U.S. Bioanalytical Methods Guidance Defines Three Levels of Validation

An FDA draft guidance on validating bioanalytical methods for evaluating drugs, their metabolites and biomarkers — techniques the agency calls “critical” for conducting successful clinical and nonclinical pharmacology studies — has been given a makeover 12 years after it was first issued.

The revised document, posted Sept. 12, is intended to assist sponsors of investigational new drugs, new drug applications, abbreviated NDAs, biologic licensing applications and supplements in developing bioanalytical method validation information used in human clinical pharmacology, bioavailability and bioequivalence studies that require pharmacokinetic or biomarker concentration evaluation. It also applies to bioanalytical methods used for nonclinical pharmacology/toxicology studies.

“Validation involves documenting, through the use of specific laboratory investigations, that the performance characteristics of a method are suitable and reliable for the intended analytical applications,” the updated guidance states. “The acceptability of analytical data corresponds directly to the criteria used to validate the method. For pivotal studies that require regulatory action for approval or labeling, such as BE or PK studies, the bioanalytical methods should be fully validated. For exploratory methods used for the sponsor’s internal decision making, less validation may be sufficient.”

The guidance defines and characterizes three types and levels of method validation:

• Full validation, which is important for analysis of a new drug entity;

• Partial validation, which evaluates modifications of confirmed bioanalytical methods; and

• Cross-validation, which compares validation parameters when two or more bioanalytical methods are used to generate data within the same study or across different studies.

The revised document also explains how bioanalytical validation parameters and principles apply to microbiological and ligand binding assays, which have “unique characteristics” of concern. In its discussion on biomarkers, the draft guidance focuses attention strictly on the validation of assays to measure in vivo biomarker concentrations in biological matrices, such as blood or urine.

“Method validation for biomarker assays should address the same questions as method validation for PK assays,” the FDA says.

For tech-savvy sponsors wishing to apply dried blood spot methodology, it is “essential” that validation is comprehensive and addresses a variety of issues such as storage and handling and stability. Because the method is not widely accepted, correlative studies with traditional sampling are encouraged, the agency says.

Coming this month: Implementing Risk-Based Verification and Validation. The FDA wants you to implement a risk-based system, if you haven’t already. Order your copy of this book now.