PeptideJournal
Regulatory & Legal15 min read

Peptide Clinical Trial Regulation: IND Process

**Every FDA-approved peptide drug — from insulin to semaglutide to tirzepatide — started with the same application: an Investigational New Drug filing.

Every FDA-approved peptide drug — from insulin to semaglutide to tirzepatide — started with the same application: an Investigational New Drug filing. The IND is the gateway between laboratory research and human testing, and for peptide developers, it comes with a unique set of requirements that reflect both the promise and the complexity of peptide therapeutics.

Table of Contents

What Is an IND Application

An Investigational New Drug (IND) application is a formal request to the FDA for authorization to administer an investigational drug to humans. No new drug — peptide or otherwise — can enter clinical trials in the United States without an active IND.

The IND exists for one primary reason: to protect human subjects. Before anyone injects, swallows, or applies an experimental compound, the FDA needs to see enough evidence that the substance probably won't cause serious harm at the proposed dose.

The FDA receives between 1,500 and 2,000 new IND applications each year across all drug categories. Once submitted, the sponsor must wait 30 calendar days before beginning clinical trials. During that window, the FDA reviews the application for safety. If the agency identifies a problem, it can issue a "clinical hold" — an order to stop the trial before it starts.

If the FDA doesn't object within 30 days, the IND becomes active and the clinical trial can proceed. This isn't approval. It's permission to test.

Why Peptides Need Their Own Playbook

Peptides occupy a strange middle ground in pharmaceutical regulation. They're bigger than small-molecule drugs (think aspirin or metformin) but smaller than full-size proteins (think monoclonal antibodies). This in-between status creates specific regulatory challenges.

Size matters. The FDA defines peptides as polymers of 40 or fewer amino acids. Molecules with more than 40 amino acids are classified as proteins — and regulated as biologics under the Biologics Price Competition and Innovation Act (BPCIA). This distinction determines whether a developer files an NDA (for peptide drugs) or a BLA (for biologics). The pathways have different requirements, different exclusivity periods, and different implications for generic competition.

Stability is a persistent problem. Peptides degrade faster than small molecules. They're sensitive to temperature, pH, light, and enzymatic breakdown. This means the FDA pays close attention to how peptide drugs are manufactured, stored, and administered — and it expects developers to address stability challenges early in development.

Immunogenicity is a real risk. Because peptides are large enough to trigger immune responses but small enough to be rapidly cleared from the body, the FDA requires immunogenicity assessments for most peptide drug programs. A peptide that generates anti-drug antibodies could lose efficacy or, worse, cause serious allergic reactions.

Bioavailability varies dramatically by route. Oral peptides face enzymatic degradation in the gut and poor absorption across intestinal walls. Injectable peptides have good bioavailability but short half-lives. Nasal, transdermal, and subcutaneous formulations each come with their own pharmacokinetic considerations. The FDA expects developers to justify their chosen route of administration with data.

In 2024, the FDA issued specific guidance on clinical pharmacology considerations for peptide drug products, covering hepatic impairment studies, drug-drug interactions, QTc prolongation risk, and immunogenicity risk. This was the agency's clearest signal yet that peptides warrant their own regulatory framework within the broader IND process.

Before the IND: Preclinical Requirements

Before a peptide developer can file an IND, they need preclinical data demonstrating that the compound is reasonably safe to test in humans. This is where many peptide candidates fail — not because they lack efficacy, but because of pharmacokinetic limitations.

Pharmacology studies must demonstrate that the peptide has a plausible mechanism of action and produces the expected biological effect in relevant animal models. For a GLP-1 agonist, this might mean showing glucose-lowering and weight-loss effects in diabetic mouse models.

Toxicology studies must follow Good Laboratory Practice (GLP) standards. The FDA typically requires at least one study in a rodent species and one in a non-rodent species (often dogs or non-human primates for peptides). These studies define the no-observed-adverse-effect level (NOAEL), which helps establish the maximum recommended starting dose for human trials.

