CRYSTAL CITY V REDUX: GUIDANCE FOR INDUSTRY BIOANALYTICAL METHOD VALIDATION DRAFT GUIDANCE (2013) VI. ADDITIONAL ISSUES DELAWARE VALLEY DRUG METABOLISM DISCUSSION GROUP STEVE PICCOLI, BMS RAND JENKINS, PPD FEBRUARY 06, 2014
Vitruvian Man c.1490 Leonardo da Vinci
Yellow highlight pertains to biomarkers.
I. INTRODUCTION This guidance provides assistance to sponsors of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologic license applications (BLAs), and supplements in developing bioanalytical method validation information used in human clinical pharmacology, bioavailability (BA), and bioequivalence (BE) studies that require pharmacokinetic (PK) or biomarker concentration evaluation. This guidance also applies to bioanalytical methods used for nonclinical pharmacology/toxicology studies. (Lines 18-23)
II. BACKGROUND Selective, sensitive, and validated analytical methods for the quantitative evaluation of drugs and their metabolites (analytes) and biomarkers are critical for the successful conduct of nonclinical and/or biopharmaceutics and clinical pharmacology studies. Validating bioanalytical methods includes performing all of the procedures that demonstrate that a particular method used for quantitative measurement of analytes in a given biological matrix (e.g., blood, plasma, serum, or urine) is reliable and reproducible for the intended use. (Lines 59-64)
II. BACKGROUND VALIDATION 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. (Lines 76-78)
V. INCURRED SAMPLE REANALYSIS Expected for all in vivo human BE studies, all pivotal PK or PD studies; nonclinical safety for nonclinical safety studies, ISR 1X for each method and species Total ISR is 7% of the study sample size Coverage of PK profile in its entirety and assessments around C max and elimination phase Two-thirds (67%) of repeated sample results should be within 20% (small molecule) or 30% (large molecule) of original values
VI. ADDITIONAL ISSUES A. Endogenous Compounds B. Biomarkers C. Diagnostic kits D. New technologies
Anderson NL, Anderson NG. Mol. Cell. Proteomics. 1.11, 845-867 (2002)
VI. ADDITIONAL ISSUES A. Endogenous Compounds Applicable only to therapeutic compounds? Biological matrix used to prepare calibration standards should be the same as the study samples and free of the endogenous analyte Use of alternate (i.e. surrogate) matrices is generally not recommended, or if justified, should have no matrix effect when compared to the study samples QCs should account for the endogenous analyte concentrations in the biological matrix (i.e. additive) and be representative of the expected study concentrations
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VI. ADDITIONAL ISSUES (CONT.) B. Biomarkers Recommendations pertain only to validation of assays to measure in vivo biomarker concentrations in biological matrices such as blood or urine. Biomarkers can play important roles in evaluating the safety and/or effectiveness of a new medical product, and it is critical to ensure the integrity of the data. Biomarkers are used for a wide variety of purposes during drug development; therefore, a fit-for-purpose approach should be used when evaluating the extent of method validation that is appropriate. Biomarker definitions per Qualification Process for Drug Development Tools (FDA/CDER, January 2014)
FDA QPDDT GUIDANCE (JANUARY 2014) A biological marker or biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention. * A biomarker can be a physiologic, pathologic, or anatomic characteristic or measurement that is thought to relate to some aspect of normal or abnormal biologic function or process. * Biomarkers Definitions Working Group (2001). Clinical Pharmacology and Therapeutics, 69, p. 89 95.
FDA QPDDT GUIDANCE (2014) For purposes of this guidance, biomarkers that can be used in the process of drug development and considered for qualification include, diagnostic, prognostic, predictive, and pharmacodynamic biomarkers, as briefly described below. Of note, these categories are not mutually exclusive; that is, a biomarker could fit into more than one category. FDA QPDDT Guidance (2014)
FDA QPDDT GUIDANCE (2014) A diagnostic biomarker is a disease characteristic that categorizes a person by the presence or absence of a specific physiological or pathophysiological state or disease. A prognostic biomarker is a baseline characteristic that categorizes patients by degree of risk for disease occurrence or progression of a specific aspect of a disease. A prognostic biomarker informs about the natural history of the disorder in that particular patient in the absence of a therapeutic intervention. It can be used as an enrichment strategy to select patients likely to have clinical events of interest or to progress rapidly.
FDA QPDDT GUIDANCE (2014) A predictive biomarker is a baseline characteristic that categorizes patients by their likelihood of response to a particular treatment relative to no treatment. A predictive biomarker can be used as an enrichment strategy to identify a subpopulation likely to respond to a treatment intervention in a particular way. It may predict a favorable response or an unfavorable response (i.e., adverse event). A pharmacodynamic (or activity) biomarker is one for which a change in the biomarker shows that a biological response has occurred in a patient who has received a therapeutic intervention and for which the magnitude of the change is considered pertinent to the response. A pharmacodynamic biomarker may be treatment-specific or more broadly informative of disease response.
VI. ADDITIONAL ISSUES (CONT.) When BM data will be used to support regulatory action, such as pivotal safety and/or efficacy or labeled dosing instructions, the assay should be fully validated For early drug development (e.g., candidate selection, gono-go decisions, POC), the sponsor should determine the extent of BM method validation
VI. ADDITIONAL ISSUES (CONT.) Method validation for biomarker assays should address the same questions as method validation for PK assays. Accuracy Precision Selectivity Range Reproducibility Stability Approach for PK assays should be the starting point for validation of BM assays; FDA realizes that some characteristics may not apply or different considerations may need to be addressed.
