Last of two parts.
A secretive experiment revealed this week, in which neurosurgeons transplanted brain cells into a patient with Parkinson’s disease, made medical history. It was the first time such “reprogrammed” cells, produced from stem cells that had been created in the lab from the man’s own skin cells, had been used to try to treat the degenerative brain disease. But it was also a bioethics iceberg, with some issues in plain sight and many more lurking.
In 2013, the soon-to-be patient, George Lopez, gave $2 million to underwrite research on cells in lab dishes and rats that was required to show that the surgery might be safe and possibly even effective. Lopez, a former physician and the wealthy founder of a medical equipment company, also paid for the legal work required to get Food and Drug Administration approval for the two surgeries. Cells were implanted on the left side of Lopez’s brain in September 2017 and the right side in March 2018.
“When individuals paying to fund research leading to a therapy are also the first to receive it, there are concerns,” said Brian Fiske, vice president for research at the Michael J. Fox Foundation, which funds research on Parkinson’s.
The researchers — stem cell biologists, neurologists, and neurosurgeons — did everything by the book. They received approval for the experimental surgeries from Weill Cornell Medical Center, Massachusetts General Hospital, and the FDA. And in a paper published Wednesday in the New England Journal of Medicine, they disclosed that the patient had funded early research.
Some medical ethicists were left uneasy, however, about four aspects of the pioneering work:
Scientific integrity: When neurobiologist Jeanne Loring of the Scripps Research Institute learned from a friend of Lopez’s in 2018 that the transplants had taken place, she said, “I was very surprised. With the patient paying for the research, it seems like something that would be done in a Third World country.”
In fact, the number of clinical trials that charge patients to enroll is growing so quickly that bioethicists have a name for it: pay to participate. That usually means researchers solicit donations or other payment from patients, which can be exploitative. But it can also work the other way, with patients approaching scientists.
The fact that Lopez sought out biologist Kwang-Soo Kim of McLean Hospital, who created the dopamine-producing neurons that were transplanted into Lopez, reduces ethical concerns about patient exploitation. And if patient payments can help defray the costs of research, more such trials can be done.
That’s how Kim saw it. His government research funding had been cut, and without Lopez’s money, his progress would have been severely slowed, he said.
Although Lopez’s 2013 check was not premised on going to the front of the line, said Kim, “when he realized that our research addressed the major issues [of] safety and efficacy, he wanted to be the first patient.” Several neurologists examined Lopez, Kim explained, “and concluded that he is a reasonable candidate for this.”
Nevertheless, Lopez’s close participation in the research — he also recruited the neurosurgeon to do the transplant — raises concerns about scientific integrity. When a patient funds research leading to a clinical trial, “scientists can be incentivized to make decisions that are optimized for the patient-funder and not the science,”said bioethicist Jonathan Kimmelman of McGill University.
For instance, the ideal patient for a single-participant trial like this might have certain characteristics, but if the patient has paid for the research, it can “create incentives to compromise on that rather than adhering to the highest scientific standard,” Kimmelman said.
There is no evidence that happened here, he added. But the review-board approvals do not guarantee it didn’t. Such institutional review boards focus on patient consent and safety. “They’re not focused on scientific merit or on how the study should be designed,” Kimmelman said. “They’re asking if the risk-benefit ratio is reasonable.” IRB deliberations are not public, and it is not known how much they considered the question of the patient’s funding Kim’s research.
Other researchers have resisted the temptation to raise money from patients in return for access to an experimental therapy. “We seriously thought about it,” said Loring, who is also the chief scientific officer of Aspen Neuroscience, which is aiming to commercialize a personalized stem-cell therapy for Parkinson’s. “There are people we’d like to treat sooner rather than later, but [a one-person experiment underwritten by the patient] could distract from a real clinical trial.”
The researchers involved in the Lopez surgeries were not part of the “GForce-PD” consortium of scientists sharing data and cooperating to bring stem-cell-based therapies to Parkinson’s patients. And they did not tell other experts what they were planning or even that the surgeries had taken place before they published the paper this week.
Informed consent: Medical ethics requires that patients understand the risks of an experimental therapy before they can consent to it. Kim argued that Lopez’s medical background and deep dive into stem cell research (attending conferences and reading scientific papers) meant he understood the risks of the never-before-attempted surgery better than the average patient.
“I’m actually pretty sympathetic to the idea that he was super-informed,” said medical ethicist Alison Bateman-House of New York University’s Grossman School of Medicine. But Lopez’s financial stake might have overshadowed his decision about being the first guinea pig. “Can he really provide informed consent after buying in to the science?” Bateman-House asked. A strong desire to show that his investment paid off could have influenced his thinking. (Lopez said that did not happen.)
Bending science to a rich person’s will: Pay-to-participate creates the perception that “researchers can just be bought,” said a bioethicist who knows some of the scientists involved and asked to remain anonymous to preserve professional relationships. “We want to believe that science advances where it’s most promising. There is something deeply inequitable about a wealthy individual commandeering research resources.”
