New Interview with FDA on Key Stem Cell Regulatory Issues & Its Own Research

FDAIt’s been a seemingly rather quiet year on the regulatory front in the US when it comes to direct-to-consumer stem cell interventions even as the number of dubious stem cell clinics continues to skyrocket.

I requested an interview with the FDA to cover the key pressing issues in this arena. I want to thank the FDA for taking the time to do this interview.

Below are their answers covering regulation of SVF, homologous use, FDA action/inaction on dubious stem cell clinics, Right To Try Laws, and the FDA’s own research on stem cells.

Paul: One of the hot topics in the stem cell arena is the production and use of stem cells from adipose tissue with the most common product being called stromal vascular fraction (SVF). A current debate is whether CBER views SVF as a biological drug product. Could you please comment on SVF and whether it is a 351 or 361 product? is it more than minimally manipulated? If such a definition/guidance is on a case-by-case basis, can you cite any examples of where SVF has been defined simply as 361? The field could really benefit from some clarity on this issue.

FDA:  FDA recognizes the importance of this issue and the necessity for clear communication regarding minimal-manipulation, SVF, and other stem cell-based products.  It is understandable that the field is eager for clarification on the categorization of SVF and other stem cell-based products and FDA develops guidance on these topics as the specific regulatory approaches are sufficiently mature.

The Agency recently issued or is actively engaged in developing draft guidance on these topics:

CBER’s 2014 Guidance Agenda is available here:

http://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/ucm338498.pdf

Paul: Another area where some additional clarity would be helpful is on non-homologous use. Is it correct to say that even if a biological product is defined as not more than minimally manipulated but it is used in a non-homologous manner (e.g. adipose used for a neurological disorder) does that product still require approval as a 351?

FDA:  In order to be regulated solely under section 361 of the PHS Act, a HCT/P must meet all of the criteria in CFR 1271.10(a), including the requirement for homologous use.

CFR 1271.10 can be accessed here: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=1271.10.

Paul: A number of stem cell researchers have noted a lack of apparent FDA/CBER action in 2014 with regards to stem cell clinics selling interventions based on SVF or other unapproved stem cell products and/or apparent non-homologous use coupled to broad claims by clinics (e.g. “our stem cell treatments can treat 20 different conditions”), etc. Without commenting on specific cases of course, could you comment on why the FDA/CBER appear to be relatively less active in regulating stem cell clinics in 2014? For example, in 2012-2013 there were numerous Warning Letters issued, but none in 2014 related to stem cells to my knowledge. It certainly seems that the problem of stem cell clinics is not going away so that’s not the explanation so less FDA action. If anything there are dramatically more of such clinics in the US now than in past years. Why is CBER not taking action?

FDA:  As discussed above, CBER is actively working to develop guidance on the issues relating to SVF and other unapproved stem cell-based products. These guidances will offer necessary clarification with regard to HCT/P regulations.

As you know, FDA cannot comment on any potential actions or open investigations.

Paul: Right To Try (RTT) laws have been passed in several states and the current trend seems to be for more states to pass such laws. What is CBER’s view of RTT? How do these state laws interface with the federal laws that authorize the FDA to regulate investigational drugs?

FDA:  State laws, such as the Right to Try laws, do not supersede federal laws. Please keep in mind that through FDA Expanded Access or “compassionate use”, investigational products often can be made available for a patient with a serious or immediately life-threatening disease who does not respond to current approved treatments for a variety of reasons.

Additionally, Right to Try Laws share similar aspects to the use of an investigational product under FDA’s expanded access. In both cases, a treating physician must recommend the experimental product and be able and willing to use it to treat the patient.  Additionally, the drug manufacturer must be willing to provide the experimental product. States cannot force drug manufacturers to provide their products, nor can they force physicians to recommend an experimental product or use such a product to treat a patient.

Paul: Many members of the stem cell community find it notable that CBER conducts its own stem cell research including on MSCs. Could you please tell us more about this research program and its goals? What has it achieved so far and what do you foresee for its future?

FDA:  The MSC Consortium, which started work in mid-2010, was established to facilitate the development of products and therapies that utilize mesenchymal stem cells (MSCs). Through research, the  Consortium aims to answer the complex scientific questions that face the development of stem cell-based products. The research of the Consortium is meant to contribute to the understanding of the underlying science regarding MSCs and the goal is that increasing understanding of MSCs will facilitate development of safe and effective MSC-based products.

