Days after Harvard Medical The school said it found falsified or fabricated data from the laboratory of an eminent heart researcher, doctors and scientists are soliciting a stop for a partly based medical trial on his work. They say that sick people should not be exposed to the risks of an experiment whose basic science has been questioned.
In the current process, funded by taxpayers, the heart stem cells are injected into the hearts of people with heart failure, in the hope that those cells – alone or in combination with others – improve the cardiac function of the patients.
The regenerative effects of those cells have been reported for the first time from an influential but controversial scientist, Piero Anversa, whose work was thrown into doubt. Harvard revealed that a year-long research had identified "falsified and / or fabricated data" in 31 articles in his lab, without specifying which publications were affected. Last year, the Brigham and Women's Harvard Affiliated Hospital, where Antwerp worked until 2015, reached a $ 10 million deal with the Justice Department to resolve allegations that data fraudulent had been used by the Antwerp laboratory in grant applications for federal funding.
On Wednesday, the New England Journal of Medicine withdrew a document and marked two others with an "expression of concern" intended to indicate that the data presented in the above articles may not be reliable. " The newspaper said it is waiting for more information on the two documents.
The New York Medical College, where Antwerp had previously worked, issued a statement stating that "a serious concern" was raised in a 17-year study. He said that an investigation was initiated.
Antwerp is not directly involved in the study of heart failure, which is managed by a national network of clinical trials supported by $ 63 million in federal funds. But given the tumult and uncertainty about the work that helped lay the foundation of the process, external researchers called for a break and a careful examination of the possibility of proceeding. The process involves inherent risks because it requires an invasive biopsy that can cause serious complications.
One patient died after their heart was punctured during a biopsy.
"I think the trial should be stopped, and they should have an external review," said Darryl Davis, a cardiologist at the University of Ottawa Heart Institute who is studying how to regenerate heart tissue. "The Antwerp data included some of the rationale behind that experimentation, and I think we need to understand better what these cells can actually do before subjecting patients to the risk of having an invasive procedure."
The Antwerp laboratory did the basic work in this field and provided the cells for a previous clinical study that was cited as part of the evidence supporting the current process. However, the National Heart, Lung and Blood Institute does not consider the process based on the work of Antwerp, according to Denis Buxton, director of the basic research and early research program of the institute. Buxton said that the process is based instead on an idea that originated from the original work of Antwerp – that cells secrete various molecules that help regenerate muscle tissue, although he said that "it is not a well-characterized effect. at the moment".
"Multiple preclinical studies have shown an improvement in cardiac function, and patients with advanced heart failure do not really have treatment options and have poor survival," said Buxton. There is "an irresistible need for new therapies that can improve the quality of life in these patients." I think the feeling is that this process has the potential to provide such an option. "
He said that a department that monitors patient safety in clinical trials should now be in charge of evaluating information on the 31 retractions required by Harvard and that patients would be advised of the council's recommendations.
The Antwerp lawyer said his client is based on scientific findings in his papers and on Antwerp I learned from the Harvard survey that a longtime colleague who left his laboratory in 2013 incorrectly altered the images. Antwerp says that, in many cases, those images can be replaced with correct images, and the result will still be valid, said his lawyer.
"There is nothing wrong with positive c-kit heart stem cells, and the study will answer questions about their efficacy in patients," Antwerp said in an e-mail.
Antwerp's work came to the fore in the midst of a broad enthusiasm for stem cells in the early 2000s. Antwerp and colleagues found that a type of heart cells called c-kit cells were able to give rise to heart muscle, opening up new possibilities to help heal patients after a heart attack or to reverse the inadequacy heart.
The discovery quickly led to clinical trials. The current study, called CONCERT-HF, is based in part on a previous clinical trial in which the Antwerp laboratory created c-kit cells to be infused into the heart of the patients. The report of the results of that process is now obscured by questions about image integrity stem cells that were created and characterized in the Anvers laboratory in Boston and then shipped to Louisville, where they were placed in patients.
Roberto Bolli, a cardiologist at the University of Louisville who led the trial, told the Washington Post that his team's work had nothing to do with cell production in Boston. He said he still has insufficient information on the problems in the Antwerp laboratory to know if they have influenced the cells supplied to patients.
"This is obviously an important concern, and we are trying to clarify this important problem," Bolli said.
The National Heart, Lung and Blood Institute said that CONCERT was not based on Antwerp's explanation of how c-kit cells work, but on an alternative mechanism that gained adherence while other researchers, who were not affiliated with the Antwerp laboratory , they discovered that the cells were not turning into heart muscle, and instead they were dying or merging with other cells. To explain the effects that cells had on cardiac function in animal studies, some researchers now say that the cells of kit c do not regenerate, but they secrete various substances, exerting what are called "paracrine effects".
Antwerp He told the Post that the CONCERT process is based on his work and he said in a telephone interview, "I'm not sure I really understand why the process should be stopped".
In the CONCERT study, cells are harvested from the heart and bone marrow of patients. Two types of stem cells are produced from these cells and then injected back into patient bodies – with patients randomly assigned to four different groups receiving c-kit cells, bone marrow-derived cells, either type or a placebo. The patient's death occurred after a biopsy of the person's cardiac cells and before the stem cells were implanted.
"I think it's time to pause and evaluate things like the CONCERT process," said Deepak Srivastava, president of Gladstone's institutes and president-elect of the International Society for Stem Cell Research. "And if there is no basis for this, I think that in most fields, most of such evidence would stop".
Elizabeth McNally, a cardiologist and director of the Center for Genetic Medicine at the Feinberg School of Medicine at Northwestern University, said that years ago she was excited by the results of the Antwerp laboratory, but then found it difficult to replicate them on her own. He described a "religious fervor" that took hold among those who believed that the c-kit cells were regenerating the heart that continued while the researchers tried to find factors that could be responsible for what he described as effects "from small to non-existent ".
"It's disappointing that it took so many years before this came out," McNally said. "It's a question of whether the process should continue, and I think that at the highest level the people who support the process should really see it again."
Charles Murry, director of the Institute of Stem Cells and Regenerative Medicine at the University of Washington, expressed concern for the safety of patients in the study.
"Since the scientific premise of this process is no longer valid, there do not seem to be any potential benefits that justify the risk," Murry He said. "If you were leading this process, I think I would stop it based on these recent developments."