Regulatory Updates in Clinical Pharmacology, Nonclinical Development, and Translational Medicine

Transcription

1 Regulatory Updates in Clinical Pharmacology, Nonclinical Development, and Translational Medicine Luana Pesco Koplowitz, MD, PhD, FCP, FFPM President and Chief Medical & Scientific Officer DUCK FLATS Pharma, LLC Elbridge, New York, USA Adjunct Assistant Professor of Medicine University of Delaware School of Medicine, Wilmington, Delaware, USA University of Miami School of Medicine, Miami, Florida, USA Department of Clinical Pharmacology Member of FDA Cardiac Safety Research Consortium

2 Regulatory Update Overview There have been recent advances in both US and European regulatory guidelines for the conduct of nonclinical and translational medicine development programs. These include: Updates on the performance of safety testing and in vitro drug-drug interaction studies Updates in cardiac safety guidelines for the conduct of thorough QT/QTc (TQT) studies Release of new European regulatory guidelines for bioanalytical method validation requirements o US bioanalytical method validation guidance draft, Revision 1, September 2013 Taken together, these enhancements will have a significant impact on the supportive nonclinical and clinical pharmacology development programs for new chemical entities and biotechnology compounds. In addition, 505(b)(2) registrations for legacy compounds would be affected by these new regulations. 2

3 Drug Metabolites in Safety Testing (MIST) Recent Updates to Guidelines FDA Guidance 2008: Safety Testing of Drug Metabolites ICH Guidelines (Step 5, FDA adoption) 2010: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 2010: S9 Nonclinical Evaluation for Anticancer Pharmaceuticals 2013: M3(R2) Questions & Answers (R2) 3

4 Drug Metabolites in Safety Testing (MIST) The guidelines require the nonclinical safety assessment of disproportionate human metabolites Where disproportionate refers to any metabolite that is present in humans at levels higher than at least one of the species used in the nonclinical safety assessment Thresholds for safety assessment: Metabolite exposure >10% of the systemic, steady-state exposure of the parent drug (2008 FDA MIST) Revised: Metabolite exposure >10% of the systemic, single-dose exposure of drug-related material (2012 ICH M3(R2) Q&A (R2)) Alternative thresholds may also relate (on a case-by-case basis) to metabolites that are disproportionate relative to their urinary or biliary excretion 4

5 Drug Metabolites in Safety Testing (MIST) Exclusions Not required for cancer drugs (ICH S9 guideline) Exceptions may also be made for other serious, life-threatening diseases on a case-by-case basis Timing Safety studies should be completed prior to initiation of large-scale clinical trials Requires early identification of disproportionate metabolites to avoid delays in development 5

6 Drug Metabolites in Safety Testing (MIST) General Toxicity Required Safety Studies Animal exposure should be equal or greater than human exposure (at minimum) Route of administration should be the same as the planned human route, unless an alternative route is needed to obtain exposure Adhere to latest ICH M3(R2) guideline Genotoxicity Minimum: in vitro assays to detect point mutations and chromosomal aberrations A positive result triggers the full battery of tests under ICH S2(R1) guideline 6

7 Drug Metabolites in Safety Testing (MIST) Required Safety Studies (continued) Embryo-Fetal Development Toxicity Required if drug will be used in women of child-bearing potential Additional reproductive toxicity studies may be required Adhere to latest ICH S5(R2) guideline Carcinogenicity Needed if drug will be administered continuously for 6 months or if used for the treatment of chronic or recurrent conditions Adhere to latest ICH S1A, S1B, and S1C(R2) guidelines 7

8 In Vitro Drug-Drug Interaction Studies FDA Guidance Recent Updates to Guidelines 2012: Drug Interaction Studies Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (Revised Draft) Objectives of the 2012 FDA DDI Draft Guidance: o To understand whether a DDI potential exists and whether a potential DDI requires dose adjustment, therapeutic monitoring, or contraindication to concomitant use EMA Guideline 2012: Guideline on the Investigation of Drug Interactions (Revised) 8

9 In Vitro Drug-Drug Interaction Studies Overview of major revisions in the 2012 FDA DDI Draft Guidance: Recommendations require an early understanding of drug clearance and human metabolism Evaluation of DDI potential for metabolites that account for 25% of parent drug AUC Evaluation of complex DDI potential if multiple enzymes together account for 25% of systemic clearance Use of PBPK modeling (i.e., SimCyp) Enzyme identification and inhibition studies for additional CYPs, UGTs, and non-cyp enzymes Substrate and inhibition evaluations for a series of transporters 9

