FDA panel votes overwhelmingly against experimental stem cell treatment for ALS

Panel members cite lack of pre-clinical data, and raise concerns over the higher mortality rate among the treatment group among a few other criticisms with Brainstorm's data.

In wanting to cover the new-age approval process constructed by the FDA for new drugs, I released an article on Monday detailing the FDA meeting once again on September 27 to examine whether an experimental stem cell treatment for ALS called NurOwn, designed by pharmaceutical company Brainstorm, would receive approval by an FDA committee.

The product NurOwn intends to take patient mesenchymal stem cells and instruct them to produce neurotrophic factors which would help reduce neuronal cell death brought on by many factors. The activated stem cells are injected into the spinal chord of patients and are expected to produce these nerve-protecting agents.

Much of this mechanism of action is above my head, but for those interested in a rundown the first speaker provided in the meeting details some of these possible effects of stem cell treatments, with one of the main arguments made being the fact that a driver of some forms of neurological disease including ALS may be the production of toxic agents from mutant astrocytes. Stem cells, whether by replacing these mutant astrocytes or by producing agents that offset the toxins produced by mutant astrocytes, may help restore homeostasis to the environment.

However, prior to this meeting the FDA was rather dubious of Brainstorm’s initial clinical findings, suggesting that it lacked key biomarker data while also citing lack of manufacturing and quality assurance for these products. In contrast to remarks from Brainstorm about the benefits of NurOwn, the FDA brought up their own assessments raising criticisms of analyses conducted by Brainstorm.

Now, I haven’t looked through the entire 8-hour meeting, focusing more on the discussion at the end to understand what the panel thought. The panel was comprised of 7 regular FDA panel members while also including 12 temporary members.

In short, there were quite a few concerning features with the data presented, with one main concern being the variability in the neurotrophic factors that would be produced, citing that some patients seem to be responders and others nonresponders to the stem cell treatment. There also did not appear to be substantial quantitative data on the neurotrophic factors that were being produced, meaning that there was no clear details on the so-called dosage needed to provide protection, or if this is even what was going on within the body of these patients.

Interestingly, several panel members also raised concerns over the actual distribution of stem cells within the patient’s CNS, commenting that even if these cells are producing these neurotrophic factors they are not likely to pass through the parenchyma of the spinal chord, and thus would not be able to reach the parts of the body where they are needed. And so, even the actual destination of these stem cells, as well as their neurotrophic factors, are up in the air.

In the end, the 19-member panel voted almost unanimously against approval of NurOwn due to lack of safety and efficacy data, with the votes resulting in 17 No’s, 1 Yes, and 1 Abstain.

I think a good example as to why NurOwn should not see approval came from Lisa Lee, Associate Vice President for Scholarly Integrity and Research Compliance at Virginia Tech, who raised the issue of promising hope while also providing false hope to patients. She notes some of the issues in the language used, as well as some statistical manipulation which may suggest that the stem cell treatment is actually effective (timestamped for her comment in particular).

I find these remarks a bit interesting given all of the approvals that have gone through in recent years, which seem to obfuscate the need for robust safety and efficacy data in lieu of providing the public with some sort of treatment.

The only person to vote yes was from Kathleen O’Sullivan-Fortin, who served as one of the patient advocates on the panel. Kathleen’s remarks seemed to focus on the anecdotal accounts provided by patients, which on one hand provide strong testimonials for these treatments, while also relying on patient accounts to make up for obscure and missing clinical data. It also plays on the fact that anecdotal accounts weaponizes real, personal remarks and makes enemies of those who would dare to criticize these treatments. This is one of the things that I have raised criticism of quite often, and it appears in Kathleen’s case that she took this approach as well, even commenting that “it is very clear that I include data that no one else considers data”, likely referring to the anecdotal accounts.

I think these remarks are an indication of the perception of the general public, who may not be able to discern much of the actual clinical data but may otherwise yearn for a treatment, and thus look for any evidence that can provide that sort of justification.

In contrast Andrew Buckley, another patient advocate and someone living with ALS, voted against the approval by raising questions on the safety and efficacy, where he even remarks that he even believed the evidence showed the contrary to actual efficacy, and even raises a point of bringing up the higher mortality rate within the treatment group (timestamp for Andrew’s response, with Kathleen’s following afterwards).

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It’s rather difficult to cover all of these meetings since it’s a bit much to have someone sit through all 8 hours and break down everything that is said. But for those who dare to entertain such an idea, I find these meetings to be an interesting insight into a drug’s approval process, or at least the process the FDA takes in order to have a committee vote. Seeing the perspectives of the people on the panel, including practicing physicians, researchers, as well as anecdotal accounts and accounts from patient advocates provides a general sense of how this sort of discourse may go about in the public, although I suppose in a more formal way.

It also provides a window into the gaps in logic that may be taken with these approval processes, and how much subjectivity actual can go on in something that should, by all accounts, appear objective.

Like with any FDA hearing, the word of the panel is not a final say for the FDA, as the FDA generally takes the word of the panel into consideration for their final response. The FDA is suggested to rule on NurOwn’s approval by December 8th, and it will be interesting to see the direction the FDA takes on this rather dubious treatment.

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