The Consortium is studying eight unique cell lines from eight distinct adult donors, who donated stem cells from their bone marrow.  The cells were purchased from commercial sources.

The type of cell into which MSCs will differentiate depends on the conditions under which they are grown.  Similarly, factors such as the age or gender of the MSC donor may affect the quality and performance of these cells. The Consortium’s research is looking at how the biological functions of MSCs may be impacted by factors such as growth environment or donor characteristics.

Additionally, the Consortium has identified the need for further characterization of MSC-based products in order to better understand the diversity amongst subpopulations of these cells. FDA researchers are working on ways to better characterize MSCs, such as through development of assays and screening for MSC molecular markers or other characteristics that correlate with biological properties of MSCs.  By identifying these correlative characteristics, researchers hope to develop ways to characterize MSCs with measurements that more reliably predict the biological functions of MSC-based products.

Specifically, the Consortium has performed research contributing to understanding the differences between samples from different donors and  the effects of cell passaging on the differentiation capacity, gene expression, and function of MSCs (Lo Surdo & Bauer, 2012; Lo Surdo, Millis, & Bauer, 2013; Bellayr et al. 2014).

The Consortium conducted an extensive membrane proteome analysis of human bone marrow MSCs (Mindaye et al., 2013a) and proteomic analysis of culture-expanded MSCs (Mindaye et al., 2013b), resulting in datasets which can serve as a basis for further research and understanding of MSCs.

The Consortium has also developed a novel immune inhibition assay in order to investigate the immunosuppressive functions of MSCs, with the goal of improving understanding of the immune-inhibitory activity of MSCs from different donors, at different passages, or grown under different conditions (Nazarov, C., Lo Surdo, J., Bauer, S. R., Wei., C-H. 2013).

In the future, the Consortium will continue to develop and refine quantitative methods to assess the biological characteristics of MSCs and to identify molecular and other characteristics of MSCs that correlate with biological functions of MSCs.

  • References
  • Bellayr, I. H., Catalano, J.G., Lababidi, S., Yang, A. X., Lo Surdo, J. L., Bauer, S. R., and Puri, R. K. (2014)
  • Gene markers of cellular aging in human multipotent stromal cells in culture. Stem Cell Research & Therapy. 5:59. doi:10.1186/scrt448.
  • Lo Surdo, J. L., & Bauer, S. R. (2012). Quantitative Approaches to Detect Donor and Passage Differences
  • in Adipogenic Potential and Clonogenicity in Human Bone Marrow‐Derived Mesenchymal Stem Cells.  Tissue EngineeringPart C, Methods, 18(11): 877‐889. doi:  10.1089/ten.tec.2011.0736
  • Lo Surdo, J. L., Millis, B. and Bauer, S.R. (2013) Automated Microscopy as a Quantitative Method to
  • Measure Differences in Adipogenic Differentiation in Preparations of Human Mesenchymal Stem Cells. Cytotherapy, 15 (12): 1527-40. DOI: 10.1016/j.jcyt.2013.04.010
  • Mindaye, S. T., Ra, M., Lo Surdo, J. L., Bauer, S. R.,  Alterman, M. A. (2013a). Improved proteomic profiling of the cell surface of culture‐expanded human bone marrow multipotent stromal cells. Journal of Proteomics, 78: 1‐14. DOI: 10.1016/j.jprot.2012.10.028
  • Mindaye, S. T., Ra, M., Lo Surdo, J. L., Bauer, S. R., and Alterman, M. A. (2013b).Global proteomic signature of undifferentiated human bone marrow 6 stromal cells: Evidence for donor‐to‐donor proteome heterogeneity. Stem Cell Research 11(2): 793-805. DOI: 10.1016/j.scr.2013.05.006
  • Nazarov, C., Lo Surdo, J.L., Bauer, S.R., Wei, C-H. (2013). Assessment of immunosuppressive activity of human mesenchymal stem cells using murine antigen specific CD4 and CD8 T cells in vitro. Stem Cell Research & Therapy 4:128. doi:10.1186/scrt339.

