FDA leader Stephen Hahn was pressured to aid Texas firm Direct Biologics

An FDA FOIA dump of text messages of former Commissioner Stephen Hahn suggests that a Texas regenerative firm called Direct Biologics benefited from political pressure on him in mid-2020. Then he was asked again to help in early 2021. This was shortly before he resigned at the start of the Biden Administration.

The push came from a GOP congressman and his wife.

As a backdrop, there is also evidence that earlier on Direct Biologics may have been marketing its biological product called ExoFlo, which is at the heart of all of this, for medical conditions without FDA permission.

The released texts raise serious questions about the agency’s decision-making during Hahn’s tenure. I believe there are several red flags here and more transparency is needed about this situation.

Direct Biologics and Rep. Michael McCaul

The texts reveal that Texas GOP congressman Michael McCaul and his wife Linda Mays McCaul each directly contacted Stephen Hahn about Direct Biologics or its ExoFlo product. After Rep. McCaul contacted him, Hahn quickly had calls with McCaul. He also arranged rapid meetings with other FDA leadership such as CBER Director Dr. Peter Marks.

Direct Biologics was seeking an okay for clinical studies of ExoFlo via something called an IND or investigational new drug application from the FDA. If allowed by the agency, an IND opens the door to specific clinical trial work. In this case, it was for COVID-19.

The firm fairly quickly got what it wanted.

What is the Direct Biologics product ExoFlo?

ExoFlo is an exosome product derived from human bone marrow MSCs or mesenchymal cells. In addition to exosomes, it apparently also contains a variety of growth factors. For an explainer on exosomes see the background section at the end of this post.

Direct Biologics describes ExoFlo as an extracellular signal product. Exosome products are often produced by harvesting and then processing secretions of cells.

ExoFlo is an allogeneic biologic, meaning that when used in patients it is not the patients’ own material. It comes from a donor.

It’s not clear and convincing to me as a stem cell researcher how an IV infusion of ExoFlo or other exosomes could be expected to help COVID.

Exosomes for COVID-19 & more without approval

For almost three years, the FDA generally has defined exosomes as drug products requiring pre-market approval. In other words, you can’t just sell them for clinical use. You have to work with the FDA first.

Even so, there was a period of a few years around 2018-2020 when some manufacturers of exosome products or physicians who got them were already marketing them for clinical use without FDA approval.

Most notably, we saw marketing of unapproved and scientifically unproven exosomes for COVID-19. 

Does Direct Biologics have a @FDACBER IND? Probably shouldn't have a statement about ordering on their website or a section for patients to ask them to consult their healthcare provider about using ExoFlo…cc @pknoepfler @LeighGTurner pic.twitter.com/UW8volnqYE

— Ross Marklein (@RossMarklein) May 14, 2020

Beyond COVID-19, exosomes have also been on the market without FDA approval for a variety of other conditions including hair loss.

Direct Biologics marketing of ExoFlo

A May 2020 tweet by Ross Marklein, professor at UGA, in response to a tweet about a key new ExoFlo paper (more on it below) included pics of what seem to be Direct Biologics marketing materials for ExoFlo.

The marketing docs posted by Marklein suggest that the firm was already promoting the clinical use of ExoFlo. This included marketing to patients.

Consistent with this, a Wayback Machine archive of the Direct Biologics website in August 2020 includes a “For Patients” page. The webpage suggests that ExoFlo was available for clinical use then. For instance, it says to patients, “Consult your healthcare provider to discuss if treatment with ExoFlo is an option for your current medical condition. If so, they will advise the best treatment plan associated with your condition.”

I found no evidence of any FDA okay for such activities.

But our exosomes aren’t drugs?

Why would Direct Biologics have been marketing ExoFlo to patients in 2020 or earlier without FDA approval? They seemed to believe they were exempt.

I found a Direct Biologics document posted on the web, in which the firm argued ExoFlo was an exception to the FDA definition of exosomes as a drug product. From the firm’s document (see this explainer on homologous use if interested.):

“We intend our exosomes to be used for what we believe are valid homologous uses and that our marketed exosomes are an exception to the general rule.”

I’m not sure they were right about that. Still, I found no evidence of FDA actions against the firm such as a letter.