Pharmacokinetics and ADME (absorption, distribution, metabolism, excretion) studies characterize how the peptide behaves in the body. For peptides, half-life is often a primary concern — many natural peptides have half-lives measured in minutes. Developers must demonstrate either adequate natural half-life or successful modification strategies (PEGylation, lipidation, cyclization, or other stabilization approaches).

Manufacturing and analytical characterization must be sufficient to produce a consistent, well-characterized drug product. This feeds directly into the Chemistry, Manufacturing, and Controls (CMC) section of the IND.

The Pre-IND Meeting

The pre-IND meeting is one of the most strategically important steps in peptide development. It's a formal meeting with the FDA — usually a teleconference — where the sponsor presents its development plan and asks specific questions.

For peptide developers, the pre-IND meeting typically covers the proposed nonclinical program and whether it's adequate to support first-in-human dosing, the CMC strategy, including manufacturing process, analytical methods, and stability program, the proposed clinical trial design, including dose escalation strategy and safety monitoring, and any unique regulatory considerations specific to the peptide's mechanism or route of administration.

The FDA's Division of Metabolism and Endocrinology Products handles many peptide drug applications, while the Division of Gastroenterology handles GLP-1 agonists for metabolic indications. Knowing which division will review your IND matters because different divisions may have different expectations.

As of 2025, wait times for pre-IND meetings have stretched from 3 months to as long as 6 months, creating challenges for smaller biotech firms with limited capital. The FDA has acknowledged these delays and is exploring AI-assisted review processes to reduce bottlenecks.

The pre-IND meeting isn't required, but skipping it is risky. The cost of a poorly designed clinical program is orders of magnitude higher than the cost of a meeting.

Anatomy of a Peptide IND Submission

An IND submission has three major components, each with specific requirements for peptide drugs.

Section 1: The IND Application Forms

Three FDA forms are required. Form 1571 covers the study details — the sponsor, the drug, the proposed clinical protocol, and commitments to comply with IND regulations. Form 1572 (one per investigator) provides information about each investigator's qualifications and study site. Form 3674 certifies that the study is registered in ClinicalTrials.gov, the national clinical trial database.

Section 2: Chemistry, Manufacturing, and Controls (CMC)

This is often the longest and most complex section for peptide drugs. It covers everything about the drug substance and drug product — what it is, how it's made, how it's tested, and how it's stored. (More on this below.)

Section 3: Pharmacology and Toxicology Data

This section presents all preclinical study results. For a peptide IND, it must include the pharmacological profile (mechanism of action, dose-response relationships, and pharmacodynamic effects), GLP-compliant toxicology studies in at least two species, pharmacokinetic data including half-life, clearance, volume of distribution, and bioavailability, and immunogenicity data from preclinical species, if available.

Section 4: Clinical Protocol

The proposed clinical trial protocol must include the study objectives, patient population and inclusion/exclusion criteria, dosing strategy (with justification from preclinical data), safety monitoring plan including stopping rules, and data collection and statistical analysis plans.

CMC Requirements for Peptides

The CMC section deserves its own discussion because peptide drugs face scrutiny here that small molecules don't.

Drug substance characterization for peptides must include the amino acid sequence (confirmed by mass spectrometry and sequencing), peptide purity (typically >95% by HPLC for clinical-grade material), identification and quantification of process-related impurities (truncated sequences, deletion sequences, racemized amino acids), characterization of degradation products, and for modified peptides, characterization of modifications (PEGylation, lipid conjugation, disulfide bonds).

Manufacturing process description must detail the synthetic route (solid-phase peptide synthesis, recombinant expression, or hybrid approaches), purification strategy (typically reverse-phase HPLC), quality control testing at each step, and GMP compliance of the manufacturing facility.