Mesoblast (MSB) buys Osiris (OSIR) stem cell unit

Mesoblast_LtdThe Australian stem cell biotech Mesoblast (MSB) has reportedly reached a deal with the American stem cell biotech Osiris (OSIR) to buy Osiris’ mesenchymal stem cell (MSC) unit.

This is a big development in the MSC field.

Osiris and Mesoblast are two major players in this particular subfield of the stem cell world so this deal, reportedly worth up to $100 million if specific milestones are reached in clinical trials in the future, will boost Mesoblast’s leadership in MSC-related clinical applications, although Mesoblast, led by CEO Silviu Itescu, refers to its cells “as “mesenchymal progenitor cells”.

Importantly, the deal includes the cellular drug, Prochymal, for the treatment of a transplant-related disease called “acute graft versus host disease”. The drug has not yet been approved by the US FDA, but is approved in New Zealand and Canada.

Presumably this means that Osiris is going to focus on other parts of its portfolio, but it’s not clear yet what all went to Mesoblast and what remains. Some are reporting that this deal means all of Osiris’ stem cell-related business will now belong to Mesoblast as FierceBiotech says for example: “Osiris exits stem cell business”.

How does this affect competitors Athersys (ATHX) and Pluristem (PSTI)?

In my new book on stem cells Mesoblast was one of just a handful of stem cell companies that I singled out as particular good citizens of the field.

Osiris stock is up almost 5% today so far and Mesoblast was up about the same amount on the ASX market so it seems investors see this as a win-win for the companies.

 

 

 

 

 

 

 

Interview with Regenerative Surgeon, Dr. Allan Wu

Dr. Allan WuOver the last few weeks, I have enjoyed talking with and interviewing Dr. Allan Wu, of The Morrow Institute on stem cell cosmetic procedures. I was impressed greatly by his talk at the World Stem Cell Summit last year.

Dr. Wu is a fellowship trained Surgical Molecular Biologist with a background in Molecular Embryology and a board certified Cosmetic Surgeon actively practicing  Aesthetic Reconstructive and Regenerative Surgery.

Below is my interview him. I hope you enjoy it and find it as thought-provoking as I did.

Paul question #1: In my opinion, one big challenge for the translational stem cell  field seems to be balancing innovation with safety. What are your thoughts on the best approach to that? If where we are at today could use improvements on either side (innovation or safety or both), what are the best ways to make a course correction for the future?

Dr. Allan Wu: There will always be novel biologic entities that stretch the very limits of our regulatory systems to the point of rendering some aspects obsolete and/or cause for revision.  The trick moving forward is to have open, honest and dispassionate communication between clinicians, scientists and Federal and State authorities and professional boards and organizations.  When you look back historically on novel therapies such as transplant medicine, IVF and ICSI, a great deal of prefacing and focus group consensus building was needed to form fair and cogent regulations to monitor safety and allow the fields to move forward.  This process has been lacking in the adult mesenchymal stem cell realm and in particular adipose derived stem cells (ADSC).  Looking back it is hard to precisely determine why we are at such a challenging juncture with the FDA, though some of blame can be placed upon ADSC being so easily accessible and profusely abundant.  That too combined with immediate marketability and high patient demand created a perfect storm in which several clinicians unwittingly (and some intentionally) jumped the gun before a clear understanding could be vetted by professional organizations.

Because legal liabilities are a reality in medicine, most physicians and surgeons turn to attorneys as a primary method to resolve very serious misunderstandings or disagreements.  The recent Regenerative Sciences Inc. case is a good example of this.  Although academic colleagues may find this approach distasteful, to their credit, the attorneys involved in the case and those in the periphery commenting upon it, have actually helped educate clinicians and their understanding of 21 CFR 1271, which until a few years ago was an obscure regulation to non-transplant surgeons.  And whether intended or not, the adversarial process helped gain a greater understanding of the FDA’s concerns.  Some of us lament that it was unfortunate either side had to legally engage one another in the first place and wonder if perhaps in the coming year a different approach modeled after our colleagues in bone marrow therapy, transplant medicine and IVF could be pursued as a viable alternative.  Regulations preserving patient safety along with the sanctity of the patient-physician relationship will never be achieved in a vacuum.  The FDA, clinicians, scientists, patient advocates, bioethicists, and yes even attorneys NEED to be involved in the process.  I think the recent legal panel video excerpts from the World Summit and STEMSO meetings this year give a great synopsis of where the current regulatory climate resides.  Pending meetings April 22-23 in Palm Springs by Select Biosciences and the World Summit in fall of 2013 will also delve into these issues further.  So stay tuned and look forward to the FDA possibly giving further guidance regarding adult mesenchymal stem cell therapy at one of the major meetings.

