• An FDA committee voted on whether seven peptides should be added to the 503A bulk list.
• An expert discussed the vote’s implications and the “genuinely uncomfortable position” clinicians may find themselves in.

An FDA committee is recommending the addition of several peptides to the 503A bulk drug substances list.

The FDA’s Pharmacy Compounding Advisory Committee, which has faced scrutiny for having several members with conflicts of interest, met July 23 and 24 to discuss peptides.

Owais Durrani, DO, an emergency medicine physician in Houston, previously wrote for Healio that “some of the most transformative drugs in modern medicine are peptides,” including insulin and semaglutide. While “the science of peptides is real, serious and worth pursuing,” Durrani wrote, the current system is messy: “a multi-billion-dollar market, a gray zone of unregulated suppliers, a regulatory system under political pressure, and real people spending real money on compounds that, for most of them, will produce nothing at all.”

The following peptides — in both free base and acetate forms — were part of the conversation:

• BPC-157 for ulcerative colitis;
• emideltide for chronic insomnia, narcolepsy and opioid withdrawal;
• epitalon for insomnia;
• KPV for inflammatory conditions and wound healing;
• MOTS-c for osteoporosis and obesity;
• semax for migraine, cerebral ischemia and trigeminal neuralgia; and
• TB-500 for wound healing.

The committee voted on the questions of whether the substances should be placed on the FDA’s 503A bulks list. State-licensed pharmacists and physicians that compound drug products can only use the compounds on this list.

During the FDA’s introductory remarks, Matthew Lash, JD, acting director of the FDA’s Office of Compounding Quality and Compliance, explained the evaluation process, and clarified that compounded drug products are primarily overseen by state regulators and “are not FDA-approved,” meaning “they’ve not been reviewed by the FDA for safety, efficacy or manufacturing quality before marketing.

“They serve an important role for patients whose medical needs cannot be met by an FDA-approved drug product, but at times have been associated with adverse events specific to the quality of the compounded drug,” Lash said. “State-licensed physicians and pharmacists seeking to operate under Section 503A may only use bulk drug substances in compounding drug products that fall in one or more of the following categories: one, if the substance is a component of an FDA-approved drug product; two, if the substance complies with an applicable United States Pharmacopeia or National Formulary monograph; or three, the substance appears on FDA’s list of bulk drug substances ... what we call the 503A bulks list. So, that’s what we’re here to discuss today.”

After roughly 4½ hours of discussion, the committee voted 8-6-1 twice to place BPC-157 free base and acetate forms on the list.

Elizabeth Rebello, MD, FACHE, FASA, CPPS, CMQ, offered a succinct explanation for her “no” vote.

“I voted ‘no’ because of the lack of efficacy data. There were no [randomized controlled trials (RCTs)], and [I] also had some safety concerns as well,” Rebello said.

Melissa Loseke, DO, said her “yes” vote was “conditional,” as she “would like to see some tighter restrictions” on who can manufacture the [active pharmaceutical ingredients (APIs)], mandatory side effects reporting and patient registries.

“Twenty years ago, I made a promise to do no harm to my patients, and the way things stand currently [is troubling],” Loseke said. “Just last week, I had a patient whose ‘research-grade’ whatever that they got ... was laced with MDMA and ecstasy. That’s not protecting the American people. So, my ‘yes’ comes from there.”

On Thursday afternoon, the committee again voted 8-6-1 twice to place KPV free base and acetate forms on the list.

“I voted ‘no’ because the clinical indications and the efficacy are not well defined, and as such, we are not withholding treatment for people because there are also many treatments that are available for both these inflammatory conditions and wounds,” Maral Kibarian Skelsey, MD, FAAD, FACMS, said. “In addition, the formulation and the chemical characterization is again not well defined, and as a topical agent, it’s not clear that we have any information about the absorption as well as allergenicity. And finally, we just talked about [how] the potential for immunogenicity needs to be addressed and examined.”

