Applied Regulatory Science

Applied regulatory science research moves “new science” into the Center for Drug Evaluation and Research’s (CDER’s) review process, closing the gap between scientific innovation and product review by expanding CDER’s laboratory and computational research capabilities. The goal of this type of research is to develop laboratory data, data-based tools, best practices, and approaches to address immediate and emerging regulatory science issues.

The work of applied regulatory scientists directly impacts the development, evaluation, and use of new therapeutic products and also helps inform decisions made by CDER reviewers. These scientists also provide expert advice to CDER review divisions on preclinical and clinical aspects of pharmacology, toxicology, and drug exposure.

Below are a few examples of the many applied regulatory science research programs underway at CDER.

Use of the humanized mouse to uncover causes of human side effects


A mouse with a humanized immune system is created by removing the animal’s bone marrow cells and implanting human thymus and liver tissue under the kidney. Human stem cells that can become various kinds of immune cells are introduced into the blood stream. Within weeks, the mouse develops a functioning immune system that can produce many of the immune cells found in humans, including various kinds of antibody-producing B cells and T cells.

The biologic drug peginesatide was approved in March of 2012 to treat low blood cell counts due to chronic kidney disease. However, reports of a sometimes fatal immune reaction known as anaphylactic shock resulted in withdrawal of peginesatide from the market in 2013.

Anaphylactic shock is an exaggerated version of a normal immune process and activated white blood cells called mast cells and basophils release large amounts of histamine and other molecules that promote inflammation, leading to contraction of bronchial muscles, fluid leakage from blood vessels, and effects on heart muscle.

FDA researchers used mast cells isolated from rats and found that activation of these cells occurred only when the multi-use-vial formulation of peginesatide was used. Studying the individual drug components, they found that the common chemical preservative phenol was the cause of activation rather than the drug’s active ingredient.

Since mast cells are not found in the blood stream at appreciable levels and are not easily obtained from human subjects, researchers used the human immune system mouse model to confirm that phenol was indeed the immunogenic agent in human mast cells. Treating these cells with phenol caused rapid histamine release, confirming that it was an easily replaceable preservative and not the active ingredient of peginesatide that was causing the adverse events in patients.


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Drug-induced pancreatitis in animal models


Programmed cell death (apoptosis) of specialized pancreatic cells black staining was increased in mice administered the antidiabetic drug exenatide (right panel) compared with controls (left). Pre-clinical studies had not indicated that the drug could cause pancreatic injury; but CDER’s additional studies were motivated by adverse event reports of pancreatitis and pancreatic cancer in individuals treated with antidiabetic drugs acting on the glucagon-like peptide 1 receptor. Learn more.

Acinar cells are specialized cells in the pancreas that store and secrete digestive enzymes linked to pancreatitis. Working with mice maintained on different diets, FDA researchers used a variety of antibody-based staining methods and gene expression patterns to assess alterations in acinar cells following treatment with antidiabetic drugs. They found that:

  • Antidiabetic drugs caused programmed cell death in acinar cells
  • High-fat diet made cellular damage worse
  • Affected cells experienced marked changes in lipid metabolism and the tendency to proliferate

CDER researchers are further characterizing the usefulness of two small RNA molecules found in acinar cells as markers of cell damage. In a variety of animal models, these RNA molecules have been found to be sensitive and specific biomarkers of pancreatic cell injury. Developing biomarkers for a variety of drug toxicities for use in animal models is a major focus of FDA’s Drug Development Tools Program.


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Computational modeling to predict toxic effects

laptopA quantitative structure-activity and relationship (QSAR) model is an analytical tool that can interpret the measurable relationships between a molecule’s structure and its biological activities. QSAR models are used to predict toxicological outcomes, such as genetic toxicity, drug-induced liver injury, and carcinogenicity. Rodent carcinogenicity studies are required for the marketing of most chronically administered drugs in the United States. Two-year rodent carcinogenicity studies are the most costly of the required toxicology studies in both time and resources, and the outcome of these studies can significantly impact the marketability of a product. 

Early screening for a drug candidate’s carcinogenic potential using predictive models, like QSAR, can help prevent drug developers from pursuing candidates likely to fail rodent carcinogenicity studies. This may ultimately reduce the likelihood that compounds under development are carcinogenic in rodents, and can result in substantial savings for both industry and regulatory agencies. 

At CDER, applied regulatory scientists are developing a web-based interface to allow CDER safety reviewers the ability to search the agency’s online data repository of rodent carcinogenicity findings using structure-based and traditional queries. In addition, these data serve as training sets for a battery of QSAR models that have been developed and validated to predict the outcome of the 2-year rodent study. In combination, these tools provide a rapid means for safety review staff to assess the carcinogenic potential of components of drug products when observational data are limited.


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Page Last Updated: 05/05/2016
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