The FDA has recently issued this draft guidance to address clinical pharmacology considerations for peptide drug products. A peptide is any polymer with 40 or fewer amino acids. These products fall somewhere between drugs and biologics and do not have the usually well-defined characteristics of either category. Since these products share specific aspects of biologics and small molecule drugs, this new guidance provides specific recommendations to address the special characteristics of these drugs. These recommendations are within the framework of the existing regulations and reference several existing guidance documents as appropriate for both drugs and biologics.
The following topics are already covered under existing guidance documents:
- Bioanalytical method validation – the general requirements are the same as those for drugs, and the May 2018 guidance on bioanalytical method validation is referenced.
- Radiolabeled mass balance studies – These may not be recommended in some cases if the basic pharmacology and nonclinical ADME provides sufficient information.
- Renal impairment studies – these are recommended for proteins and peptides with molecular weight less than 69 kDa.
The following areas need to be specifically covered in an existing guidance document, and the current draft guidance provides recommendations on addressing these.
- Immunogenicity – A multitiered approach is recommended with assessment of risk as a first step, which should be assessed for all peptide drug products as described in the guidance for protein products. Peptides less than 8 amino acids may not require these studies and immunogenicity risk should be evaluated and discussed with the Agency. The effect of antibody titers and neutralizing antibodies on the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and clinical safety should be evaluated.
- Hepatic impairment is usually not a concern for peptides, and such studies are generally unnecessary. However, if nonclinical metabolism studies suggest a significant role of hepatic enzymes (>20 % hepatic metabolism) or when certain modifications to the peptide make it more susceptible to hepatic metabolism or excretion in bile, a dedicated hepatic impairment study may be needed. A Hepatic impairment study may also be recommended in certain situations, and the assessment of need for hepatic impairment study should be discussed with the Agency. Based on the pharmacology of the peptide drug, PD assessments should be included as appropriate.
- Drug interactions – Peptide drugs are usually not expected to be involved in pharmacokinetic drug interactions. Still, certain modifications to the peptide molecule may make them more susceptible to interact with enzymes and transporters. Peptide drugs are also known to be involved in PK-based drug interactions either by directly or indirectly modulating enzymes or transporters or based on the mechanism of action such as delay of gastric emptying. Some peptide drugs were found to be involved in PD-based drug interactions. The risk for each peptide drug to be involved in PK- or PD- based interactions should be evaluated and discussed with the Agency.
- QTc assessment – Peptides generally have a low likelihood for proarrhythmic risk, and a thorough QT study is not recommended unless nonclinical or clinical data suggests a high potential that needs further evaluation. The risk assessment should be completed and a proposed plan created according to ICH E14 guidelines and discussed with the Agency.
- Labeling considerations – The relevant recommendations in the existing guidance documents for drugs and biological products are applicable to peptide drug products. As with drug and biological products, the final prescribing information should include a summary of the appropriate clinical pharmacology information.
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