10 In Vitro Drug-Drug Interaction Studies The affect of concomitant drugs on the metabolism of NCEs: Evaluate if a single enzyme accounts for 25% of clearance in humans -ORif multiple enzymes together account for 25% of clearance Need to consider P450s CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A and UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15 Consider case-by-case CYP2A6, 2J2, 4F2, and 2E1 and other non-cyp Phase I enzymes (MAO, FMO, XO, alcohol/aldehyde dehydrogenase) Complex DDI: consider minor elimination pathways in special populations (renal/hepatic impairment, polymorphic enzyme responsible for major pathway, subjects on strong inducer of minor pathway) Complex DDI: additional assessment if NCE is metabolized by polymorphic enzyme (CYP2D6, 2C9, 2C19, UGT1A1) 10

11 In Vitro Drug-Drug Interaction Studies The affect of NCEs on concomitant drugs via inhibition: Need to consider CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 Reversible and TDI inhibition Basic models (conservative approach) o Reversible: R 1 = 1 + [I]/K i (where I is steady-state C max total and K i is unbound) o TDI: R 2 = (K obs +K deg )/K deg (where K obs = (k inact [I])/(K i +I)] If R>1.1 (R>11 for oral CYP3A inhibitors), recommend in vivo study and/or thorough evaluation using mechanistic PBPK dynamic model The affect of NCEs on concomitant drugs via induction: Consider CYP1A2 (AhR), 2B6 (CAR), 3A4 (PXR), and CYP2C (if 3A4 positive) Measure mrna change in hepatocytes (n=3) rather than CYP activity 11

12 In Vitro Drug-Drug Interaction Studies NCE as substrate of transporters: All NCEs to be tested as substrates of P-gp and BCRP Also OATP1B1, OATP1B3 (if hepatic or biliary clearance is 25% of total clearance; i.e., most drugs), and OAT1, OAT3, and OCT2 (if renal clearance is 25% of total clearance) NCE as inhibitor or inducer of transporters: NCE to be tested as inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 Other transporters (e.g., MRPs, MATE, BSEP) based on drug class, observed unexpected DDIs, or as new assays become available Validated in vitro transporter induction assays not yet available 12

13 In Vitro Drug-Drug Interaction Studies Additional work recommended by 2012 FDA DDI Draft Guidance: Evaluation of metabolites 25% of parent drug AUC Evaluation for potential complex DDI if multiple enzymes together account for 25% of systemic clearance Enzyme identification studies for CYPs (7-11 enzymes), UGTs (7 enzymes), and non-cyp Phase I ( 4 enzymes) Inhibition studies for 7 CYPs and induction studies for 3 CYPs Substrate studies for 7 transporters Inhibition studies for 7 transporters Greatly increased role for PBPK modeling and less focus on detailed in vitro methodology 13

14 In Vitro Drug-Drug Interaction Studies Enzyme/ Transporter CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4 NCE as Substrate NCE as Inhibitor NCE as Inducer yes yes 1A2, 2B6, 3A4 (2C) CYP2A6, 2J2, 4F2, 2E1 case-by-case as available as available MAO, FMO, XO, A/ADH case-by-case as available as available UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15 yes in vivo as available P-gp, BCRP yes yes not available OATP1B1/B3, OAT1/3, OCT2 yes yes not available MRPs, MATE, BSEP case-by-case as available not available 14

15 Cardiac Safety QT/QTc Interval Prolongation History of Cardiac Safety Guideline Development The catalyst for formalized cardiac safety guidelines and assessments was a series of high-profile drug withdrawal cases between the 1990s & early 2000s, many involving torsade de pointes (TdP) arrhythmia. Terfenadine (Seldane ) Cardiac toxicity only with rare overdose (>900mg) after approval Removed from market in 1997 Cisapride (Propulsid ) reported to cause tachycardia & dizziness in clinical trials Initial published reports of QT prolongation As of Dec. 1999, drug associated with 341 reports of heart rhythm disturbances, including 80 deaths Taken off US market, but available to patients on limited-access protocol 15