While there was some ambiguity on how the FDA viewed exosomes in early 2019, the agency clearly defined exosomes as drugs in a December 2019 notification to the public. The Direct Biologics document seems to have been an internal response to this FDA notification to the public on exosomes. The FDA also said this in the notification:

“There are currently no FDA-approved exosome products. Certain clinics across the country, including some that manufacture or market violative “stem cell” products, are now also offering exosome products to patients. They deceive patients with unsubstantiated claims about the potential for these products to prevent, treat or cure various diseases or conditions. They may claim that they these products do not fall under the regulatory provisions for drugs and biological products – that is simply untrue. As a general matter, exosomes used to treat diseases and conditions in humans are regulated as drugs and biological products under the Public Health Service Act and the Federal Food Drug and Cosmetic Act and are subject to premarket review and approval requirements.”

That’s strong language from the FDA on exosome marketing overall during that time.

A paper and some skeptical scientists

Direct Biologics did eventually get FDA clearance to do a Phase II clinical trial on ExoFlo for COVID-19.

A major reason why they got the clearance may have been that paper on a Phase I trial on ExoFlo published in May 2020 and Tweeted on as indicated above. The authors included some who became Direct Biologics leaders the next month.

How strong was that paper?

The team published their small open label, uncontrolled trial study of ExoFlo in the respected journal Stem Cells & Development.

The paper sparked a response including some important questions in the same journal from members of ISCT, a global society of gene and cell therapy researchers. The authors then replied to that. This exchange still left some important unanswered questions in my view.

I have several concerns about the ExoFlo Phase I clinical trial paper that I will write about separately in the future. However, two points worth mentioning here are that I cannot find evidence that the team had an IND or some other clearance from the FDA for the Phase I study reported in the paper and I could not find the trial registered on Clinicaltrials.gov. If indeed the Phase I study did not have FDA approval and if the data in the paper were a key part of the successful Phase II IND application, should the FDA have allowed the data to be included in that Phase II IND application?

Their paper does say this about compassionate use:

ExoFlo flows at the FDA under Stephen Hahn

Soon after the ExoFlo Phase I trial paper was published in May 2020, Rep. McCaul sent it to FDA Commissioner Stephen Hahn and pushed him to act quickly.

Take a look at the Hahn texts below from June 2020.

We see exchanges that seem to be about Direct Biologics between Hahn and Keagan Lenihan, who was the FDA Chief of Staff until last year. The “Peter” mentioned appears to be Dr. Marks.

If you search the web for the “scd.2020.0080.pdf” paper mentioned by McCaul, you can easily find that the pdf is the Phase I trial paper discussed above.

Direct Biologics had a powerful advocate in McCaul and interestingly his wife Linda asked Hahn for help on ExoFlo too later (more below).

The texts above indicate that at one point Rep. McCaul threatened to take the matter up higher, probably to complain to Trump or his inner circle about Hahn, who was criticized extensively by Trump on other matters in 2020.

It seems like the pressure from McCaul worked. Hahn was extremely responsive.

See the texts below from the same day and then the next day. In the second text below, Hahn indicates the meeting must occur that day (he later explains in another text not shown that “most” is a typo and he meant “must”).

There was a major sense of urgency here.

Numerous FDA calls and meetings apparently took place rapidly.

I don’t know for sure how things usually work internally at the FDA and CBER, but my impression as someone following the cell therapy and broader biologics arena for about a dozen years is that this is highly unusual.

Am I just naive?

Does this kind of political pressure on behalf of firms in one’s state or district happen regularly? I wouldn’t think so.

Also, at least during the period of the Hahn texts released by the FDA, I don’t see evidence of other pressure like this in those texts more generally in the cell therapy space, which includes exosomes. Although I didn’t read every one of them, I did read hundreds and did numerous text searches of the documents.

Politics and data

So why did it go down this way for ExoFlo?

I worry that Stephen Hahn might have been trying to keep his job in the Trump Administration. As a result, did agency procedures and vetting of data suffer? We need to learn more about what went on behind the scenes at the FDA.

Contrary to what Rep. McCaul said in the first image of texts above about already knowing that ExoFlo was safe and effective for COVID, I don’t see that being the case based on that one trial paper and information more broadly available.

There is a potential caveat here. Trial sponsors also frequently submit unpublished data to the FDA, which could have been more convincing here.

We just can’t be sure in this case.

It’s also possible that philosophically Hahn’s approach to running the FDA was to speed things like ExoFlo along, especially during COVID, and the political pressure was secondary. However, I haven’t seen that to widely be the case in the texts released by the FDA or in his public statements.

Deficiencies resolved or a political decision?

