Just under three years ago, the Food and Drug Administration deemed 19 peptide drugs too dangerous for distribution by compounding pharmacies, which mix components of approved drugs to create tailor-made medications for people who have difficulty taking commonly available products.
Now, under Health and Human Services Secretary Robert F. Kennedy Jr., the agency is poised to reverse course. This is despite few clinical studies supporting the effectiveness or safety of these peptides, which are chains of amino acids intended to help regulate the body’s functions and have become popular among fitness and longevity enthusiasts.
In February, Kennedy said the FDA acted illegally in 2023 by classifying 19 peptides as too dangerous for compounders, whose final products are neither tested nor approved by the FDA. Kennedy, who describes himself as a “big fan” of peptides, has used these therapies himself.
“It was illegal because they’re not supposed to do that unless there’s a safety signal,” Kennedy said. on “The Joe Rogan Experience” podcastreferring to adverse drug events. “And they didn’t have a safety signal. They’re not allowed to look at effectiveness. They’re not allowed to say, ‘Well, we don’t think these products are effective,’ or anything. They can only look at safety.”
But three former FDA officials, very familiar with how the agency created the criteria for evaluating peptides, say Kennedy misinterpreted their work. The agency’s decision in 2023 to ban certain peptides was supported by numerous documented safety concerns, they said. FDA regulations also require the agency to evaluate both safety and effectiveness before approving a substance’s composition.
“It would be a disruption of the societal compact that we have had since 1962 for drugs to be studied to see if they work before they are marketed in the United States,” said Janet Woodcock, former acting FDA commissioner.
If Kennedy justifies reversing previous work by suggesting there are no safety concerns, that would give a false sense of safety to more than a dozen unapproved and untested drugs, the officials said.
There has been little new scientific data on the 19 peptides since the FDA’s decision in 2023 to classify them as dangerous. But demand for the drugs exploded as influencers flooded social media with promises of sculpted physiques, glowing skin, luscious hair, fast-healing wounds, youthful energy and blazing sex lives.
The demand has given rise to a booming gray market, where wellness spas, multilevel marketers, and telehealth websites offer vials of “research-grade” peptides labeled “not for human use” to the public.
“More and more people want to use them,” said Lauren Colenso-Semple, a muscle physiology researcher and science communications specialist who follows scientific studies of peptides as part of her work. “That’s what’s changed.”
FDA-approved peptide medications, such as insulin and oxytocin, have been available for decades. Newer ones, such as semaglutide and tirzepatide, widely known as GLP-1, have exploded in popularity for weight loss and shown promise. to treat other conditionssuch as addictions and neurodegenerative and liver diseases. The popularity of these drugs has led the public to become more familiar with injectable products and helped bring attention to other gray market peptides.
Last year, at a conference in Las Vegas promising radical life extension, two women became seriously ill after receiving a peptide injection the FDA had classified it as dangerous. Although Nevada regulators investigated and fines to healthcare professionals involved in administering the peptides, investigators were unable to determine the exact cause of the reaction. The doctor who ran the booth where the women got sick said he didn’t believe the peptides were causing their reactions, but he apologized for the incident and said he would review his practices.
The Alliance for Pharmacy Compounding, one of the largest industry associations pushing for the FDA to change its stance on peptides, acknowledges that it knows little about the safety of individual peptides sold to the public. (Its CEO says it is an advocacy organization, not a scientific one.) But the group says the public would be safer if peptides were processed through regulated compounding pharmacies rather than the gray market. The FDA would have to forgo the usual human clinical trials in order to bring about this change, an alliance spokesperson said.
“Where we don’t have research, clinical trials, what we have a ton of is, shall we say, testimonials, patient affidavits, attesting to the wonders of the drug,” said Scott Brunner, the alliance’s chief executive officer. “And RFK Jr. is one of those witnesses.”
On the Rogan podcast, Kennedy did not elaborate on exactly how the FDA would allow drugmakers to begin distributing peptides, describing it only as “some sort of action” aimed at making “about 14” peptides “more accessible.” He also did not specify which peptides he wishes to make available. (Neither the FDA nor HHS responded to ProPublica’s requests for additional information.) But several regulatory shortcuts exist, and ultimately Kennedy could simply declare the ingredients legal.
“He has all the authority,” Woodcock said, comparing such a statement to former HHS Secretary Kathleen Sebelius’s 2011 unilateral reversal of the FDA’s decision to lift age restrictions on the emergency contraception Plan B. (A judge ultimately concluded that Sebelius’ decision is arbitrary and capricious and canceled it.)
