Meeting review of unique stem cell ethics symposium @UCDAVIS

On Thursday here at UC Davis School of Medicine we held our second annual Stem Cell Ethics Symposium. The symposium was organized by Drs. Mark Yarborough and Nanette Joyce as well as me.

In this post I report on key take homes from the meeting and summarize the specific talks.

As far as I know, this is one of the few events in the world where there is such a wide diversity of stakeholders present both as speakers and in the audience to specifically discuss stem cell ethics for a full day. The participants included numerous patients and patient advocates, bioethicists, stem cell researchers, physicians, attorneys, institutional compliance officers, and more.

Stem cell ethics meeting

One of the things that I most appreciated about this meeting is that diverse views were welcomed and we dealt head on with some of the most challenging ethical issues related to stem cells.

I also got to meet in person some people I had only previously known on-line including keynote speaker Tim Caulfied, patient advocate Ted Harada, and advocate and frequent commenter on this blog, Cathy Danielson, which was fantastic. My colleague Leigh Turner was also present. Old friend and Huntington’s Disease advocate, Judy Roberson, was there as well. You can see the picture above of Ted, Judy, and me.

After a great introduction by our new Dean of the School of Medicine, Dr. Julie Freischlag, Nanette Joyce started things off with a very powerful talk about her experiences with her ALS patients. Her patients are facing incredibly intense challenges as they deal with all that ALS brings. Both in her medical specialty and amongst her patients, she noted, there is growing interest in stem cell treatments. Dr. Joyce expressed her concern over the lack of evidence of safety and efficacy, and how elements of hype have entered into the arena of ALS and stem cells. ALS is a very heterogeneous disease with ups and downs as well in individual patients, but life expectancy on average is very short after diagnosis.

One of Dr. Joyce’s patients, Michael, then gave a talk about his experiences with ALS. I found it really striking. Literally every day he goes on-line and checks out resources to search for opportunities for ALS patients such as clinical trials. Michael indicated that as far as he knows he’s not eligible for any trials so far. This was a theme that several people mentioned during the day: just because there are trials out there does not mean that patients with ALS or other conditions can be part of them. Patients are seeking other opportunities.

Next up was Ted Harada, who spoke passionately about his experiences with ALS, the ups and the downs, what is really like to get a stem cell treatment and be in a clinical trial. His talked about his willingness to take risks. He said he’d literally rather die trying something than not try to do something about his ALS. Ted has had two rounds of treatment for ALS as part of the Neuralstem clinical trial and he reported that it has really helped him. One of Ted’s concerns is that he may not be eligible to get a future third treatment from Neuralstem for various technical rules of the clinical trial, which is one reason he is such a strong advocate for Right To Try laws. However, Ted said he feels that most likely few or no patients will be directly treated as a result of Right to Try, but rather that it will open up a dialogue and create other positive outcomes that lead to more patient opportunities.

From both Michael’s and Ted’s talks, i also learned that it can take a very long time (potentially a few years) to definitively diagnosis ALS. Patients facing ALS are likely to have a much higher level of risk tolerance than others might imagine. Understandably they have a strong drive to take action.

I spoke next and focused on the growing challenge that the FDA and the stem cell field face of chains of stem cell clinics that appear to be selling unapproved stem cell drugs without FDA licensing. I talked a bit about the growth in providers offering unapproved stem cell “treatments” at Cell Surgical Network as an example. More broadly, the clinics argue that what they do is beyond the scope of the FDA’s regulatory authority. I discussed new FDA guidances that bear on this issue and which would seem to directly contradict the views of many of the clinics, squarely placing them and their products in the FDA sphere from my perspective. The clinics of course disagree. I also emphasized how the FDA currently is asking for comments on these guidances for the next couple weeks.Tim Caulfield

Tim Caulfield spoke next, giving a wonderful talk. In the stem cell world, hype is not just limited to dubious stem cell clinics. Tim focused on hype in the stem cell field and in particular hype involving scientific publications. He even talked about hype about hype. In the current environment there are strong pressures for scientists to hype their work, including in particular in abstracts. What is the relationship between hype in science articles and in the media? He discussed how widespread pressure to commercialize biomedical research including stem cell efforts sometimes has negative consequences and can contribute to hype.