16 Cardiac Safety QT/QTc Interval Prolongation History of Cardiac Safety Guideline Development, continued To ensure patient safety and to more accurately project benefit-risk projections, there has been growing interest in evidence-based evaluation of ECG intervals other than QT/QTc. Regulatory agencies stipulate that PR and QRS measurements be assessed and analyzed as part of QT/QTc studies. As an example, the pregabalin (Lyrica TM, Pfizer) FDA New Drug Application review experience exemplifies an approach to evaluate results of a clinical development program, as profiled in the next slide. 16

17 Cardiac Safety QT/QTc Interval Prolongation History of Cardiac Safety Guideline Development, continued Mean PR interval increase (placebo adjusted) supported by exposureresponse analysis Incidence of advanced atrioventricular block (AVB) on active drug compared with placebo, investigating dose dependency and high-risk subgroup analysis (see below) o Outlier analysis comparing incidence on active drug and on placebo, and exposure dependency if any for the following subjects: Absolute PR interval >200 to 220 ms / PR interval increase from baseline >25% High-risk subgroup analysis evaluating placebo-adjusted PR prolongation as well as incidence of second- and third-degree AVB for the following subgroups: Subjects with baseline PR interval >200 to 220 ms / Subjects on concomitant medications known to prolong PR interval, or cause AVB Additional analyses can include relevant adverse event and serious adverse event analysis. 17

18 Cardiac Safety ICH Guidelines S7B: The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (October 2005) E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 2005) E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers (November 2008), (Revision 1, October 2012) Four New Questions Added to Address: Sex Differences New Technologies Late Stage Monitoring Heart Rate Monitoring 18

19 Cardiac Safety Sex Differences The thorough QT study is primarily intended to act as a clinical pharmacology study in a healthy population using a conservative primary objective defining the drug s effect on QT. However there are gender differences and it is encouraged (but not mandatory) to include both men and women in any QT study. Postpubertal males have lower heart rate-corrected QT intervals Females have a greater risk to develop symptomatic long QT syndrome & drug-induced TdP arrhythmia Females have a higher intrinsic HR than males Females have a longer corrected QT interval than males 2/3 of drug-induced TdP occurs in females 19

20 Cardiac Safety Incorporating New Technology NOTE: This new Question 9 supersedes Questions 4A & 4B in the ICH Guideline E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers (November 2008 ) Since ICH E14 was issued, 12-lead continuous recording devices have largely supplanted cart recordings in thorough QT studies without a formal validation process because of their performance in the context of a positive control. The impact of other innovative technologies can be assessed in studies incorporating a positive control. Twelve-lead continuous recording devices and other new technologies can be used in late phase clinical trials. In cases where a thorough QT study is not conducted, a sponsor can provide alternate methods for validating the technology. 20

21 Cardiac Safety Late-Stage Monitoring Clarification of Approach to QTc in Late-Stage Clinical Development Intensive ECG monitoring in clinical trials has two main objectives: To provide protection to patients who might have large (>500 ms) QT interval changes To identify the frequency of marked QT increases The recommended intensity of the monitoring and assessment in late-stage trials will depend on: Magnitude of QTc prolongation seen in the TQT study or early clinical studies Circumstances in which substantial QT prolongation might occur Pharmacokinetic properties of the drug Characteristics of the target population Presence of adverse events that can increase proarrhythmic risk Other characteristics of the drug (safety pharmacology, toxicology, drug class, etc.) 21

22 Cardiac Safety Heart Rate Correction Changes in heart rate could variably influence a drug s effect on repolarization, and correction methods with different characteristics are often applied. Bazett s vs. Fridericia Correction While Bazett s correction is frequently used in clinical practice, it is now considered an inferior method due to the over-correction at elevated heart rates and under-correction at heart rates below 60 beats per minute (bpm). Therefore, Bazett s correction is no longer warranted in all applications unless there is a compelling reason for a comparison to historical Bazett s corrected QT data. Other Points to Consider: The method(s) of correction, criteria for the selection of the correction method, and rationale for the components of the correction method should be specified prior to analysis to limit bias. Alternative methods of correction should only be used if the primary method fails the pre-specified criteria for selection of correction method. Corrections that are individualized to a subject s unique heart rate QT dynamic are not likely to work well when data are sparse or when baseline data (upon which the correction is based) do not cover at least the heart range observed on study drug. 22

