Overview
The biopharmaceutical industry and other stakeholders are pressuring the US Food and Drug Administration (FDA) to harmonize its regulatory guidelines for oligonucleotide-based therapies. The request aims to eliminate discrepancies in the development, manufacturing and approval requirements for these innovative treatments, which have shown great potential in the fight against various genetic and infectious diseases.
Introduction
Oligonucleotides are small nucleic acid sequences designed to modulate gene expression, offering a promising approach to the treatment of rare diseases, neurological disorders and cancer. However, the lack of uniformity in FDA guidelines has created challenges for companies in the sector, resulting in longer and more costly regulatory processes. Proponents of harmonization argue that standardizing guidelines would bring greater clarity for companies, reducing regulatory uncertainty and speeding up the development of new therapies. In addition, the adoption of consistent approaches could align US standards with those of other international agencies, such as the European Medicines Agency (EMA), facilitating the global approval of these therapies. Recently, industry associations, researchers and representatives of biopharmaceutical companies submitted comments to the FDA calling for greater regulatory alignment and more collaboration with international agencies. It is hoped that the FDA will take these considerations into account when updating its guidelines for oligonucleotide-based therapies, promoting a more favorable environment for innovation and scientific advancement. The harmonization of guidelines could represent a significant advance for patients awaiting new treatment options, ensuring that safe and effective therapies reach the market in a more agile and efficient manner.
FDA Publication:
In November, the FDA published a draft guidance on non-clinical safety assessments of oligonucleotide-based therapies (ONTs).
The document details expectations for pharmacological characteristics, pharmacokinetics and toxicity studies.
Stakeholders’ recommendations:
Several stakeholders have recommended that the FDA harmonize its guidance with international guidelines and a recent final guidance from the agency itself.
PhRMA’s position:
- It called on the FDA to harmonize its guidance globally, aligning itself with the work of the International Council on Harmonization (ICH).
- He highlighted recent ICH guidelines on non-clinical safety assessment of ONTs and a document under development on QTc and pro-arrhythmic risk.
- He argued that global standardization minimizes unique regional requirements, promoting more efficient supply chains and increasing patient access to medicines.
BIO’s position:
- Requested alignment of FDA guidance with ICH guidelines on clinical and non-clinical assessment of QT/QTc interval prolongation and proarrhythmic risk.
- It asked the FDA not to finalize its guidance before the adoption of the ICH S13 guideline on the non-clinical safety of ONTs.
AAM’s position:
- Representing manufacturers of generics and biosimilars, he pointed to uncertainties about how the guidelines would be applied to abbreviated applications for new drugs (ANDA).
- He pointed out that the guidelines did not seem to involve the Office of Generic Drugs (OGD).
- Requested specific guidelines for ANDAs, including recommendations for immunogenicity assessments and comparability of impurities.
- It expressed concern about challenges faced in clarifying the immunogenicity of peptides and wished to avoid similar problems with ONTs.
Harmonization with EMA:
- AAM has asked the FDA to harmonize its guidelines with the requirements of the European Medicines Agency (EMA).
- Requested alignment with the EMA’s draft guideline on the development and manufacture of ONTs, open for public consultation until January 31.
- It recommended that the FDA accept non-clinical immunogenicity evaluations for ONTs developed with recombinant DNA substances, ensuring the feasibility of submission via the ANDA route.
Further considerations
Off-target effects:
- The FDA highlighted concerns about off-target hybridization-dependent effects in ONTs.
- As ONTs can bind to untargeted RNA or DNA sequences, they can cause adverse effects not detected in toxicology studies.
- The FDA recommends off-target evaluations using appropriate in silico and in vitro methodologies.
Factors to take into account:
- ONT risk factor and sensitivity.
- ONT elements and their expected metabolites.
- Potential hybridization for transcriptome, nuclear and mitochondrial genome.
PhRMA recommendations:
- He asked the FDA to clarify that evaluations should focus on longer metabolites.
- He argued that short metabolites are less likely to have adverse effects.
- It recommended that sponsors have flexibility in deciding the relevance of hybridization to transcriptome and genome.
BIO’s position:
- It pointed out that many ONT metabolites do not have sufficient concentration for significant effects.
- It suggested that off-target hybridization assessments are only useful up to n-2 at the 3′ end, as long as there is no endonuclease-mediated cleavage.
A Risk-Based Framework for AI Credibility
The draft guidance introduces a risk-based framework for assessing and establishing the credibility of AI models. This involves defining the model’s context of use—how it addresses specific regulatory questions—and determining the activities required to validate its performance.
This framework is consistent with the FDA’s approach to reviewing drug and biological product applications that include AI components. Sponsors are encouraged to engage with the FDA early in the development process to discuss AI credibility assessments and applications.
Collaboration and Public Engagement
The draft guidance reflects input from a diverse range of stakeholders, including sponsors, manufacturers, developers, and academics.
It was informed by:
- An FDA-sponsored expert workshop held by the Duke Margolis Institute for Health Policy in December 2022.
- Over 800 comments from external parties on discussion papers published in May 2023.
- The FDA’s extensive experience with AI-driven regulatory submissions.
The FDA is now seeking public feedback on the draft guidance, with a 90-day window for comments. Stakeholders are invited to weigh in on how well the guidance aligns with industry experience and whether the proposed engagement options with the FDA are sufficient.
Other Issues Addressed by PhRMA:
- Requested that the FDA explicitly state that ONT tests in hERG trials are not recommended.
- He advocated the use of substitutes during the development of ONTs, in line with the 3Rs principles of toxicology (substitution, reduction and refinement).
- Requested flexibility for alternative tests without the use of animals.
- It recommended updating the criteria for determining the first dosage in humans.
Conclusion
Harmonization of FDA guidelines for oligonucleotide-based therapies is a growing demand among stakeholders in the biopharmaceutical industry. Regulatory standardization has the potential to reduce barriers in the development and approval of these innovative treatments, ensuring greater predictability for companies and accelerating the availability of new therapeutic options for patients. By considering the recommendations of PhRMA, BIO and AAM, the FDA can align its guidelines with global standards and promote a more efficient and innovation-friendly regulatory environment. Collaboration between regulators, industry and researchers will be key to ensuring that advances in oligonucleotide therapy are translated into concrete public health benefits.
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References
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