Why Empower Supports Adding 7 Bulk Drug Substances to the 503A List

RE: Comments on Docket No. FDA-2025-N-6895: Pharmacy Compounding Advisory Committee; Bulk Drug Substances Nominated for Inclusion on the Section 503A Bulk Drug Substances List

Dear Members of the Pharmacy Compounding Advisory Committee (PCAC):

I. Introduction
Empower Pharmacy’s core mission is to provide access to personalized, affordable medication through innovation with a commitment to quality, service, and people. Since 2009, we have grown into the nation’s largest, most advanced compounding pharmacy and outsourcing facility serving healthcare markets across the country. I am writing to you as Director of Government Affairs to work collaboratively with the FDA and to help continue our efforts to expand access to safe and quality medications for patients throughout the country.

We thank the FDA and PCAC for its efforts to consider updates to the 503A bulks list to keep pace with industry advancements while protecting patient safety. Our goal is to work collaboratively with the FDA to ensure the proposed changes are well-supported, clear, and designed to support effective compliance. We believe you are taking a positive step forward overall and want to express our endorsement of this proposal.

Empower Pharmacy respectfully submits these comments in support of the nomination of seven bulk drug substances currently under review for inclusion on the Section 503A Bulk Drug Substances List: BPC-157, KPV, TB-500, MOTs-C, Emideltide (also referred to as delta sleep-inducing peptide, or DSIP), Semax, and Epitalon. Empower operates at the intersection of clinical demand and regulatory compliance. We serve millions of patients through licensed prescribers who practice regenerative medicine, neurology, endocrinology, longevity medicine, and more. We have both an operational stake in regulatory safeguards and a clinical obligation to present evidence that informs the Committee’s deliberations. We appreciate the consideration of the following comments in your discussions and decision making at the July PCAC meeting.

II. Regulatory Context
Section 503A of the Federal Food, Drug, and Cosmetic Act authorizes licensed pharmacists to prepare patient-specific compounded medications using bulk drug substances that appear on the FDA-approved 503A Bulks List. Each of the seven substances nominated here lacks a currently approved drug equivalent in the United States. This creates a circumstance where patients and prescribers are left without a regulated pathway, and many turn to unregulated gray-market sources, an outcome that categorically worsens the safety profile the FDA seeks to protect. Inclusion on the 503A Bulks List would not confer drug approval; it would bring these compounded preparations into a quality-controlled, prescription-based, pharmacist and prescriber-supervised framework that is materially safer than the current unregulated alternative.

The standard for Bulks List inclusion is appropriately different from full NDA approval. This Committee is tasked with evaluating whether the available evidence supports a plausible risk-benefit profile for individualized compounded use. We urge the Committee to apply that standard here, with recognition that Phase III RCT data, while ideal, cannot be the default threshold for substances whose entire history of development has occurred outside the NDA pathway. Lastly, we ask the Committee to contemplate whether an unregulated gray market of substances with high patient demand is deemed safer than one with FDA and regulatory oversight.

III. Evidence Summary by Substance

A. BPC-157 (Ulcerative Colitis)
BPC-157 (body protection compound 157) is a pentadecapeptide endogenous to human gastric juice. Its cytoprotective and mucosal-healing properties are among the most extensively studied of any compound on this list. A 2025 systematic review published in The American Journal of Gastroenterology identified 36 studies spanning 1993–2025 and documented BPC-157’s effects on mucosal integrity, IBD models, anastomotic healing, GI fistulae, and anti-inflammatory cytokine modulation.¹ A concurrent systematic review in HSS Journal confirmed its emerging role in orthopaedic soft tissue recovery.² Early phase I human pharmacokinetic work by Veljaca and colleagues established tolerability with no reported toxic effects at studied doses.³ A 2025 pilot human study by Lee and Burgess reported no adverse events with IV-administered BPC-157.⁴ BPC-157’s origin as a peptide fragment of gastric juice, a substance the human body produces naturally, provides an inherent biological consistency that supports a favorable safety inference pending controlled trials.

