Does stem cell clinic IRB approval mean much? Insights from blinding cases

Could the blinding of three women at a stem cell clinic have been prevented by better oversight or was the clinic acting outside of the scope of oversight by its institutional review board (IRB)?

More broadly, when is an IRB conducting proper oversight and how do we know? When on the other hand is it not being careful enough or even outright enabling risky behavior by those selling non-FDA-approved, experimental stem cell “treatments”?

It can be hard to really be sure. What makes this area particularly muddled is that most of what IRBs do is confidential. We in the stem cell community are as a result left with a bunch of questions in general and about specific cases such as the blinding of these women.

When things go wrong and patients have bad outcomes how much is the responsibility of an IRB versus the stem cell clinics doing the actual experiments? Stem cell clinics often point to their IRB-approved status as some kind of merit badge, but how much does that approval mean? My goal in today’s post is to tackle that last question.

stem cells eyes

Kuriyan, et al. 2017 NEJM Figure 2A showing patient with severely damaged eyes leading to loss of sight

Over at BuzzFeed reporter Peter Aldhous has been following the story of the three women who were blinded by experimental offerings of US Stem Cell, Inc. In Aldhous’ new article he focuses more on US Stem Cell’s IRB. This IRB was run by an organization called the International Cellular Medicine Society (ICMS), which in theory was responsible for overseeing work of US Stem Cell.

There are a host of questions about what happened leading to the women losing their vision and what if any role the ICMS IRB had in overseeing the experiments on these patients. Did US Stem Cell wander outside the scope of ICMS IRB oversight in this case? Could the ICMS IRB have done a better job? If the ICMS IRB did its job well here, I still wonder how they can help to prevent more bad outcomes like this from happening? Presumably the ICMS IRB is overseeing work by many other stem cell clinics as well. How much risk is there at those places? If a business doesn’t follow its IRB’s rules, what happens then? It’s hard to find answers to questions like these. Continue reading

SCOTS Study on Stem Cells for Vision: Still Questions as Patient Alleges Harm

Eye injection

Eye surgery image from Wikipedia. Is clinics injecting stem cells into an eye a good idea? OK with FDA?

I’m hearing more questions from the community about alleged harm from stem cell clinics selling stem cells for a number of vision-related conditions and some concerns include the so-called SCOTS study.

I first blogged about SCOTS early this year and back then I myself had questions too. Some commenters then raised concerns or questions about SCOTS in weighing in on that post.

In my opinion SCOTS is almost certainly not a traditional FDA phased clinical trial, which raises issues right from the get go. I’m not aware of the trial having, for instance, an IND. Patients must pay $20,000 to participate and that brings additional questions.

The listing is here (reminder in general that a listing on that website does not equal FDA approval or some kind of NIH approval of the actual clinical science). The company mentioned as the responsible party is Retinal Associates of South Florida in collaboration with another business, MD Stem Cells.

A self-reported SCOTS study patient, George Gibson, made allegations to Scientific American that he lost vision after participating in the study:

“But not every story of stem cell therapy has such a rosy outcome. George Gibson was in his late 60s when he partially lost his vision during heart surgery. He says he paid $20,000 to get stem cells injected into his eye with the guarantee that he would be able to read a few more lines on an eye chart. Gibson claims that instead, he lost vision in that eye completely, but his assertions could not be verified. There have been other reports of vision loss in stem cell procedures performed elsewhere. Gibson didn’t get one of the first-come-first-serve slots to speak at the hearing; instead, he and his wife stood outside the meeting room during breaks with big signs that read, “I lost my sight to the SCOTS stem cell procedure!!!”

To be clear, this outcome has not been independently verified and the SCOTS investigators dispute the allegation.

Another SCOTS patient, Doug Oliver, who has also commented on this blog, has apparently had the opposite kind of experience. He self-reported a very striking positive outcome after receiving the stem cells in SCOTS and this has gotten a lot of media attention.

Two case report publications are listed as associated with the SCOTS study:

So what is going on here?

The short answer is that we as a community don’t know yet.

