The FDA may not require companies to prove that stem cell therapies are safe and effective prior to approval.

Cardiac stem cell therapy could gain FDA approval far earlier than most people expect, despite the fact that these therapies have consistently failed to produce any convincing evidence of safety and efficacy.

Under the old FDA rules stem cell therapies would not have stood a chance of approval. Companies would have been required to demonstrate in a pivotal clinical trial that the therapy was both safe and effective. But two major changes over the past year indicate that the FDA is preparing to substantially lower the requirements for approval of stem cell therapy and other regenerative medicine therapies.

First, the 21st Century Cures Act, passed last year, contains a provision supporting an accelerated pathway for regenerative medicine.

Second, Trump’s new FDA commissioner, Scott Gottlieb, has consistently favored lowering the bar for drug and device approval, and it is now clear that this includes stem cell therapy. Last week he outlined in a speech the “steps FDA is taking to modernize its regulatory approach to new cell and gene based therapies”:

“…more emphasis needs to be placed on how new technologies perform in clinical use; during routine care. Long-term risks and benefits need to be carefully monitored. This is similar to the way that we evaluate many medical devices. Our questions related to these new platforms would increasingly relate to their long-term performance. More of our emphasis will naturally shift to our post market tools.”

In case it’s not clear, and that’s probably what he intends, Gottlieb is recommending lower approval standards here. He wants to replace randomized controlled trials performed prior to approval with observational studies performed after approval. Gottlieb has consistently sought to lower barriers to the market, though this isn’t always clear from the technical and unemotional tenor of his language.

But stem cell companies are listening to Gottlieb and they get the message. At least two companies are already seeking to take full advantage of these lowered requirements.

One company, Mesoblast, recently announced plans to exploit “a potential accelerated pathway for its proprietary allogeneic mesenchymal precursor cell (MPC) product candidate (MPC-150-IM) for patients in the most advanced stages of chronic heart failure, defined as New York Heart Association (NYHA) stages Class III and Class IV.”

According to the company: “Based on cumulative clinical results to date and the serious and life-threatening nature of this disease, we believe there is a pathway for accelerated entry of this product candidate into the market to provide a paradigm shift in treatment.”

The company is performing two clinical trials, a phase 2b trial and a phase 3 trial. The phase 2b trial includes 159 patients with end-stage heart failure receiving support from a LVAD.

The primary endpoint of the trial is the amount of time patients can be weaned from the LVAD in the 6 month period after randomization. The ongoing phase 3 trial will randomize 600 patients with mild to moderate CHF to active treatment or sham-treatment.

The company belies that a positive result in the phase 2b trial, which it expects to complete in the first half of next year, along with positive interim results of the phase 3 trial, could serve as the basis for FDA approval.

Another company that will likely seek to take advantage of this pathway is Capricor, the stem cell company founded by the prominent Cedars-Sinai researcher Eduardo Marbán.

I’ve written previously about the company’s efforts to spin negative results. A recent press release from Cedars-Sinai for a study in rats begins: “Cardiac stem cell infusions could someday help reverse the aging process in the human heart, making older ones behave younger, according to a new study from the Cedars-Sinai Heart Institute.”

Tim Henry, a Cedars-Sinai cardiologist who is a co-principal investigator of the Capricor trials, confirms that the company hopes to use the latest data from its clinical trials to support an early approval.

But the company’s main hopes now focus on an extremely narrow niche indication for hypertrophy associated with Duchenne muscular dystrophy (DMD). Capricor appears to be following the controversial model successfully adopted by Sarepta, which gained approval for a DMD drug with only the scantest evidence of efficacy.

Opening Pandora’s Box Of Stem Cells

Bob Harrington (Stanford), the chairman of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, expressed concern about the pathway to early approval. “We need to be pretty certain that something actually offers a clinical benefit before putting it on the market.” Harrington emphasized that he was expressing his own opinion and was not speaking on behalf of the FDA.

Sanjay Kaul (Cedars-Sinai) took issue with Gottlieb’s remarks, in particular his statement that stem cell therapies can be monitored in a way that “is similar to the way that we evaluate many medical devices.”

As Kaul points out: “How many of the post-marketing commitments have been fulfilled for medical devices? What action has the FDA taken over the last 5 years if the post-marketing commitments are not fulfilled or if they don’t establish effectiveness or safety in clinical use? Given the recent trend of approving medical devices with marginal effectiveness, this can be hardly viewed as reassuring, especially for gene and cell-based therapies that have over-promised and under-delivered.”

Concerned about the dangers of a slippery slope, Kaul argues that more, not less regulation, may be needed. “Given the track record of cell-based therapies (lack of scientific rigor and ethical failings), one could argue for greater scrutiny and oversight pre-approval rather than relaxing the standards.”

The most likely path to early approval will involve a narrow indication for a small, underserved population. Capricor’s focus on DMD and Mesoblast’s focus on LVAD patients are good examples. But, make no mistake about it, the companies have no interest in limiting themselves to small niche populations.

Initial approval is just the wedge to open the door to the market. The Mesoblast press release points out that “there are more than 250,000 NYHA Class IV patients and 1.3 million NYHA Class III patients in the United States alone, representing a potential multi-billion dollar opportunity for Mesoblast.”

So we are faced with the specter of an extremely expensive therapy with no solid evidence of benefit potentially being offered to an enormous portion of the population.

Most of the early approvals for experimental therapies have been for small niche indications; cardiac stem cell therapy, by contrast, with the imprimatur of the FDA, cardiac stem cells could be marketed to large and highly vulnerable portions of the population.

Furthermore, this could be only the early model for many more new and experimental therapies. With the explosive growth and acceptance of CRISPR as a tool that may be used to design new therapies, nothing should be more important than making sure that we proceed more, not less, carefully, before we unleash Pandora’s new therapies.

Clearly we are in new territory that will bring a tremendous challenge to regulators; it is terrifying to think that FDA leadership is leaning in the direction of less rather than more scrutiny of experimental therapies.

Related reading:

• The GiveAway Act
• Dissecting The Press Release For A Failed Stem Cell Trial
• After Yet Another Failure, Stem Cell Leaders Double Down
• Stem Cell Therapy To Fix The Heart: A House Of Cards About To Fall?
• Circulation Retracts Paper By Stem Cell Pioneer And Its Own Editor
• Recent €23 Million Biotech IPO Relied Heavily On Questionable Research

This article has been republished from Larry’s blog CardioBrief as part of a licensing agreement between Everyday Health and the limbic.