How Scott Gottlieb may transform the FDA’s approach to stem cells

The Trump FDA commissioner nominee Dr. Scott Gottlieb Dr. Scott Gottliebcould dramatically alter how the agency regulates investigational stem cell therapies. How might such changes unfold? There are potential upsides and downsides to  the seismic shift that could be in the offing.

Gottlieb has written in the past about his perception of FDA over-regulation of stem cells such as in this piece in the WSJ. There he made a number of assertions that signal his view at least back then that when it comes to regulation of stem cells by the FDA, less is more.

More recently, a speech he gave at an ISSCR meeting in Berkeley last year is much more balanced in tone than the 2012 WSJ piece. This quote from the Berkeley talk, for example, is balanced and emphasizes standards:

“Expediting the development of these novel and transformative technologies like gene- and cell-based therapies doesn’t necessarily mean lowering the standard for approval, as I believe other countries have done. But it does mean having a framework that’s crafted to deal with the unique hypothetical risks that these products pose.”

Still that WSJ article is concerning.

For instance, he and his co-author Coleen Klasmeier, both former employees of the FDA, strongly criticized a federal court ruling in 2012 that the FDA could regulate laboratory-proliferated stem cells as a biological drug. Oddly, much of the basis for their criticism was far broader than the reality of the court ruling. They suggested, for instance, that the ruling opened a veritable Pandora’s box of FDA over-reach potential that extended to all autologous uses of stem cells (lab-grown or not) and beyond, but that was not the case as the ruling was focused on lab-grown stem cells. Even so they made largely unsupported generalizations such as the following:

“If the FDA’s victory is upheld on appeal, then conceivably nothing done as part of clinical practice is beyond the agency’s reach.”

In the intervening years since the 2012 court ruling and the WSJ article, we have seen that the sky hasn’t fallen from the FDA having obtained the defined authority to regulate lab-expanded stem cells as drugs. In fact, oddly enough if anything the more time that has passed, the less inclined FDA’s CBER biologics branch that oversees stem cells has been to take action on stem cell biologics. It’s hard to view the FDA issuing less than one warning letter per year to stem cell clinics even as there are upwards of 600 of these clinics as a form of overreach.

From a scientific and medical perspective, there are good reasons to regulate lab-grown stem cells as drugs. The cells are known to change their differentiation properties, accumulate mutations and epigenetic changes, and undergo other significant alterations in the dish in the lab. There is also, perhaps more directly related to the FDA’s mandate on biologics, substantial potential for contamination of cells in a lab during proliferation.

Since 2012, another big change has been the explosion of adipose stem cell clinics onto the scene, which use more than minimally manipulated liposuctioned material to make a biological drug product via enzymatic and other steps. However, the clinics argue their products aren’t drugs and they generally do not have any FDA approval to market stem cells. Nonetheless such offerings are being sold at hundreds of clinics around the country. How would a newly minted FDA commish Gottlieb view these clinics? Through the same lens as the autologous, homologous bone marrow-based approaches? What about the clinics using bone marrow and amniotic cells in non-homologous manners that make such products drugs? Continue reading

New paper shows huge American stem cell clinic industry: 570 locations

My colleague Leigh Turner and I today published a new paper in Cell Stem Cell documenting for the first time the American stem cell clinic arena in a comprehensive way, which we found as of February has a remarkable 570 clinic locations via 351 businesses.

These numbers are way beyond the predictions of most researchers and policy makers for stem cell clinics in the U.S., and point to a burgeoning, huge industry from coast to coast (see map below of clinic locations that we found in our research that is Figure 1 of the paper).

Figure 1 Turner Knoepfler Stem Cell Clinics

We focused on those businesses that as best as we could determine do not have FDA approval for marketing stem cell treatments. This means that even if relatively few patients are seen at each of the 570 locations, tens of thousands of Americans each year may be getting stem cell offerings that do not have formal FDA approval.

The businesses in general market fat, bone marrow, and amniotic-related stem cells for a surprisingly wide range of conditions too, pretty much from head to toe and A to Z in a medical dictionary of conditions. It’s not clear scientifically if there are data to concretely support the use of these types of stem cells for such a wide spectrum of conditions.

Our goal was to document this direct-to-consumer marketed industry as fully as possible even as we excluded those businesses that had INDs or operated outside the U.S. A challenge in that regard is that the FDA keeps information about INDs private.

Importantly on the other hand some businesses while having no formal FDA approval may still be compliant because they fall within specific categories of usage. For instance, in some cases with a subset of these clinics such as those that use largely unmodified bone marrow cells for autologous use in homologous orthopedic conditions, no FDA “drug” approval is likely needed.

However, in many other kinds of treatment scenarios that we documented there is a strong likelihood that FDA pre-approval would be needed because of issues such as non-homologous use and/or more than minimal manipulation. Such a large industry with unclear regulatory oversight and pre-approval is a big concern overall.

Still, I do not condone the use of words like “non-compliant” or “shady” to describe all at once this entire clinic marketplace or to characterize the full list of businesses in our database because of a number of reasons including the issue mentioned above with bone marrow being used in a homologous way in some cases as well as the overall complexity of this arena and the lack of clarity from the FDA.