NGAL Rapid ELISA Kit CE IVD An ELISA for the determination of human NGAL in urine or plasma as a marker of acute renal injury which may lead to acute renal failure
VI. ADDITIONAL ISSUES (CONT.) C. Diagnostic Kits Does not apply to POC patient Dx [CDRH; i.e., PMAs and 510(k)s] but only to analytical methods used during drug development Does not apply to CLIA-regulated entities or to assays designed to quantify/identify genes or genetic polymorphisms Manufacturer data may not ensure reliability to support drug development, as the kits are designed to show presence, severity and progression of disease (CLIA)
VI. ADDITIONAL ISSUES (CONT.) Use of commercial Dx kit for BM, drug, or Tx biologic recommendations: LBA kits used in PK/PD must demonstrate sufficient precision and accuracy Dx kit manufacturer validation may not ensure reliability in DD Site-specific validation (specificity, accuracy, precision, stability) under conditions of use Sparse calibration standards (one- or two-point) should be further validated Actual QC concentrations should be known; ranges not sufficient
VI. ADDITIONAL ISSUES (CONT.) Use of commercial Dx kit for BM, drug, or Tx biologic recommendations: QCs with known concentrations must be prepared and tested independent of the kit supplied QCs Standards and QCs should be in sample matrix Reference standard vs. endogenous analyte (e.g. isoforms) should be evaluated If multiple kit lots, lot-to-lot variability and comparability should be addressed for critical reagents Batches (e.g. ELISA) should include sufficient replicate QCs on each plate to monitor accuracy; predetermined individual plate and run acceptance criteria
Schematic of the Exactive Plus EMR
VI. ADDITIONAL ISSUES (CONT.) D. New Technologies Encouraged, but should be supported by established technology until new approach becomes accepted practice DBS is not yet widely accepted; comprehensive validation will be essential Storage and handling temperature Homogeneity of sample spotting Hematocrit Stability Carryover Reproducibility (ISR) Correlative studies with traditional sampling Sponsors are encouraged to seek feedback from the appropriate FDA review division early in drug development.
RECOMMENDATIONS FOR BIOMARKER ASSAYS AND DIAGNOSTIC KITS Outcomes summarized by Russell Weiner from Session VI. New Issues Speakers/Panelists/FDA Working Group
FOCUS ON KEY ISSUES Non-FDA approved biomarker assays In-house developed, commercial kits, research use only (RUO), lab developed tests (LDTs) Definitive Quantitative Relative Quantitative Dealing with QCs FDA approved Dx kits
GUIDING PRINCIPLE When biomarker data will be used to support EFFICACY (not safety) or labeled dosing instructions, it is critical to ensure the integrity of the data and therefore the assay should be fully validated Industry recommendation When data will be used to support pivotal determination of effectiveness or label dosing instructions, utilize a fit-forpurpose approach for BOTH assay validation and for setting assay acceptance criteria
NON-FDA APPROVED BIOMARKER ASSAYS It is recognized that obtaining appropriate biomarker reference standard or blank matrix may not always be possible. Additionally, reference standard may not be identical to the endogenous biomarker. As a consequence, developing and validating the biomarker assay CANNOT always be done to meet the standards of a PK assay (refer to the Lee et al. 2006 biomarker white paper) Industry Recommendations Definitive Quantitative: When appropriate reference standard AND blank matrix are available the assay should be validated to meet the same standards as a PK assay
NON-FDA APPROVED BIOMARKER ASSAYS Industry Recommendations (cont.) Relative Quantitative: When appropriate reference standard AND blank matrix are NOT available The assay should be validated and assay acceptance criteria should be set in a fit-for-purpose manner and DO NOT need to meet ALL of the same standards as a PK assay. However, every effort should be made to evaluate critical assay parameters (e.g. standard curve performance, stability, specificity, parallelism, etc.) QC samples may not be able to be prepared with known concentrations. Therefore, QC ranges may be prepared by pooling L/M/H biomarker containing matrix and used as analytical QCs for assay run acceptance
APPROVED DIAGNOSTIC KITS It is recognized that Dx kits are likely not approved for our intended use and may lack critical information Industry Position Supplement the lab s validation data by conducting additional assay verification experiments in a fit-for-purpose manner. This can include evaluations of stability, specificity, drug interference, parallelism, standard curve performance, etc. Assay Verification- Proof of analytical performance of critical assay characteristics in your lab (evaluate the fit for- purpose assay performance)
APPROVED DIAGNOSTIC KITS Industry Position (cont.) Dx assays with sparse calibration standards should include additional verification experiments using additional standards to evaluate the calibration range and standard curve performance. The goal of conducting these additional experiments is to generate a sufficient body of evidence that support using the Dx assay as intended by the Dx manufacture WITHOUT modification.
NEW TECHNOLOGIES Definition of New technology Post-successful use in NDA DBS is not a technology, but a sample preparation method
Hubble Frontier Field Abell 2744 - Pandora s Cluster Hubble Space Telescope Aug-Nov 2013, 63-hr exposure
GALILEO GALILEI Misura ciò che è misurabile e rendi misurabile ciò che non è così. Portrait by Giusto Sustermans
GALILEO GALILEI Measure what is measurable, and make measurable what is not so. First validate. Then measure. Portrait by Giusto Sustermans
ACKNOWLEDGEMENTS Brian Booth Russ Weiner Marie Rock Participants of Crystal City V