2/19/2012 @ 11:55AM |4,265 views
Last week I wrote about a pending lawsuit by the FDA against Regenerative Sciences, a medical company that developed a stem cell treatment for orthopedic injuries. While adult stem cell therapies have been fraught with concerns about safety and efficacy, this case is particularly important not only because it is unprecedented — the FDA is attempting to classify non-embryonic stem cells as drugs – but also because it brings into focus the disconnect between the pace of scientific progress and the struggle of regulators to keep up with rapidly evolving technologies.
I spoke with three people with a unique perspective on what’s at stake – a lawyer who specializes in FDA regulation, a lab director of an in-vitro fertilization clinic, and a bioethicist – to get a sense of how the case is viewed in their industries. One common thread that emerged from these conversations is that the FDA is conflicted, even confused, about how to regulate stem cell-based products. The prolonged legal battle with Regenerative (it dates back to at least 2008) is due largely to the fact that the agency recognizes the absurdity of coming down with a one-size-fits-all regulatory approach that would apply to every clinic offering such treatments.
To be sure, stem cell medicine has a terrible reputation. Stem cell therapies that purport to treat everything from shot knees and slipped disks to autism, multiple sclerosis, and Parkinson’s disease are rightly regarded by many as modern-day quackery. That is because unscrupulous doctors have seized on the promise of this exciting new science and used it to peddle unproven treatments to desperate and ill-informed patients.
In 2010, CBS aired a 60 Minutes special titled 21st Century Snake Oil, in which Doug Sipp, a researcher at the RIKEN Center for Developmental Biology in Japan and a critic of stem cell fraud, who also runs the watchdog blog Stem Cell Treatment Monitor, warned of the dangers of blossoming stem cell medical tourism. That same year, NPR aired a story called “Offshore Stem Cell Clinics Sell Hope, Not Science.” And in 2011, the journal Nature reported on Texas governor Rick Perry’s crusade to soften the FDA’s position on stem cell clinics, whose number in the U.S. is estimated to be around a dozen. The International Society for Stem Cell Research (ISSCR), a non-profit organization of medical doctors and scholars, also functions as a myth buster for clinically untested treatments. On its website, the group writes that the mesenchymal stem cell, which is at the heart of the FDA lawsuit and is used by Regenerative in its procedures, has “become a cell of intense interest” but “has not yet been shown to have a clear-cut advantage over existing therapies, is not considered a standard of care for any condition and does not have regulatory approval for the routine treatment of any disease.”
Against this background, the FDA is grappling with a difficult decision – how to curb the proliferation of unproven stem cell treatments hawked by unconscientious doctors, while recognizing that this branch of medicine holds a legitimate promise whose full potential is only beginning to be discovered.
Areta Kupchyk, a partner at the law firm Nixon Peabody who counsels clients on FDA regulation and development of new biotechnologies, including human tissue and stem cells, says cell-based products are tough to regulate because they are individualized and manipulated to different degrees for uses in individual patients.
“The FDA has been trying to figure out how to regulate stem cell product development because it is so difficult — individual hospitals, individual doctors are performing individual procedures. It has had a very difficult time over the years trying to regulate something that’s not a big manufacturing facility. It’s very hard to get your arms around something like that as a regulatory agency,” Kupchyk told me in a telephone interview.
She noted that where minimal manipulation is concerned, the FDA may face a special challenge. One of the arguments in the agency’s case for regulating Regenexx, a procedure in which adult stem cells are extracted, cultured in a special serum, and reinjected back into the same patient, is that the cells are more than minimally manipulated.
“I can understand why the FDA is focusing on minimal manipulation — that is something they have been focusing on for a number of years. But they haven’t been able to articulate what minimal manipulation means. They’re regulating on a case-by-case basis and they’re not informing the public well on where they draw the line,” Kupchyk said. ”One good reason they’re not coming down is that this area is rapidly evolving and there are products created out of cells that have never been used or created before. So they’re struggling with new products, they are not sure how they are going to work in the body. This case could be very important in forcing the FDA to define it more clearly.”
