January 25, 2021

The Niche

Trusted stem cell blog & resources

Great interview with Lee Buckler on stem cell industry, regulatory issues, and Celltex

As I’ve been writing this blog for the last couple years it has served as a catalyst for me to meet dozens of really interesting people. One such person is Lee Buckler, a true stem cell industry guru.

Given all the complex events of late in the stem cell field, I asked Lee if he would do an interview and he kindly obliged. We used a question and answer format.

I found Lee’s answers to be remarkably interesting and informative. I would especially note that I appreciate Lee’s refreshing frankness and willingness to answer tough questions. Lee Buckler

1. First of all Lee, could you tell us about your background, your current work, and your interest in stem cells.

Lee: Thanks Paul for the opportunity to discuss this with you and your readers.  You do a great service to the sector and I have increasingly enjoyed following your output.

In terms of my background, I’ll admit right away that I’m a recovering attorney who has now worked in the cell therapy sector for 12+ years.  I got into the industry when Allen Eaves of Stem Cell Technologies took a gamble on bringing me into his organization in 1999.  He was and remains a valuable and inspiring mentor among many.  I’m also indebted to many of the leadership and members of the International Society for Cellular Therapy (ISCT) who mentored me over the six years I was that organization’s Executive Director, to my past employers and colleagues, and my current consultants and network who educate me daily.

I’m fond of saying my specialty is understanding the sector in its breadth.  In a highly specialized sector like cell therapy, most people have to specialize in narrow vertical niches of expertise.  Few people have the luxury of developing an expertise as I have in a relatively simple but intimate, comprehensive, and current sense of what is happening globally particularly on the industry side of the sector.  I translate that into business development, competitive intelligence, market research/analysis, sales lead generation, and other kinds of work for our clients.  We also track industry metrics like revenue, markets, trends, etc.  This is where my interest lies – in understanding, tracking, and communicating activity on the commercial side of the sector.  We work for companies of all ilk and size ranging from outrageously early-stage technology companies to some of the largest multinational lifescience, pharma, or healthcare companies in the world.

2. What is your opinion of the 483 report on CellTex?  Do you view the report as of serious concern from your perspective?  Do you see it as a setback for the company?  For the adult stem cell field or just for a segment of the field?

Lee: No company wants to receive a 483.  It’s at least bad PR.  They are always serious or but some ‘observations’ are relatively simple to address while others can be devastating to the entire business model and/or survival.  I’m not a regulatory expert nor (as is obvious to all) am I a scientific or clinical expert but having some expertise and knowledge of how this industry works I’m of the impression that this 483 letter from the FDA raises issues which are relatively fundamental rather than simply technical.

As you have described here on this blog one of the issues which the public CellTex response to-date does not seem to adequately address in my opinion is what appears to be very significant, outstanding, and fundamental disagreement on whether the CellTex product is a 351 product (thus requiring it to be used only under IND or BLA) or a 361 product which CellTex currently alleges.

As I understand it, their business model and product/service relies primarily (if not exclusively) on selling something which certainly the FDA (and most legal and industry experts) believes contravenes the current FDA regulatory framework.  Of course as you have blogged here before this is all under legal challenge by Regenerative Sciences Inc so this may eventually change.  Furthermore, CellTex certainly always has the opportunity to change its primary business model and/or product/service (at least until the current regulations are successfully overturned or changed) to something which is compliant.  This is what Regenerative Sciences did.  They stopped selling an expanded cell product (which was neither under IND or BLA) within the USA and are now simply selling a non-expanded cell product/treatment in the US and have licensed (and presumably earning a revenue stream from) the expanded product/treatments to companies for use outside the U.S.

For those companies which have invested in ensuring regulatory compliance, any enforcement of the current paradigm only strengthens the rationale for such an investment by eliminating what they would be perceived to be unfair competitive threats from products which are being marketed without having to support or recoup the heavy investment associated with regulatory compliance.  So I don’t see this as a threat to the compliant side of the industry.  It is however, yet another example of what would appear to be FDA’s increasing commitment to enforcing regulatory compliance and pursuing those who they perceive to be pursuing non-compliant business practices.  If your product/treatment is so clearly in contravention as what I have perceived CellTex to be this should be a worrisome trend.