B. KPV (Wound Healing and Inflammatory Conditions)
KPV (Lys-Pro-Val) is the C-terminal tripeptide of alpha-melanocyte-stimulating hormone (α-MSH), an endogenous neuropeptide with well-established anti-inflammatory properties. Dalmasso et al. published seminal mechanistic data in Gastroenterology demonstrating that KPV is actively transported into intestinal epithelial cells via the PepT1 transporter, where it reduces NF-κB-driven cytokine expression, providing both a credible delivery mechanism and a plausible therapeutic rationale for inflammatory bowel conditions.⁵ Kannengiesser et al. confirmed anti-inflammatory efficacy across multiple murine IBD models.⁶ A 2025 comprehensive review in the International Journal of Medical Sciences catalogued KPV’s wound healing role, including fibroblast migration stimulation, collagen deposition, and antibacterial activity against MRSA, and concluded it holds significant promise for acute and chronic wound management.⁷ KPV’s derivation from an endogenous human peptide and its compact tripeptide structure, conferring greater metabolic stability than many larger peptides, strengthen its safety profile.

C. TB-500 (Wound Healing)
TB-500 is a synthetic analogue of thymosin beta-4, an endogenous actin-binding protein integral to cell migration, tissue remodeling, and inflammatory resolution. Rahaman and colleagues published pharmacokinetic characterization of TB-500 and its metabolites in 2024, establishing absorption and metabolic parameters in vitro and in vivo.⁸ A 2026 review in the Journal of the American Academy of Orthopaedic Surgeons Global Research & Reviews identified therapeutic peptides including TB-500 analogues as mechanistically grounded candidates in orthopedic tissue repair applications.⁹ The wound-healing indication reviewed by FDA represents precisely the therapeutic context in which the mechanistic pathway from native thymosin beta-4 to clinical outcomes is most defensible, and where compounded access could address an unmet clinical need for patients with chronic or complex wounds not responsive to standard care.

D. MOTs-C (Obesity and Osteoporosis)
MOTs-C (Mitochondrial Open Reading Frame of the 12S rRNA type-C) is a 16-amino-acid mitochondrial-derived peptide with AMPK-activating properties relevant to both metabolic and skeletal health. Lee et al. first characterized its role in reducing obesity and improving insulin resistance in a foundational 2015 Cell Metabolism paper.¹⁰ Reynolds et al. published a Nature Communications study in 2021 demonstrating that MOTs-C levels increase approximately 12-fold in human skeletal muscle during acute exercise, establishing meaningful physiological relevance in human biology, not merely animal models.¹¹ Yi and colleagues provided a 2023 review in Frontiers in Physiology documenting MOTs-C’s regulation of bone metabolism through AMPK-dependent osteoclastogenesis inhibition and TGF-β/SMAD-pathway stimulation of osteoblast activity.12 Both obesity and osteoporosis represent enormous unmet needs in aging populations, and the physiological plausibility of MOTs-C’s mechanism supports continued investigation through a regulated compounding pathway.

E. Emideltide (DSIP) — Opioid Withdrawal, Chronic Insomnia, and Narcolepsy
Emideltide (delta sleep-inducing peptide, DSIP) is a naturally occurring nonapeptide first isolated and characterized by Schoenenberger and Monnier in 1977.¹³ Multiple human clinical studies have investigated its sleep-regulating properties. Schneider-Helmert and Schoenenberger tested IV DSIP in chronic insomniacs and reported increased sleep duration, improved efficiency, increased delta-wave activity, and notably no daytime sedation, a profile meaningfully different from benzodiazepine and Z-drug alternatives.¹⁴ A subsequent double-blind study by Bes et al. in Neuropsychobiology confirmed normalized sleep architecture in chronic insomniacs, with effects sustained over follow-up periods of three to seven months.¹⁵ The opioid withdrawal indication carries particular national urgency. A 1984 patent application by Scherschlicht and Tissot, based on clinical observations in approximately 100 inpatients, described resolution or marked improvement in withdrawal symptoms in 97% of opiate-dependent and 87% of alcohol-dependent patients.¹⁶ DSIP’s mechanism, modulation of opioid receptor activity and HPA axis dampening without addiction potential, positions it as a uniquely compelling candidate to help alleviate the ongoing opioid crisis that continues to claim tens of thousands of American lives annually.