Within a relatively short time after these and other text messages from mid-June 2020, the firm had its IND okayed by the FDA.

On July 29, 2020, Direct Biologics announced in a PR that it had received the go-ahead from the FDA to move forward with a Phase II trial of ExoFlo.

Note that the firm profusely thanked Rep. McCaul for helping to make this happen:

“We are also very grateful for the steadfast support of Congressman Michael McCaul, U.S. Representative for his congressional district in Texas. Through his leadership, vision, and support of Direct Biologics, Congressman McCaul has been and continues to be an integral part of the quest to bring a real solution for patients suffering from COVID-19.”

Again, what we don’t know is what FDA experts who reviewed the firm’s IND materials thought of the firm’s data.

Would the FDA team have cleared the IND (and so quickly) anyway without the pressure?

There is reason to think at least some FDA officials had concerns. In one June 16, 2020 text above, it seems that Dr. Marks (“Peter” in the text) or his CBER staff felt there were ongoing deficiencies that needed to be addressed.

If that’s correct, were the issues quickly resolved?

Or did politics win out over data for Hahn?

Not all congresspeople have the same access

In a brief web search, I could only find one other example of a Congressman reaching out to the FDA about unproven cell therapies for COVID-19. It sounds like it was an entirely different experience (emphasis mine):

“Dr. Jack Zamora is a cosmetic doctor in Denver and another proponent of stem cell therapy.

Zamora is on the board of Vitro Bio Pharma, a stem cell lab in Golden.

He is submitting an application to the FDA next week for the emergency use of stem cell treatment, which he insists are known to have no side effects.

Zamora said at this point, the U.S. has nothing to lose but time.

“Once you have reached the level of severe sickness and illness where every other measure has been exhausted, really what’s the loss here?” he said.

Colorado Congressman Scott Tipton (R) told FOX31 he has personally called the FDA about fast-tracking the use of stem cell treatment, but hasn’t received a response.”

No luck it seems.

Evidence of other political influence efforts on the FDA may be buried in Hahn’s texts or be redacted or may have never made it to Hahn himself. There were vast numbers of redactions in Hahn’s texts. The (b)(6) and other redaction codes in whited-out regions of text refer to specific (yet still pretty general) reasons for redactions.

As to ExoFlo and the FDA, perhaps Hahn already knew Rep. McCaul as Hahn is from Texas and was chief medical executive at MD Anderson Cancer Center there. I did find that Linda Mays McCaul was or is on something called the Board of Visitors at MD Anderson.

Ms. McCaul advocating with Stephen Hahn for ExoFlo

Ms. McCaul also directly reached out to Stephen Hahn on ExoFlo. This was in early 2021.

FDA texts, some included below, indicate that Ms. McCaul wanted Hahn’s help quickly on ExoFlo. Some of her language in the texts is striking in that it suggests she may have been working for or on behalf of Direct Biologics in some way. It’s hard to be sure.

Linda McCaul seems to have been directly asking the FDA Commissioner for help with the company’s emergency IND for a particular patient.

‘I have a patient’: Ms. McCaul role with Direct Biologics?

It’s notable that Linda McCaul says, “I have a patient…”

Yet I don’t see that she’s a physician or biomedical researcher, although she does have an impressive background including in oceanography.

She also says (emphasis mine):

“We had Exoflo delivered…”

“We have been waiting for FDA approval”

“we are still in” (probably she means phase 2 trials but with a typo.)

Who is the “We” here in all these statements? Why does she phrase these and other statements in that way indicating she is so personally involved? What was her role if any with Direct Biologics or was she working on behalf of a hospital? I wish we had answers to these kinds of questions.

Here are more texts that followed, still involving the conversation between Linda McCaul and Hahn on the same day. To me, the language here continues to reflect the same kind of apparent tight connection for Ms. McCaul with ExoFlo.

Insider politics

Whatever the meaning of her language here, she got what she wanted for ExoFlo apparently within just hours.

Hahn replies, “Good news.”

He seemed fine with her texting him and even gives her his personal cell number (see text above).

Overall, in my view the Hahn texts indicate that politics and pressure yielded unusual access to the FDA Commissioner, which could have strongly influenced his decisions too.

COVID crisis as context

It seems likely to me that Linda and Michael McCaul believed that by pushing ExoFlo forward that they were helping people suffering from COVID.

I get that.