Where I think things will get increasingly interesting over the next 24-36 months (aside from any development in RSI’s legal challenge) is in those products which are much murkier in terms of where they fall within the current regulatory framework.  There are several products allegedly containing live cells being sold into – or expected to be imminently sold into – particularly into the orthopedic and aesthetic markets which the sponsor companies allege are what we call 361 products and thus can be brought to market without regulatory approval.  These are typically minimally manipulated products (although even this definition continues to rapidly evolve as has been evidenced recently by the FDA’s apparent thinking that enzymatic digestion of lipoaspirate constitutes more than minimal manipulation) but it is difficult to imagine how some of the marketed applications for these products can be considered homologous use.   These are two of the five criteria which are used in the determination of the appropriate regulatory pathway for a cell-based product.  I’m watching  this side of the industry with keen interest.  Many orthopedic companies and plastic surgery clinics appear to be willing to act in a way which some regulatory experts say pushes the envelope of these definitions on the notion that they will bring these products to market without engaging the FDA for a designation, make what money they can and deal with the FDA when they catch up to them.  I’m not suggesting that these companies are acting untoward, illegally, or in bad faith in any way as this is clearly and simply a commercial decision based on a notion that they have at least a credible legal argument that the product falls under the regulatory pathway they have pursued.  They have no legal or regulatory obligation to seek the FDA’s opinion in advance for such products.

3. Can you comment more generally on how you see CellTex in the spectrum of adult stem cell companies?

Lee: As you know, there is a vibrant debate about the level of evidence which is and/or should be required to bring products/treatments to market.  I’ve blogged often and engaged in much discussion about this issue in my LinkedIn group.  I like to think I was one of the early “industry insiders” who was not shy about encouraging a certain tolerance for what most people call “stem cell tourism” clinics (see blog posts here and here).  I believe there is something of a double-standard often applied by the staunch critics of these clinics as to what evidence is required to treat people.  For example, there are ample examples of products brought to market which have very little evidence of safety and certainly not of efficacy but these products are presumed at least safe enough to allow because they are the kind of products which have been established as having a “low-risk” profile and are produced in facilities which are compliant with certain, minimum production requirements.  Cell-based products which fall under what we call the 361 framework (e.g, Osteocel, Grafix, DeNovoNT, etc) are examples of such products.

Similarly on the clinical side, we have entrusted medical doctors with the right to treat patients with products for indications for which there is often very little efficacy data but which are legally and commercially available for other indications. The assumption is that these products are at least safe but given the potential for unknown patient-specific adverse reactions (such as potential drug-to-drug interactions for example) this hardly seems to me a safe assumption.  Nonetheless in our risk-based system this is a risk we have decided to accept.  Particularly for no-option patients, given the relative safety profile of carefully produced autologous cell products in particular, the risk-benefit analysis of allowing unproven autologous cell therapies seems to me to present a similar risk-benefit profile as the examples I cited above.

I also believe that profit is never evidence of an intent to be careless of patient safety or even treatment.  I’m also a strong believer in people’s right to choose and that to some extent (albeit within limits) the right protections lie in things like informed consent, transparency, and accountability rather than paternalistic approaches which pretend to try to protect people from their own choices.  Finally, I also believe that simply locating a clinic in a jurisdiction which allows a company to bring a product/treatment to people faster than might be possible in the US or Europe is not evidence of an intent to be careless of product safety, high clinical standards, good science, and informed consent. In other words, I think there is a legitimate way to do what is commonly referred to as stem cell tourism.

Having said that, if you choose to do business in the United States, it seems to me short-sighted, foolish, or begging for a fight to choose to set up a business model which seems so clearly in contravention of federal regulation. Based on all I know and have read, this is what CellTex did.  They appear eager to be taking on this fight.