23 Cardiac Safety A Note on Positive-Control Blinding While this section has not been updated, it is important to clarify the need for positive-control blinding in the TQT study. Per the current guideline, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: The thorough QT/QTc study should be adequate and well-controlled, with mechanisms to deal with potential bias, including use of randomization, appropriate blinding, and concurrent placebo control group. As this study has a critical role in determining the intensity of ECG data collection during later stages of drug development, it is important to have a high degree of confidence in the ability of the study to detect differences of clinical significance. The confidence in the ability of the study to detect QT/QTc prolongation can be greatly enhanced by the use of a concurrent positive control group (pharmacological or nonpharmacological) to establish assay sensitivity. The positive control should have an effect on the mean QT/QTc interval of about 5 ms (i.e., an effect that is close to the QT/QTc effect that represents the threshold of regulatory concern, around 5 ms). Detecting the positive control s effect will establish the ability of the study to detect such an effect of the study drug. 23

24 Bioanalytical Method Validation - Guidelines In order to reflect advances in science and technology, the FDA (Center for Drug Evaluation and Research) guidance on Bioanalytical Method Validation is currently undergoing revision. CDER Guidance for Industry, Bioanalytical Method Validation (May 2001) CDER Guidance for Industry, Bioanalytical Method Validation (Draft, Revision 1, September 2013) The European Medicines Agency (EMA) has also recently issued a new guidance to incorporate current trends in this field. EMA Guideline on Bioanalytical Method Validation (21 JUL 2011) 24

25 Bioanalytical Method Validation CDER - Overview of Updates and Revisions Chromatographic Methods and Ligand Binding Assays (LBA) Chromatographic assays are primarily used for drug and metabolite analysis while LBAs are primarily used to quantify biotherapeutics, biomarkers, and anti-drug antibodies. Due to the assay differences, the guideline is being revised to: o Differentiate lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ) measurements for accuracy, precision, and calibration curves o o Expand on matrix interaction differences Clarify stability, sampling, and stock solutions New sections to address issues and technology updates o Endogenous Compounds o o o Biomarkers Diagnostic Kits Dried Blood Spot (DBS) Methodology 25

26 Bioanalytical Method Validation CDER - Overview of Updates and Revisions, continued Expansion on Incurred Sample Reanalysis (ISR) (ISR is intended to verify reliability of reported subject sample analyte concentrations) o SOPs should be established to address the following points: Total number of ISR samples (7% of the study sample size) Provision for adequate coverage of PK profile Acceptance criteria for sample results Updates to clarify documentation o o o System Suitability/Equilibration Description of potential interferences for drug or metabolites in LBAs Appendix with examples of tables to include in validation report 26

27 Bioanalytical Method Validation Chromatograph vs. LBA Method Development Measurement Chromatograph Ligand Binding Assay (LBA) Accuracy Precision Calibration Curve LLOQ Calibration Curve ULOQ Calibration Curve/ Standard Curve/ Concentration - Response The mean value should be within 15% of the nominal value except at LLOQ, where it should not deviate by more than 20%. The precision determined at each concentration level should not exceed 15% of the coefficient of variation (CV) except for the LLOQ, where it should not exceed 20% of the CV. Analyte peak (response) should be identifiable, discrete, and reproducible, and the back-calculated concentration should have precision that does not exceed 20% of the CV and accuracy within 20% of the nominal concentration. Analyte peak (response) should be reproducible and the back-calculated concentration should have precision that does not exceed 15% of the CV and accuracy within 15% of the nominal concentration. Standards/calibrators should not deviate by more than 15% of nominal concentrations, except at LLOQ where the standard/calibrator should not deviate by more than 20%. The mean value should be within 20% of the actual value except at LLOQ, where it should not deviate by more than 25%. The precision determined at each concentration level should not exceed 20% of the CV except for the LLOQ, where it should not exceed 25% of the CV. Analyte peak (response) should be identifiable, discrete, and reproducible and back-calculated concentration should have precision that does not exceed 25% CV and accuracy within 25% of the nominal concentration. Analyte response should be reproducible and the backcalculated concentration should have precision that does not exceed 20% CV and accuracy within 20% of the nominal concentration. The standard calibrator concentrations should be within 25% of the nominal concentration at LLOQ and within 20% of the nominal concentration at all other concentrations. 27

