Why Getting Peptide Drugs Approved Is So Confusing — and What the Industry Wants to Fix | Research

The takeaway

Peptide drugs are booming but FDA regulatory guidelines weren't designed for them, creating classification disputes and inconsistent nonclinical testing requirements that slow drug development.

Regulatory gap identified
Existing ICH guidelines for small molecules (M3) and biologics (S6) don't cleanly apply to peptides, creating inconsistent requirements across the industry

What the researchers found

Peptide therapeutics entering clinical development have increased significantly over the past decade, but regulatory frameworks haven't kept pace. A key challenge: existing FDA/ICH guidelines (ICH M3(R2) for small molecules and ICH S6(R1) for biologics) were not designed for peptides, which fall somewhere in between. Regulators and drug companies interpret these guidelines differently for synthetic and conjugated peptides, creating inconsistency in nonclinical testing requirements.

The symposium addressed four specific challenges: (1) discovery and optimization of combination peptide therapeutics, (2) toxicological requirements for peptide drug-device combination products (like auto-injectors), (3) regulatory classification disputes — are synthetic peptides drugs or biologics? — and (4) genotoxicity testing requirements, which may be unnecessary for many peptides but are still often required.

Why it matters

The peptide drug market is booming (GLP-1 agonists alone are projected to exceed $100 billion), but the regulatory path for bringing new peptides to market remains unclear. When regulators and companies disagree on whether a peptide should be regulated as a small molecule or a biologic, it can add years and millions to development timelines. Clarifying these rules would accelerate the pipeline of peptide therapeutics for diseases with unmet needs.

The numbers in context

40th Annual Meeting of American College of Toxicology (2019) · ICH M3(R2) and ICH S6(R1) guidelines discussed · 2016 HESI Genetic Toxicology Technical Committee assessment reviewed · Significant increase in peptide drugs in clinical development over the past decade

How the study worked

Summary of a symposium at the 40th Annual Meeting of the American College of Toxicology (November 2019), featuring industry and regulatory scientists presenting and discussing regulatory challenges for peptide therapeutics.

Who was studied

Not applicable (regulatory science symposium summary)

What this study cannot tell us

This is a symposium summary, not original research. It presents perspectives from a specific meeting rather than a systematic analysis of the regulatory landscape. Published in 2021, it predates the GLP-1 agonist market explosion and the FDA's 2023 peptide-specific guidance updates. Focuses primarily on US FDA regulation with limited international perspective.

How to read the evidence

This is a symposium summary and expert opinion piece, not primary research. It captures regulatory perspectives from industry and FDA scientists but doesn't present clinical data.

When this study was published

Published in 2021, based on a 2019 symposium. The regulatory landscape has continued to evolve, particularly with the massive commercial success of GLP-1 peptide drugs, which has likely accelerated regulatory attention to peptide-specific issues.

The bigger picture

The regulatory ambiguity described here has real consequences for patients. When it takes longer to get a peptide drug approved because the regulatory pathway is unclear, patients with unmet needs wait longer for treatment. As the peptide therapeutics market continues to explode — driven by GLP-1 drugs, antimicrobial peptides, and peptide-drug conjugates — the pressure to modernize regulatory frameworks will only increase.

Questions still open

Has the FDA updated its guidance for peptide therapeutics since this 2019 symposium, given the explosion of GLP-1 drugs?
Should there be a third regulatory category specifically for peptides, rather than forcing them into small molecule or biologic frameworks?
Do genotoxicity testing requirements for peptides need to be modernized based on the scientific evidence that most peptides pose minimal genotoxic risk?

Common questions

Why are peptide drugs so hard to regulate?

The FDA has two main sets of rules: one for small chemical drugs and one for large biological drugs (like antibodies). Peptides fall in between — they're made of amino acids like biologics but are often manufactured by chemical synthesis like small molecules. Different regulators and companies interpret which rules apply differently, leading to inconsistent requirements.

What's the difference between classifying a peptide as a drug vs. a biologic?

The classification determines which FDA center reviews the application, what safety testing is required, and how generic/biosimilar versions can be approved later. Biologic classification typically requires more extensive testing and creates different competitive dynamics. For the same peptide, classification can vary depending on whether it's made synthetically or biologically.

Read the original research

Development and Regulatory Challenges for Peptide Therapeutics.

International journal of toxicology, 40(2), 108-124

View on PubMed ↗Publisher’s paper ↗

Citation

Zane, Doris; Feldman, Paul L; Sawyer, Tomi; Sobol, Zhanna; Hawes, Jessica. (2021). Development and Regulatory Challenges for Peptide Therapeutics.. International journal of toxicology, 40(2), 108-124. https://doi.org/10.1177/1091581820977846