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In 2016, the Food and Drug Administration put the emerging stem cell cottage industry on notice. At the time, a few hundred clinics were peddling experimental stem cell therapies costing between $2,000 and $25,000 for conditions ranging from chronic pain to autism to multiple sclerosis without solid scientific evidence that they worked. Federal regulators asserted that the stem cells being sold — usually taken from a patient’s body and slightly processed before being re-injected — were drugs, and therefore required a rigorous approval process.

After contentious public hearings, the agency offered a sort of compromise. For three years, starting in November of 2017, regulators would exercise “enforcement discretion.” In other words, mostly look the other way. The idea was to give the stem cell clinic operators time to convince the agency their products were safe and effective before the crackdown came. The alternative would be to shut down or move abroad.

But according to a new analysis, the period of enforcement discretion led to a boom in the unauthorized stem cell business. “Embedded in that plan was a good idea that had a disastrous outcome,” said Leigh Turner, who conducted the analysis. Turner is a bioethicist and public health researcher at the University of California, Irvine, who has been tracking the stem cell industry for more than a decade. He found that when the FDA’s grace period expired in late May 2021, after being extended due to the pandemic, nearly 1,500 businesses were operating 2,754 clinics — a fourfold jump from four years ago.

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STAT spoke with Turner about the report, which was recently published in the journal Cell Stem Cell. Excerpts from the conversation are below, lightly edited for clarity.

It seems like the FDA’s approach backfired here. How much worse is the situation now than it was before the agency hit the pause button?

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It’s a dramatically larger marketplace. In 2016, my colleague Paul Knoepfler and I found 351 businesses operating 537 clinics. So we’re talking about a substantial increase. I think one thing that’s happened is that in addition to there being more dedicated stem cell clinics, we’re also seeing run-of-the-mill orthopedic clinics or sports medicine clinics or pain management clinics adding stem cells to the services they advertise. It’s just become commonplace. If you live in San Diego or Orlando or lots of other places, it’s just another business down the street.

But it’s also a bit complicated. Since 2016, I think we’ve gotten better at searching for these companies and analyzing them. So there’s real growth, but the research tools have also improved, and that’s important to acknowledge.

What do you think the FDA could have done differently?

I think it was a mistake to set such an extended grace period. Thirty-six months was far too long. If there was a serious intention to provide better oversight of this marketplace, an outer limit of a year to beef up enforcement activities and have conversations with businesses makes sense. The problem with three years is that it didn’t make anyone particularly fearful. So what happened was that most existing businesses didn’t contact the FDA, and a pile of other operators used that time to pour into the marketplace.

You’ve been pushing the FDA to do more about this for years, in part to protect patients from being harmed physically or financially from these clinics. Have you seen a corresponding uptick in adverse patient events as the market has expanded?

That’s a really tough one to answer, partly because there’s no robust reporting mechanism and partly because there are huge financial incentives for these clinics not to disclose when things go wrong.

In 2020, former FDA Commissioner Stephen Hahn wrote a commentary in JAMA pointing out that underreporting of adverse events from these clinics is a big problem. There have been some efforts to track such injuries — Pew published a report this summer that there’s no shortage of people who have suffered different kinds of harms as a result of being administered these unapproved products. But when we hear about a complication, it tends to be a really serious one, like the women who were blinded in Florida. So while there seems to be an increase in the number of reports being published, there also seems to be growing recognition that we’re probably only finding out about a small number of these events.

Your analysis found that more than one-third of all U.S. stem cell clinics are in three states: California, Florida, and Texas. On first glance, this seems somewhat unsurprising, given that these are the three most populous states. But is there something else going on in those places that is creating a commercial niche for unproven stem cell products?

On the surface, the numbers don’t seem interesting, that’s true. But as you move beyond the big three, it doesn’t quite track as neatly with population. Places like Florida and Arizona also have other things going on, including elderly populations with a number of comorbidities. I suspect that income is also a factor. This is very much an out-of-pocket economy. We know that people go on crowdfunding sites to cobble together funds to go to these clinics. So we expect these businesses to show up more often in middle- to upper-class communities.

A lot of these clinics have emerged in places where there’s an existing commercial ecosystem of particular kinds of clinics, like cosmetic surgery clinics in California and ortho clinics in Colorado. So population size matters, but I don’t think that’s the whole story.

This starts to go beyond the data a bit, but I find myself thinking about how California, Florida, and Texas are places that aren’t known for having particularly rigorous state medical boards. It’s a hypothesis more than anything, but I think it merits further study to see to what extent the regulatory environment has on where stem cell businesses pop up. Maybe what’s going on here is that people set up shop in places where the odds of having a medical license suspended or revoked is just basically negligible. And I would say Texas and California and Florida are pretty good examples of that.

In the last five years, Congress passed two pieces of legislation — the 21st Century Cures Act in 2016 and the Right to Try Act in 2018 — that aimed to expand access to experimental treatments. Do you see any evidence that they have played a role in accelerating stem cell clinic expansion?

I think they have contributed in a couple ways. Some businesses mention specific legislation in their advertising materials, whether it’s federal legislation, or state legislation like what exists in Texas, and emphasize the importance of individual choice.

But I think the larger point is that the ideology that animates a substantial part of this marketplace taps into concepts of medical freedom or health freedom. The rhetoric is not that they’re selling something that isn’t approved. They’re selling something the FDA doesn’t have to approve it’s a decision for you to make with your doctor and there shouldn’t be any role for faceless bureaucrats in D.C.

It’s the same kind of rhetoric we’re seeing right now from the anti-vax movement. In fact, some of these businesses sell things like stem cell “immune boosters.” We really don’t know anything about how effective they are or how many people have received them and gone into their communities thinking they don’t need to wear a mask or get a vaccine.

Given the intense politicization of the pandemic response in the U.S., it feels like we’re now living in an America that’s more deeply divided on government decision-making over health and more deeply skeptical of scientific expertise than ever before. What do you think that portends for the likelihood that these clinics are here to stay?

That’s an intriguing question. I think it will have a lot to do with which party is in power over the next few years. That would have a real effect on whether the FDA decides to offer a more robust response to the marketplace than it has mustered so far.

But the reality is there are just way more businesses now to deal with. I mean, when you have 1,480 businesses and nearly 3,000 clinics, where do you even start? I don’t think we’re ever going to have a day when the FDA takes action against all of them. That’s just not feasible.

I think that what the FDA needs to do is focus more actions against the higher-profile, more egregious operators and have that action serve as a warning for the rest of the marketplace. It has started to do that. It obtained a permanent injunction against US Stem Cell Clinic, which was a business that had blinded several women and caused real harm. And there have been rumblings and rumors that the outcome of the case that’s still in federal court against the California Stem Cell Treatment Center and Cell Surgical Network could be a stepping stone to increased enforcement actions if the FDA wins.

Personally, I’ve found the number of businesses pouring into this space to be demoralizing. But it also raises the question for me of what would it take to reform this marketplace? To give the FDA its due, it has increased the number of warning letters it has sent and taken a few bad actors to court, but those actions just haven’t seemed to amount to all that much. And I have to wonder if stem cell clinics selling products without any hard evidence behind them are just going to exist on a larger and larger scale, and it’s going to be another one of those things where people can be scammed and taken advantage, and sometimes harmed, and no one’s going to do much about it. I think that’s possible. Or maybe there will be a crackdown. But you know, after five years of hearing that language, I think it’s fair to say, “Well, when is that actually going to arrive?”

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