“The secretary can do whatever he wants.”
The list of lots
The FDA’s journey to regulating compounding pharmacies – and by extension the peptides they seek to distribute – has been long and tedious. Much of the regulatory fight has focused on which ingredients compounders should be allowed to use.
Under a 1997 law, the first passed by Congress to regulate the industry, compounders can only use ingredients that are part of an approved drug, have what’s called a USP monograph (essentially a third-party certified recipe for a drug used primarily by generic drug makers) or be listed as an FDA-approved substance.
This FDA list, known as the “bulk list,” is at the center of the ongoing debate over peptides.
Litigation and pressure from industry and lawmakers delayed creation of the bulk list for decades, leaving compounders uncertain about many substances, not just peptides.
“Everything was a struggle. It was a huge struggle,” said a former FDA official who spent more than 30 years working on compounding policies. The former official asked not to be named to avoid public debate with the industry.
The need for this list became even more urgent in 2012, when more than 60 people died caused by fungal meningitis contracted from a drug produced in a compounding center and distributed to hundreds of people. Congress passed another law further regulating large labs that sell drugs to doctors’ offices and hospitals rather than to individual patients. The new law also prompted the agency to speed up the listing of lots.
The FDA asked industry to nominate substances for inclusion on the list. He did this by naming thousands of ingredients, including, for example, purified water and asparagus.
“They put everything in,” the official said. “Literally thousands of nominations with no justification as to why it needed to be there. »
Each substance would need to be reviewed individually before it can be added to the list of bulk substances. The agency should seek public comment, and an advisory committee of health and pharmacy experts should review the FDA’s research.
Reviewing them “was a massive effort. The agency moved glacially, but in reality we were moving as quickly as possible,” the official said.
In 2017, under pressure to act more quickly, the FDA proposed an interim solution. He significantly reduced the list of designated ingredients, quickly examined each remaining substance and classified them into three categories. The first was for substances with enough of a safety history that the agency felt comfortable letting compounders use them while the final list was compiled. The second category included substances considered too risky to mix. And the third included those that did not have enough supporting information for the FDA to make an informed decision and therefore would not be used for the compounded preparation.
This categorization did not constitute a formal regulation; rather, the agency used its discretionary power not to go after preparers who used ingredients it deemed safe – those in the first category.
In 2023, the FDA placed 19 peptides in Category 2, which already included a handful of substances considered by the agency to be dangerous.
This is what Kennedy called “the war on peptides.”
In explaining its decisions, the FDA pointed to well-established research in peptide drug development that injectable peptides carry the risk of causing adverse reactions. military. Such reactions can range from responses with “no clinical manifestations” to irritating skin rashes or life-threatening conditions such as anaphylactic shock, which restricts breathing and impairs motor function.
Peptides occur naturally in the body but break down quickly after serving their function. Peptide drugs, on the other hand, are manufactured to last longer in the body to create a therapeutic response, such as controlling appetite or promoting new blood vessel growth, bone or muscle density.
“Now that it has been modified to do something else, the immune system may recognize it as foreign and there is a potential risk of an unwanted immune response,” Colenso-Semple said.
The manufacturing process can also introduce impurities, such as bacteria or heavy metals, into peptide drugs. They are also sensitive to environmental conditions and can change their chemical composition if stored at the wrong temperatures or shaken too vigorously, increasing the risk of an immune response or decreasing their effectiveness. And when a substance is injected rather than taken orally, it bypasses most of the body’s natural defenses.
The risk of immune response is common to peptide drugs in general. But some peptides also pose specific potential risks.
The FDA reviewed the data to assess these risks and found limited human studies of a few peptide therapies; most have only been studied in animals or in clinical populations such as HIV patients. Human data found by the FDA for individual peptides indicated harmful potential. Subjects in studies of six individual peptides – growth hormone-releasing peptide-2, ibutamoren mesylate, ipamorelin, CJC-1295, AOD-9604, and melanotan II – experienced adverse events, including death. (It hasn’t been proven whether the deaths were caused by the peptides or something else.) Ultimately, the FDA decided there wasn’t enough data to allay known safety concerns.
“Of course, any adverse event can be a red flag,” said another former FDA official who worked in the compounding division when the peptides were classified as dangerous. The former official asked not to be named because he works in public health and does not want to distress the current administration. “Additionally, if there is no clinical data on a substance and the substance is known to have a propensity to be harmful, this could make it an appropriate placement on the Category 2 list.”
Are they safe?