Stability data must demonstrate that the peptide remains within specification during the proposed shelf life. The FDA expects accelerated stability studies (elevated temperature and humidity) and real-time stability data. For peptides, degradation pathways often include oxidation of methionine residues, deamidation of asparagine, aggregation, and cleavage at labile bonds.

Drug product formulation must address excipient selection (all excipients should be listed in the FDA's Inactive Ingredient Database), the chosen delivery system (vials for injection, prefilled syringes, auto-injectors, tablets for oral peptides), and compatibility between the peptide and the container closure system.

The FDA's expectations for CMC data increase as development progresses. At the IND stage, a "phase-appropriate" level of characterization is acceptable. By NDA submission, the CMC package must be comprehensive.

The Clinical Trial Phases

Once the IND is active, clinical development follows a well-established sequence.

Phase I: Safety and Dosing

Phase I trials are the first test in humans. They typically enroll 20 to 80 healthy volunteers (or patients with the target condition, for serious diseases). The goals are to establish that the peptide is safe at therapeutic doses, determine the pharmacokinetic profile in humans, identify the maximum tolerated dose, and detect any dose-limiting toxicities.

For peptide drugs, Phase I often includes single ascending dose (SAD) and multiple ascending dose (MAD) studies. Immunogenicity monitoring begins here — blood samples are collected to check for anti-drug antibodies.

Phase I typically takes 6 to 12 months. About 63% of drugs that enter Phase I eventually advance to Phase II, but only about 14% of drugs that enter Phase I will ultimately receive FDA approval.

Phase II: Efficacy Signals

Phase II trials enroll 100 to 300 patients with the target condition. These studies test whether the peptide actually works — whether it produces a measurable clinical benefit at tolerable doses. Phase II also refines the dosing strategy and identifies the most promising dose(s) for Phase III.

The STEP trials for semaglutide and the SURMOUNT trials for tirzepatide both generated massive Phase II datasets that shaped the Phase III programs and ultimately led to FDA approval.

Phase II typically takes 1 to 2 years. The dropout rate is steep — roughly 33% of Phase II candidates advance to Phase III.

Phase III: Confirmatory Trials

Phase III trials are the large, confirmatory studies that the FDA relies on for approval decisions. They typically enroll 1,000 to 5,000 patients (sometimes more) and compare the peptide drug against placebo or an active comparator.

These trials must demonstrate statistically significant and clinically meaningful efficacy, establish the safety profile in a large population, and provide enough data to write the drug label (dosing, contraindications, warnings, adverse reactions).

Phase III is the most expensive phase — a single trial can cost $50 million to $200 million. About 58% of drugs that enter Phase III eventually receive FDA approval.

For peptide drugs, Phase III trials also generate the immunogenicity data the FDA needs to assess long-term safety. The development of neutralizing antibodies against a peptide drug can reduce efficacy over time, which is why long-term follow-up data is increasingly important to the agency.

Accelerated Pathways for Peptide Drugs

Not every peptide drug has to follow the standard 10-to-15-year development timeline. The FDA offers four expedited programs that can apply to peptide therapeutics.

Fast Track designation is available for drugs that treat serious conditions and fill an unmet medical need. It provides more frequent meetings with the FDA and the option for rolling review (submitting completed sections of the NDA as they're finished, rather than waiting for the entire package).

Breakthrough Therapy designation is for drugs that show substantial improvement over existing treatments. It provides all Fast Track benefits plus intensive FDA guidance on the development program.

Accelerated Approval allows the FDA to approve drugs for serious conditions based on surrogate endpoints — biomarkers that are reasonably likely to predict clinical benefit but haven't been fully confirmed. The drug can reach market faster, but the sponsor must conduct confirmatory post-marketing studies. Several peptide drugs have used this pathway.

Priority Review shortens the FDA's review period from 10 months to 6 months. It's available for drugs that offer significant improvements in the safety or effectiveness of treatment.

Tirzepatide (Mounjaro/Zepbound) received Fast Track designation for its type 2 diabetes indication. Retatrutide, the triple GLP-1/GIP/glucagon agonist currently in Phase III trials, is also advancing through an expedited pathway.