The number of scientists and clinics developing or providing adult stem cell treatments is another reason the FDA may be at a disadvantage trying to establish hard-and-fast new rules, Kupchyk added. “If the FDA is successful in this case, it’s going to raise a lot of questions for everyone out there who’s trying to develop new uses for stem cells for patients. There may be a chilling effect, certainly, and it’s very expensive to test new products [through the formal regulatory framework]. If every single physician or clinic who was doing something similar applied, the FDA would not be able to handle it. That’s another reason they’re not coming down on every single case.”
I was curious to hear the perspective of Marlane Angle, a lab director at a San Francisco in-vitro fertilization clinic and a former technical expert for Irvine Scientific, a manufacturing company that has produced the first FDA-cleared cell culture for use in such clinics. Angle, who is a member of the American Society of Reproductive Medicine and one of the first IVF lab inspectors credentialed by the College of American Pathologists, testified last year on behalf of Regenerative that the safety protocols in place for its procedures exceed those at many IVF clinics she has seen.
“If you interview the average person, I think you would find that there should be some oversight. If you start to look at this product as being the patient’s own stem cell, how can the FDA claim Regenerative is manufacturing [cells]– they’re culturing them,” Angle told me in response to a question about the agency’s rationale to sue the company on the claim that its manipulation of stem cells is tantamount to manufacturing a new drug.
“They seem to have lost perspective on using autologous stem cells. There’s just no way you could apply manufacturing standards. I would love to have been a fly on the wall [during FDA's deliberations],” Angle said. “It’s like they are trying to come up with a law that takes into account every possible point of abuse that could happen.”
Unlike fertility clinics in the U.K. and other European countries, IVF clinics in the U.S. are not nationally regulated. That means the government has no say over how embryos are cultured or even how many embryos can be transferred at the same time to a single female. (Remember Octomom? She was an outlier and certainly a “misapplication of the technology,” Angle said).
Angle added that risky procedures such as heart transplants have a much higher potential health impact on a patient’s life than either IVF or stem cell treatments. “The FDA does not come into a cardiology practice and tell doctors how to do their surgeries or how to do heart replacements. And yet they feel they can come into a stem cell clinic.”
The FDA’s decision to regulate Regenexx on the grounds that the procedure does not satisfy the standards of Good Manufacturing Practices, rather than Good Tissue Practices, which are observed in blood and human tissue transplantation, is also puzzling to Kupchyk, a former FDA employee in the agency’s division for drugs and biologics.
“I’m curious how they came to the conclusion that the clinic is manufactuing. With stem cell therapy, it has to be based on an individual patient, for each person [the physicians]are deciding whether and how to use their stem cells,” Kupchyk said.
I also spoke with Christopher Scott, a scholar at the Stanford University Center for Biomedical Ethics. He walked me through the autologous stem cell controversy with a succinct but comprehensive analysis.
“In principle, I agree with the concern going into this slinging too wildly. This case has two edges: in this country and others, we have an epidemic of transplant clinics offering so-called cures and therapies to patients that have not been proven and have not passed muster with federal agencies. So that’s one pressure coming into this debate – the reverse is that we don’t want to overregulate therapies to the extent that we would cause the field to stumble,” Scott told me via telephone.
He cited as an example the way gene therapy was stalled by the FDA in its early stages. “There were concerns that the science was moving too quickly, so the FDA stopped all trials and the field was effectively shut down. There was such a severe reaction on the part of regulatory agencies that the science was effectively moribund, and now it is slowly coming back to viability.”
A second example worth considering, Scott noted, is bone marrow transplantation, a medical procedure that is also largely unregulated. Since most autologous stem cell treatments are nearly identical or variations of bone marrow transplantation, he said, the challenge for regulators and translational scientists is how to use what they understand from the procedure’s history and literature to help create a regulatory structure that would be efficient.
Stem cell medicine will learn to settle the question with time, Scott believes. “However, that doesn’t resolve the issue now about companies and clinics who want to do this to a desperately ill patient on their doorstep. There are cases when physicians are justified morally looking at a single patient and treating them with the best available, most promising treatment.”
“The question for us as a society is when something done at the edge of clinical care becomes something we want to study,” Scott observed. “My feeling is that in many cases clinics are scrambling to get approval, but don’t have the gravitas that the clinical literature provides that would give comfort to a regulatory agency or even an advisory board to say ‘go ahead and do it.’ So until we have a better idea of what the adverse effects would be, these things are moving too quickly.”
“FDA understands this is very edgy science and there’s a lot of hope into it.”