F. Semax (Cerebral Ischemia, Migraine, and Trigeminal Neuralgia)
Semax is a synthetic heptapeptide analogue of ACTH(4-10) developed at the Institute of Molecular Genetics in Moscow and registered as a pharmaceutical drug in Russia since 1994 for ischemic stroke and cognitive impairment. Of all seven substances under review, Semax carries the most substantial human clinical evidence base. Gusev et al. enrolled 110 ischemic stroke patients and demonstrated that Semax administration produced sustained plasma BDNF elevation, accelerated functional recovery, and improved Barthel index scores regardless of rehabilitation timing.¹⁷ Mechanistically, Dolotov et al. confirmed that Semax upregulates BDNF and TrkB expression in the rat hippocampus, the molecular pathway directly responsible for neuronal survival and synaptic plasticity in the peri-infarct penumbra.¹⁸ Semax has accumulated more than 226 PubMed-indexed citations since the 1990s. The volume and consistency of this evidence base, even acknowledging its concentration in Russian-language literature, represents a scientifically serious foundation. For migraine and trigeminal neuralgia, conditions where existing pharmacotherapy imposes substantial tolerability burdens, Semax’s neurotrophic and anti-inflammatory properties present a clinically relevant alternative worth supporting through regulated compounding access.

G. Epitalon (Insomnia)
Epitalon (Ala-Glu-Asp-Gly) is a synthetic tetrapeptide analogue of epithalamin, a pineal gland-derived peptide with documented pinealotropic activity. Khavinson et al. published evidence in the Bulletin of Experimental Biology and Medicine in 2003 demonstrating that Epitalon induces telomerase activity and telomere elongation in human somatic cells, representing one of the few instances of a compounded peptide with independently confirmed human cellular evidence.¹⁹ This finding was independently replicated by Al-Dulaimi et al. in 2025 in Biogerontology, confirming Epitalon-mediated telomere lengthening in human cell lines.²⁰ A comprehensive 2025 review in the International Journal of Molecular Sciences catalogued Epitalon’s antioxidant enzyme upregulation and melatonin synthesis stimulation.²¹ Most directly relevant to its insomnia indication, Ivko et al. demonstrated that Epitalon regulates human circadian rhythm gene expression during accelerated pineal aging, a mechanistic link of direct clinical relevance.²² Given the prevalence of insomnia in aging populations and the significant tolerability and dependence risks of current pharmacotherapy, a non-habit-forming, physiologically grounded alternative warrants regulatory support.

IV. Overarching Considerations and Recommendations
We respectfully ask the Committee to weigh five overarching recommendations. First, the 503A Bulks List framework exists for exactly this category of substance: clinically meaningful, biologically plausible, individually prescribed compounds that lack commercial drug equivalents. The appropriate evidence standard is not NDA-level; it is whether plausible risk-benefit data exists to support individualized clinical use under licensed prescriber oversight. We also recognize the important role that FDA-registered 503B outsourcing facilities play in expanding access to compounded medications under a distinct statutory framework. While the nominations before the Committee concern substances for use under Section 503A, the Committee’s recommendations should acknowledge that qualified 503B outsourcing facilities likewise serve an important public health function by producing compounded medications under FDA oversight when commercially available options do not adequately meet patient needs. A regulatory approach that supports both Sections 503A and 503B, as Congress intended, strengthens patient access while maintaining appropriate quality standards.