From IND to Approval: The NDA or BLA

After Phase III, the sponsor compiles all data into a New Drug Application (NDA) for peptide drugs (40 or fewer amino acids) or a Biologics License Application (BLA) for larger protein therapeutics.

The NDA includes the complete safety and efficacy data from all clinical trials, the final CMC package covering manufacturing, quality control, and stability, proposed labeling (prescribing information, patient information, medication guides), a risk management plan (Risk Evaluation and Mitigation Strategy, or REMS, if required), and post-marketing study commitments.

The FDA reviews the NDA over 10 months (standard review) or 6 months (priority review). The review is multidisciplinary — medical officers, pharmacologists, chemists, statisticians, and other specialists each evaluate their respective sections.

An FDA Advisory Committee meeting may be convened for the agency to seek outside expert input. The advisory committee votes on whether the drug should be approved, but the FDA isn't bound by the vote.

If approved, the drug receives a specific indication (or indications), and the labeling defines exactly how it can be marketed. The sponsor can then seek additional indications through supplemental NDAs.

The Current State of Play: 2025-2026

Several developments are reshaping the peptide IND process.

AI-assisted review. FDA Commissioner Robert Califf's successor, Dr. Marty Makary, has introduced artificial intelligence tools to streamline the review process. The FDA completed a pilot program using generative AI to assist reviewer workstreams. This could reduce review times for INDs, though the exact impact on peptide applications remains to be seen.

Reduced animal testing. The FDA Modernization Act 2.0 (signed in December 2022) allows sponsors to use alternative methods to animal testing — including organ-on-a-chip technology, computational models, and human cell-based assays — to support IND applications. Commissioner Makary has announced plans to further reduce animal safety testing requirements, though the specific alternative study designs that will be accepted haven't been fully defined.

Pre-IND meeting delays. Wait times for pre-IND meetings have stretched to 6 months in some cases, creating cash-flow problems for smaller biotech companies. The FDA has acknowledged the delays and is working to expand capacity.

Increased peptide IND activity. The peptide therapeutics market is projected to reach nearly $50 billion in 2026. The GLP-1 agonist market alone is expected to hit $73.86 billion. This growth is driving a wave of new IND filings for next-generation GLP-1 drugs, multi-agonist peptides (like retatrutide), oral peptide formulations, and peptide-drug conjugates for oncology.

Compounding enforcement driving formal development. The FDA's crackdown on peptide compounding is pushing companies that previously relied on the compounding pathway to pursue formal drug development. This means more IND filings for peptides that were previously available through compounding pharmacies — though most of these are years away from approval.

In 2025, the FDA approved 46 novel drugs, including one new peptide therapeutic and three oligonucleotides (a related class often grouped with peptides as "TIDES"). The pipeline of peptide candidates in clinical trials continues to grow.

FAQ

How long does it take to get an IND approved?

The FDA has 30 days to review an IND after submission. If the agency doesn't place a clinical hold during that period, the IND becomes active and the sponsor can begin clinical trials. However, getting to the point of IND submission typically requires 2 to 4 years of preclinical work. The entire process from IND to NDA approval averages 10 to 15 years, though accelerated pathways can shorten this.

How much does it cost to develop a peptide drug through the IND process?

Estimates vary, but developing a new drug from discovery through FDA approval averages $1 to $2 billion when you account for the cost of failed candidates. A single Phase III clinical trial for a peptide drug can cost $50 million to $200 million. The CMC development alone — including manufacturing process development, analytical method validation, and stability testing — can run $10 million to $50 million.

Can a peptide that's already been compounded skip preclinical testing?

No. The fact that a peptide has been available through compounding pharmacies doesn't exempt it from the IND process. The FDA requires the same preclinical safety data regardless of a compound's history in compounding. In practice, some preclinical literature may be available for widely used peptides like BPC-157 or thymosin alpha-1, but the sponsor would still need GLP-compliant studies in the specific formulation intended for clinical use.

