FDA warns Northwestern’s Richard Burt on reporting patient deaths, other issues in stem cell trials

The FDA recently issued a lengthy warning letter to Northwestern University over the clinical trial practices of its Dr. Richard Burt and this letter just popped up on the FDA website. To my knowledge this is an unprecedented event as I’m not aware of another warning letter to a major university for a stem cell trial. Burt received the FDA warning letter late last year for a number of serious problems with his stem cell trial including failure to promptly report patient deaths to the FDA.

Richard Burt Warning Letter

Another issue noted by the FDA was lack of proper oversight of other participating investigators in the trial at locations around the globe. The list goes on and on of big problems detailed in this long letter. Notably the issues in this mid-November 2016 warning letter were reportedly “addressed” according to a follow up letter from the FDA (see close out letter link at bottom of the warning letter webpage) so hopefully that means at least some improvement.

However, this warning letter raises many longer term concerns. For instance, if Dr. Burt’s team did not report patient deaths properly to the FDA, did they also not tell future prospective trial participants about how often deaths occurred? As such, were trial participants properly consented in terms of being informed about potential risks to them?

The wording of the letter signals the seriousness of this situation and the FDA says at the start:

“We have determined that you violated regulations governing the proper conduct of clinical studies involving investigational new drugs, as published in Title 21, Code of Federal Regulations (CFR) Part 312…”

Has this big, complicated trial gone a bit out of control?

In addition and more broadly, other aspects of Dr. Burt’s stem cell clinical trial work have potentially problematic issues that still may not be resolved and that raise difficult bioethical questions. These other concerns will be the subject of a follow up post.

Early, but encouraging data from Asterias on stem cells for spinal cord injury

asteriasAs I posted recently, Asterias Biotherapeutics has had good early safety results so far in its historic stem cell trial for spinal cord injury and now the company presented some early, encouraging hints at efficacy.  However, a caveat here is that this is not an RCT (randomized controlled trial).

Ed Wirth, CMO of Asterias, presented the early data at the 55th Annual Scientific Meeting of the International Spinal Cord Society. You can take a look at the very interesting talk slides here. Asterias is a subsidiary of BioTime.

According to the press release (PR) from the company, while only 4 of 5 patients are 90 days or more after treatment, all patients have shown some improvement in motor function and a subset have a substantial improvement, meeting the target at this point. This trial is funded in part by CIRM so kudos to our state’s stem cell agency on this.

MIT Tech Review is on the story to for more background. I’ve also posted from Dr. Wirth’s PowerPoint the study design image below.asterias-sci-stem-cell-study-design

Bottom line. Overall, I think this development is encouraging. While still early in the clinical trial and drug testing process, the fact that there is a good safety profile and early indications of possible efficacy yield real hope. Still, it is important to be cautious in interpreting early data. We’ll all need to follow this trial and then look for future RCT results to clarify how promising this drug is overall in the long haul.

I’ve posted the key bullet points from the Asterias PR below the fold.

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End of line for StemCells Inc., pioneering & controversial stem cell biotech

A sad, but not surprising day for the stem cell field as the biotech StemCells, Inc. announced that it is winding down its operations after terminating its spinal cord injury trial called the Pathway Study. The data generated so far did not justify continuing the trial.stemcellsinc-logo

StemCells, Inc. (stock symbol STEM) has struggled financially for quite some time. In February of this year I asked if the company could cheat death given how bad things were looking and what I was hearing through the stem cell grapevine. Unfortunately the answer appears to be “no”.

I interviewed the leadership of the company two years and they were optimistic about the company’s outlook at that point. However, STEM CEO Marty McGlynn departed earlier this year and that was seen as another sign of things not looking bright.

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Huge clinical trial patient fees allowed by FDA at times, details often secret

stem cell monopolyI am often critical of for-profit stem cell clinics on this blog for numerous reasons. For instance, one thing that concerns me greatly about these clinics is that they charge patients to get experimental “treatments” that have not been proven to be safe or effective.

But as some patients have pointed out to me over the years, certain FDA-approved stem cell clinical trials also charge patients to receive unproven stem cell therapies.

Should someone (even if that someone is an academic clinical researcher) be able to charge a patient a large access fee to be in a clinical trial in which that patient will be subject to an experimental therapy that could ultimately be proven unsafe and ineffective?

I have serious doubts about this.stem cell monopoly quote

You might be surprised to learn that the FDA in some instances allows patients to be charged to be in trials including stem cell trials and others. Those running the trials can request permission from the FDA to charge patients. The agency then has to evaluate the request. The FDA has a draft guidance on this, but frankly it’s difficult to learn that much from that document in terms of details in how this plays out.

