Therapeutic misconception & the planned Duke Cryo-Cell cord clinic

One of the core problems in the world of unproven stem cell clinics is something called therapeutic misconception. I’ll talk more about that in a minute, but first, let me tell you what brought this to mind now.

Surprisingly, the story starts at Duke University.

A Duke cell therapy team and the biotech Cryo-Cell have big plans for an unproven, for-profit cell therapy clinic for kids to open in just a few months. One of my main concerns with the Duke Cryo-Cell plan is that their efforts are based on minimal, often conflicting data, and corporate profit seems to be a central goal (e.g., see image below from a company presentation).

Here on The Niche, I’ve been critical of their efforts. I knew I would get some pushback on my criticisms of what they are planning and I got some intense reactions. These responses have included hate mail and personal attacks.

Cryo-Cell presentation
Cryo-Cell presentation slide focused on revenue. The talk didn’t mention a central goal of helping children, at least not that I heard. Screenshot. Note that an FDA-cleared IND or compassionate use program is not equivalent to a final drug approval. The cord cell drug in this case has little concrete data behind it.

Parent’s Guide to Cord Blood Foundation: Duke Cryo-Cell defender

Now Frances Verter of Parent’s Guide to Cord Blood Foundation wrote a long piece in part to try to rebut my concerns and criticisms.  I disagree with much of what she wrote, but at least she was civil and carefully explained her thinking.

In the article, Verter lays out her arguments both for why she thinks I’m wrong and the reasons why the Duke Cryo-Cell effort is supposedly worthwhile.

The cord blood product in question is not approved as a drug by the FDA and is not clearly scientifically proven. It is just part of a compassionate use program.

Verter’s piece lists many clinical studies and some results in this general area of clinical research, but I’d say there’s no clearly convincing data. Overall, there’s really “no there there” to support a big new clinic.

Stem cell clinic parallels

It’s interesting that to make some points she in part quotes stem cell clinic doc Chris Centeno.

Centeno has been critical of me for using the term “unproven” about stem cell clinics like his cell therapy clinic chain Regenexx. His argument seems to be that much of accepted modern medicine is still unproven by data. I disagree.

By bringing Centeno into this Verter just adds another parallel between the Duke Cryo-Cell effort and the existing stem cell clinics. If the FDA allows the Cryo-Cell clinic to open I’d imagine that hundreds of stem cell clinics across the U.S. will applaud.

It all goes toward the risky idea that solid clinical trials and clearly encouraging data just aren’t necessary for cell therapies prior to selling them.

In another parallel, Verter emphasizes parent testimonials from families who already got off-study infusions from Duke and unproven stem cell clinics often rely on such testimonials for marketing.

Duke, Cryo-Cell, & therapeutic misconception

Now let’s bring therapeutic misconception back into the discussion.

A friend mentioned to me that Verter’s new piece is an example of therapeutic misconception. What is that?

The most basic definition seems to be when patients misunderstand clinical research as though it was a beneficial treatment.

How does it apply here?

Research by Duke/Cryo-Cell is being falsely equated with a promising treatment for kids. In reality, it’s just research. In this case, in my view, the misconception starts with the groups marketing the research as though it was a treatment. Then this confuses the patients (or parents) leading to false hope.

Unfortunately, this kind of conflation of cell research with cell treatments is pervasive.

It is particularly common in the unproven stem cell clinic world. Many clinics wrongly market experimental stem cells as a beneficial treatment but somehow also research. The clinics’ intent seems to be to encourage therapeutic misconception among potential customers. Maybe we need a new term for when a sponsor is encouraging therapeutic misconception?

As to Verter’s piece, I’m also concerned by her inclusion of pictures of happy children and parents both in this piece and others on Duke/Cryo-Cell. Is that to send the message that the experimental cord infusions are treatments that will bring family happiness?

Demand doesn’t equal justification for unproven clinics

Another issue with Verter’s article is that it wrongly seems to argue that parental demand justifies the planned unproven clinic.

Just here in the U.S. there is a vast number of Americans desperately seeking treatments for other conditions but do we open for-profit clinics with unproven cell therapies for heart disease, paralysis, and many other conditions? Wait, with this idea we’re back to the huge American unproven stem cell clinic industry again, right?

Would the FDA give an explicit OK for unproven cell therapy clinics for millions of customers around the U.S. for diverse conditions? No way.

So why should Duke/Cryo-Cell be a special case where the agency lowers the bar for a clinic? It shouldn’t.

