FDA Readies New Regulatory Efforts For Dose Optimization
U.S. Food and Drug Administration (FDA) regulators are planning to discuss new regulatory efforts to address dose optimization failures in drug development. Dose optimization is a frequent cause of FDA rejection of a drug approval application.
The FDA announced it will hold a public workshop on the application of physiologically based pharmacokinetic (PBPK) modeling for dose selection methods. The FDA said, “The purpose of the workshop is to obtain input on scientific approaches for the conduct and assessment of PBPK modeling within the framework of drug development and regulatory decision making.”
A high percentage of total drug application rejections by the FDA during the first review stage were attributed to dose selection related uncertainties. Dose optimization failure was deemed a more crucial factor than failure to meet primary endpoints, inconsistency in results, or comparatively poor efficacy, among others.
One example is Merck’s application for its sleeping pill suvorexant. The drug maker and the advisory committee differed on the proper dosage for elderly and non-elderly patients. The disarray over proper dose optimization eventually led to Merck’s receiving a Complete Response Letter (CRL) from the FDA.
PBPK modeling is defined by the FDA as “…a mathematical modeling technique for predicting drug behavior in humans. A PBPK model takes information about a drug’s physical, chemical, and other properties, as well as information about processes in the body, and turns them into mathematical equations to predict what will happen when a patient takes the medication.”
Key PBPK concerns that will be discussed include:
- Determining PBPK gaps in knowledge
- Appropriate PBPK simulation inclusion in drug labeling
- Determining the best format for PBPK simulation presentation in various sections in drug labeling
- Presentation of uncertainties in simulations in drug labeling
A concept paper on best PBPK practices and principles in drug development and regulatory reviews will be prepared from the public workshop, said the FDA.
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