More tough FDA draft guidance on stem cells…still no action

FDA logoThe FDA released more draft guidance with strong relevance to the stem cell field.

This October 2015 new draft guidance follows about a year after three other previous draft guidances that made it clear the current FDA thinking on various issues including stromal vascular fraction (SVF; fat stem cells) was much more restrictive than generally thought in the for-profit stem cell clinic field.

“Industry” apparently hasn’t been happy about this.

For instance, December 2014 FDA draft guidance very clearly indicated that fat-related stem cell products like SVF are more than minimally manipulated and hence are drugs requiring pre-approval and licensing. Another draft guidance on the same day surgical exemption issued a few months earlier also seemed (appropriately) to point toward more stem cell products being drugs requiring pre-marketing approval.

Still, to my knowledge the FDA has not actually finalized these guidances or taken any action based on them.

The new 2015 draft guidance aims to provide clarity and answer questions on the issue of homologous use. My sense is that this draft guidance, if ever finalized, would limit the unapproved uses of specific human tissues including amnion.

One particularly telling phrase from the new guidance stood out to me:

Generally, if an HCT/P is intended for use as an unproven treatment for a myriad of diseases or conditions, the HCT/P is likely not intended for homologous use only.

This sure sounds like how hundreds of stem cell clinics are using unapproved adipose and amniotic “stem cells”. Thousands of patients are spending millions of dollars right now on interventions violating multiple FDA perspectives mentioned in the various draft guidances.

Yet despite all this “tough talk” in draft guidances, by all accounts the FDA seems to be doing nothing to back it up in the way of actual actions on stem cell clinics violating these proposed rules or via finalized guidances. For instance, the CBER branch of the FDA suddenly stopped taking actions on stem cell clinics almost 2 years ago and since has done little if anything.  In the same period of time the number of stem cell clinics has roughly doubled. That is an equation for trouble and risks to patients.

What gives with the FDA?

In part I think they are just unbelievably slow in how they take steps on things, but that glacial slowness isn’t working to protect patients in the context of the warp-speed stem cell clinic world. They may also be getting political pushback on what seems to be emerging as a firming up path to regulating adipose stem cell products as drugs.

A big HT to Alexey Bersenev for pointing out the new draft guidance (see #5 in his post and another post). I recommend reading his post for another valuable view on this. He also points out that stocks have dropped for some companies related to this draft guidance and the FDA will hold a public hearing next year on these new draft guidances.

At this snail-like pace from the FDA we can expect these guidances might be finalized (assuming they ever are) in some revised form in…about 2-3 more years. By then there will probably be more than 1,000 stem cell clinics in the US selling unapproved stem cell drugs…

I’m all for public engagement by the FDA and responsiveness to feedback, but the FDA doesn’t have time to move so slowly.

ARM Asks FDA for Clarification on Draft Guidance on Minimal Manipulation

Alliance for Regenerative MedicineIn the last few months the FDA has taken steps toward crystalizing regulatory oversight of stem cell and more broadly cell and tissue-based therapies.

These steps come in the form of several draft guidances  (see herehere, and here.

The Alliance for Regenerative Medicine (ARM) has responded to the draft guidance on Minimal Manipulation. For example, ARM has requested that the FDA clarify the term “main function” for human cell and tissue products (HCT/Ps). ARM rightly points out that HCT/Ps can have more than one function. For example, adipose tissue in the draft guidances was said to have a structural function, but fat of course also has roles in metabolism.

In the Press Release it says:

“We’re pleased to see the FDA provide additional insight into their regulatory decision-making process on this important topic,” said Michael Werner, executive director of ARM. “We do ask, however, that the FDA provide clarity on a number of important points within the guidance, given the complexity, significance and impact of this issue. We also encourage FDA to hold a public hearing to engage with stakeholders in a full airing of the topic.”

The idea of public meetings is also potentially worthwhile. More clarity and engagement from the FDA is always a good thing.
One of the challenges for the FDA in regulating these products is that both compliant biotechs such as those represented by ARM and unlicensed stem cell clinics fall under a shared regulatory umbrella.

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.