4. Can you help my blog readers understand the difference between say Osiris and Neuralstem versus other stem cell outfits that begin work without even any contact with FDA?  Why might companies use these radically different business models?

Lee: I think the distinction on its most basic level is the companies you cite are making every effort to operate in a fashion which is compliant with the regulatory requirements of the jurisdictions in which they are operating.  I can’t imagine how CellTex thought they were doing similarly.  They were clearly operating at least on the very edge of – if not in clear contravention of – what almost everyone believes to be clearly in contravention of the regulations.  There are plenty of examples products/treatments where the issue of regulatory compliance is arguably murky.  In my opinion, what CellTex is doing was not one of these.

Companies naturally want to get to market as quickly as possible but to do so in what so clearly appears – by most measures – to be in contravention of federal law/regulation seems to me to be a risky proposition inviting an inevitable and costly battle likely before you’ve recouped your cost.  In the case of Regenerative Sciences they were allowed to operate in such a fashion for several years.  Perhaps this turned out to be worth the risk but the FDA’s enforcement team  seems prepared to act sooner now than was the case in 2008.

There are certainly examples of US-based companies which have chosen to locate clinical trials – perhaps even production facilities – outside the US for reasons of lower regulatory hurdles, more favorable reimbursement mechanisms even for products still in clinical trial, and more attractive production or other operational costs. This is a legitimate commercial practice in what is an increasingly global business environment but I would only want to be involved in a company that at least attempting to comply with local legal and regulatory requirements.  It seems to me either (a) CellTex believed they were not in contravention (as some have argued but it is difficult for me to imagine) or (b) they were prepared to take the risk that they would be able to avoid FDA enforcement for at least a period of time, or (c) they got into this inviting the very fight they appear now to be headed into.

Despite reports that the whole CellTex thing is a “blow to the entire stem cell industry”, I think it’s only a blow to those looking to overturn current regulation or otherwise fight or avoid compliance.  The FDA’s enforcement of the current regulatory framework is good news for the compliant (dare I say, legitimate?) side of the industry.

5. What are your top 3-5 favorite adult stem cell companies and why?  How close are they to full FDA approval and getting to the bedside with their products?

Lee: As a consultant, it would likely be ill-advised to pick favorites but since you asked about late-stage companies I’ll point you to a couple blog posts in which I discuss those companies which are in late-stage trials (including the number of patients involved in those trials) as well as those products which are already commercially available.

6. What is your opinion of the question of whether autologous stem cell products are drugs?  What if the cells are grown in culture to say expand from a million to a billion cells prior to transplant?  What if the cells are stored for a prolonged period of time prior to use?  How does the term “minimal manipulation” fit in here?

Lee: As I said as early as 2009 in a blog post, I suspect that regulatory agencies like the FDA and EMA will eventually loosen the regulatory restrictions around the use of autologous cells but this will be only be possible once there is an incontrovertible body of evidence of their safety.  For instance, stem cell transplantation was essential grandfathered into the existing regulatory framework (even certain transplant uses of cord blood stem cells) given how long they had been part of the practice of medicine with a well-defined risk profile.  I think the same could eventually be true even for autologous products which currently are required to go through the full clinical trial IND and BLA process to get to market.  The perfect example might be the eventual allowance of autologous cells which are expanded in culture for a short period of time within certain acceptable conditions, devices, and/or reagents.  Barring a successful challenge of the regulation by Regenerative Sciences,  this is not going to happen anytime soon. I certainly would not expect any significant relaxation of the current regulatory framework within the next 10 years though within that time-frame we might start to see a relaxation of the interpretation of the regulations through updates to guidance.

To answer your question about storage, I’m not aware of any regulatory distinction between cells that are cryopreserved for a short versus long period of time.  I believe the science to-date leads us to believe that cells are not materially affected by the duration of their cryopreservation.

