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.

icmslogo

More specifically in the recent blinding case there also seems to be uncertainty about why US Stem Cell injected the fat stem cells into both of each patient’s eyes and whether ICMS OK’d that or not. ICMS flat-out says “no”:

“The International Cellular Medicine Society (ICMS) Institutional Review Board (IRB) did not approve the bilateral treatment techniques or practitioners utilized by US Stem Cell / Bioheart that resulted in the three cases of blinding complications that was described in the New England Journal of Medicine, Brief Report, published March 16, 2017.”

I don’t know for sure, but I would tend to believe that the ICMS IRB did not approve the bilateral injections. The ICMS statement also makes some other reasonable points such as that the approved “trial” with US Stem Cell injection of stem cells into the patients’ eyes apparently never officially began and then was withdrawn. ICMS also points out that in other ways the stem cell experiments on the patients that actually took place were apparently outside the context of the approved trial and did not follow the approved guidelines. So in a sense it is possible that what US Stem Cell did with these patients was technically not the subject of oversight by the ICMS IRB.

Still I have some concerns about the ICMS IRB itself.

The mission of the ICMS IRB is unusual in some ways in my view. ICMS has a policy statement for physicians that seems focused on freeing up the doctors to experiment as near the end it says the following: “No other group has done more to protect a physician’s right to practice stem cell and regenerative medicine.” By contrast, if you read the FDA’s IRB page the focus of an IRB must be on protecting patients rather than protecting doctors’ freedom to conduct for-profit, experimental, non-FDA approved stem cell medicine.

Aldhous also points to more issues with the ICMS IRB such as it having a number of members who have their own stem cell clinic businesses selling non-FDA approved interventions. According to the BuzzFeed piece, some of the IRB members have in addition had concerning issues with regulatory bodies. Also notable is the fact that a few years back the ICMS IRB received a critical inspection report from the FDA.

Since the FDA more generally is tasked with overseeing IRBs themselves too and not just stem cell clinics, we can hope that the agency is overseeing stem cell clinic IRBs as well, but with no activity in this area for years I wonder what’s up with the FDA and stem cell-related IRBs. It’s one of those “who’s watching the watchers” situations.

Another vision “trial” of sorts called SCOTS has been controversial as well with no FDA approvals and some patients who participated in SCOTS have alleged that they were blinded by stem cell offerings there too. It’s not 100% clear who the SCOTS IRB provider is, but it might be ICMS as well as the SCOTS clinicaltrials.gov listing includes a trial identifier ICMS-2013-0019 that suggests as much. I’m going to try to get clarification on this.

If more broadly the ICMS IRB is now trying to move in a positive, more rigorous direction then it has a lot of work to do with potentially dubious stuff that it has approved in past years it seems and with for-profit entities still claiming ICMS IRB approval when what these folks may now be doing was actually not specifically approved by the ICMS IRB.

Stem cell clinics love to advertise their “IRB approval” as though it is some kind of regulatory good housekeeping seal of approval, but how much weight should be given to that? Today’s bottom line unfortunately is that IRB approval of experimental for-profit stem cell clinic offerings that lack FDA approval may in some cases mean very little on its own.

For you patients out there considering stem cell treatments don’t just accept “IRB approval” from a stem cell clinic as meaning everything will be OK and that the work has been subject to rigorous oversight already. Probe deeper with common sense questions including about which IRB is involved and that IRB’s track record, Google the IRB and see what you find, ask the clinic if the IRB approved exactly what they are now doing, and err on the side of caution overall.

15 thoughts on “Does stem cell clinic IRB approval mean much? Insights from blinding cases


  1. @Paul, Thanks for shedding some light on a topic I never fully understood. The example in Florida is really a disgrace for patient protection and should be an eye opener to patient advocate groups. It certainly appears that many of the IRB’s are set up to simply to circumvent the rigorous role of the FDA.


      • In the case of these blinded patients, it wouldn’t surprise me at all that it wasn’t the stem cells that did the damage but the medical procedure itself. I had a detached retina a few years ago and went through hell but I thank my surgeon every day for saving the vision in my right eye.


