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The Agency recently issued or is actively engaged in developing draft guidance on these topics: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

Short-term safety of lab-grown stem cells for arthritis: encouraging, but key caveats

A new paper suggests a hopeful short-term safety profile of laboratory-grown stem cells for treatment of arthritis, but there are some important limitations to the study too.

A debate continues to bubble over whether to classify laboratory-propagated stem cells as biological drugs.

Study design MSCs arthritis

A persistent issue has been whether the growth of stem cells in culture increases risks of negative outcomes for patients including 4 prominent and broadly applicable issues of risk: infection, benign but destructive tissue growth, cancer, and autoimmune reactions.

A fifth concern, particularly in the case of systemic IV administration of stem cell products, is pulmonary embolism (PE) as stem cells in the vascular system tend to trigger clots around themselves and accumulate in the lung rapidly. This could also manifest with local administration of stem cells that escape to the bloodstream via broken blood vessels.

The clinical use of laboratory grown stem cells has a number of potential medical applications including for conditions as diverse as arthritis, cardiovascular disease, and multiple sclerosis just to name three out of a host of others for which interventions are offered.

Published data on the safety of clinical use of laboratory grown stem cells has been rather lacking over the years. For this reason, it was good to see this recent publication specifically on this topic as it relates to treatment of arthritis of the knee and hip:

Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: A systematic literature review

The paper from Peeters, et al. in The Netherlands was published in the journal Osteoarthritis and Cartilage. Figure 1 showing the study design and selection process is above.

The analysis included 8 studies that fulfilled all inclusion criteria and encompassed 844 total procedures. The authors focused primarily on the use of bone marrow-derived MSCs injected into the articular space for the treatment of osteoarthritis.

Encouragingly, serious adverse events (SAE) were relatively uncommon (4 reported equating to <0.5% of procedures) and only a subset (2) of those was definitely attributable to the therapy itself.

One PE and one case of infection were therapy-related.

Twenty nine additional potentially events were possibly related to the stem cell therapy. Therefore, if there were 30 possible adverse events related to the stem cell therapy out of 844 procedures that is a rate of 3.6%.

The authors conclude that this kind of stem cell therapy is probably safe, however there are several important limitations to this paper that lower its impact.

  • One is the relatively short term follow up: a mean of only 21 months. While acute adverse events seem to be rare with the use of propagated stem cells injected into joints, longer term side effects (e.g. many kinds of tumors would be likely to manifest after years, not months) cannot be reasonably evaluated from this analysis.
  • A second issue is that variability in methods amongst the 8 studies makes analysis more difficult. Some studies followed patients for only months, while others followed them for years. Some studies used bovine serum for cell expansion, while others did not. There were other differences as well.
  • The authors also discuss the likely possibility of publication bias due to studies that have adverse events being more likely to remain unpublished or excluded. This is a serious challenge without a ready solution.

The authors of the systematic analysis paper pointed out the limitations mentioned above themselves, for which they should be commended.

Overall, I would say this study is encouraging  in terms of short-term safety with the limitations mentioned above and a note to readers added that this study does not prove efficacy.

The more data that is published in this area the greater clarity we will all have the strengths and weaknesses of this kind of stem cell therapeutic approach.

Interview with Arnold Caplan, Part 4: the FDA and the Future

Today is part of 4 (the last) of my interview with Dr. Arnold Caplan, MSC godfather and guru.

You can read parts 1-3 of the interview herehere, and here.

In this post I focus on my discussion with Caplan on translation of stem cells to patients and the FDA.

During our conversation we talked about some of the challenges facing the efforts to make safe and effective stem cell therapies (including those based on MSCs) available to patients.

Of course one key element is regulatory oversight, which is important for protecting patients, but which, according to some in the field, is too onerous and slows everything down far too much.

When I asked Caplan about the FDA, he said, “There is no sinister plot.” What he was referring is the ubiquitous, but false claim by some in the non-compliant stem cell sector that the FDA and Big Pharma (and some academic scientists) are engaged in a plot to kill stem cell therapies because they are supposedly a threat to the profit stream of Big Pharma.

However, Caplan continued, “The FDA is inhibitory to translation of stem cell therapies to patients. There is no sense in regulating MSCs as a drug.”

Caplan went on to describe an interesting, new proposal that he is working on with Mike West and Andy VonEschenbach (former FDA commissioner, 2006-2009 and now a proponent of FDA reform, exemplified by his widely read editorial in the WSJ). In the new framework envisioned in the proposal, there would be progressive approval and after early phase success companies could get FDA approval to get paid for patient treatment as part of the process. Another element overall would be a greatly streamlined overall process that gets stem cell-based medicines to patients more quickly.

This priority fits with the results so far of my blog’s poll on FDA reform (still time to participate) where the top pick amongst respondents for a reform at the FDA in the stem cell field was speeding up the clinical trials process.

Caplan concluded on the FDA with a powerful overall take-home message, “A test of any civilization is laws and we need the FDA, but we also need faster access for patients to stem cell therapies.”

I really enjoyed talking with Dr. Caplan (thank you!) and I hope you enjoyed this series of blog posts on the interview.

 

Interview with Arnold Caplan Part 2: propagation, placebos, patients, and publishing

I recently interview Arnold Caplan, the father of the MSC field, and published part 1 of the interview (you can read it here).