In terms of innovation, Dr. Guoping Fan (UCLA, Dept. of Genetics) and I have been working on and off the last 5 years on ideas and projects to quantitatively or semi-quantitatively establish safety parameters for clinical stem cells using genomic tools.  We are not alone in this quest, and though I do not speak for the FDA, I do find recent activities at CBER quite telling.  On an FDA webpage entitled “Supporting the development of mesenchymal stem cells as clinical therapies” they detail their work on a limiting dilution assay, which could indicate a philosophic shift towards defining “minimal manipulation” and safety standards for stem cells on an assay based approach.

As I’m sure you are aware, the technology in genomic and personalized medicine is growing at an exponential pace.  The thought of doing rapid point-of-care analysis using genomic assays like sequencing, methylation status, RNA expression profiles and proteomics is no longer a pipe dream, but a pending reality due to tremendous strides in nanotechnology and hyperspeed computing.  Our colleagues on the personalized medicine front are essentially building a “bridge” towards regenerative medicine. As wireless and open-source infrastructures mature, all forms of regenerative medicine from iPS to MSC will benefit.  For example, our counterparts in Spain (Estreller’s lab) completed an interesting study last year looking at osteocytes derived from ADSC and compared their epigenetic signature to osteosarcoma cell lines (MG-63).  Thankfully the ADSC derived osteocyte heat maps looked nothing like the correlated tumor cell lines despite being cultured for close to a month.  This technology in its present state, however, is not tenable from a point-of-care context, but with lab-on-a-chip design and network innovations, these kind of assays will eventually become available for stem cell pre-deployment safety assurance.

Paul question #2. What are the top cosmetic procedures utilizing stem cells today?

Dr. Allan Wu: Cell assisted lipotransfer (CAL) for various forms of tissue augmentation has taken off like wild-fire in Japan and the rest of the regulatory world that does not forbid the procedure.  The procedure itself is almost a decade old, and who would have thought adding the stromal vascular fraction (which contains ADSC) would have such a tremendous impact on free fat grafting?  Dr. Kotaro Yoshimura, the inventor of the procedure, and other colleagues outside of Japan, has had tremendous results with breast, hand and facial augmentation.  Though breast augmentation seems like a frivolous application of science, the cross-translational knowledge and skill is reaping rewards for our colleagues in wound care and cancer reconstructive surgery, thus creating unanticipated novel “spinoff” therapies.  To date the world medical literature has not reported a single teratoma or cancer as a result of appropriate CAL use.

It is important to note that as other countries continue to innovate and develop CAL and related techniques, the United States could find themselves in a predicament in which novel stem cell therapies could belong to foreign countries with a different regulatory philosophy.  Ironic too since the U.S. has significantly funded basic sciences research in regenerative medicine, and a horrible shame in that (even if the regulatory climate were to change over night) we may find ourselves eventually “locked out” due to a growing international patent thicket.  In short, our government needs a coherent, consistent and pro-active policy for regenerative medicine especially if we plan on using regenerative solutions to combat the rising cost of domestic health care and also support a promising new industry that will have direct material impact upon the American economy.

So hypothetically speaking (and to address your “course correction” in question #1), if I were POTUS or the FDA, I would find a way to at least allow SVF use in the form of CAL, but require regulatory oversight.  In this way clinicians lacking a major research budget would be able to operate without a costly IND.  In exchange all clinicians would mandatorily submit close follow up data to an independent national registry to monitor the safety of the procedure in much the same way our colleagues in infertility and transplant medicine do already.  Should a negative pattern develop, the procedure can immediately be placed on hold until further study is done to determine necessary corrections in cooperation with the FDA.