  2. No credible IRB would have approved bilateral injection of an experimental therapy (of any sort–cell,drug) into both eyes. If you look at the withdrawn clinicaltrials.gov listing (sponsor Bioheart) the protocol description (which is very skimpy) says injection into the “eye” not “eyes”.

    IRB service is a huge amount of work and there are limitations to how much volunteer IRBs can effectively execute a monitoring function. An annual report or update to the IRB would likely not have prevented this protocol breach, if that is what this terrible event is.

    The ICMS website states that the injections were not done under their IRB protocol but their statement is confusing. They refer to the ICMS protocol (NCT02024269) being withdrawn which implies that the status of the clinical trial listing was changed, but says nothing about whether the IRB protocol itself was stopped with notification of their IRB–These are two separate processes.


    • Thanks for your comment, Marie. You raise some really good points. I wish I knew why CBER has been so dormant when it comes to oversight of stem cell clinics and their IRBs for the past several years even as the stem cell clinic industry has ballooned enormously.


    • Hi Jeanne, While skimming through IRB info on the FDA website yesterday I saw that IRB members can be paid. As to oversight of IRBs, that seems to be the FDA’s job. Paul


  3. Paul,

    You guys are the experts here, but most stromal vascular fractions contain pre-adipocytes, mesenchymal stem cells (MSC), endothelial progenitor cells, T cells, B cells, mast cells as well as adipose tissue macrophages plus BioHeart added platelets…..and who knows what the ratio of cell types was or the rationale for this…What medical scientist/stem cell biologist do this ??


    • Correct analysis of the cellular make up of fat cells when RPE Retinal pigmental Epithelial replacement cells are need and shown to safe and effective in 44 patients in one eye from OCATA phase clinical trials now Astellas Pharm……. Where are the phase two and 3 three studies from Astellas ? This is a sad scientific/ medical design experiment gone wrong ….This should never happen on any IRB who should have known of OCATA ‘s work in the field…..


  4. Why is everyone all the sudden talking about news that happened 2 years ago…Its seems more an attack than any concern for what happened. The 3 cases were settled out of court and the procedure isn’t being done anymore. You guys working for Big pharm?


    • “..the procedure isn’t being done anymore..” Did you even read the article? The SCOTS trial is still recruiting.

      So can you give me a dollar for every patient I find who gets fat stem cells for an ophthalmic disorder? Hope you can put money where your mouth/post is.

      Or are you working for a fat stem cell clinic?


  5. I think it is important to keep this tragic case of blindness regarding the Florida Stem Cell Clinics in some perspective. My father, a 30 year career Naval Surgeon, once told me after Vietnam, that if I ever wanted to practice a safe profession, then please do not go into medicine or surgery. In all of his 75 years, not once did my late father ever tell me that he had perfected surgery. He only practiced it. Surgery is a practice and mistakes will happen in any branch of medicine or surgery. But relatively speaking, and I’m not a numbers person, stem cell procedures probably have a safety profile that I’d be willing to bet is far superior to just about any other medical practice on the books. I’ve never had stem cell therapy but I do receive Platelet Rich Plasma Injections on occasion into my arthritic knees. PRP apparently is also not FDA approved. However, the long term relief I get from PRP (Okay! Anecdotally speaking!) is something I’m willing to pay for over FDA approved knee replacement devices. No doubt. We need the FDA. However more importantly we need an FDA that is independent of the very industries it is supposed to be regulating.


  6. It might be worthwhile to define the differences between an IRB approved protocol and an IND, and when one is needed versus the other. There seems to be a lot of confusion as why a clinic needs to bother with the FDA as long as they have an IRB approved protocol and are operating under the practice of medicine.