Asare B. Christian, MD, MPH, ABPMR, ABAARM, said he voted ‘yes’ “in the context of limited information that we’ve received. There were no significant risk issues raised with this peptide, and voting ‘yes’ allows [for] ... better opportunities to characterize it, study it, and potentially present this to patients,” Christian said. “Having this opportunity to maybe study this more is something I think is worth exploring for others who don’t have any options besides what we have available.”

The committee voted 8-6-1 again, so TB-500 will be added to the 503A bulks list in both acetate and free-base forms.

Although many of the ‘yes’ votes did not state their reasoning, Loseke said she voted to put TB-500 on the list “primarily because of the ongoing discrepancies in the information we’re receiving.” Haleem Mohammed, MD, MBA, said he voted ‘yes’ because “I’m allowing for prescriber-directed compounding in a licensed pharmacy against a lower documented harm rate.”

William C. Zamboni, PharmD, PhD, said he against putting TB-500 on the list “for the lack of fundamental information and data to evaluate and know how to use the drug, and with added concern that this particular drug is being used in combination with other peptides.”

Skelsey, who also voted ‘no’, said she did so “because of the paucity of efficacy data and because of the concern that there is overlap between the function of thymosin beta-4 and its ability to promote tumor progression and metastasis, and the lack of any evidence that there is a distinction between these compounds.”

The last votes on Thursday for MOTS-c in free base and acetate forms both passed 7-5-2.

In each previous vote, the abstention came from Timothy D. Fensky, RPh, DPh, FACA, a representative from the National Association of Boards of Pharmacy, who said the organization does not wish to support or oppose any of the peptides being added to the list. This time, he was joined by Christian.

“I abstained from this due to the fact that everything we’re looking at here has limited data, and this is one peptide that, through clinical experience, does have this potential immunogenicity that I see in my clinic, even though it’s limited,” Christian said. “So, I don’t have enough to make a decision on this one.”

In explaining her ‘no’ vote, Rebello cited concerns about data efficacy and safety “related to injectable drugs.” Zamboni said there was a “lack of fundamental information to evaluate the drug and to even know how to use it.”

On Friday morning, the votes on emideltide failed with 6 ‘yes’ votes, 7 ‘no’ votes and 1 abstaining both times.

“As a clinician, as a member of another advisory committee, it’s impossible for me to not take the FDA’s recommendations at heart with respect to safety and efficacy,” Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP, said of his ‘no’ vote.

Loseke said she voted to add emideltide to the list “based on evidence that was provided to me for a well-defined molecular substance: decades long of human exposure affairs, zero reports, benign safety profile and a legitimate role in individualized patient care that FDA products do not fully serve at this time.”

The votes on epitalon succeeded with 7 ‘yes’ votes, 4 ‘no’ votes and 1 abstention.

Christian offered a more detailed explanation of his decision for this peptide specifically, and several other ‘yes’ voters echoed his comments.

“I think it’s about patient access. That’s where I’m coming from. Because all the presentations we’ve had so far don’t have any strong evidence, and as a physician, I’m always quantifying risk,” he said. “Even when I give somebody gabapentinoids, which are actually FDA-approved, there’s all this risk that I have to manage. So, that’s why I’m making all these choices. It’s all about, really, patients, and a lot of the things that have been presented here haven’t really stressed significant safety signals, and for a physician, it’s about “First, do no harm.’”

Explanations of the ‘no’ votes were similar to those of the previous compounds.

“I voted ‘no’ for a significant lack of information and data to evaluate the product and also how to prescribe it. I’m also unclear [about] physicians, how they’re actually determining what dose to use of these particular agents, and I’m going to look into this on my own just to try to figure out how they’re figuring out what dose and frequency and other items to use for these particular products,” Zamboni said.

On Friday afternoon, the committee voted 8-5-1 for semax in both acetate and free-base forms. Most of the ‘no’ voters cited safety concerns.

“We all want to advance medical care and really provide access for patients for safe and effective medication and treatment approaches,” Friedhelm Sandbrink, MD, said. “I don't think that we can skip the rigorous scientific studies that are needed when we endorse any kind of product and make it available. I think [about] the low quality of the current evidence .... So, I voted ‘no’ in particular because I feel like that would presumably provide an endorsement and lead patients away from other evidence-based therapies that we have.”

