Important Recent Regulatory Science Initiative Updates from the US FDA Division of Applied Regulatory Science (DARS) 2021 Annual Report
Pragnesh Panchamvedi, RAC, ERT, DABT
Managing Toxicologist | Regulatory Toxicology | American & European Board Certified Toxicologist I New Approach Methodologies | Next Generation Risk Assessment | Regulations | Risk & Safety Assessment | Consulting
The Division of Applied Regulatory Science (DARS) is located within US FDA’s?Office of Clinical Pharmacology?and tackles emerging regulatory questions and develops and implements new regulatory review tools and approaches.
DARS closes the gap between scientific innovation and regulatory review.
Recently, the DARS published its 2021 annual report. Some of the interesting key highlights related toxicology reported by DARS are as below:
1) Computational pharmacology and toxicology
(Q)SAR Model Development
DARS is developing computational models that use chemical structure to predict drug adverse outcomes, also known as (Quantitative) Structure-Activity Relationship [(Q)SAR] models.
Models being developed include:
Impact of Expert Knowledge on Model Predictions
The current international guideline (ICH M7 [R1]) recommends using both (Q)SAR models and scientific expertise to assess how likely a drug impurity may lead to genetic mutations.
DARS conducted a study to evaluate whether expert review was always needed or for only certain cases. Decreasing the need for expert review would make the review process more efficient.??
Evaluating Nitrosamine Safety
DARS collaborated on the development of a computational method to identify comparators to nitrosamine drug substance-related impurities using chemical structure. This enables the evaluation of these impurities and provides information to support its regulatory limit in a drug product without laboratory toxicology data about the specific impurity. Results are being used to inform international harmonized policy for nitrosamine safety with regulatory authorities worldwide.
Quantitative Systems Pharmacology (QSP) Modeling
QSP is a computational model that characterizes biological and pharmacological systems. DARS is evaluating potential roles for QSP modeling to inform regulatory decision making.
Additionally, a database of QSP submissions was created to better understand current QSP modeling practices and identify opportunities for QSP in drug development.
2) Evaluating the safety of widely-used over-the-counter drugs
Does the Heart Burn Medication Ranitidine Convert to a Probable Carcinogen in Humans?
FDA received a citizen petition which proposed the common over-thecounter medication ranitidine could convert to a probable human carcinogen (NDMA) in humans. In response, DARS conducted a randomized, placebo-controlled clinical trial with a sensitive analytical method to measure NDMA in urine and blood. The DARS study, published in JAMA, found no evidence of elevated NDMA content in the urine or blood after participants were given ranitidine.?
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The results from the DARS clinical trial and additional in vitro studies do not support the conclusion that ranitidine converts to NDMA in humans.
These findings will inform whether FDA may consider allowing ranitidine products back on the market.
Are Sunscreen Active Ingredients Absorbed?
Pertaining to sunscreens (also a type of widely used over-the-counter product), historical assumptions posited that the active ingredients in sunscreens were not absorbed. While new data showed that sunscreens were absorbed, the?studies necessary for addressing this absorption issue?were not pursued until DARS initiatives led the way.
DARS conducted 2 clinical trials, both published in JAMA, that confirmed that sunscreen active ingredients can be absorbed and showed the feasibility of studies that FDA was requesting from industry.
3) Immunogenicity of Complex Generics and Biosimilars
Impurities associated with the synthesis of generic peptide drugs raise concerns about immunogenicity from these products. DARS is assessing methods to predict immunogenicity of peptide impurities using different types of nonclinical models. These methods can also be applied to other product categories, including biosimilars.?
4) Microphysiological systems and induced pluripotent stem cells
Liver Microphysiological Systems
Liver?microphysiological?systems (MPSs, also known as organ-on a-chip) were introduced over 10?years ago as promising tools for predicting liver drug effects. Yet?MPSs are still not routinely used in regulatory applications, in part due to a lack of criteria for ensuring reproducibility of results.?
DARS characterized a liver MPS with regards to reproducibility of toxicity, metabolism, and drug distribution results. Results indicate that the liver MPS can be used reproducibly in general drug evaluation applications. MPSs give drug developers another tool to test new therapies for patients with unmet needs.
Human Induced Pluripotent Stem Cells
Human induced pluripotent stem cells (iPSCs) are cells created in the lab. These cells can be any cell type found in the body, including heart and liver. Using iPSC-engineered heart cells, heart effects associated with different medications can be predicted as well as a medication’s effect on the heart of an individual patient based on their specific genes. DARS is also studying iPSC-engineered liver cells.?
DARS is studying how well these laboratory engineered heart and liver cells predict a medication’s effect in people and what standards are needed for them to be reproducibly used in regulatory applications.
5) Alternative methods
DARS is leading FDA efforts to advance the use of alternative methods (cell- and computer-based models) that have the potential to enhance safety and efficacy assessments and address the “3Rs” (replace, reduce and refine animal testing).
DARS is working to fill information gaps with applied research to advance new policy and guidance in this area.
This includes advancing standards, quality control criteria and best practices for different alternative methods technologies.
Reference: https://www.fda.gov/media/156610/download