28 Bioanalytical Method Validation Additional Issues and Technology Updates Endogenous Compounds Accuracy of measurement of the analytes poses a challenge when assay cannot distinguish between the therapeutic and endogenous counterpart. In such situations, the following is recommended: Biological matrix used to prepare calibration standards should be the same as the study samples and free of the endogenous analyte QC samples should be prepared by spiking known quantities of analyte(s) in the same biological matrix as the study samples Biomarkers Guidance recommendations only pertain to the validation of assays to measure in-vivo concentrations in biological matrices such as blood or urine A fit-for-purpose approach should be used when evaluating the extent of the method validation that is appropriate Method validation for biomarker assays should address the same questions as method validation for PK assays 28

29 Bioanalytical Method Validation Additional Issues and Technology Updates, continued Diagnostic Kits - FDA makes the following recommendations: Biological matrix used to prepare calibration standards should be the same as the study samples and free of the endogenous analyte Performance of diagnostic kits should be assessed in the facility conducting the sample analysis to ensure reliability of the kit method for drug development purposes o If analyte source in the kit differs from that of subject samples, testing should evaluate the differences in immunological activity with the kit reagents o Individual batches using multiple assay plates (e.g., 96-well ELISA plates) should include sufficient replicate QC samples on each plate to monitor accuracy 29

30 Bioanalytical Method Validation Additional Issues and Technology Updates, continued New Technologies Generally, the use and submission of data based on new technologies should be supported with data generated by established technology, until the new approaches become accepted practice. Although the Dried Blood Spot (DBS) methodology has been successful in individual cases, the method has not yet been widely accepted. Therefore, a comprehensive validation will be essential prior to using DBS in regulated studies. 30

31 Bioanalytical Method Validation EMA-History of Guidance and Overview Previously did not have specific guidance for bioanalytical method validation Adopted by the Committee for Medicinal Products for Human Use (CHMP) on 21 July 2011 Describes when partial validation or cross validation may represent an appropriate alternative approach to the complete validation of an analytical method Provides recommendations for the validation of bioanalytical methods applied to measure drug concentrations in biological matrices obtained in animal toxicokinetic studies and all phases of clinical trials Separates validation recommendations for chromatographic and LBA analytical methods Addresses specific aspects for the analysis of study samples 31

32 Thank You! DUCK FLATS Pharma, LLC Elbridge, New York 32

33 References Carlson GF, MD;; Fiszman ML, MD, PhD;; Geiger MJ, MD, PhD;; Gintant, GA, PhD;; Gottfridsson C, MD, PhD;; Gutstein, DE, MD;; Killeen M, MD;; Kleiman R, MD;; Eric L. Michelson, MD, Nada A, MD, MS, MFPM;; Pesco Koplowitz L, MD, PhD;; Strnadova C, PhD;; Rodriguez I, MD;; Sager, PT, MD. The Evaluation and Management of Drug Effects on Cardiac Conduction (PR and QRS Intervals) in Clinical Development. Am Heart J. 2013;;165(4): Center for Drug Evaluation and Research (CDER). Guidance for Industry Bioanalytical Method Validation. May Available from: CDER. Guidance for Industry Bioanalytical Method Validation. Draft (Revision 1) September European Medicines Agency (EMA). Guideline on Bioanalytical Method Validation. 21 July EMA. Guideline on the Investigation of Drug Interactions (Revised) Food and Drug Administration (FDA). Drug Interaction Studies Study Design, Data Analysis, and Implications for Dosing and Labeling (Draft) FDA. Drug Interaction Studies Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (Revised Draft) FDA. Safety Testing of Drug Metabolites

34 References International Conference on Harmonisation (ICH). E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available from: ICH. E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers. November ICH. E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers (R1). October ICH. S7B: Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. October ICH. Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. M3(R2) 2010, M3(R2) Q&A (R2) Van Amsterdam, Peter;; The EMA Bioanalytical Method Validation Guideline: process, history, discussions, and evaluation of content. 16 NOV Presented at 5th EBF Open Symposium. Wang, HF PhD. What s Unique about Ligand Binding Assay Bioanalysis and What Have We Learned from Outsourcing? Pharmaceutical Outsourcing. Posted: May 01, 2010 (accessed 10/2013). Available from: 34