Cell and gene therapy is an exploding area of new technology and innovation in the pharmaceutical industry. Mapping of the human genome that led to discovery of pathways for intervention in disease states drives this innovation in drug development. Many of these discoveries are improving the prognosis of diseases that previously had no therapeutic intervention. As small molecules coupled to larger conjugates, these new therapies are targeted toward biological compartments that were inaccessible to large protein or monoclonal antibody drugs. Delivery systems as well as the active warhead often need separate methods for analysis. As more customized therapeutics and cell-specific therapeutics are developed for use in treating a variety of diseases, regulatory agencies are focusing more attention on guidance for industry. Recent discussions at scientific meetings have also offered guidance on laboratory methods to assess pharmacokinetic and pharmacodynamic data of oligonucleotides. Oligonucleotide therapeutics, such as single-stranded or double-stranded RNA, or DNA/RNA hybrids require additional analytical tools to assess concentrations in biological matrices, interference of metabolites, immunogenicity risk, and safety risk. Most of these therapeutic entities have modifications either to the backbone or conjugations to large molecules to improve bioavailability or biodistribution. Modifications for oligonucleotide therapeutics should not be considered inert. Oligonucleotides are small molecules; however, delivery systems and modifications introduce the complexity of large molecule bioanalysis. In addition to the analysis of the impact of these drugs on biological systems, the impact of linkers and conjugates must also be considered. Methods must be developed and validated to cover both active and putative inactive domains. This webinar will address developing and validating methods for oligonucleotide therapies. The focus will be on considering checkerboard strategies for initial development of methods, adjustments for complex and difficult matrices, and analyzing the impact of metabolites. We will consider the standard requirements for bioanalytical method development and validation and how those requirements fit with bioanalysis of oligonucleotides. Case studies will be presented supporting strategies for resolving issues observed with bioanalysis of oligonucleotide therapeutics.
Regulatory agencies are charged with confirming that therapeutic drugs are safe and effective. Data on critical pharmaceutical parameters are collected with validated methods. Pharmacokinetic and pharmacodynamic data is also required and needs validated methods. With limited regulatory guidance for cell and gene therapy drugs, sound scientific judgement is needed to develop and validate rugged assays for bioanalysis. Recent updates to guidance documents have addressed large molecule therapeutics but have not provided detailed information on regulatory expectations for oligonucleotide therapeutics. Even with several marketed drugs, there is still concern over consistency in bioanalysis. As more oligonucleotide therapies are submitted in regulatory filings, there can be uncertainty that laboratory practices to develop and validate rugged methods are appropriately harmonized with regulatory expectations. For some of these drugs, the oligonucleotide may be coupled to a large molecule to improve bioavailability and biodistribution. Since required methods may address bioanalysis of not just the active warhead but the linker and conjugate molecules, difficulties may arise that are unique to this drug class. This webinar addresses methodology to ensure validation of complex methods supporting bioanalysis of oligonucleotide therapeutics is consistent with typical regulatory expectations.
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