FDA finalizes guidance for hepatitis B drug development

Regulatory NewsRegulatory News | 11 April 2022 |  By 

The US Food and Drug Administration (FDA) has finalized its guidance on developing drugs to treat chronic hepatitis B virus (HBV) infection.

The final guidance, issued on 06 April 2022, covers development starting with the initial investigation new drug application (IND), through the new drug application (NDA)/biologics license application (BLA), and the postmarketing period. The document finalizes draft guidance issued in November 2018. (RELATED: Hepatitis B Virus Drug Development: FDA Offers Draft Guidance, Regulatory Focus 01 November 2018)

The guidance includes considerations for nonclinical and early phase clinical development considerations, efficacy and safety in Phase 3 trials, patient-reported outcome measures, and special populations. The guidance does not address development of vaccines or blood-derived products. 

Changes in the final document include considerations and recommendations related to:
  • Studies evaluating oligonucleotide-based investigational drugs
  • Drugs developed to modulate innate and adaptive immune responses
  • Updates to trial design considerations
  • Updates to recommendations for safety monitoring
  • Updates to efficacy extrapolation from adult to pediatric patients
Oligonucleotide-based investigational drugs, which seek to knockdown viral protein expression, are an active area of antiviral drug development, FDA noted in the guidance. However, these drugs have the potential for toxicities that may not be detected in toxicology studies. The agency recommended that developers conduct sequence dependent off-target assessments using appropriate in silico and in vitro methodologies to identify potential off-target mismatches that can be investigated and potentially monitored during clinical development. An overall risk assessment of potential off-target effects should be provided with the off-target assessment data, FDA wrote.

“The Division recognizes that many additional factors, such as temporal and cell type specific expression, pharmacokinetic (PK) properties, and hybridization-dependent efficiencies may be considered in the overall risk assessment of potential off-target effects,” FDA wrote in the final guidance.

For drugs developed to modulate innate and adaptive immune responses, FDA suggested that nonclinical studies describe the specific mechanism of action of the drug and demonstrate that immune modulation in cell culture and animal models of HBV infection results in suppression of HBV replication or that the HBV covalently closed circular viral DNA (cccDNA) reservoir is reduced.

For efficacy extrapolation from adult to pediatric patients, FDA said this should be approached on a “case-by-case basis” since the dynamic relationship between viral replications and the host immune response in pediatric patients may differ from adults. When extrapolation of efficacy is possible, developers can focus on identifying dosing regimens that achieve pediatric exposures similar to adults. Additional clinical data is needed to assess if antiviral activity in pediatric patients is comparable to what has been observed in adult trials. “Early discussion with the FDA on the appropriate endpoints and pediatric trial design is encouraged,” the agency wrote.

The final guidance also noted that HBV DNA suppression, with or without HBsAg loss, is considered a validated surrogate endpoint that can be used to support a traditional approval. Drug sponsors who want to use any other surrogate endpoints to support an accelerated approval should discuss those plans with the FDA, according to the guidance.

Final guidance on chronic HBV infection drug development


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