To stem cell clinics: do your homework & take FDA “current thinking” seriously

FDA draft guidanceOne of the difficult things about the regulatory sphere that covers stem cells in the US is that many aspects are confusing or puzzling both to the public and so-called experts. We’ve been talking through some of the questions that come up in this area in posts and comments on this blog.

  • What does a warning letter really mean? What triggers it?
  • Why do some businesses selling stem cells get inspected and others don’t?
  • What do some entities get warning letters over the years, while others don’t?
  • What weight does a draft guideline have?
  • How about a finalized one?
  • If a business disagrees with an FDA guideline or action, what should it do?
  • If a business operates without FDA approval (maybe because they disagree with the FDA) when it seems that it should need that approval and yet the FDA takes no action, does that mean anything?

The list goes on and on.

It’s kind of like trying to read tealeaves. One of the FDA reforms I advocated for in my book, Stem Cells: An Insider’s Guide, is more clarity and better communication.

Despite the many questions and confusion out there, I would say one thing is clear: Take FDA “current thinking” very seriously.

While current thinking as articulated in guidances (draft or otherwise) is not formally equivalent to a regulation, it would seem to have the power to trigger action based on the historical record.

Therefore, one broader lesson in this arena would seem to be that the FDA can pull the trigger on actions like visits and warning letters based on their current thinking even if that current thinking is not formally crystalized beyond draft guidances or even without any draft guidances. For instance, it seems pretty clear that the FDA right now views SVF as a drug and while it may not have done much about this action wise yet, the odds are that such action will be coming sooner or later. The same goes for non-homologous use of bone marrow and amniotic stem cells such as for neurologic conditions. In other words, what the FDA staff think is going to be their basis for actions. SVF

As a result, it kind of goes both ways in the sense that guidances (draft or otherwise) are not formal regulations and “only” reflect current FDA thinking, but at the same time “FDA current thinking” shouldn’t be underestimated in terms of importance as it clearly can play a big role as the basis for action.

Too often I’ve heard clinics or other advocates say things like, “these are just draft guidelines” or “the FDA hasn’t been clear on that yet”. The reality is that no matter what any of us might like (e.g. increased FDA clarity), it is not the FDA’s responsibility to make sure everything is crystal clear for every stem cell clinic out there. Rather, it is the physicians’ responsibility to do their homework on the FDA and all relevant regulations, current thinking, etc.

If a clinic wants to challenge the FDA I can respect that if it is done responsibly, but it is a very different matter and a risky game to do such a challenge operationally by administering what by all accounts the FDA considers to be unapproved drugs into patients and then waiting to see if anything happens on the regulatory front.

This game of stem cell chicken is particularly risky if you are “treating” medical conditions outside of your specialty and do not have any rigorous training in stem cells as well as having little if any expertise in FDA regulatory affairs. And, no, a weekend resort or other similar quickie “course” on stem cells doesn’t really count.

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.

Top 10 myths about 3-person IVF mitochondrial transfer

It’s been somewhat of a helter-skelter time for the new technology often referred to as 3-person IVF or mitochondrial transfer as the UK considers whether to legalize this experimental technology for use in humans.

I believe that this technology is not ready now for use in humans and for more background on why as well as other opinions you can see articles here.

The admirable goal of this experimental 3-person IVF approach is to prevent transmission of mitochondrial diseases from mother to child, but it raises many complicated scientific and ethical questions. Like advocates of the use of this technology in humans, I too want to see new options for people with mitochondrial diseases to be able to have healthy families, but unfortunately this technology although well-intentioned could int reality end up doing far more harm than good, especially if implemented too soon.

The two main methods proposed for this technology are outlined in images from the UK HFEA.

3-person IVF

Unfortunately in the fray, some myths have popped up that we now often see quoted in newspaper articles as facts.

Here are what I believe are the top myths or inaccuracies that have arisen and the facts that counter them.

Myth: This technology would cure mitochondrial diseases. Fact: The technology, even if proven successful and that’s a big ‘if’, would prevent some children from being born with mitochondrial diseases. It would not treat or cure them.

Myth: This technology has been conclusively proven safe in animals and would definitely produce healthy babies. Fact: Animal studies are mixed as to whether this approach is safe. Some that are limited in scope are encouraging, while others have raised serious warnings. More studies, particularly in primates, would be needed for a conclusive determination. As this technology is highly experimental it is unknown if the human babies produced would be healthy. In fact, it might put them at risk.

Myth: This technology would only be used for treating mitochondrial disease. Fact: One of the leading advocates of this technology in the US, Dr. Shoukhrat Mitalipov, has already asked the US FDA to approve this technology for treating infertility as well. Therefore, in addition to mitochondrial diseases this technology could well be used for infertility as well as for other purposes that even today’s backers might find not so clear-cut from a bioethical perspective.

Myth: This technology involves transfer of mitochondria. Fact: This technology does not involve moving mitochondria. Instead it involves moving entire nuclei or so-called “spindles” that are groupings of chromosomes, from one human egg or embryo to another.

Myth: This technology does not lead to human genetic modification. Fact: This technology conclusively does create genetically modified human embryos and hence it would produce human beings that are GMOs. Mitochondria have a genome including genes. Plants that only have a single added gene are definitively called GMO.

