FDA warning points to tougher regulation of fat stem cells & clinics

FDA logoLast week I blogged about how the FDA had issued a warning letter to a series of three co-owned fat stem cell clinics across the US.

What does this FDA action mean on the broader stem cell clinic arena, particularly to those selling fat stem cells?

The FDA is still in the process of getting public comment and finalizing draft guidelines related to stem cell clinical products including fat stem cells aka adipose stem cells and stromal vascular fraction or SVF.

Even so, the FDA just issued this new warning letter at least partially related to SVF to a series of co-owned clinics in CA, FL and NY here in the US going under the names Irvine Stem Cell Treatment Center, Miami Stem Cell Treatment Center, and Manhattan Regenerative Medicine Medical Group.

In the letter the FDA explicitly calls SVF a biological drug in this context and mentions that there’s no IND and no BLA (for more on these key acronyms see here) at the clinics.

As discussed in the comments on my first post on this warning letter, the FDA language is a bit puzzling in the language used in the part calling the SVF a drug. The letter first mentions several target conditions as an implied possible reason for the definition as a drug and then only later indirectly mentions more than minimal manipulation as possibly involved. Non-homologous use is also mentioned. Overall this letter is not very clear. A helpful FDA reform would be a commitment to clear writing in its public communication.

Still the relatively unambiguous wording in the letter calling SVF a drug here is striking given that the FDA again has not to my knowledge finalized its guidance on SVF. It’s hard not to read the letter as meaning the FDA has every intention of defining SVF as a drug in many if not all cases.

This is a big deal because scores of stem cell clinics in the US are injecting SVF into patients on a daily basis without any FDA approval, licensing, etc. It’s not clear why these three co-owned clinics got the first FDA warning letter in the last few years on stem cells when there are all these other clinics doing very much the same thing. That’s also puzzling and leaves an important open question. More broadly as far as I know there’s no public information on how the FDA assesses which entities to focus its limited resources upon at any one given time.

What does this mean for all those other fat stem cell clinics out there? It’s bad news for them as the FDA could and really should be taking a close look at them too. The FDA is slow at times to take action as I’ve been critical of them about in the past, but once they get going, those not following the rules have reason to be concerned.

What about those recent still only draft FDA guidances (e.g. see a nice piece by Alexey on the situation with fat stem cells here)? I suppose they could change or take a long time to be finalized, but this warning letter can be viewed as a strong signal that the guidances are unlikely to change in their core points.

One of the largest collective users of SVF in the stem cell clinic world is Cell Surgical Network (CSN), with whom Irvine was previously affiliated. I contacted CSN more than a week ago by email for comment on the warning letter and to get their perspective on this development, but have not received a reply. To my knowledge, CSN has not been subject directly to FDA action, but I do not know when the apparent split with the Irvine clinics occurred.

Until more information about what the FDA is doing & thinking (at least as expressed by their written words) hits the  public domain, the key puzzles mentioned above will remain open for speculation. However, this letter possibly signals a major turning point for regulation of clinical use of adipose stem cells, particularly in the clinic realm.

FDA Warning Letter to Irvine Stem Cell Treatment Center Clinics Across US

The FDA has sent a Warning Letter to the Irvine Stem Cell Treatment Center. The leader of Irvine Stem Cell Treatment Center is Dr. Thomas Gionis and the letter was addressed to him. Interestingly, this letter, dated December 30, 2015, contains redactions.

At one time this clinic was part of the larger Cell Surgical Network (CSN) chain of clinics, but it seems it is no longer listed on the CSN website. You can see, however, that Gionis and Irvine are listed on this archived page from the CSN website.

Both publicly and on this blog, CSN in the past argued that it doesn’t need FDA approval for its stem cell product or its use (herehere and here), but recent FDA draft guidances imply otherwise in my opinion. Note that this new Warning Letter does not mention CSN.

You can see a screenshot of the top of the Warning Letter below.

This is post number one in a series on the breaking news on this development.

Gionis Irvine FDA Warning Letter

A Warning Letter is a serious form of FDA action. For instance, the Texas stem cell clinic Celltex received one and later moved its clinical operations to Mexico in part as a result. It’s unclear at this time what impact if any the Warning Letter will have on Irvine Stem Cell Treatment Center (note that it has multiple locations in NY, CA, and FL, each mentioned in the letter), but it’s definitely bad news for the clinics in my view.

The Letter outlines three major areas of problems:

  • (1) the adipose stem cell product being used (stromal vascular fraction or SVF)  is an unapproved biological drug
  • (2) non-homologous use of the product
  • (3) more than a dozen specific problems related to the production of the stem cell product SVF at the Irvine facility that the FDA termed, “a number of significant objectionable conditions”.

All three general areas of issues are serious.

The first two problems related to the FDA defining the SVF as a drug product and its use in what the FDA calls a nonhomologous fashion probably will have the broadest impact across the US. More than one hundred clinics use SVF in the US without having any FDA approval or licensing, and they use it in similar ways to Irvine that are likely to be deemed nonhomologous use as well.

As a result, this Warning Letter should be a wakeup call to these clinics. Despite the quietness of the FDA in the last two years on stem cell clinics, this could indicate a period of greater activity has begun.

The section defining the SVF as a drug in the letter is this one, emphasis mine:

“Your SVF product is intended to treat a variety of diseases and conditions, including, but not limited to, autism, Parkinson’s disease, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), cerebral palsy, and amyotrophic lateral sclerosis (ALS), and is therefore a drug under section 201(g) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 321(g)] and a biological product as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)]. It is also a human cell, tissue, or cellular and tissue­based product (HCT/P) as defined in 21 CFR 1271.3(d).”

The relevant section on non-homologous use:

“In addition, your SVF product fails to meet 21 CFR 1271.10(a)(2)’s criterion that the HCT/P be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.”

The other dozen or so issues with the production and the facility practices of Irvine Stem Cell Treatment Center are quite significant as well in my view and include sterility practices.

The FDA inspected several Irvine Center clinic locations, but apparently not the one that seemed to kinda pop up last year in my neighborhood here in Sacramento. I’m not sure if this local one exists currently.

Irvine has responded to some ongoing issues raised related to the series of inspections, but not sufficiently says the FDA. Notably, the section on responses included this partially redacted phrase:

“you have terminated your relationship with the (b)(4)“.

I wonder if this refers to CSN? Hard to know.

Even though this Warning Letter does not mention CSN, the issues raised therein are in my view likely to be at least somewhat of interest to active CSN clinics too. I’m planning to contact CSN leadership to ask for a reaction to the letter and clarify whether CSN and Irvine are indeed no longer affiliated as would seem to be the case.

Irvine has only a few more days left of the 15 day response period to address the concerns raised by the FDA.

Stay tuned for more on this breaking news in follow up posts. This is a long Warning Letter with much to think about in it.

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.

Stem cells sold for better sex part 2: bigger & better penis?

Does size matter?

Can a man get bigger and could he do it via stem cells?

Today’s post is the 2nd in a series on stem cells being sold allegedly for a better sex life. You can read the first post here.

An increasing number of men around the world are paying a lot of money for stem cell “enhancement” procedures. Such a procedure could put their health in danger as they strive to be bigger in that area. Men are also more often writing in to this blog asking about this topic, weighing risks to potential benefits.

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