Money issues: Cryo-Cell funding for Parent’s Guide & more

If this was all about just doing clinical trials it would be one thing but again we’re talking about for-profit clinics.

It struck me that Verter’s article acknowledged that her organization gets substantial annual payments from Cryo-Cell.

Since the Duke team is also financially tied with Cryo-Cell and has also been getting millions of dollars from a philanthropic organization for their cord blood research on kids, I believe money is a big motivating factor driving the rush to open a new clinic.

I’m not clear why, but Verter argues the financial aspects of the deal should be considered separately from the ethical issues:

At the end of the day, the ethical aspects of the Duke EAP need to be separated from the financial aspects. An ethicist can make a strong case that it is unethical to charge families for compassionate treatment of a child that has disabilities which impact daily life. But the financial reality is that Duke does not have the resources to scale up their EAP. This means that the Duke EAP will never get bigger unless another entity, such as Cryo-Cell, licenses the technology and offers it commercially.

I appreciate that she acknowledged the ethically thorny side of charging for compassionate use.

However, it’s puzzling to me that she thinks that the Duke EAP needs to get much bigger, but it may go back to her belief that the Duke offering is promising or that parents need something even if it is a shot in the dark.

I also noted that Verter claims that the FDA allows firms running compassionate use programs to profit from the efforts. The regulatory language she linked to is a little vague even if it does mention profit in passing. She might be technically right.

Still, historically, has any compassionate use program before ever splashed around huge financial hopes in the tens of millions of dollars in income all from their “compassionate” clinic based on so little data? Has any compassionate use program opened a clinic hoping for thousands of paying customers and the customers are kids? If so, I’ve never seen anything like that. It seems radical to me. Have there been other such cases?

A place for compassionate use more generally

To be clear, I believe there can be a place for compassionate use (more technically called “expanded access”) for certain seriously ill patients without other options.

However, caution is needed in evaluating such programs and monitoring them as they may evolve over time.

When a sponsor is planning to enter into the squarely for-profit realm with such programs they should be subject to even more oversight and scrutiny first.

Otherwise, participants getting the experimental offering risk become more like customers.

Will the unproven clinic open in early 2022?

I have called for the FDA to freeze the Duke compassionate use program to give time for the agency to investigate before the dubious Cryo-Cell clinic opens.

Verter argues it isn’t likely the FDA will do that.

If she’s right about that, then the agency will have undermined their own stance on cell clinics overall.

Also, I believe the FDA can then expect a wave of new requests from other biotechs or universities (or stem cell clinics) for more for-profit but unproven cell therapy clinics for heart disease or diabetes or dozens of other conditions based on minimal or conflicting data under the umbrella of compassionate use. Is it going to okay those too?

Such a trend could weaken the FDA approval system overall.

As I’ve said before, this is about real people in the form of potentially thousands of vulnerable children who might get experimental injections portrayed as treatments.

Verter’s piece doesn’t make it clear to me how that can be a good thing.

References

11 thoughts on “Therapeutic misconception & the planned Duke Cryo-Cell cord clinic”

  1. I have asked this question before and I will ask it again here. Can anyone tell me why giving someone a small amount of cord blood (the storage fees for which have already been paid) costs $15,000 ?

  2. I want to reiterate a few bullet points on the FDA’s Expanded Access (Compassionate Use) regulations. The criteria to receive EA approval include:

    – The product under development treats a serious condition
    – The condition does not have an effective standard of care
    – The product has been demonstrated to be safe
    – The manufacturer of the product is continuing to pursue market approval
    – The EA will not interfere with recruiting patients for clinical trials towards full approval

    Notice what is NOT a criteria for EA approval:

    – It does not matter that previous clinical trials missed their primary endpoints and only worked for sub-groups, so long as there is SOME efficacy and the product is SAFE.
    – The FDA’s primary concern is safety. Duke is offering a product that has been through multiple clinical trials in hospitals and has an excellent safety profile. This cannot be equated with the unproven products at fly-by-night clinics.
    – The patients in the EA do not count towards data for market approval. The FDA has been explicit about that for decades, read the regulations.
    – The manufacturer is allowed to charge a fee under a cost recovery plan filed with the FDA. Read the regulations.
    – The manufacturer is allowed to charge administrative expenses (for EA groups) and allowed to hire a third party to run the program. Read the regulations.

    Specifically, Bernie Siegel is in error about the timeline: Cryo-Cell does not need the Duke product to receive a BLA in order to open an infusion clinic offering the product on an EA basis.