Myth: Mitochondria are just like little batteries that can be swapped out. Fact: Mitochondria are vital for energy production in cells, but there’s a whole lot more that they do as well. There is strong evidence that the mitochondrial genome, for example, “talks to” the nuclear genome, and has pervasive effects on cellular and organismal functioning. Therefore the notions that mitochondria are simply like replaceable batteries or that mitochondrial transfer would be just like transfusing blood into an anemic patient are misleading at best.

Myth: This technology would remove all diseased mitochondrial DNA. Fact: This technique is not perfect and it is essentially certain that at least some small amount of diseased mitochondria would remain. The consequences of the resulting heteroplasmy are reason for concern and it is possible that the diseased mitochondria might preferentially replicate, increasing their relative numbers.

Myth: Women with mitochondrial diseases have no other options for creating healthy families. Fact: There are several other options. One option is to utilize pre-implantation genetic diagnosis (PGD), which has proven potential to lead to healthy offspring and is an option for most women with mitochondrial diseases. PGD technology is only going to continue to improve as well, potentially expanding options further. Another possible option is to utilize an egg donor to be fertilized by the partner’s sperm, with the downside being that the mother to be would not be genetically related to the child produced. A third option is adoption.

Myth: This is not a new technology. Fact: While some unauthorized fertility experiments were conducted in the 1990s (eventually prohibited by the FDA) that have some resemblance to 3-person technology, they were different in important ways. For example, the technology used in the 1990s involved cytoplasm transfer between eggs rather than the more extreme intervention of nuclear or DNA transfer (as now proposed in the UK) and it did not involve mitochondrial disease. It is important to point out that even so the experiments in the 1990s led to some negative outcomes including chromosomal damage and developmental disorders.

Myth: IVF was a risky technique originally and was successful for the UK and the world so 3-person technology will do the same. Fact: While 3-person technology does involve IVF, it is a much more severe medical intervention and far riskier both to the children to be created and the country that allows the work. The pioneering work that the UK did on IVF was noble and successful, but the situation with 3-person technology is not quite analogous. The lesson from the success of IVF is not that 3-person technology will similarly prove to be safe, effective or bring honor to the UK. On all three accounts that optimistic perspective could be flat-out wrong.

Breaking: New FDA Draft Guidance Views Fat Stem Cells As Drugs

FDAWith a new document released today the FDA is more clearly on a path to regulate dubious stem cell clinics in the US.

There are more than 100 such American clinics that are selling stem cell “treatments” to patients and almost all of them use non-FDA approved stem cell products isolated from fat tissue.

The clinics have argued that they do not need FDA approval and just keep on raking in big profits from vulnerable patients.

They have claimed no need for FDA approval because they believe that the stem cells isolated from fat tissue that they use are not “drugs” because they are “not more than minimally manipulated.” In English that means that the clinics are arguing that the purified fat stem cells are basically the same as overall fat tissue.

To me that doesn’t make any sense.

A groundbreaking draft guidance statement today by the FDA for the first time sends the message to the clinics that the clinics are very likely wrong and could be subject to future regulatory action.

It is important to point out that this FDA statement that mentions fat stem cells is “draft guidance” meaning that it is not yet finalized, but make no mistake that this is the clearest snapshot to date on the FDA’s views on fat stem cells and it is unlikely to fundamentally change during the comment period.

The bottom line is that fat stem cells are viewed by the FDA as drugs that must be vetted and approved prior to use by physicians and clinics.  It also reinforces statements from draft guidance issued earlier in October that narrowed exceptions to the same-day surgical procedure guidance for use of biological materials such as stem cells.

In the new document today, the FDA even sets out isolation of fat stem cells as an example of more than minimal manipulation (emphasis mine):

Example 10-1: Original relevant characteristics of adipose tissue, a structural tissue, to pad and cushion against shocks generally include its bulk and lipid storage capacity. A manufacturer recovers adipose tissue by tumescent liposuction and processes the adipose tissue to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells. The HCT/P generally is considered more than minimally manipulated because the processing breaks down and eliminates the structural components that provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement.

A tissue product that is “more than minimally manipulated” again is a biological drug requiring prior FDA approval before use in patients.

I agree with this new FDA draft guidance because again fat stem cells are to my mind (as a cell biologist who has been studying cells for more than two decades) different than fat tissue. Fat stem cells constitute a biological drug that should be approved by the FDA in advance as well as tested in clinical trials before experimental, for-profit use on patients.

Another issue that applies is “homologous use” meaning that a product such as fat stem cells can only be used in a similar fashion or it is automatically a drug. For example, fat stem cells in theory could only be used therapeutically in a manner related to fat tissue-related health problems. The clinics today use fat stem cells to treat pretty much every condition from head-to-toe, which is clearly non-homologous use.

You can make a comment to the FDA on this draft guidance by following the instructions below pasted from the FDA guidance page.

How to make a positive difference? I encourage you to make a quick comment supporting the definition of fat stem cells as more than minimally manipulated and hence biological drugs. It is the safest thing for patients and the best way to go for the stem cell and regenerative medicine field.

Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov.  Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

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.