Alison SorkinAlison Sorkin, Deputy General Counsel for University of Colorado Health, talked about Right To Try from her experiences in the trenches. With the passage of the Right To Try Law in Colorado, Sorkin was there for the intense repercussions. The next working day after the law was passed, patients starting contacting the University of Colorado seeking treatment specifically under the law. Sorkin talked about strict the Colorado law actually is, making it very limited in scope in reality. She also discussed problematic issues with the specifics of the law such as that patients would be responsible for paying for all of their own healthcare for 6 months after treatment under Right To Try as insurers would be exempt from having to provide ANY coverage. There seems to be a growing sense that Right To Try in Colorado may not actually lead to any patients getting non-FDA approved drugs. However, the FDA is paying close attention to Right To Try and one potential consequence of the various Right To Try laws passed in states is that the FDA could be influenced in terms of policies on expanded access (compassionate use).Leigh Turner

Leigh Turner gave a very timely, excellent talk on the FDA, stem cell clinics that do not have FDA licensing or approval, and the potential consequences of this current dynamic. Leigh went into helpful detail on the clinic claims, the types of stem cells they use, and how these relate to the new FDA guidances. He discussed Cell Surgical Network and Stemgenex. It is notable that Leigh gave specific examples and names clinics by name, which I agree is vital to the discussion of the regulatory sphere and the place of stem cell clinics.

Gerhard Bauer, my colleague here at UC Davis and one of my favorite stem cell scientists, gave a wonderful talk on his experiences and perspectives over the decades as a pioneering stem cell and gene therapy clinical researcher as well as earlier as a regulator at the FDA of Austria. Gerhard’s discussion ranged from his experiences in these roles to also his own person experiences as someone who has dealt with doctors and also lost many friends to disease including HIV. I also appreciate how he provided his views from his real world experiences wending his own clinical trials through the processes and how much work it takes just to get an IND. How great it feels to get to that point!

A few additional notes

Mary Ann Chirba, a voice for increased patient autonomy in terms of their cells, was going to be a speaker, but got snowed in at Boston. Richard Garr, Neuralstem CEO, was also scheduled originally to speak, but couldn’t make it. They were missed, but still we had a diverse, dynamic group of perhaps 70-80 attendees.

A big thanks to Julie Bechtel who helped to arrange the event.

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.

Interview with Neuralstem CEO Richard Garr

Richard GarrI invited Neuralstem CEO, Richard Garr, to do a Q&A interview and he kindly accepted. The interview provides some novel insights into this major biotech in the stem cell sector.
1. How is Neuralstem doing today? What programs are underway that you find particularly exciting? 
Garr: Neuralstem is moving on all cylinders these days on both our cell therapy and small molecule clinical programs.  We have just completed all the transplantations of our phase two ALS patients, with the data lock coming early in January, and hopefully the phase2/3 starting early next year; and in September we expect to transplant our first SCI patient at UCSD (chronic thoracic ASI-a patients).  We continue to dose phase 1 patients in our stroke trial in China.  On the small molecule side, the MGH group presented our 1b data in MDD patients at ASCP this past june and it was frankly, stunning; showing clinically meaningful improvement in all the patients who took the medicine as well as reaching statistical significance in treatment of depression measures, as well as cognitive improvement.  It is a first in class neurogenic drug, and we we will be going into a phase two we believe sometime near the end of the first quarter next year.
2. How are the financials?
Garr: The financials are stronger than they have ever been, and the last Q showed roughly $30 million in cash and equivalents.  Our burn rate continues to be a fraction of the industry norm thanks to our near virtual model, and generous funding of our ALS trial by the NIH and ALSA.
3. Where do you see the company in 5 years? 10 years?
Garr: We expect to commercialize the cell therapeutics ourselves, certainly in the U.S. With partners world wide in selective markets.  We expect to take the small molecule drug through, at least phase two, but ultimately to partner it out.  We have a wholly owned subsidiary in China, and a partner with an option on markets in Korea, Vietnam, Malaysia, Indonesia and Singapore, so we see a great deal of our growth also coming in Asia in the long term in cell therapy.
4. What makes Neuralstem  unique as a stem cell biotech company?
Garr: I don’t know that we are unique, but we are built differently than most.  We were built to move our technology forward, in every therapeutic area to which it might apply; we don’t look for other technologies for a particular disease, and we don’t look to expand beyond what we own.  So we, from that point of view, we are perhaps more focused than other companies on a particular way of treating diseases.  On the cell therapy side, we only have looked at incurable disease from the start; we believe that that is what our technology is capable of, and that has been our goal from the beginning.  That is now and has always been the ethos of our company.
5. How important is patient involvement in the stem cell biotech arena? Building on that, what is your view of Right To Try laws?
Garr: We have always been a much more “patient centric” company than most.  And we have always had an intimate relationship with various patient advocacy groups.  It is part and parcel of our make up.  And yes, that is why I got involved with the RTT movement.  There are roughly 30,000 ALS patients, 5,000 newly diagnosed each year;  and there is literally nothing our there for them to significantly improve their quality of life or their life span.  We believe our ALS therapy is doing both; our trials have not yet been powered to demonstrate that to the level that it meets various existing FDA early access programs, and I think that with the right safeguards RTT can provide a structure to build such programs around.  My view of RTT is that it is dependent on, and must work with the FDA.  It is built so that it relies on FDA diligence on safety; and I can tell you from our own experience that when you develop treatments for terminal diseases (and the law only applies to terminal diseases) you have spent (at least) tens of millions of dollars before you ever get into a phase one human trial, and you have a great deal of safety data before and after such trials.  The law also requires that you be actively engaged in at least a second FDA trial, so these eligible treatments are under the constant villigance of the FDA in order to be eligible.  I understand that there are many issues to be worked out in terms of liability and payments to mention just a few; but these are the types of issues this industry deals with every day, this is not peace in the middle east we are trying to solve here.  And so when critics of RTT bring up issues with the implementation, to me that is a separate issue from whether or not RTT is the right thing to do; and while those are serious issues, they are “second level” issues.   Also, it is a transitory program; that is, it’s only meant to provide access until the drugs are either approved by the FDA and available, or shown not to work.  As Ted says, it’s a right to try, not a right to cure.  Everyone involved understands that.
6. What is the IP portfolio like for Neuralstem? I understand there has been a conflict with StemCells, Inc. and Greg Schiffman commented on that in my interview with StemCells, Inc. leadership. Can you please let us know the Neuralstem perspective on this?
Garr: I won’t comment on the ongoing litigation other than to say this; the end will speak clearly for itself.  With respect to our IP position, it should be understood that NONE of our patents are being challenged in this litigation, only STEM’s patents are being challenged in this litigation.  We have patents issued worldwide which cover both our cell therapy and small molecule platforms.
7. How important is social media in this day and age for biotechs? As both a scientist and blogger myself, I note your blog as being unique and valuable to patients, investors, and the larger community. What prompted you to do a blog? What has your experience been like with it so far?
Garr: I think that social media is an essential part of communication today, with all the stakeholders in a company.  I started the blog because of the intense interest in what we are doing from the patient and caregiver communities, and as it has evolved, that has become the main focus.  It is complicated by the fact that we are a public company which brings in an entirely new and different set of rules and regulations that inform what you can and can’t say (about ongoing trial data for instance) but those are simply rules that one lives with.  Social media is changing the way patients communicate with each other.  That’s a genie you can’t put back in the bottle.  We see patients in trials blogging about their progress (or lack thereof).  They are not like juries where you can quarantine them until they reach a decision. It’s all about community, and patients and their support groups are always looking for more community in these stressful situations, it is a human instinct, and I believe a good one.  We reach out to comfort each other, that is what is behind the exponential growth here.  The industry is going to have to figure out a way to accommodate the new reality of social media and clinical trials, just like every other industry has had to learn how to adapt to the internet age.