  7. Texas Applied Biomedical Services 9/24/12
    Public Health Service
    Food and Drug Administration Center for Biologics Evaluation and Research
    1401 Rockville Pike
    Rockville, MD 20852­1448

    September 24, 2012
    By Facsimile Transmission and Overnight Delivery CBER­ 12­ 09

    Ms. Mildred Joyce Heinrich, President/Chairperson Texas Applied Biomedical Services dba Texas Applied Biotechnology Research Review Committee IRB dba TABS Research Review Committee IRB # 1
    12101 Cullen Boulevard, Suite A
    Houston, Texas 77048

    Warning Letter

    Dear Ms. Heinrich:
    This letter describes the results of a Food and Drug Administration (FDA) inspection of the Texas Applied Biomedical Services Research Review Committee (TABS RRC) that concluded on April 25, 2012.
    The FDA investigator conducted the inspection of this Institutional Review Board (IRB) to determine if the IRB’s activities and procedures for the protection of human subjects comply with FDA regulations published in Title 21, Code of Federal Regulations (CFR), Parts 50 and 56. The FDA conducted this inspection under its Bioresearch Monitoring Program, which includes inspections
    designed to review IRB operations relating to clinical studies of FDA regulated products and to ensure that human subjects are protected from undue hazard or risk during the course of clinical studies.

    We have determined that the IRB significantly violated applicable federal regulations governing the operation an responsibilities of IRBs as published under 21 CFR Part 56 (available at http://www.gpoaccess.gov/cfr/index.html). This letter requests prompt corrective action to address the violation cited and discusses your IRB’s written response to the noted violations. The applicable provisions of the CFR are cited for each violation.

    1. The IRB failed to ensure that no member participated in the initial or continuing review of a project in which the member had a conflicting interest. [21 CFR § 56.107(e)].

    3/27/2017

    2012 > Texas Applied Biomedical Services 9/24/12
    approval of clinical studies sponsored by (b)(4) (hereafter, (b)(4)) in which the members had a conflict of interest. Both you and (b)(6) voted to approve protocols sponsored by (b)(4) even though you had both provided consulting services to (b)(4), assisting with writing protocols and formed consent documents, for which payment was requested.

    In your letter, you disagree with the observation that TABS IRB members had a conflict of interest with the review of the (b)(4) clinical studies. You explain that one of the IRB committee members assisted in the initial drafting of the (b)(4) clinical study protocols and that consulting services provided to (b)(4) by Texas Applied Biomedical Services and/or J Heinrich Consulting are not conflicts of interest. You further explain that the consulting services provided to (b)(4)
    “were maintained separate and apart from any TABS Research Review Committee functions and actions.”

    1. We disagree with your explanations. The two members in question had a conflicting interest when they participated in the initial review and approval of the protocols and informed consent documents, which they assisted in drafting. Conflicting loyalties, whether conscious or not, may influence the IRB’s deliberations.

    2. The IRB failed to prepare, maintain and follow its written procedures for conducting its initial and continuing review of research. [21 CFR §§ 56.108(a) and 56.115(a)(6)].

    The IRB does not have a written procedure regarding the IRB’s method of reviewing protocols and consent forms to ensure safeguards are in place for children who participate in a clinical study. The meeting minutes dated January 8, 2012, show that the IRB approved an investigational (b)(4)
    study involving children (b)(4) years old

    In your letter, you acknowledge that TABS RRC had not previously reviewed clinical investigational research studies involving pediatric subjects. You also state that an SOP (standard operating procedure) will be written addressing pediatric clinical studies in accordance with 21 CFR Parts 50
    and 56. In your response to this letter please submit a copy of your new SOP addressing clinical studies involving pediatric populations.

    3. The IRB failed to fulfill membership requirements. [21 CFR § 56.107].

    The IRB did not possess the professional competence necessary to provide complete and adequate review of the specific research activities. For example:

    A. On January 8, 2012, the IRB reviewed and approved an investigational (b)(4) study involving pediatric and adult subjects with disorders of the (b)(4). Review of the IRB’s records indicates that the IRB lacked the professional competence necessary to review this study and determine whether it met the criteria for approval under 21 CFR 56.111, including whether risks to subjects were “reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.” The IRB did not include an individual with professional competence in the treatment of (b)(4) disorders (e.g., a physician), nor is there any documentation to show that the IRB invited individuals with competence in this area to assist in the review of this study, as permitted by 21 CFR 56.107(f).

