PEPTIDE-L WAVE! PCAC Approves Four Bulk Drug Substances for the 503A List

See what we did there?

Well, readers, some big things have taken place.  “Big things” have happened: we previewed these for you in our two-part FDA’s Pep(tide) Rally! What Compounders and Industry Need to Know blog posts (Part I, Part II).

Yesterday, on Day 1 of FDA’s Pharmacy Compounding Advisory Committee (PCAC or Panel) Meeting, the assembled Panel voted to approve for inclusion on the list of bulk drug substances that may be used in compounding under section 503A of the FDC Act (the so-called Category 1 list) the first four of seven bulk drug substances to be considered during this two-day meeting.

With no exaggeration, this is a “sea change” and the “moment” for peptides; it’s just hard to imagine FDA would reverse course given the current administration’s MAHA agenda and HHS Secretary Robert F. Kennedy Jr.’s open support for wider access to peptides (see, for example, his noteworthy appearance on the Joe Rogan podcast, where important drug policy is now announced….).

The PCAC recommended inclusion of four of the most talked-about peptides on the market—BPC-157, KPV, TB500, and MOTS-c.  For BPC-157, KPV, and TB500, the Panel split 8 to 6, with one abstention, reaching that same 8-6-1 result separately for both the free base and the acetate forms.  MOTS-c cleared by a narrower 7-5-2 margin.  The votes are “advisory,” but they are notable because they run flatly against the recommendation of FDA’s own scientific review team.  You can access information about the PCAC, including FDA’s briefing documents, here.

By way of background, the nominations for all of the substances to be considered for inclusion had actually been withdrawn by their nominators at the eleventh hour, with no accompanying explanation; however, the Agency elected to evaluate each substance on its “own initiative,” prioritizing them for consideration given the level of public interest.  We believe that sponsors withdrew the nominations so that their use(s) would not be arguably or otherwise limited to the nominated “indications” should they be added to Category 1.  A multidisciplinary team drawn from the Office of Compounding Quality and Compliance (OCQC), Office of Pharmaceutical Quality (OPQ), and Office of New Drugs (OND)—including OND’s Office of Specialty Medicine (OSM) and Division of Rare Diseases, Pediatrics, Urologic, and Reproductive Medicine/Specialty Medicine (DPT-RPURM/SM)—assessed each substance against FDA’s review criteria and, balancing safety in the context of the proposed use, recommended against their inclusion on the 503A list.

Running through all of the FDA presentations was a foundational concern: identity and characterization of the substance.  As FDA put it, you cannot build meaningful quality standards until you can answer the deceptively simple question of “what is BPC-157?”  FDA repeatedly stated that these are substances described in the literature with a variable number of amino acids and no settled salt, ester, or free base form.  Because different salts and esters of the same active moiety can carry very different physicochemical, toxicological, and PK/PD properties, the Agency stressed that identity and characterization are not technicalities but prerequisites to any compounding standard(s).

The public hearing captured the broader fault line between FDA and non-Panel speakers/Panel members.  Clinicians, telehealth prescribers, and suppliers largely urged a “yes with guardrails” approach, including an FDA-evaluated “greenlist” of FDA-registered API suppliers (NOTE: API suppliers are not, and never can be, “FDA-approved” as many speakers repeatedly referred to them).  The pro-peptide participants also advocated a need for legitimate prescriber-patient relationships, mandatory MedWatch adverse event reporting (NOTE: FDA lacks this congressionally delegated statutory authority to require 503A ADE reporting), and enhanced disclosure that the preparation is compounded—effectively arguing that a blanket prohibition simply pushes patients to an international and research-use-only grey market.  On the other side, public health voices, including but not limited to CSPI’s Peter Lurie and Public Citizen’s Nina Zeldes, opposed inclusion, pointing to inconsistency with FDA’s own compounding standards, safety risks (six of the seven nominated peptides were nominated at least in part for injection, which raises a host of safety concerns), the availability of approved alternatives, and the risk that 503A “listing” would be misunderstood by patients as an FDA “approval.”  Public health speakers also warned that any Category 1-type listing would set a precedent for bypassing approval and strip the incentive to develop these substances under the IND framework.  Pressed on this, FDA invoked its integrity and cautioned that erosion of trust in the Agency’s safety and effectiveness determinations would, itself, endanger public health.

The two remaining substances taken up on Day 1 drew their own distinct debates.  The peptide TB500 was promoted largely for wound healing, tendon and ligament repair, and recovery.  Supporters, including clinicians who described it as part of the so-called “wolverine stack” taken alongside BPC-157, again urged a regulated 503A pathway over the grey market.  FDA and several panelists focused on a potential cancer signal, although FDA acknowledged there are no studies on TB500 itself (… Did we just write that?  No studies?).  Nonetheless, the Panel voted 8-6-1 to recommend inclusion of both the free base and acetate forms, with dissenters citing the paucity of efficacy data, concerns about overlap with tumor progression, and the substance’s proposed use as an injectable.

MOTS-c, a mitochondrial-derived peptide, closed out Day 1.  Opponents—including the Partnership for Safe Medicines, Public Citizen, and the Collaborative for Evidence-Based Medicine—argued that the substance lacks scientific backing, is not well characterized, and that listing would amount to a large, uncontrolled human trial without necessary adverse event reporting.  The Partnership for Safe Medicines’ Shabbir Imber Safdar framed the proponents’ case as a set of myths: that listing gives patients quality-made peptides, that patients will choose licensed dispensers when licensed options exist, and that FDA can permit measured access with guardrails.  On the last point, he said FDA lacks the resources to enforce the guardrails supporters proposed.  Georgetown University’s Adrienne Fugh-Berman was blunter still, calling MOTS-c not merely a harmless supplement but a poorly characterized experimental drug, and arguing that market interest is a reason to study a substance, not to legalize it.  In the closest vote of the day—which, in these authors’ opinions, didn’t feel all that close in the moment—the Panel recommended inclusion of the free base and acetate forms by a 7-5-2 margin, with two members abstaining.  As with all votes taken, victory cheers rang from the audience when PCAC read out the results.

A few points worth keeping in mind as this plays out.  First, the vote is advisory and one input among many; FDA has said it will continue reviewing the comments and data submitted through the docket and will announce any final decision through notice-and-comment rulemaking, not at the PCAC Meeting.  Second, while PCAC recommendations usually track FDA’s ultimate decision, the Agency has gone the other way at least once before, according to Matthew J. Lash, Acting Director, OCQC.  For now, the Committee has SPOKEN, and these four substances appear slated for inevitable inclusion on the 503A list—although timing is still a major question for industry stakeholders.  One question that likely merits a rather immediate answer is whether FDA will place these substances immediately on its interim Category 1 list—as it has with all of the other substances it has reviewed with much less fanfare.  And will it exercise enforcement discretion if compounders start compounding them immediately, like it has with all other substances the PCAC and FDA placed on the Category 1 list?  We bloggers hope FDA’s decision on these gating issues comes promptly as we are sure that the compounding pharmacies are fully primed to the opportunities these decisions present; and they welcome guardrails.

We believe Day 1’s results portend further good news for the peptide industry and consumer market today—stay tuned for our post covering Day 2!