Placing peptides on the list of dangerous substances hasn’t changed much for compounders. Because these peptides are not components of an approved drug and do not carry a USP monograph, the compounders were not authorized to distribute them anyway.
“All it did was put an exclamation point on it,” Brunner said. In the months since the FDA’s announcement, his organization has repeatedly warned its members not to distribute peptides.
But the list prompted at least two peptide companies to sue the FDA, arguing that it was dragging its feet in creating the overall list of permitted compounding substances. To date, only six substances have passed the listing process, none of which are peptides and none of which are injectable. As the lawsuit progressed in federal court, the FDA agreed to expedite review of four peptides named in the lawsuit: CJC-1295, AOD-9604, thymosin-alpha, and ipamorelin acetate. It also decided to move forward on two other peptides not listed in the complaint: kisspeptin and ibutamoren mesylate. Online marketing claims that these peptides help with weight loss, muscle building, anti-aging, insomnia, tissue repair, and sexual dysfunction, among other things. Marketers also claim that thymosin alpha, one of the most studied peptides, may help with immune function, Lyme disease, and COVID-19.
In the final months of the Biden administration, the FDA convened the expert advisory committee and presented its research on the six peptides. In reports of up to 158 pages, the agency detailed the science behind the risk of immune response in synthetic peptides, listed documented adverse events associated with the drugs, and summarized limited research on human subjects. In each case, the FDA recommended that the peptide not be listed as a bulk product for compounders.
“I can’t imagine anyone looking at this data and feeling comfortable” making it publicly available, Colenso-Semple said.
The peptide industry was given just 10 minutes before the committee to present its arguments that all six peptides were safe. Speakers presented anecdotal evidence of their own and others’ practices. Although peptides cannot be legally used by compounders, many have been distributing these drugs because the FDA has been lax in enforcing its regulations.
“Many peptides placed in Category 2 have been used successfully by thousands of our practitioners treating hundreds of thousands of patients who use these compounds to boost cellular function and give the body what it needs to fight diseases including obesity, diabetes and addiction,” said Dan DeNeui, CEO of one of the peptide companies that sued the FDA.
His wife, Terri DeNeui, a nurse practitioner and founder of their company Evexias Health Solutions, presented information from a survey of 508 patients treated with various peptides, which found that 19% reported uncomfortable side effects and less than 1% experienced an adverse event.
They also argued that peptides would be more safely distributed by regulated compounding companies than in the gray market – the argument is now being made by the Alliance for Compounding Pharmacies. The drugs’ active ingredients would be manufactured in an FDA-registered and inspected facility, and compounders would be supervised by state boards of pharmacy to ensure sterile conditions.
That’s “much better than what many consumers do,” getting advice in message boards and “ordering a substance that claims to be a peptide and may or may not be,” Brunner told ProPublica.
While this argument addresses the quality control concerns associated with the gray market, it does not answer the fundamental question of whether peptides are safe.
“These are completely unapproved drugs,” one of the former FDA officials said. “Would you let a pharmaceutical company do that? No. No way.”
Ultimately, the advisory committee sided with the FDA and approved its initial decision that the six peptides were too risky for distribution to the public.
What is happening now?
Unhappy with the advisory committee’s decision, the compounds industry has amplified its argument that the FDA’s review process for the bulk product list is flawed. The advisory panel had few compounds working on the topic and did not give enough time for those opposed to the peptide ruling to present their arguments, industry advocates say.
With a new administration, including the Secretary of Health who has used peptides himself and is trying to promote alternative health practices, they see an opportunity. They hope that the FDA will appoint more members with compounding experience to the committee and facilitate the application of peptides while continuing the established regulatory process.
“Given the magnitude of the demand – demand that will be met, if not by a state-licensed compounding pharmacy, then by the black and gray markets – we believe that the lens that the FDA is using regarding these peptides, at least some of the peptides, is not the right lens,” Brunner said. “They want research, clinical trials. They want a certain level of certainty that, frankly, is appropriate for most drugs, but not at the moment.”
There are regulatory shortcuts that would allow the FDA to avoid the more laborious approval process. The FDA could simply remove Category 2 peptides, those it considers dangerous. This could place them in Category 1, allowing them to be used in composition. Or, it could announce that it is changing its enforcement strategy and not going after compounders who work with these substances.
None of this would be safe for the public, Woodcock says. Congress intended for the FDA to “reference a substantial body of evidence on the safety and effectiveness” of ingredients on the bulk list, she said.
“This was not intended to be a pathway for unapproved drugs to enter the market,” she said. “Even Congress didn’t think that. »