    B. On January 26, 2012, the IRB reviewed and approved two studies involving subjects with (b)(4) The IR did not include an individual with professional competence (e.g. a physician) in the treatment of (b)(4), nor is there any documentation to indicate that the IRB invited individuals with competence in this area to assist in the review of this study, as permitted by 21 CFR 56.107(f).

    We note that the meeting minutes dated January 26, 2012, failed to include documentation of any consult with a (b)(4) specialist that was taken into account by the IRB committee in its decision to approve the studies.

    In your letter you state that all future studies involving pediatric subjects will be more closely scrutinized. Also in your letter you reference an FDA Guidance for IRBs and Clinical Investigators ­Informed Consent Document Content which provides that FDA does not require the informed consent document to contain a space for assent by children. We do not accept your explanation. The
    observation on the Form FDA 483 does not speak to whether FDA requires the Informed Consent document to contain a space for assent by children. Instead, the FDA investigator observed that the IRB failed to determine at the time of the initial review that the research study was in compliance with 21 CFR Part 50 Subpart D. Additionally, please note that 21 CFR Part 50, Subpart D requires
    IRBs to find and then document that the clinical investigations involving children as subjects meets the requirements of Subpart D.

    The meeting minutes for January 8, 2012, fail to document
    additional requirements for review of this study involving pediatric subjects.
    5. The IRB failed to prepare and maintain adequate documentation of IRB activities. [21 CFR §
    56.115].

    The IRB failed to maintain IRB membership rosters for 2008 through 2012 in accordance with 21 CFR 56.115(a)(5). The IRB membership rosters do not identify members by their representative capacity and any employment or other relationship between each member and the institution. This is a repeat violation identified during the FDA inspection conducted in 2000. See https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm323868.htm

    Based on the repeated deficiencies found during the last three inspections, we have no assurance that the IRB procedures are adequately protecting the rights and welfare of the human subjects of research. For this reason, in accordance with 21 CFR §§ 56.120(b)(1) and (2), and effective immediately,

    FDA will withhold approval of all new studies subject to 21 CFR Part 56 and reviewed by the IRB; and No new subjects are to be enrolled in any ongoing studies subject to 21 CFR Part 56 and approved by the IRB.

    These restrictions will remain in effect until such time as FDA has evidence of adequate corrective actions and notifies you in writing that the IRB’s corrective actions are satisfactory. These restrictions do not relieve the IRB of its responsibility for receiving and reacting to reports of unexpected and serious reactions and routine progress reports from ongoing studies.

    You are to notify this office in writing, within fifteen (15) business days of receipt of this letter, of the actions yo have taken or plan to take to bring the IRB into compliance with FDA requirements. Your response should address each item listed above, and should include any documentation necessary to show that full and adequate correction has been achieved. Include the projected completion dates for each action to be accomplished. If you do not believe your IRB is
    in violation of FDA requirements, include your reasoning and any supporting information for our
    consideration.

    Include with your response, a copy of the IRB’s written communication to each of the affected sponsors and clinical investigators, notifying them of the current FDA imposed restrictions. Please also provide an updated list of all studies being reviewed by your IRB, identify those that are subject to 21 CFR Part 56, and list all studies that are affected by the above restrictions.

    Your failure to respond to this letter, or implement adequate corrective action, may result in FDA taking further administrative actions, as authorized by 21 CFR 56.120, 56.121, and 56.124. These actions include, but are not limited to, the termination of ongoing studies subject to 21 CFR Part 56 and approved by your IRB, and the initiation of regulatory proceedings for disqualification of
    your IRB.

    On the basis of your response, FDA may schedule a reinspection to confirm the adequacy of your corrective actions.

    Please send your written response to:

    Lillian Ortega
    Division of Inspections and Surveillance (HFM­664) Office of Compliance and Biologics Quality
    Center for Biologics Evaluation and Research 1401 Rockville Pike, Suite 200N
    Rockville, MD 20852­1448
    Telephone: (301) 827­6335
    We request that you send a copy of your response to the FDA District Office listed below.
    Sincerely,
    /S/
    Mary A. Malarkey, Director
    Office of Compliance and Biologics Quality
    Center for Biologics Evaluation and Resear

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