However, in my view as a stem cell biologist who closely follows clinical trials, I don’t think they went about it the right way. I’d also like to know more about Ms. McCaul’s potential connections to ExoFlo or Direct Biologics suggested by the language in her texts. Maybe there is a reasonable explanation there.

Also, admittedly, Hahn’s tenure coincided with some of the toughest moments of the COVID pandemic.

There was an urgent effort to find new therapies. I don’t envy Hahn and the other FDA officials who had to make some extremely difficult decisions quickly. However, that had to be balanced by the need for solid data. FDA review officers had to be allowed to do their jobs.

Hahn under pressure more broadly

I wonder what Stephen Hahn was thinking at the time of these texts.

A House Subcommittee is currently investigating Trump Administration pressure on Hahn related to other unproven COVID treatments. They just issued a new report on pressure campaigns on Hahn. His testimony before the Subcommittee doesn’t directly bear on ExoFlo as far as I can tell. Howvever, it shows he was under incredible pressure on many fronts at that time. We have this example (emphasis mine):

Also, note that date mentioned of June 15, 2020, which was the day after McCaul emailed Hahn pressuring him and the same day that Hahn started working to arrange FDA meetings on ExoFlo. Not a great few days for Commissioner Hahn. In many ways he was probably doing his best against the pressure, but it seems like it didn’t always work out well.

I’ve reached out to Hahn, Rep. McCaul, and Direct Biologics for comment on this situation but have not heard back so far from any of them.

An official FDA spokesperson gave me this comment when I queried about this situation:

“Throughout the pandemic, the FDA career staff has worked around-the-clock to make the best, science-based decisions on behalf of the American people in a rapidly evolving and unprecedented public health emergency.”

That’s not very specific.

The bigger picture and looking ahead

Where do things stand now for Direct Biologics and their ExoFlo product? They have continued to move forward with trial efforts with the FDA, more recently into a Phase III COVID study. I’m very curious to see how that proceeds. Will they publish a Phase II trial paper soon so the field can evaluate the data?

More broadly in the regenerative medicine space, I have written about my concerns about how the FDA has green-lighted INDs from stem cell clinic firms during the pandemic. Was some of that the result of political pressure too? I think it’s likely.

For historical context, the FDA has in the past admitted that it has given in to political pressure at times and made missteps as a result, most notably in the ReGen Biologics case. Remarkably, that situation sparked the FDA itself to arrange an external review of what transpired inside the agency. It ultimately reversed its drug approval in that case.

In 2020-2021 did politics trump science or did data win out in guiding FDA decisions on ExoFlo as it should have?

Hopefully we can learn more facts of this case.

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Background: exosomes as a new type of unproven drug

For background, exosomes are little secreted cellular bubbles that have potentially clinically useful stuff inside. The FDA has repeatedly defined exosomes as drugs and did so as early as 2019. For that reason, one needs FDA drug-level approval to legally market any exosome product for clinical use. Further, you need the FDA’s okay to even do clinical trials on them.

Exosomes have some promise for specific conditions. Still, they must go through clinical trials to be proven safe and effective for particular conditions. You need robust data. To date, the FDA has not approved any exosome therapy.

Those selling or promoting exosomes often argue for overly simplistic views where exosomes only can do good stuff. The reality is that we don’t know that is true. Also, exosome safety and efficacy profiles will likely vary dramatically depending on the methods used to make them, the resulting quality of the exosomes, storage and shipping conditions, and various patient characteristics.

Overall, it’s relatively early days for research on the possible clinical application of exosomes.

References and notes

• Leonid Schneider and Elizabeth Woekner deserve a major HT on this topic. They have a key previous post, researched by Elizabeth and written by Leonid, about Direct Biologics.
• Note for convenience I have included the six files of Hahn’s texts in a searchable form below. The versions on the FDA website are not searchable.
• Hahn Texts File 1
• Hahn Texts File 2
• Hahn Texts File 3
• Hahn Texts File 4
• Hahn Texts File 5
• Hahn Texts File 6
• Oddly, even now in September 2022, if you search the web or YouTube for “ExoFlo hair loss”, for instance, you can still find people seeming to be selling ExoFlo for that today. To me that appears to be non-compliant marketing of an unapproved drug by those physicians. Did these care providers buy ExoFlo from Direct Biologics in past years and now are continuing to sell it as a medical treatment?
• Direct Biologics Clinicaltrials.gov listings.
• ExoFlo COVID paper.
• ISCT response to the ExoFlo paper and then Authors reply to that.