FDA issues draft guidance of clinical pharmacology, labeling considerations for peptide drug products

The US Food and Drug Administration (FDA) has released a draft guidance outlining the agency’s clinical pharmacology and labeling considerations for peptide drug products.

When finalized, the guidance will represent the agency’s thinking on development programs for new drug application (NDA) peptide drug products. “The intent of this draft guidance, when finalized, is to assist industry in the conduct of these development programs,” FDA wrote on the agency’s webpage for the draft guidance.

The draft guidance follows the publication last year of a set of concept papers from the European Medicines Agency (EMA) proposing quality guidelines for manufacturing synthetic peptides and oligonucleotides (RELATED: EMA proposes quality guidelines for synthetic peptides and oligonucleotides, Regulatory Focus 22 September 2022).

FDA noted that because some peptide drug products are similar to small-molecule drugs and biologics, several guidelines that technically apply to peptide product development already exist, such as a final guidance on bioanalytical method validation. In addition, FDA recommends against performing radiolabeled mass balance studies for peptide drug products with “known metabolism and elimination pathways,” while studies that evaluate renal impairment on pharmacokinetics should be conducted for proteins and peptides weighing less than 69 kilodaltons (kDa).

According to the draft guidance, all peptide drug products should undergo an immunogenicity risk assessment, which FDA said is “similar to therapeutic proteins and involves understanding certain product-specific factors” such as molecular size and structure, process-specific factors, subject-specific factors, and study design and product use factors.

The agency noted that the risk factors for the immunogenicity of peptide drug products align with a 2014 final guidance on assessing immunogenicity for therapeutic protein products. FDA said sponsors should use the scientific principles outlined in the 2014 final guidance and a 2019 final guidance on detecting anti-drug antibodies (ADAs) in therapeutic protein products to conduct a “multitiered clinical immunogenicity assessment.” Generally, the need for multiple assays may be dictated by the product’s immunogenicity risk, the agency said.

Regarding clinical impact analyses, FDA said a peptide drug product clinical immunogenicity assessment should evaluate how ADA could impact the product’s pharmacokinetics, pharmacodynamics, efficacy, and safety, with further evaluation in these areas for individuals who are ADA positive.

While hepatic metabolism “rarely plays a significant role in the clearance of peptides,” FDA acknowledged recent evidence that hepatic impairment could play a role in the pharmacokinetics of certain peptide drug products. They noted a hepatic impairment assessment may be appropriate for peptide drugs “substantially metabolized by liver enzymes,” cyclic peptides susceptible to being substantially metabolized by liver enzymes, products eliminated through biliary excretion, those conjugated with a lipid group, developed with the liver as a target organ in the indication, have “target-mediated drug disposition,” and for drugs being developed for diseases where hepatic impairment is a risk.

The agency noted that sponsors should discuss hepatic impairment early to identify an appropriate approach for a hepatic impairment assessment.

“For peptide drug products being developed for this population, the sponsor should assess the need for performing a hepatic impairment assessment and provide adequate justification for not performing an assessment based on the characterization of the peptide drug product,” FDA wrote.

For drug-drug interactions, sponsors should consider pharmacokinetic interactions, such as products that are substrates for human cytochrome P450 (CYP) enzymes and/or are inhibitors and inducers of CYP enzymes and transporters.

While this is not a common occurrence, FDA said there “are cases when peptide drug products can be substrates of certain peptide transporters or amino acid transporters and could be subject to drug interactions.”

Sponsors should also be aware of any pharmacodynamic interactions, such as when vasopressin is used concomitantly with catecholamines, which can have “an additive effect on mean arterial pressure and other hemodynamic parameters.”

If appropriate, QTc prolongation risk and proposed QTc assessment plans should also be submitted to the agency. “Peptides comprised of only naturally occurring amino acids have a low likelihood of direct ion channel interactions, and a thorough QT study is generally not scientifically warranted unless the potential for proarrhythmic risk is suggested by mechanistic considerations or data from clinical or nonclinical studies,” the agency wrote.

Regarding labeling, peptide drug products that “are primarily metabolized by proteolytic or hydrolytic enzymes” should contain a statement that the drug “is expected to be metabolized into small peptides by catabolic pathways.”

Information on the drug’s interaction with CYP inhibitors or inducers is not necessary, but the label should contain immunogenicity information.

“In general, the labeling for peptide drug products that are less than eight amino acids that are without concerns for impurities and/or aggregates do not need to include immunogenicity information because an immunogenicity assessment would likely not be relevant to the assessment of a drug's safety and effectiveness,” FDA wrote.

FDA is accepting comments on the guidance until 11 December 2023 at https://www.regulations.gov/docket/FDA-2023-D-3391.

Draft guidance

FDA issues draft guidance of clinical pharmacology, labeling considerations for peptide drug products

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