The advancement of next generation therapeutics, including oligonucleotides, cell therapies and gene therapies, to marketing authorization requires an understanding of developmental and reproductive toxicology (DART) to be included on the drug label. However, traditional DART approaches, including the route of administration, may be neither relevant nor feasible due to the complexity and novelty of these new medicines. Current regulatory guidance lacks clear advice on how best to evaluate DART and how to integrate traditional toxicology datasets to understand risk for reproductive potential or risk to a developing fetus for patients receiving these novel therapies. This symposium will discuss the challenges and potential strategies, including the feasibility of in utero dosing, to inform potential risk to patients receiving next generation drugs. Case studies will be presented to describe approaches that have been taken to derisk developmental and reproductive toxicity based on assessing route of administration, drug exposure, duration, genomic integration, and rare event analyses. Outcomes and interpretation of data will be discussed. Additionally, general considerations based on current FDA and EMA health authority policy for next generation therapies tested in DART studies will be presented.
For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects in vivo were carefully reported and used as a basis to calculate safety margins for drug candidates. To complement this time-consuming and costly assessment, gained insights into observed toxicity findings were translated into high-throughput in vitro enzymatic or cellular assays for the early detection of off-target activities or toxicity mechanisms in drug discovery. While these methods are invaluable for initial prioritization, the potential off-targets that can be monitored remain limited to hundreds, failing to account for the estimated 2,500 druggable proteins at risk across the entire proteome. In addition, they often fail in bridging toxicity observations between animal models and humans. As a result pharmaceutical companies are still faced with complex in vivo toxicity issues of which the mechanism, understanding of species relevance and translatability to humans is still hampered. In recent years, technological or NAMs (New Approach Methods) as AI/ML deep learning techniques, multi omics approaches in vitro and in vivo, high dimensional imaging and micro physiology systems are touted as game changers that promise to revolutionize pharmaceutical toxicology testing and address existing limitations in tackling in vivo toxicity challenges.
In this session, we will present an overview of the current technology landscape through case studies and explore the impact of ongoing technological advancements. The speakers will share real-world case studies that highlight difficulties encountered in traditional observational toxicology and examine whether the described technologies contribute to faster, safer, and more effective resolutions.
Educational Support Provided by: atai Life Sciences
Mental health concerns are rising globally. Psychedelics represent a novel treatment strategy for many of these disorders. This session will address the toxicity testing of psychoactive/psychedelic drugs by presenting examples of data-driven nonclinical toxicity testing by considering the specifics of the individual molecule, indication and treatment regimen. While psychedelics are a “hot topic” currently, the approach to thinking through the toxicology methods / regulatory strategy, is applicable to all novel molecules with activities that might compromise study execution. This symposium will focus on multiple different pharmacologies that are grouped into “psychedelic” and interrogate the overlap of pharmacologic on-target (dissociative) effects and toxic/ NOAEL dose levels. Speakers will address depression, anxiety, and opioid-use-disorder programs and individually focused on: A classical 5-HT2A psychedelic, A serotonergic-biased active enantiomer, and A non-serotonergic dissociative drug. In addition to the, the session will also address the CRO-side challenges of study execution and implantation of new methods to address questions of specific concern at the FDA. The session will then close with a panel discussion focused on the challenges and solutions different programs have found in the context of: Schedule 1 drug testing, different regulatory expectations around the world, the potential utility (or impediment) of historical information in the literature. The nonclinical safety assessment of these psychoactive drugs provides a great opportunity to look at the interplay of guidance documents, different global regulatory expectations, and drug-specific decisions around the appropriate studies and species for nonclinical safety testing.
This symposium will explore the evolving regulatory and scientific landscape surrounding new approach methodologies (NAMs), with a focus on the latest contributions from key industry organizations. Attendees will gain insights into the efforts of the Biotechnology Innovation Organization (BIO), the IQ Microphysiological Systems (MPS) Affiliate, the NC3Rs (National Centre for the Replacement, Refinement), and the European Federation of Pharmaceutical Industries and Associations (EFPIA) to advance the application of NAMs in research and regulatory frameworks. Highlights include case studies from the BIO NAMs Taskforce, showcasing the replacement of laboratory animals in regulatory filings, foundational work by the IQ MPS Affiliate on integrating MPS into drug development, and EFPIA’s recent publication on the progress and potential of NAMs. Additionally, the NC3Rs will present an overview of their collaboration with the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Association of the British Pharmaceutical Industry (ABPI) focused on integrating NAMs into the development of new medicines. This session will provide a comprehensive overview of industry initiatives driving innovation in NAMs.
Educational Support Provided by: Eli Lilly and Co., Inc.
The development of biologic therapeutics requires developmental and reproductive toxicity (DART) studies to support post investigational new drug (IND) development in clinical trials that include women of childbearing potential (WOCBP) and/or to reduce the intensity of contraceptive requirements. Non-human primates (NHPs) tend to be the only pharmacologically relevant species for most biologics and the latest shortage of monkeys poses timing and financial challenges for the industry. Other biologics may not have pharmacological activity in NHPs or any animal species. To mitigate the challenges and limitations, approaches on using transgenic mice and/or surrogate molecules to leverage the assessment of reproductive and developmental liability of biologics will be discussed. Experience of the speakers in the use of transgenic models or surrogate molecules for DART testing and regulatory acceptance worldwide. Presentations will include the preliminary work that is involved in establishing/characterizing a transgenic model or surrogate molecule including the timing and extent of the characterization of the model or molecule. The issue of sufficient Historical Control Data (HCD). The success or failure of the program. Were NHPs studies eventually conducted or still deemed necessary and the translation of the results to the product label. Perspectives from regulatory agencies and case studies from the pharmaceutical industry will be presented in this session.
This session is a companion to the ACT Symposium from 2017 “What to Do When Things Go Wrong” and 2019 “Keep Calm and Carry On: Challenging Case Studies”, where early career professionals will present case studies with unanticipated situations. Four professionals in different areas (consulting, industry, and regulatory) will state the issue they experienced, the impact of the issue, handling/management of the issue, and how this issue was resolved (either positively or not). This year we will hear from a pathologist that observed unexpected findings in control animals, a consultant derisking a nonclinical program with misidentified clinical observations that resulted in a clinical hold, a consultant performing risk assessments of heavy metals in feminine products, and an experienced toxicologist on challenges in drug review process. We will also have an open panel discussion with an industry veteran to answer questions about navigating as an early career professional. Audience engagement and questions are highly encouraged!
This Symposium is being presented in collaboration with the ACT Early Career Professional Subcommittee.