In a number of different stem cell studies over the years we’ve heard about individual patients having striking outcomes. Anecdotal reports of alleged potential harm or benefit should definitely be paid attention to and given consideration, but what we really need is comprehensive data from properly controlled studies to have confidence that an investigational stem cell therapy is (or is not) safe and effective.

Related to this specific study, I’m very happy for Doug, but the SCOTS study needs to show/publish all the data including any potential adverse outcomes before we can know what is going on with this investigational treatment. Last week I emailed Dr. Steven Levy, MD who is running the study asking if I could do a brief email Q&A with him for the blog, but so far no reply. Dr. Jeffrey Weiss is listed as the Principal Investigator so I may reach out to him as well if I don’t hear from Dr. Levy.

Great 2nd Place ISSCR Essay Related to Vision and Stem Cells

Hikita2smallerISSCR and I held a short essay contest for a free registration to ISSCR 2014 in Vancouver. The winning piece was written by student Mohamed Gatie, but there was a great 2nd place essay by Sherry Hikita that deserved acknowledgment. I’m publishing that essay below and Sherry will be receiving a free signed copy of my book and a free stem cell t-shirt. Sherry was formerly at UCSB and is now a scientist at the very cool stem cell biotech, Asterias.

Here is Sherry’s essay:

It was pitch black.  My eyes were wide open but I could not see anything.  I could, however, smell something delicious.  I gingerly felt where the silverware was on the table, but without being able to see, I realized it would be incredibly difficult to use these utensils.  Dining with my hands was better.  I could at least feel where different foods were on my plate and could feed myself, though identification of the meal was another challenge.  This might be chicken.  Or pork?  There may have been a carrot but the other objects were a mystery.  My “Dining in the Dark” meal (hosted by Foundation Fighting Blindness to raise awareness about retinal degenerative diseases) lasted only 30 minutes, but this period of being sightless was a truly profound experience.  My motivation to investigate and develop a stem-cell based therapy for macular degeneration has been fueled by the intellectual challenge, the potential of stem cells and the worthwhile endeavor of restoring vision to those who cannot see.  But this particular experience turned into a much higher octane fuel.  I knew, with great relief, the lights would be turned on soon and I would continue living, with vision.  But for those who are blind and vision impaired, there is no such relief.  Our servers were vision-impaired people who shared their stories and challenges, while graciously providing advice for the unexpectedly difficult task of navigating a meal in the dark.  I did not see their faces but I heard their voices and felt their hopes for research that might enable restoration of sight.  These people are my jet fuel and motivate me to keep learning and striving as a stem cell scientist.  And the ISSCR and its annual meetings are critical for helping me continuously develop my craft.

Stem Cell Pioneer Masayo Takahashi Interview on iPS cells, clinical studies, & more

Masayo TakahashiIn the interview below I talk with Dr. Masayo Takahashi, who is leading a team conducting the first ever in-human clinical study based on iPS cells. The work began with patient enrollment on Aug. 1, 2013 in Japan.

1. Can you tell us a bit about your background? As an M.D./Ph.D. and ophthalmologist do you also see patients in addition to doing research? How did you first get interested in stem cells? Are your interests primarily in iPS cells?

Yes, I have outpatient clinics in two hospitals next to RIKEN and see the patients with retinal degeneration.

I encountered the concept of stem cells at Prof. Gage’s lab in the Salk Institute in 1995. At that time I decided to make treatment for retinal degenerative diseases using stem cells. So I applied the concept of stem cells for retinal transplantation for the first time (Mol. Cell. Neuroscience 1998)

After several years of research in Japan I moved to ES cells because I realized that somatic stem cells cannot be expand enough for many patients as a standard treatment. With help of Dr. Sasai we made retinal pigment epithelial cells from ES cells ( PNAS 2002). When I saw the pigmented clumps of cells in the dish that Dr. Sasai asked me to evaluate in 2000,  I was confident that RPE will be the first ES-derived cell used in a successful clinical treatment and it will be industrialized.  I reported the first treatment of animal model using primate ES cells (Invest. Ophthalmol. Vis. Sci. 2004)

But I hesitated to develop a treatment with ES cells because I myself as an ophthalmologist did not want to use immune suppressant for the elder patients with tiny eye diseases. So it was natural that I immediately moved to iPS cells in 2005 when I heard about iPS cells before the article came out.

