piero Anversa, MD, the US National Institutes of Health (NIH) has pressed pause on an unrelated cardiac stem cell study.
Earlier this week, the agency’s National Heart, Lung, and Blood Institute (NHLBI) announced it has halted the phase II CONCERT-HF trial—at least for the time being—following calls for journal articles to be retracted in related fields of cell therapy research that raised questions about the “scientific foundations” for CONCERT-HF.
“While none of the articles in question derive from the CONCERT-HF trial itself, the NHLBI convened CONCERT-HF’s Data and Safety Monitoring Board (DSMB) over an abundance of caution to ensure the study continues to meet the highest standards for participant safety and scientific integrity,” an NIH statement reads.
Launched 4 years ago, CONCERT-HF has enrolled three-quarters of its target number of 144 patients, one of the trial investigators, Timothy Henry, MD (Cedars-Sinai Medical Center, Los Angeles, CA), told TCTMD. The trial is testing two different forms of stem cell therapy in patients with ischemic heart failure, documented coronary artery disease (CAD), and evidence of myocardial injury, LV dysfunction, and symptoms of heart failure. Participants are being randomized to one of four arms: a placebo infusion, mesenchymal stem cells, c-kit+ cells, or a combination of these two cell lines, all delivered by transendocardial injection.
The chief problem with CONCERT-HF for the NIH are the c-kit+ cells, the same type of cell used in Anversa’s laboratory.
To TCTMD, Henry stressed that the cells being used in CONCERT-HF have no connection with the Harvard lab, but are manufactured at the University of Miami Miller School of Medicine’s Interdisciplinary Stem Cell Institute and are subject to “constant” review. Moreover, while media reports have pointed to the sole death seen in CONCERT-HF as evidence of a safety signal, Henry noted that this death, a right ventricular perforation resulting in hemopericardium and tamponade following cardiac biopsy, was previously reported in the rationale/design paper, published earlier this year.
As such, Henry said he thinks it was “unethical” to stop the trial without scientific reasons.
The NIH says the pause will allow the DSMB to complete its review, something Henry acknowledges is “fair” and common practice in clinical trials. He also agrees with plans to check the safety and purity of the cell lines being studied. “Our argument is: do both of those things, but don't stop the trial unless there's some scientific evidence to stop the trial,” Henry said. “That's why I think this is dangerous, that the NIH lets publicity or politics within the NIH . . . drive their decisions.”
A Field in Turmoil
After years of set-backs, negative trials, and the Harvard debacle, Henry personally believes the likelihood of any cardiac stem cell therapy regenerating myocardial cells and improving ejection fraction in heart failure patients are slim. “But it’s important to distinguish the difference between acute MI trials, heart failure trials, and refractory angina trials, for example. They're different and the mechanisms of benefit, the cells that are used, and the delivery methods are different. So this [controversy] does not reflect the whole field. This issue was all based on whether cells can cause myocardial regeneration and it was rat and mice studies, and that continues be a very controversial area.”
On the contrary, Henry continued, “the evidence for cell therapy for refractory angina and critical limb ischemia is really good, again, nothing to do with regeneration. But for the casual reader, it’s like: ‘Oh, stem cells for the heart are bad.’ Well, it's way more complicated than that.”
Also contacted by TCTMD, Eduardo Marbán, MD, PhD (Cedars-Sinai Medical Center), similarly lamented the impact the controversy will have on the field. “c-kit+ heart cells are dead,” Marbán said in an email. “All claims regarding their efficacy and superiority, by whatever mechanism, have either been debunked or are suspect. The bar for continuing ongoing trials or for starting new clinical trials using c-kit cells should be very high—higher than normal, given the history of scientific fraud underlying the original claims of efficacy.”
Other cell lines have been much more extensively studied than c-kit+, he notes. “An important distinction must be made, however, between c-kit cells and other cell types currently in clinical development. Some such cell types have neither been tainted by the recent retractions, nor called into question by multiple high-profile failures to replicate earlier claims of efficacy.”
Of note, Marbán himself holds equity in and is the founder and scientific advisory board chair for Capricor Therapeutics, which is developing another cell therapy known as CAP-1002, an allogeneic cardiosphere-derived cell.
To TCTMD, Henry stressed that he had worked on multiple trials, funded by multiple different companies, and has no stock or equity in any particular cell line. He was the primary investigator for ALLSTAR, which was funded by Capricor, the NIH, and the California Institute for Regenerative Medicine. Many of the people quoted in the many media reports following this controversy have powerful intellectual, academic, or financial stake in the outcome of ongoing studies, Henry added, making it that much more difficult for the public to understand what’s at stake.
Anversa told the New York Times that it was his former lab member Jan Kajstura, PhD, who committed fraud and that he himself was unaware this was happening, a claim that’s been widely rejected by other experts in the field.