Mohammed, who voted ‘yes,’ stressed that the committee’s recommendations do not approve drugs.

“Nobody put a finished product on a shelf. We took a decision that patients are already making, and we try to keep it inside a system that has rules and regulations,” he said. “I do not support watching an influencer video, clicking a TikTok link, and getting mystery vials shipped from overseas. What I support is a licensed pharmacy under a state board, a valid prescription from a licensed clinician who has seen the patient — preferably in person — taken a thorough history, run labs. [I support having] medications tested for potency, tested for sterility, screened for the impurities that actually cause harm. The demand does not vanish when we vote ‘no.’ Our patients want peptides. They go to a website, they call it research material, label it not for human consumption, and we as physicians deal with the consequences afterwards. The FDA has zero control over that channel.”

Of the votes on Thursday — for BPC-157, KPV, TB-500 and MOTS-c — Durranis said he was “not surprised by the direction,” but was “a little surprised by the margins.”

“Everyone watching this expected the committee to move toward access, given how it was constituted in June and how clearly the secretary has signaled where he wants this to land. What I did not expect was six ‘no’ votes on three of the four compounds,” he said. “That is a real split, and it deserves more attention than it is going to get because the story tomorrow is going to be written as a rubber stamp and that is not what happened in that room.”

Although the outcome was anticipated, Durrani said he did not agree with the votes based on the evidence in front of the committee.

“FDA staff reviewers went through all seven compounds and recommended against every one of them, and for TB-500 they could not identify a single human clinical study,” he said. “Recommending a substance for compounding when your own reviewers found no human data is a hard position to defend on the science. It is defensible on other grounds — the protection against contamination — which is a different conversation, and I think the committee was mostly having that conversation.”

Of the Friday decisions for emideltide, epitalon and semax, Durrani said “they drew the line somewhere with emideltide, which is worth something.”

“Six of seven still went through, and a committee that recommends the large majority of what it reviews, over the objection of its own staff scientists, is not a committee applying a demanding evidence standard in my opinion. It is worth noting, though, that the ones that passed were not resounding ‘yeses’,” Durrani said. “Epitalon cleared at 7 to 4 and semax at 8 to 5, with abstentions on both, and Thursday’s votes were similarly split. These were narrow margins on almost every compound, not a confident panel. What I hope is that the one ‘no’ vote, along with how close the rest were, gives the broader FDA some pause as this moves into rulemaking. The agency does not have to accept these recommendations quickly, or at all, and the fact that even this panel balked at one compound, and hesitated on the others, is reason to slow down and look hard at the rest rather than hurry them onto the list.”

Overall, Durrani said it is important to remember that “this is not an approval” even if some speak about it in that way.

“A ‘yes’ vote means a licensed pharmacy can make the ingredient for a prescription. It does not mean anyone reviewed the science and concluded these work. Nothing is legal tomorrow either way,” he said. “The recommendations are nonbinding, the agency still has to act, and formal rulemaking runs into 2027. Anyone selling these next week on the strength of today’s headlines is trying to dupe patients.”

However, Durrani also noted that a benefit in the votes is that millions of people currently buy these compounds from anonymous overseas sellers and licensed compounding pharmacies are “unambiguously safer than research-only shipments from abroad.”

For practitioners, Durrani said “the harder problem is the gap between what was evaluated and what will be prescribed.” For example, BPC-157 was evaluated for ulcerative colitis, but “almost nobody is asking their doctor for these for ulcerative colitis.” Instead, they are asking for fat loss, longevity and recovery benefits.

“Once a substance is on the 503A list, clinicians can write off-label for whatever the market wants. That puts physicians in a genuinely uncomfortable position, because the one honest answer we have been giving patients, that these are not available through legitimate channels, stops being true,” Durrani said. “What replaces it is a much harder conversation about evidence that most visits are not built to have. The clinician who declines becomes the obstacle standing between a patient and something they believe will help, and the clinician who writes the prescription is doing it without the safety profile that normally makes off-label prescribing reasonable.”

Owais Durrani, DO, can be reached at owaisdurrani@gmail.com.