In evaluating nominated bulk drug substances, we respectfully encourage the Committee to apply the framework established in 21 C.F.R. § 216.32, which directs consideration of factors including the substance’s physical and chemical characterization, safety, evidence of historical and current clinical use, and the scope of available supporting information. This framework appropriately reflects the distinct purpose of the Section 503A Bulks List and differs from the evidentiary standard applicable to approval of a new drug application. While evidence of clinical effectiveness is an important consideration, it should not be treated as the dispositive factor in determining whether a substance is appropriate for compounding under Section 503A. Rather, the Committee’s primary focus should remain on protecting public health by evaluating the totality of the evidence across the regulatory factors established for compounded preparations.

Second, regulated access is categorically safer than the status quo gray market. When substances are excluded from the Bulks List, patients do not stop using them. They go to research chemical suppliers, international vendors with no accountability to American regulatory standards, wellness clinics with unclear sourcing practices, and unregulated online sellers with no sterility testing, no verified purity, and no clinical oversight. That is the actual alternative the Committee is choosing if it declines to recommend inclusion, not a comparison between compounded peptides and a nonexistent FDA-approved equivalent. This is a public health argument, not simply a defense of pharmacy access. A patient seeking BPC-157 for a treatment-resistant GI condition or DSIP for opioid withdrawal does not disappear from the landscape when licensed pharmacies cannot serve them. The FDA’s oversight interest is better protected—and the patient is materially safer—when that demand is met through a quality-controlled, traceable, prescription-based, pharmacist and physician-supervised system than when it is pushed outside any regulatory framework entirely.

Third, several of these substances: BPC-157, KPV, MOTs-C, DSIP, and Epitalon, are endogenous to the human body or derived from endogenous peptides. This biological origin carries real-world safety implications that distinguish them from novel synthetic agents with no human physiological precedent.

Fourth, we urge the Committee to consider whether the substances before it warrant a recommendation pathway beyond simple approval or exclusion. PCAC deliberations are frequently framed as binary determinations. For substances where identifiable concerns exist alongside credible evidence of clinical value, as is the case for several of the peptides reviewed here, the Committee has an opportunity to recommend inclusion with specific, substance-appropriate conditions rather than treating those concerns as categorically disqualifying. Formulation restrictions, sourcing documentation requirements, or adverse event reporting obligations can address legitimate regulatory concerns without foreclosing patient access through licensed pharmacies. We respectfully ask the Committee to preserve that middle category where the evidence supports it, and to recognize that a conditional recommendation is both a regulatory option and the outcome most consistent with patient safety when the alternative is unregulated access.

Fifth, we further recommend that FDA establish a post-market data reporting framework to accelerate evidence generation for future regulatory review. Any such framework must pair adverse event reporting with aggregate dispensing volume data to be analytically meaningful. Ten adverse events represent a very different safety signal depending on whether the denominator is 80 prescriptions or 800,000. Without utilization context, adverse event reports alone can create a distorted picture of risk, one that is incomplete by design and ill-suited to drive sound policy decisions. Reporting obligations imposed on compounding pharmacies for these substances should, therefore, include standardized aggregate dispensing volume as a required data element alongside any adverse event submissions, so that safety information can be interpreted with the context necessary to understand it accurately.

Finally, we encourage the FDA and the Pharmacy Compounding Advisory Committee to convene more frequently so that the substantial backlog of pending bulk drug substance nominations can be reviewed in a timely manner. Predictable and regular Committee meetings promote regulatory certainty for patients, prescribers, pharmacies, and FDA alike, while ensuring that scientific evidence is evaluated without unnecessary delay. We also respectfully request that the Committee ensure all stakeholder comments, scientific submissions, and supporting evidence received through the public docket and presented during the Committee process are fully considered before final recommendations are made. The strength of the PCAC process lies in its ability to evaluate the complete administrative record, incorporating the perspectives of patients, clinicians, researchers, compounders, and other interested stakeholders to inform balanced, evidence-based recommendations. Empower Pharmacy respectfully recommends that the Committee recommend all seven substances for inclusion on the Section 503A Bulks List.

Thank you for your consideration,

Deeb D. Eid, PharmD, RPh, FMPLP
Director of Government Affairs
Empower Pharmacy