    FYI, there are companies that specialize in providing consulting about EA regulations, and there are companies that specialize in running EA programs. There is an annual “Expanded Access Summit” conference in this field. I encourage everyone who wants to know more about EA to follow the field. There have been cases of block-buster drugs that went through huge multi-site EA programs. There have been big controversies about the prices charged in EA programs before. The EA topic may be new to this audience but it was not born with Duke’s exclusive license to Cryo-Cell.

    Frances Verter, PhD

    1. @Frances,
      A few thoughts came to mind from your comment. Thanks for making it.

      The criteria you outline seem to set a very low bar for an EA program. Does the FDA do its own data analysis in this kind of case? For example, the post-hoc subgroup analysis from the most recent Duke paper in this case is debatable. If for the moment one accepts that the post-hoc might be showing a real sign (which I tend to doubt) then is Cryo-Cell’s EA clinic only going to have participants who fit into a narrow window of clinical criteria based on the post-hoc analysis?

      The Sutter trial missed its endpoints too in generally the same area of research so isn’t that a relevant factor here for the FDA to consider or would you say it was too different to compare?

      Also, I would also argue that a Cryo-Cell clinic seeing potentially 1000s of customers could interfere both with the Duke (or Cryo-Cell’s?) clinical trials and that of other research groups.

      Do you know of any more specific FDA regulations that explicitly discuss profit from an EA program?

  3. Paul, I believe you may have overlooked the stated intention of Cryo-Cell. The company intends to successfully undertake full and complete FDA sanctioned clinical trials and secure a Biologics License, before commercializing its products. That is an obvious condition precedent to the opening any clinic using that technology. A long and winding road, it is.

    In your blog you write: “A Duke cell therapy team and the biotech Cryo-Cell have big plans for an unproven, for-profit cell therapy clinic for kids to open in just a few months. One of my main concerns with the Duke Cryo-Cell plan is that their efforts are based on minimal, often conflicting data, and corporate profit seems to be a central goal.”

    According to Cryo-Cell’s most recent press statement dated October 27, the company sets forth: “Cryo-Cell is working to develop…a pipeline of potential cord blood- and cord tissue-derived cellular products to be tested in Phase 2 and Phase 3 randomized, placebo-controlled clinical trials to further determine safety and efficacy of these products in babies with hypoxic ischemic encephalopathy, children with cerebral palsy, children with autism spectrum disorder and other conditions. Cryo-Cell’s cellular therapies with strong signals in Phase 3 clinical trials are expected to be moved through formal FDA approval pathways to Biologics License Applications (BLA) and commercialization.” 

    I cannot comprehend how the company can possibly open any clinics using these technologies “in a few months.” I do not understand how you can make that suggestion. Please clarify. On what information do you rely, how does that fit in with Cryo-Cell’s stated intention and jibe with their press release?

    Further, you express concern that the FDA might grant a Biologics License to Cryo-Cell based upon scanty proof of a trial offering compassionate use and expanded  access. Further such approval might therefore might somehow weaken FDA and embolden “unproven” stem cell clinics. I’m sorry but I disagree.

     Should any cell therapy company secure that level of success and secure a Biologics License, I believe that company should be applauded by the entire world. We all will have our proof, after strict rigorous regulatory compliance. An approved cell therapy product will be allowed to be manufactured and marketed in the US.

    That is what we all should want- not what we should fear.

    My comment posted on your blog the other day was not meant as a personal “attack”- it was written as criticism (perhaps a bit severe) of your blog piece and what I still perceive as an “over the top” and unnecessarily incendiary attack on Duke University’s research. Critics make it tough for the criticized. I was criticizing the critic’s work- not the critic!

     Dr. Verter has provided a complete overview of the Duke program. The guide she authored is factual and detailed enough that parents can make up their own minds whether the Duke program is meritorious. Usually there are two or more sides to any story.

     I sincerely hope that Duke’s critics might carefully reconsider their comments in light of the more complete record that recognizes the existing legal and regulatory framework, Duke’s compliance and the humanitarian aspects of these trials. 

    Finally Paul, in your reply to me on your previous Duke blog you rightfully (and rather gently) pointed out that I, unlike you, am not a scientist- and I gladly acknowledge that fact. However, I am in fact a lawyer- and you are not. I believe if the rules are followed and there is full compliance under the law, that Duke’s clinical trials should continue. Further, commercialization of university IP is encouraged by the federal government and mandated by the Bayh-Dole Act. Profits are a great thing so long as there is patient access to the product, the product is fairly priced and is safe and effective.