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Cons Outweigh Potential Pros to BPC Plan on Stem Cells & FDA

BPC report stem cels

There is considerable interest in FDA regulatory reform here in the U.S. for stem cell therapies. The goal is to get new treatments to patients faster, but is there a way to do that without sacrificing proven safety and efficacy?

You need convincing data on both safety and efficacy or speed becomes dangerous.

A group called the Bipartisan Policy Center (BPC) recently issued a report related to these central questions of American regulation of new stem cell products. You can see a screenshot from the cover of the report above. The report argues for a new paradigm of FDA regulation of stem cells with reduced regulatory steps.

While I support the notion that there need to be reforms at the FDA related to regulation of stem cell-based therapies, looking at it scientifically based on the current state of stem cells in the US, the potential cons of what the BPC report recommends outweigh the possible pros.

Pursuing the BPC plan at this time would be a high-risk experiment that could yield benefits and harms or most likely some complicated combination of both, but again I believe the risks are considerable making the report imprudent overall. Others, including some stem cell colleagues feel otherwise so I think a lively debate could prove to be healthy on this topic.

Below I outline the potential pros and cons as I see them.

Possible Pros. The report does a good job of highlighting the potential positives that could come from the proposed regulatory reforms:

  1. Speeding therapy to patients. The most prominent possible upside would be speed in the form of getting new stem cell therapies into patients more quickly.
  2. Helping American competitiveness. A second positive, depending on one’s perspective, would be possibly increasing American competitiveness in the global stem cell arena.
  3. Generating money. Finally, because the plan specifically allows companies and non-profits to charge for experimental stem cell therapies, those entities doing the research could benefit from that income and in theory that could support furthering of the research.

Possible Cons. Perhaps because the report is intended to convince readers of its thesis that we need regulatory reforms that accelerate getting stem cell therapies into patients, it doesn’t discuss risks or potential cons to the recommendations. However, as a scientist I find it disappointing that the report ignores potential risks to its recommendations.

In science, especially clinically-related science, we cannot afford to ignore risks. For this reason, the report reads as being somewhat more political than scientific, perhaps not an entire surprise given that two former politicians led the way on it.

The significant cons to the recommendations if implemented include the following:

  1. Risk of medical harm.  When the BPC Plan on Stem Cells characterizes stem cells as different than drugs, it goes against decades of science. Biological drug products released onto the for-profit market without full vetting will pose some risks of increased medical harm to consumers. For instance, dropping the requirement for Phase III trials as they recommend in some cases would be risky. Ignoring that increased risk seems unwise as it needs to be part of the equation and discussion in risk-benefit analysis for any new regulatory paradigm.
  2. Charging research subjects. There is a tradition in biomedical science of not charging patients for receiving experimental treatments. In fact, more often patients are paid to be subjects.  I believe that taking patients’ money to allow them access to an unproven, experimental treatment is unethical. Unfortunately, some are already doing this in the U.S., but the BPC report if implemented would make that practice far more common. I understand that the translational stem cell field could benefit from generate some funds in support of clinical studies, but this shouldn’t come from patients.
  3. Unintentionally helping predatory clinics. The BPC recommendations, while still requiring some approvals such as an IND, are significantly weaker than the current regulatory framework. From what I’ve heard from the for-profit clinic folks, they see this report, even if it isn’t implemented and even though it still requires an IND, as a victory. Why? Because they believe that the report represents a shift in their direction ideologically. They see it as somewhat of a capitulation by the academic and biotech sectors toward the notion that the FDA is wrong on stem cells. This is very worrisome. The report even uses some of the memes of the stem cell clinics and their proponents such as arguing, as mentioned earlier, that stem cells are not drugs and that patients have a right to get transplants of their own cells even if those cells have been turned into a product.
  4. Encouraging global deregulation. This plan could also be taken as a template in many other countries around the world for their own regulatory changes toward weaker oversight, which could amplify risk to thousands more patients globally.
  5. Fostering a sense of potentially unhealthy, international competition. I’m an American and we have a great country here, but I have reservations about framing stem cell regulatory debates in a nationalistic or political kind of way that could lead to harmful competition. Again to me the BPC report comes off as too political and not scientific enough, and that is especially true when it discusses national priorities. There is a palpable sense in the report that those who wrote it are worried about the US falling behind Japan on stem cells.

Overall, I recommend that the FDA not adopt the BPC recommendations because that would be just too risky and raises serious bioethical concerns. We need a different plan that more cautiously approaches regulatory changes and openly acknowledges that there would be risks.

One such plan I could potentially support would be focused squarely on a relatively simpler path to FDA triggering of Fast Track, Accelerated or Priority Review or Breakthrough Therapy Designation for stem cells.