What happens if the FDA puts a clinical hold on a peptide IND?

A clinical hold stops all clinical activities under the IND. The sponsor cannot enroll new patients or dose existing patients (in most cases). The FDA issues a clinical hold letter explaining the deficiencies. The sponsor must address all concerns and submit a response. The FDA then has 30 days to lift or maintain the hold. Clinical holds are relatively rare — the FDA places holds on about 5-10% of new INDs.

Are peptide biosimilars possible?

For peptides with 40 or fewer amino acids, the traditional generic drug pathway (ANDA under the Hatch-Waxman Act) applies, not the biosimilar pathway. Generic peptide drugs must demonstrate pharmaceutical equivalence and bioequivalence to the reference product. For larger peptide-like molecules classified as biologics, the biosimilar pathway under the BPCIA applies. As of 2025, generic liraglutide (a GLP-1 agonist) has entered the market following patent expiration.

How are clinical trials for peptides different from small molecule trials?

Peptide clinical trials typically require immunogenicity monitoring (testing for anti-drug antibodies at regular intervals), injection site reaction assessments (for injectable formulations), more intensive pharmacokinetic sampling (because peptide half-lives can be short and variable), and specialized bioanalytical methods (ligand-binding assays rather than the mass spectrometry methods used for small molecules). The trial designs are similar, but the safety monitoring plans are more extensive.

The Bottom Line

The IND process is the only legitimate pathway for getting a therapeutic peptide from the laboratory to the pharmacy. It's expensive, slow, and designed to be rigorous — because the alternative is letting untested compounds into human bodies.

For the peptide industry, the IND process is becoming more important, not less. As the FDA restricts compounding and tightens enforcement against unapproved peptide products, formal drug development is the only path forward for companies that want to bring peptide therapies to market legally. The growing pipeline of peptide candidates in clinical trials — from oral semaglutide formulations to triple-agonist peptides — shows that the industry is responding.

For patients, understanding the IND process helps set realistic expectations. When a peptide is described as "in clinical trials," that means it has cleared the preclinical bar and the FDA has allowed human testing — but it's still years away from being available as an approved medication. And when someone is selling a peptide that has never been through the IND process, that should be a red flag about both legality and safety.

References

  1. FDA. "Investigational New Drug (IND) Application." U.S. Food and Drug Administration. https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application

  2. FDA. "Clinical Pharmacology Considerations for Peptide Drug Products." U.S. Food and Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-pharmacology-considerations-peptide-drug-products

  3. NIH Clinical Center. "What Is an IND?" National Institutes of Health. https://www.cc.nih.gov/orcs/ind/what-is-an-ind

  4. PMC. "Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators." Clinical and Translational Science. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435682/

  5. FDA. "Implementation of the Biologics Price Competition and Innovation Act of 2009." https://www.fda.gov/drugs/guidance-compliance-regulatory-information/implementation-biologics-price-competition-and-innovation-act-2009

  6. PMC. "2024 FDA TIDES (Peptides and Oligonucleotides) Harvest." Pharmaceuticals. https://pmc.ncbi.nlm.nih.gov/articles/PMC11945313/

  7. FDA. "Guidance for Industry: IND Meetings for Human Drugs and Biologics; Chemistry, Manufacturing and Controls Information." https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ind-meetings-human-drugs-and-biologics-chemistry-manufacturing-and-controls-information

  8. eCFR. "21 CFR Part 312 — Investigational New Drug Application." https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312

  9. Premier Research. "CMC Considerations for Pre-IND Meetings." https://premier-research.com/perspectives/cmc-considerations-for-pre-ind-meetings/

  10. ScienceDirect. "Therapeutic peptides: Historical perspectives, current development trends, and future directions." Bioorganic & Medicinal Chemistry. https://www.sciencedirect.com/science/article/pii/S0968089617310222