Top 10 questions for stem cell field bouncing around on a Friday morning

top ten listWhat are the most interesting questions for the stem cell field in 2014 right now?

What’s on your mind?

I’m not going to give this deep thought, but rather just list those questions bouncing around at the moment in no particular order. You can see a lot of translational/clinical things are on my mind. I’ve put possible answers, but these are highly speculative and/or based on hope in some cases.

  • What’s next for ACT’s hESC-based clinical trials and Takahashi’s iPS cell-based clinical study for macular degeneration? I’m optimistic on safety for ACT and hopeful on efficacy, while it’s harder to predict for the iPS cell study.
  • How will ViaCyte’s new early hESC-based trial for Diabetes go? I’m cautiously optimistic.
  • In a year, where will the iPS cell IP/patent arena stand and who is BioGatekeeper? I expect no more clarity in a year overall, but BioGatekeeper will be outed by then or much sooner.
  • Will the trend of for-profit networks of stem cell clinics exploding across America continue? Unfortunately, yes.
  • Is the FDA planning to get back into the ballgame of regulating such stem cell clinics or has it punted due to (fill in the blank: budget problems at the agency, other priorities, a change of philosophy, etc.) Who knows? It’s been a disappointing year for the agency in this area.
  • Will the FDA apply Fast Track, Accelerated or Priority Review or Breakthrough Therapy Designation to any emerging stem cell products? It’s about time. They should.
  • What will the impact of the likely growing number of state Right To Try laws be? I expect it will increase both risk and innovation, but unfortunately much more of the former than the latter.
  • Was the flood of very high profile stem cell paper retractions so far in 2014 an aberration or will it painfully continue? I hope it does continue, but it’s a worry as the field needs public trust and respect.
  • Will a big pharma acquire a small biotech like Athersys, ACT, StemCells, Inc., Neostem, in the coming year? More money is sure flowing from big to small (witness ViaCyte’s new influx of money) and we saw this with happen California Stem Cell. I think we’ll see this trend of money flow or even acquisitions accelerate although there are structural obstacles to being acquired for certain companies.

What questions are on your mind right at the moment related to stem cells and regenerative medicine?

Note this post is simply informational and is not financial advice. Only make financial decisions after consulting with a certified financial planner, which I am definite not. I hold no stake in any of the companies mentioned.