7. Can you comment on the issue of state versus federal regulation of the stem cell field?  Many of my new acquaintances in the adult stem cell field in Texas and elsewhere, for example, view autologous adult stem cell therapies as not within the scope of regulation by the FDA at all, but rather as (a) belonging to the patient and (b) within the definition of “the practice of medicine” that physicians should be able to conduct without FDA  scrutiny as long as they have IRB.  What are your thoughts on this?

Lee: This is the fundamental issue before the courts right now in the Regenerative Sciences v FDA (PDF of court document) case.  Frankly, I can’t imagine the courts striking down the FDA’s jurisdiction to regulate what are commonly thought of as “manufactured” autologous cell products (i.e., more than minimally manipulated).  Critics of the FDA’s approach are often inflamed by the notion that the government should have the right to restrict the clinical use of one’s own cells under a physician’s care.  What I believe this argument fails to appreciate is that these at some point cells produced ex vivo – although originating from your cells – actually become, or have a significant potential to become – something quite different from, or contain things quite different than, what was taken from you in the first instance. These cells are now an artificial and manufactured product which does not – or may not – exist in nature.  It is common scientific understanding that cultured cells can differ in some very fundamental ways from cells in vivo.

Having said that there is no doubt the case presents some interesting and complex constitutional, jurisdictional, and legislative questions all of which are being framed and argued by a brilliant, skilled and experienced legal team.  I’m watching with the keenest of interest.

8. There is significant concern in the stem cell field over practitioners giving stem cell treatments with only IRB oversight because IRBs might vary greatly in terms of their level of rigor.  How different is one IRB from another?  Is it an exaggeration to say that some IRBs are dramatically less stringent than others or is there indeed a lack of uniformity that is potentially problematic?

Lee: The IRB system was set up to attempt to regulate, monitor, and control experimental physician activity.  Just as physicians are regulated by their own state medical boards and yet there is a wide-divergence of physician competence the same can certainly be said of IRBs.  It is one mechanism, one layer of “protection” that is certainly useful but not fool-proof and likely should not be relied on as a sole mechanism of patient protection particularly where the risk-profile of treatments such as those which are newly emerging is higher than in more established areas of clinical science.

I hope that was helpful and certainly look forward to engaging in an active comment thread!

I wanted to thank Lee again for the interview.

The opinions above are of course only Lee’s and do not necessarily reflect those of this blog.

About Lee

After 6+ years with the Stem Cell Technologies group, I spent 2+ years with Progenitor Cell Therapy (one of the leading cell therapy manufacturing companies in the world), and then launched a consulting company (Cell Therapy Group) exclusively focused on the cell therapy, stem cell, and cell-based regenerative medicine sector.  We have a handful of consultants (some on the business side and some PhDs on the science side) who are exclusive to the group and then a number of others who we have under non-exclusive master services and confidentiality agreements that we bring in on projects as needed and appropriate.

As a way of giving back to the sector and connecting people with information about the industry, I blog at CellTherapyBlog.com, tweet to a loyal and engaged following of 1,600+ from @celltherapy, host my online profile at LinkedIn.com/celltherapy, have a cell therapy stream  on YouTube, administer cell therapy industry-related video content on BioBuisiness.TV, and run the LinkedIn Cell Therapy Industry Group which is all about the vibrant and current peer-to-peer exchange of information and opinion among its now 3,300+ members.  As you know, social media platforms come and go so I’ve also had cell therapy related stakes in platforms which don’t seem to be gaining tractions – like that on FriendFeed, etc – and my newest efforts  are early-stage experiments include Pinterest/celltherapy and EmpireAvenue/celltherapy (the latter admittedly more for fun).

Finally, I’ve also diversified my entrepreneurial efforts through a marketing partnership with Stem Cell Partners on certain uses for the technology briefly outlined at CellWasher.com and we’re also slowing building a recruiting support service under the RegenerativeMedicineJobs.com and soon-to-be-launched CellTherapyJobs.com brands.

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