2. As the leader of the pioneering first ever in human study of an iPS cell-based therapy, can you fill us in on the process that went into making the trial a reality beginning with patient enrollment on Aug. 1? How long ago did you start preparing for the trial? What steps did you have to go through? Do you think some of your pre-clinical data may be published soon?

As reported in the Invest. Ophthalmol. Vis. Sci 2004, we had Proof of Concept with ES-derived RPE and ready to go into the preparation for the clinical trial. So that we started preclinical study with human iPS cells from 2007. Then we confirmed that the hiPS-RPE have the suitable characteristics for the clinical use in the aspect of quality, quantity, consistency and safety. These data was finally accepted in the Stem Cell Report.

3. Can you tell us how many patients have been enrolled so far? Are autologous iPS cells from any enrolled patients already being made? For the average patient how long do you predict it will take from their enrollment to their treatment?

We cannot announce the enrollment because of the confidentiality of the patients.

The surgery will be held 10-12 months after enrollment.

4. What method is being used or will be used to make the iPS cells? Sendai Virus for example or another approach? Why did you pick this method?

We decided to use a plasmid (episomal vector) according to the discussion with CiRA

5. How will you validate the new iPS cells from each patient? Will you, for example, do a whole range of tests such as genomics, gene expression, epigenetics, in vitro differentiation, and in vivo behavior in animal models? Do such validation tests present challenges such as being costly and time consuming? Why are they important?

We will choose suitable iPS lines severely from genomics, morphology, stem cell markers and karyotype. CiRA will help us.  We have technique for good RPE cell differentiation from 100% of iPS cell lines we choose so far.

We did in vivo efficacy test in the preclinical research but we will not do it again in the clinical research. On the other hand, we will do the tumorigenicity test for each patient’s iPS-RPE at least for the first several patients’ iPS-RPE.

They are very much  time and money consuming. However, it is important to evaluate thoroughly because it will be the first trial.

6. It would be very helpful if you could explain to us the difference between a clinical study and a clinical trial? I understand you are starting with a clinical study. How does that work and assuming all goes well with this study, what would be the next step? A clinical trial?

A clinical study is under the medical practitioner’s law. It is a unique system in Japan that is like a practitioner’s exemption.

Clinical trial is the ordinary system in the world under the pharmaceutical law. The pharmaceutical law has been changed to be more regenerative medicine friendly, so that in the next clinical application we will use the ‘clinical trial’ track.

Our first auto-transplantation of iPS-RPE sheets might become ‘an advanced therapy’ (that is also unique system in Japan). I do not think it will go under clinical trial because it is too expensive to be a commercialized standard treatment.

7. Many patients have asked me how many years it might take before we have iPS cell-based therapies for macular degeneration are fully approved and in common use. What’s your take on that?

It depends on the regulation in each country. However, it will not become in common use before 10 years. ( In Japan, by chance,  it will be 5 years or so.)

8. In the long run, do you think patients can be treated via iPS cell-approaches entirely in an autologous fashion or is it important to establish iPS cell banks for potential matching and allogeneic use? 

To make the treatment as a standard one, the cost should be decreased. In that sense allogeneic transplantation will be necessary. Also we should think about how to bring the cost down of autologous transplantation.

9. Advanced Cell Technology is conducting a similar kind of clinical approach but using hESC. Can you comment on that and how your study and theirs are similar or different?

We will treat wet type Age related macular degeneration (AMD) with RPE sheets, while ACT are treating dry type AMD with cell suspension.

10. What excites you most about stem cells and where do you see the field in general say in 5-10 years?

With ES or iPS cells, the regenerative medicine will go into the industrialized stage at least in the field of RPE.

The effect of regenerative medicine will not depend on the donor cells but depend on the host condition and the surgery skill. We should think of it as medical treatments. Furthermore, the regenerative medicine therapies, especially retinal regenerative medicine, will be completed with rehabilitation (low vision care), so we should think about total medical system.

As for the stem cells, the potential of evaluating patients’ iPS-derived retinal cells is exciting. We have never evaluated patients’ retinal cells.