Assessing CDERs Safety-Related Regulatory Science Needs and Identifying Priorities: Report and Request for Comments by May 18

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Assessing CDERs Safety-Related Regulatory Science Needs and Identifying Priorities: Report and Request for Comments by May 18

Author: Sherry Ward, AltTox

This report (March 2015; “Assessing CDERs Drug Safety Related Regulatory Science Needs and Identifying Priorities Report”) identifies drug safety-related regulatory science needs and priorities related to the mission of FDA’s Center for Drug Evaluation and Research (CDER) that would benefit from external collaborations and resources. FDA hopes to foster collaborations with external partners and stakeholders to help address these needs and priorities. This notice asks stakeholders conducting research related to these needs to describe that research and indicate their interest in collaborating with FDA to address safety-related research priorities.

Federal Register announcement:

Comments are due May 18, 2015.

The full announcement and the CDER report are available by searching for the following:

Seven CDER Drug Safety-Related Research Needs are identified in this report:

  1. Improve access to postmarket data sources and explore the feasibility of their use in safety signal analyses
  2. Improve risk assessment and management strategies to reinforce the safe use of drugs
  3. Evaluate the effectiveness of risk communications of drug safety information to health care providers and the public
  4. Improve product quality and design, manufacturing processes, and product performance relating to safety
  5. Develop and improve predictive models of safety in humans, including nonclinical biomarkers
  6. Improve clinical trial statistical analyses for safety, including benefit-risk assessment
  7. Investigate clinical biomarkers of safety, including standards for qualification

Details on specific topics of interest for research need #5, “Develop and Improve Predictive Models of Safety in Humans, including Nonclinical Biomarkers,” are expanded in the appendix as follows.

A. Improve Nonclinical Science Testing Paradigms to Predict Human Risk

  1. Evaluate and promote the use of models to assess organ-specific, drug-induced toxicities – Refer to CDER S&R Needs Section V.A.1.
  2. Develop methods for using nonclinical data to predict the safety of biologics – Refer to CDER S&R Needs Section V.A.2.
  3. Develop and validate models to predict allergic responses to small and large molecules – Refer to CDER S&R Needs Section V.A.1.

       In addition:

  • Develop additional tools to model kidney injury similar to the algorithms to monitor drug-induced liver injury that incorporate clinical observations such as Hy’s law
  • Improve the understanding of the pharmacokinetics of biologic molecules during pregnancy (e.g., determining exposure of the fetus to biologic products)
  1. Evaluate and promote the use of cell- and tissue-based assays
  • Develop and evaluate in vitro and non-mammalian methods for assessing developmental and reproductive toxicity, based, for example, on embryonic stem cells or embryo studies in non-mammalian species such as zebrafish
  • Develop and evaluate in vitro potency models to reduce animal use (e.g., the use of the botulinum toxin)
  • Develop and evaluate in vitro and in vivo assays capable of identifying carcinogenicity mechanisms relevant to human cancer so that such information can be incorporated into carcinogenicity assessments
  • Evaluate quantitative imaging (e.g., positron emission tomography, magnetic resonance imaging, computed tomography, etc.) and other advanced approaches (e.g., metabolomics) for identifying new biomarkers and predictors of safety

B. Develop and Evaluate the Utility of Mechanistic/Modeling Approaches

  1. Quantitative structure-activity models – Refer to CDER S&R Needs Section V.C.1.

       In addition:

  • Develop and implement approaches to link chemical structures and substructures to a wide range of information about product safety, disease targets, and toxicity mechanisms
  • Expand in silico disease/toxicity model development and quantitative structure-activity relationship model development (e.g., for predicting bacterial mutagenicity of drug impurities) and updating of content and training sets
  1. Pharmacometric models – Refer to CDER S&R Needs Section V.C.2., VII.B.
  2. Systems biology models – Refer to CDER S&R Needs Section V.C.3., IIA.4.

      In addition:

  1. Computational methods and in silico modeling
  • Develop simulation models for

o Clinical trials that can reveal interactions between drug or device effects, patient characteristics, and disease variables that influence outcomes

o Product life cycles and risk assessment

  • Develop computer models

o Of cells, organs, and systems to better predict product safety and efficacy

o To integrate pharmacokinetic, pharmacodynamic, materials science, or mechanistic safety data to predict clinical risk-benefit and to further assess postmarketing safety issues in different patient populations

  • Develop and apply data mining, knowledge building, and data visualization tools to inform computer model development, clinical risk prediction, and regulatory decision-making

o Develop/implement semantic text mining tools for extracting hidden relationships

o Develop/implement interaction mapping tools (nodes/edges, heat maps, etc.) for data visualization and exploration

  • Expand the cheminformatics toolkit to enable similarity searches of regulatory documents by structures and substructures
  • Identify computational approaches for rapid search and retrieval of data
  • Create an ontology for molecular toxic drug targets