Today in part 2 we cover more topics of great importance related to MSCs including propagation, placebos, and patients as well as publishing.

A hot topic in the stem cell world more generally, but especially in the MSC field is what happens to stem cells when they are grown in a lab. Many important questions are being asked. Are the propagated stem cells basically the same as the starting stem cells? If not, how are they different? Should people be concerned about getting transplants of propagated cells?

I asked Caplan about how MSCs react to growth in culture. He acknowledged that MSCs grown in culture do change. “The longer you culture MSCs, the less they can differentiate,” said Caplan, “however, the MSCs retain their ability to inhibit immunosurveillance and to secrete trophic factors”. As discussed in the first segment of this interview, Caplan’s view is that it is these two functions rather than any stem cell-related properties of MSCs that are of the greatest therapeutic importance.

Caplan also mentioned another way in which culturing might change MSCs and in this case have clinical significance. After transplantation, high passage MSCs are more likely to become coated with clotting factor in the donor’s body and become trapped in the lung, reducing their efficacy. Thus, perhaps as is true with so many types of stem cells, lower passage is likely to be safer and more effective.

We also discussed how MSCs are likely to work clinically. One topic was the very important 2012 paper from Katarina LeBlanc’s team on autopsy data from patients who had received MSC transplants. The paper argued for quite limited engraftment of MSCs in support of the idea that nearly all transplanted MSCs do not engraft and rather function in a “hit and run” way to aid patients.

Caplan also acknowledged that many patients receiving MSC transplants (or transplants of other stem cells or even other kinds of medical interventions) definitely experience a significant placebo effect. The placebo effect that some patients experience with treatments can be substantial, up to 30%. However, Caplan passed on the experience of many physicians who are transplanting MSCs in RCTs where, according to Caplan, the doctors can easily tell which patients received placebo and which received stem cells, because those who received MSCs are doing so much better.

Interestingly, Caplan also pointed out that paradoxically for some patients, allogeneic MSC transplants might be more promising than autologous. In this regard, he mentioned how MSCs from healthy people appear to be more functional than MSCs from multiple sclerosis (MS) patients.

Caplan mentioned that there are 100s of patients receiving MSCs worldwide. I asked him why then are there so few publications. Caplan responded, “if only they would publish it would help everyone and the field.” I also would like to see more publications in this area.

Stay tuned for part III of the interview coming up in a few days.

Insightful interview with Arnold Caplan: Part 1: MSC history, nomenclature, & properties

Arnold CaplanA few days ago I had a long, very enjoyable phone conversation with the father of the mesenchymal stem cells (MSC) field, Dr. Arnold Caplan.

Dr. Caplan is Professor of Biology, Director Skeletal Research Center at Case Western. He coined the phrase “mesenchymal stem cell” in the late 1980s.

I’m going to break the interview into 4 parts. Today is Part 1, focused on the history, nomenclature, and properties of MSCs. I learned a lot to put it mildly from talking with him. (See Part 2 of the interview here, covering patients, propagation, publishing, and placebos).

I asked Caplan about the history of the MSC field and he responded that he called the cells by the “MSC” name to be intentionally provocative. According to Caplan, “The dogma of the day was that adult animals only had hematopoietic stem cells, but no other stem cells in other organs.” As a result, the notion that other tissues such as fat or bone marrow could have stem cells such as MSCs was somewhat heretical. I admire Caplan for challenging the orthodoxy. He recalled one seminar he gave at which “esteemed colleagues” in the audience were muttering some not so nice things about his presentation on MSCs.

Of course the new dogma today has caught up with Caplan. It is that every organ and tissue likely has its own compliment of stem cells and most people in the stem cell field believe in MSCs. But I think this scientific history of MSCs is very important to know in order to understand these cells. It also helps us keep an open mind about what we might all consider the new reality in the future that overcame today’s dogma. By the way, what is today’s dogma in the stem cell field? That’s a topic for a whole different blog post I hope to do in the future some day later this year.

Another important issue that we discussed is the inherent heterogeneity of what people call “MSCs”. Just as some folks pronounce “mescenchymal” one way with the accent on the end while others pronounce it with the accent in the middle (see Merriam-Webster here for the different pronunciations), so too do people call very different kinds of cells by that one name. I have heard people say that MSCs are pericytes, fibroblasts, endothelial cells, endothelial cell precursors, adipose progenitor cells….and the list goes on.

I asked Caplan about this and his response was that “I dogmatically say that all MSCs are pericytes.” He went on to explain that in his way of thinking pericytes respond to inflammation or injury by becoming MSCs.

Interestingly, Caplan has now transformed the MSC acronym to stand not for “mesenchymal stem cell”, but rather “medicinal signaling cell”, which he believes is a more accurate name for the cells. He went so far as to say that the therapeutic properties of MSCs are “not connected to stem cells”, but rather “MSCs work by secreting powerful bioactive molecules.”

These molecules have two major areas of action: (1) inhibiting immunosurveillance and (2) trophic effects. The latter function itself manifests in four ways via anti-apoptotic effects, anti-scarring, stimulation of angiogenesis, and mitotic effects on surrounding cells.

The gestalt of MSC function was nicely synthesized by Caplan in another way when he called the cells “a multi-drug site-regulated dispensary”.

Stayed tuned for three more posts on this interview with this leader in the MSC field including tackling key topics such as clinical and regulatory issues related to MSCs.