I’ll have more to say about the paper, but I hope you find it a valuable resource.

Stem cells run amok: Jill Howlin’s satirical cartoon look

Jill Howlin’s drawings about science and policy have a unique, edgy style that packs a punch. I have invited her to weigh in here now and then with new illustrations that touch upon stem cell or other innovative biomedical matters.Jill Howlin stem cell treatment run amok

Jill’s new drawing today relates to some key stem cell issues such as clinical safety, choice of stem cells, homologous use, and more. You can read my post from this week on the myth that stem cells are homologous to all tissues.

Jill tells me that she put an Irish humour spin on this cartoon.

Also see her past cartoon on Donald Trump and pay walls in science and medicine. I have also drawn some of these science political cartoons as well for the blog myself (see examples here) at times, but I think Jill has a lot more talent.

You can follow Jill on Twitter.

Bioheart on the edge in 2015?

Bioheart logoStem cell biotech company Bioheart ($BHRT) has had a rough 2015 so far.

Could this year be a decisive, negative tipping point for the company?

It has a number of clinical trials going, but from my view things seem increasingly uncertain.

An oddity amongst stem cell biotechs, Bioheart and its leadership have at times seemed to toy with what some might view as controversial projects. Kristin Comella, CSO of Bioheart, has played a major role in other ventures including in the past with the Ageless Institute, a stem cell clinic. Earlier this year, investors reportedly including Brenda Leonhardt (ex-wife of Bioheart founder, Howard Leonhardt) filed a lawsuit against Bioheart for millions in alleged unpaid debt.

Comella and Bioheart are also involved in what I view as concerning training of physicians in the use of a fat-based stem cell product that might be an unapproved biological drug from the FDA’s perspective. Comella provided some insights on Bioheart and the doctor stem cell training in a recent interview I did with her. She didn’t seem concerned with the FDA.

Bioheart has another puzzling venture, US Stem Cell Clinic, LLC, (“SCC”), which it describes in this way:

“a partially owned investment of Bioheart, Inc., is a physician run regenerative medicine / cell therapy clinic providing cellular treatments for patients afflicted with neurological, autoimmune, orthopedic and degenerative diseases. SCC is operating in compliance with the FDA 1271s which allow for same day medical procedures to be considered the practice of medicine. We isolate stem cells from bone marrow and adipose tissue and also utilize platelet rich plasma.”

Recent FDA draft guidances at the very least call into some doubt the compliance of some of the offerings of US Stem Cell Clinic, LLC. The FDA could back down on the requirement for the fat-based stem cell product SVF to be approved in advance as a biological drug, but then again it might not.

Investors seemed worried. Bioheart stock has taken a beating recently, down almost 60% in the last 3 months and almost 7% just today. Overall it seems that something has got to give soon.

Disclosure: I own no stock in Bioheart or its direct competitors. This piece is not financial advice.

Interview with Bioheart CSO, Kristin Comella: trial update, MD stem cell training & FDA

Kristin ComellaI invited the Chief Scientific Officer (CSO) of Bioheart, Kristin Comella, to do an interview after hearing some buzz that this could be a critical time for the company and that it might have been recently visited by the FDA.

Note that Comella not just Bioheart CSO, but also the primary instructor for physician training in stem cell methods offered by the company US Stem Cell Training.

Can you update us on how Bioheart is doing with its clinical trials/INDs?

Comella: Our completed clinical trials of MyoCell to date have been primarily targeted to patients with severe, chronic damage to the heart who are in Class II or Class III heart failure according to the New York Heart Association, or NYHA, heart failure classification system. We have completed various clinical trials for MyoCell including the SEISMIC Trial, a 40­patient, randomized, multicenter, controlled, Phase II­a study conducted in Europe and the MYOHEART Trial, a 20­patient, multicenter, Phase I dose­escalation trial conducted in the United States. We were approved by the FDA, to proceed with a 330­patient, multicenter Phase II/III trial of MyoCell in North America and Europe, or the “MARVEL Trial”. Thus far, 20 patients, including 6 control patients, have been treated. Initial results for the 20 patients were released at the Heart Failure Society of American meeting, showing a significant (35%) improvement in the 6 minute walk for those patients who were treated, and no improvement for those who received a placebo. On the basis of these results, we have applied for and received approval from the FDA to reduce the number of additional patients in the trial to 134, for a total of 154 patients. The SEISMIC, MYOHEART, and MARVEL Trials have been designed to test the safety and efficacy of MyoCell in treating patients with severe, chronic damage to the heart.

In addition, we  received approval from the FDA to conduct a Phase I safety study on 15 patients of a combined therapy (MyoCell with SDF­1) called the REGEN trial. Advancement of the MyoCell and MyoCell SDF­1 clinical development programs is contingent, among many factors, upon the Company obtaining access to sufficient funding to execute the necessary clinical trials to achieve proof of efficacy and regulatory authorization to market such products.