    1. Hey Bernie,
      Cryo-Cell itself said it expects to open the clinic in January 2022 as I quoted here: https://ipscell.com/2021/06/duke-cryo-cell-plan-big-stem-cell-clinic-for-kids-for-unproven-infusions/ Their webpage now seems different but still says early 2022. Frances’ post on the Cryo-Cell announcement still references Jan 2022: https://parentsguidecordblood.org/en/news/cryo-cell-granted-exclusive-rights-duke-therapies?fbclid=IwAR3RbDei-M5–oq47nEG4i-m-jk4szLBdEwc8D2Y3W3yD9B6PC2-Ku_zejU. Then I thought I had read somewhere else it might be February 2022. Maybe they were overly optimistic?

  4. I enjoy your articles but this one has to me a certain feel of dogma. In particular about something being more wrong because it is compassionate but is “for profit.” Virtually every hospital in the US is a profit making (or losing) entity. They just massage the accounting so that they can justify not-for-profit status with the IRS. Doctors and labs are almost entirely “for profit” entities, as well. So how much would it matter if the Duke initiative had structured itself to do the same services, but as a hospital-like “non-profit”?

    Secondly, it’s hard to have much faith in the FDA’s processes and decision making. Certain things go through evaluation quickly, others are stifled for decades while the rest of the world yawns at how backward and prescribe-a-pill-to-treat-the-symptom oriented, US medicine remains, as well as how FDA focuses seem heavily influenced by the wants and don’t wants of big Pharma (pill makers).

    All this said, I’m mostly aligned with your views on this Duke thing as being aggressive, particularly in that its starting focus is on children. I live in central Mexico and stem cell therapy is very common, and doctors for the most part view it as just one more tool in the kit — not a be all, end all. Aside from US/Mexican border towns, you don’t encounter much in the way of marketing and advertising of stem cell therapy here. It usually is just listed on the clinic’s schedule of services, along with whatever else they practice. It’s been around and in the general population for over a decade, and is internationally regulated.

    As a result, a lot of expats living here, and chronically ill folks from up in the US, rely upon access to SC therapy for assistance with a long list of maladies. They just have to travel to get it, or go to some fly by night pop up clinic in the US.

    As a final point, down here, the labs take pride in the high quality SC’s they harvest from birth byproducts that in the US literally just get bagged and sent to a landfill. It’s all sourced from placentas and umbilical cords and endometrial materials. In the US, there are millions of severely, chronically ill folks (especially since C19 messed up so many of us who were previously much healthier) — yet the FDA seems to yawn at concepts like compassionate use of MSC’s for long covid or other autoimmune disorders. Down here, MSCs are the primary prescription for autoimmune. I’ve ventured to the FDA website to see the nature of their lingering foreboding about SC’s, and frankly their 5 cited concerns are almost laughably trivial. For example, one concern is about insufficient studies about injection site pain or adverse reactions. Since most MSC therapies involve nothing more than an IV in the arm, and a bottle of saline drip containing the cells, it would seem like there’s a century of worldwide data about the IV needle injections.

    Fortunately, there is a lot of international research ongoing, in places like Germany, Japan, and China, to name a few, and there’s a long history of safe incorporation of MSC therapy into treatment plans for patients of virtually all ages, to successfully treat and in many cases entirely cure a large array of diseases.

    Cheers!

    Jeff Fisher

    1. Thanks for your comment, Jeff. I value your perspectives. I have pretty strong feelings about kid patients/their families having to pay to be subjects of clinical research especially if the experiments are wrongly portrayed as already known to work when the data aren’t there.

      I also wonder sometimes about decision-making inside the FDA. How can a big infusion clinic based on a compassionate use program & little data like Duke’s be permitted, while the FDA says many of the hundreds or thousands of cell clinics across the U.S. are “bad”? It’s worrisome to think about politics potentially playing a role in some of this Duke/Cryo-Cell stuff at the agency. I hope that’s not the case.

  5. Thank you for keeping our disagreements polite.

    You raise an interesting question, “historically, has any compassionate use program before ever splashed around huge financial hopes in the tens of millions of dollars in income all from their “compassionate” clinic based on so little data?”

    I have a companion article which gives a list of Expanded Access programs in advanced cell therapy that were approved from 2017 through mid-2021:
    https://celltrials.org/news/expanded-access-programs-advanced-cell-therapies

    If you go through that list and look up the sponsors, you will find that some of them have been the subject of controversy about charging patients. That list is the starting point if you want to look beyond Duke.

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