I would also try to define “minimal manipulation” on an objective assay basis to give industry a clear regulatory pathway and “set the goal posts” so to speak.  This should free up the ability for startups to work on innovative, but safe and well defined forms of manipulation, which eventually could include limited tissue culture techniques.  Smart money always likes to operate in fields where it believes it can succeed.  Providing entrepreneurs more transparent and well defined grounds to operate would do much to alleviate anxiety and simultaneously foster greater venture capital interest in the field.

Paul question #3. Where do you see stem cell therapies and the field being in 5-10  years? What are you most excited about in this area looking to the future?

Dr. Allan Wu: We are quickly finding that stem cells serve dual function as direct “mechanics” in regeneration and repair, but also secretory factories pumping out relevant stimukines/factors.  One company in particular, Personal Cell Sciences, has cleverly capitalized on this concept by converting conditioned media from ADSC cultures into specialty formulated autologous skin creams.  What I find fascinating are the lesser known fractions of the media, the exosomes, nanosomes and liposomes, which are being largely ignored.  Strange too since exosome miRNA can and do exert effects on the stemness quartet of NANOG, SOX2, OCT4 and TCF3.  I would bet that the supposed “junk” that we have ignored in conditioned media will find further clinical application in cosmetic surgery and wound regeneration within the next 5-10 years.   So the excitement generated here is the real option of inducing regenerative capabilities without cells all together.  This could lead to additional forms of cure not requiring as rigid or delicate of preservation or handling.

One other major breakthrough is using stem cells as a Trojan horse for gene therapy.  There are several companies and centers focusing on mesenchymal stem cells as the ideal vehicle for correcting heritable disease traits.  Great strides have been made this year using zinc finger technology to literally “edit” or correct foul genetic code in autologous cells ex-vivo.  I joke with operating room staff and warn them someday patients will not only have beautiful skin like Suzanne Somers, but also carry the same genetic profile of skin cells with the help of “edited” autologous stem cells.  Perhaps not 5 years and possibly not even 10, but using the stem cell as a general gene therapy work horse is a likely reality and also points to the importance of building that “bridge” between regenerative and personalized medicine.

Paul- I also asked Dr. Wu to react to my in-press article in Regenerative Medicine calling for academic fellowship training programs for physicians in cellular and regenerative medicine. Such as fellowship would include a curriculum training physicians in a number of areas such as FDA compliance, GMP, ethics, cell biology and so forth.

Dr. Allan Wu: Your curriculum reminds me of a funny conversation I had with a witness to an FDA inspection five years ago.  The inspector informed a practitioner his process was not GMP compliant after which the clinician implored, “but we get our GMP from a good chemical company!”  The field officer (without loosing composure) gently explained GMP did not stand for guanine monophosphate, but actually meant Good Manufacturing Practices.  To make matters worse, the clinician responded “…well we really do a good job manufacturing the cells…”  It just goes to show you how raw some clinicians’ understanding of regulatory issues were not long ago and why the FDA might have become a bit weary of clinicians the last few years.  The story does, however, highlight the need to educate physicians, as this is a specialty in the truest sense of the word.

And I think your idea is very insightful.  Several universities have established research centers for regenerative and translational medicine, however there are no ACGME accredited training programs in clinical regenmed.   Why build new tools for clinicians if in the end they won’t even know how to use them or even know which tools are immediately or legally available to them?  (This is also why I say our government needs a coherent regenerative medicine policy!)

Nowhere in medical school is 21 CFR 1271 even covered either.  Regulatory language and subject matter material for regenerative medicine is not a requirement for medical education at this juncture.  Medical students are lucky to be exposed to it in electives or side commentary from academic professors.  So the idea of a specific and formal post-graduate clinical and basic science fellowship will address a real unfulfilled need in medicine.  The current generation of regenerative physicians and surgeons has a difficult time with the regulatory concepts and language.  Some of this is due to unfamiliarity, but some of it is also due to misinformation.  Including the medico-legal and regulatory training in your curriculum will be critical if we hope to move the field further and work with the FDA.  The basic science training in cellular molecular biology would also help clinicians distinguish true science from hype and hopefully eliminate use/adoption of some commercial products which are more “snake oil” than real science.  So providing a fellowship would do much to improve the integrity and credibility of practitioners and the industry as a whole.  I might also add here that certification of facilities and the labs are also part of the equation and would point readers to Dr. Alan Trounson’s article on his “alpha lab” concept. (note from Paul–readers, you can see that article here).