Bioheart has spent over $125 million researching cellular therapies for patients and supporting clinical trials. We are committed to bringing more treatments forward and all revenue that is brought into the company is put towards advancing this science. Our FDA phase 3 MARVEL Trial for congestive heart failure patients is budgeted to cost $10 million dollars for 100 patients. Trying to complete double blind placebo controlled trials is very expensive and there is limited funding for companies who are trying to complete these trials.

How did you and Bioheart get interested in stem cell training courses for MDs? Is US Stem Cell Training owned by Bioheart? Is there some common ground between the missions of the two?

Comella: We are currently offering courses for physicians through US Stem Cell Training which is a wholly owned subsidiary of Bioheart. The field of regenerative medicine is expanding very rapidly and physicians may not have adequate exposure to these topics during medical school. Our goal is to provide physicians with the latest research in cellular medicine. The course includes didactic lecture and hands on demonstration with topics including:

  • Stem Cell Biology
  • Embryonic Cells
  • Induced Pluripotent Stem Cells
  • Bone Marrow Stem Cells
  • Adipose Stem Cells
  • Platelet Rich Plasma
  • GMP Training
  • Regulatory Environment
  • Fat Harvesting Procedure
  • Bone marrow isolation Procedure

The course is constantly updated with new research and data as more studies are published. The goal is to familiarize physicians with the latest research and how this may affect their practice. We also host a monthly webinar series which includes journal clubs and guest lecturers. This field is growing and we want to provide physicians an opportunity to learn more about regenerative medicine. Many patients are asking their physicians questions about regenerative medicine and our hope is to bridge the gap between basic research and clinical practice.

What are your views on the recent FDA draft guidances including on adipose in which the FDA suggested that SVF is a biological drug?

Comella: The FDA has recently released a draft guidance document regarding the use of human cell and tissue products used during the same surgical procedure from adipose tissue and has requested comments from the public on this guidance. Please note that guidance documents represent the FDA’s “current thinking on the scope” of the topic. “FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.”

We do not believe that the current draft guidance document will affect our ability to offer in-clinic cell therapy from fat to our patients. We understand that the FDA’s draft document has elicited much resistance from the public and highly respected organizations such as AABB Center for Cellular Therapies and The Academy of Regenerative Medicine have voiced their opposition.

It is impossible to predict what the FDA will do regarding any in clinic therapies so I can only tell you what has happened in the past. In December of 2014, the FDA visited our lab as well as three physicians who are doing SVF procedures. The FDA took no action against anyone and did not stop the SVF procedures. Many of you have seen that these procedures can provide benefit to patients who have failed other therapies. Our primary goal has been and will continue to be safety and well-being for our patients.

Oftentimes, emerging technologies are met with skepticism and criticism. When stents were first introduced as an option for patients having a heart attack, many famous cardiologists criticized them because of the risk of restenosis (blockage). Yet stenting is now a common cardiac procedure. Cellular medicine has existed since the 1960s and is commonly used for cancer patients under the term Bone Marrow Transplant. These treatments were never put through double blind placebo controlled trials; nevertheless, we accept them as the standard of care. In addition, cellular medicine for degenerative diseases has been the subject of thousands of animal studies and clinical trials. Many of these studies date back to the 1980s. I think a fair question to ask a patient who has failed to benefit from traditional medicines and therapies is “how many studies would you like to see before you try to harness your body’s own healing potential”. Most patients are willing to try something experimental and, provided that companies are clear on the possible risks versus rewards, these therapies should not be withheld from the public.

I think that the body’s natural healing mechanisms are fascinating. The ability to harness this natural healing potential to reverse the effects of degenerative diseases or injuries is very powerful. We have a lot to learn about regenerative medicine but we are now starting to realize the potential by bringing these therapies to clinic. With any new therapies, there are challenges to bringing them to market. In addition, it is difficult to navigate the regulatory environment because these therapies are unlike any others currently available to patients. Cellular therapies should not be regulated in the same way as drugs and devices and many regulatory bodies are trying to establish new rules and guidelines. I am not sure that a person’s own cells should be regulated in the same way as a drug that is manufactured. It is important to advance science with patient safety as the primary interest. We have treated patients whose lives have completely changed for the better because of regenerative medicine and this is why I love this field!

Was US Stem Cell Training or Bioheart recently visited by the FDA? If so, how did the visit go and could you please provide a copy of the 483 form?

Comella: In December of 2014, we had an unannounced inspection from the FDA of our lab as well as three physicians who are doing SVF procedures. The FDA requested copies of our protocols and information about all of the materials that are utilized in the SVF process. They also specifically requested information regarding several IRB protocols. The FDA toured our lab facilities as well as the facilities of three different physicians. The FDA took no action against anyone and did not stop the SVF procedures. No warning letters (i.e. 483s) were issued. We received notice that all the documents were sent to CBER who reviewed and at this time they have no additional questions. Therefore the investigation was closed. Please note that this is the second investigation for Bioheart and we have not received any warning letters (483s). Our lab is a registered FDA tissue bank (FEI: 3005825762) and we are subject to unannounced FDA inspections.