The problem here isn’t that Lopez received a transplant that thousands of other Parkinson’s patients wish they could try, but that a massive research effort was launched on his behalf because he paid for it. “In my opinion we have an obligation to make sure that scarce resources, such as scientists themselves, are directed toward the greatest possible good,” Kimmelman said. “If a model like this takes hold — and it’s not hard to imagine — then academic medical centers might move their research to where the money is, not where the greatest scientific promise and medical need are.”
The wealthy can buy safer neighborhoods to live in, better education for their children, better medical care, and much more. “The gorilla in the room is the justice issue,” said Bateman-House, as the rich go to the front of the line. The potential benefit to other Parkinson’s patients mitigates the me-first aspect of this case, however, she said, “so I’m OK with it if it advances the science. But it has to be publicly shared.”
Secrecy: That finally happened with the publication of a paper describing the transplant, and the creation of the dopamine cells, in the New England Journal of Medicine on Wednesday. But the surgeries took place in 2017 and early 2018.
The scientists originally told STAT six months after the second surgery that they were willing to go public about their work. They would discuss what they had done, focusing on the research Kim did to create the cells, but not announce any results, since it was too soon to know whether the transplants helped Lopez.
Rumors were flying that unnamed researchers in Boston had carried out this experiment. But Kim and his colleagues changed their minds about discussing their work, deciding to wait until it was clear how Lopez was doing.
“The impact of negative outcome,” Kim said in 2019, “will be unmeasurably huge, as we experienced in the gene therapy field,” when the 1999 death of a patient in a gene-therapy study effectively froze the field for more than a decade. “This is why our team decided to be cautious and pursue this case without any premature public announcement. We believe that our plan is still the best course and that it is reckless to pursue the publicity without real data.”
The NEJM paper — and a STAT story about the experiment that was published Tuesday — therefore appeared 32 months after the first surgery.
“That seems like an awfully long time,” said Bateman-House. “It’s OK to wait until you have more data before disclosing results, but at least give us something in real time. You have an ethical responsibility to disclose what you’ve done, such as in a paper presented at a medical meeting.”
Alternatively, said Scripps’ Loring, they could have shared their plans with the “GForce-PD” research consortium. But they didn’t breathe a word about their plans, or even the fact that the surgeries had taken place.
“There is a lot riding on this,” said Loring. “It would have been nice to get a heads-up.”
Re this: “When a patient funds research leading to a clinical trial, “scientists can be incentivized to make decisions that are optimized for the patient-funder and not the science” – when researchers get a grant from the NIH/NIS, they do not get it from “science” but from the government-funder, and the same concerns should apply. Or not? Why not?
“That usually means researchers solicit donations or other payment from patients, which can be exploitative”
Oh yes, imagine actually paying for the extra-special services you are going to receive, how exploitative! Gosh, that’d only be like everything else under the sun.
In my old age I have become jaded and can’t help but wonder if the ethicists would have had the same issues if the stem cells had been fetal.
This research will become public and even though Mr. Lopez paid for it, the knowledge will benefit everyone. My mother died from the effects of Parkinson’s and seeing this vibrant woman’s body waste away and then her mind is just one of many things I would never want to see someone else die from. If this therapy works then its one more horrid disease that humans have defeated.
I’m not a bioethicist but have been a long-time member of my institution’s IRB. I think the stated ethics concerns are exaggerated. IF the fundamental hypotheses were sound, IF the investigators and surgeons were qualified to do the work, IF the approvals were in place, IF the patient was truly a good match for the procedure to be done, I don’t see a serious problem with the patient self-funding himself to the so-called ‘front of the line’. If the method works, he will have contributed to positive outcomes for other people, most of whom will not have equal resources, to follow.
I agree with Brent. This story seems to be a tempest in a teapot.
What about companies started by rich people to find treatments for their child with a rare disease? STAT has done a few stories on these companies and I don’t recall a lengthy disclaimer attached with the points raised above. The child would undoubtedly be first in line for an approved treatment (or enrolled in the trials).
What about N-of-1 clinical trials? STAT’s done some stories on those as well, same deal.
And finally, what about Sarepta and their never-proven DMD treatments? Talk about “scientific integrity” …
It is relatively uncommon for “minor” maladies to find reasonable funding. Why it unethical to fund such research from a private source? Would it have been ethical if the research funds had been directed at a more common problem such as cancer? Given the motivation of the patient it seems to me that to ask the patient to fund something such as cancer, which he did not suffer, and not fund research for his own malady is unethical in the extreme.
We live in a time where everything new is a sensation. Given the risk of failure in this instance, it makes good sense to hold off announcing a risky procedure until the outcome is reasonably certain. It is not hard to find problems created by premature press releases…
Well said Richard.
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