china presentation 07nov2013 finalich guidelines (step 5, fda adoption)! 2010: m3(r2) nonclinical...

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

Luana Pesco Koplowitz, MD, PhD, FCP, FFPMPresident and Chief Medical & Scientific Officer

DUCK FLATS Pharma, LLCElbridge, New York, USA

Adjunct Assistant Professor of MedicineUniversity of Delaware School of Medicine, Wilmington, Delaware, USA

University of Miami School of Medicine, Miami, Florida, USADepartment of Clinical Pharmacology

Member of FDA Cardiac Safety Research Consortium

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Regulatory Update OverviewThere 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 requirementso 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.

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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)

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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


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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

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Required Safety Studies

General Toxicity§ 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

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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

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In Vitro Drug-Drug Interaction Studies

Recent Updates to Guidelines

FDA Guidance§ 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)

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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

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The affect of concomitant drugs on the metabolism of NCEs:§ Evaluate if a single enzyme accounts for ≥25% of clearance in humans -OR-

if 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)

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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: R1 = 1 + [I]/Ki (where I is steady-state Cmax total and Ki is unbound)o TDI: R2 = (Kobs+Kdeg)/Kdeg (where Kobs = (kinact[I])/(Ki+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

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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

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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

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Enzyme/ TransporterNCE as

SubstrateNCE as

InhibitorNCE as Inducer

CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4

yes yes 1A2, 2B6, 3A4 (2C)

CYP2A6, 2J2, 4F2, 2E1 case-by-case as available as availableMAO, FMO, XO, A/ADH case-by-case as available as availableUGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B15

yes in vivo as available

P-gp, BCRP yes yes not availableOATP1B1/B3, OAT1/3, OCT2 yes yes not availableMRPs, MATE, BSEP case-by-case as available not available

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Cardiac Safety – QT/QTc Interval ProlongationHistory 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®) § 1986- reported to cause tachycardia & dizziness in clinical trials§ 1987- 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

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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 (LyricaTM, Pfizer) FDA New Drug Application review experience exemplifies an approach to evaluate results of a clinical development program, as profiled in the next slide.

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Cardiac Safety – QT/QTc Interval ProlongationHistory of Cardiac Safety Guideline Development, continued § Mean PR interval increase (placebo adjusted) supported by exposure-

response 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.

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Cardiac Safety – ICH GuidelinesS7B: 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

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Cardiac SafetySex 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

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Cardiac SafetyIncorporating New Technology

NOTE: This new Question 9 supersedes Questions 4A & 4B in the ICH GuidelineE14 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.

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Cardiac SafetyLate-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.)

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Cardiac SafetyHeart 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.

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Cardiac SafetyA 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.

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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)

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Bioanalytical Method ValidationCDER - 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 Expand on matrix interaction differenceso Clarify stability, sampling, and stock solutions

§ New sections to address issues and technology updateso Endogenous Compoundso Biomarkerso Diagnostic Kitso Dried Blood Spot (DBS) Methodology

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Bioanalytical Method ValidationCDER - 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 documentationo System Suitability/Equilibrationo Description of potential interferences for drug or metabolites in LBAso Appendix with examples of tables to include in validation report

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Bioanalytical Method ValidationChromatograph vs. LBA Method Development

Measurement Chromatograph Ligand Binding Assay (LBA)

Accuracy The mean value should be within 15% of the nominal value except at LLOQ, where it 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%.

Precision 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.

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.

Calibration CurveLLOQ

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 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.

Calibration CurveULOQ

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.

Analyte response should be reproducible and the back-calculated concentration should have precision that does not exceed 20% CV and accuracy within 20% of the nominal concentration.

Calibration Curve/ Standard Curve/ Concentration -Response

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 standard calibrator concentrations should be within 25%of the nominal concentration at LLOQ and within 20% of the nominal concentration at all other concentrations.

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Bioanalytical Method ValidationAdditional Issues and Technology Updates

Endogenous CompoundsAccuracy 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

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Bioanalytical Method ValidationAdditional 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 purposeso 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

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Bioanalytical Method ValidationAdditional 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.

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Bioanalytical Method ValidationEMA-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

Thank You!Thank You!

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DUCK FLATS Pharma, LLCElbridge, New York

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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):489-500.

• Center for Drug Evaluation and Research (CDER). Guidance for Industry Bioanalytical Method Validation. May 2001. Available from: http://www.fda.gov/cvm.

• CDER. Guidance for Industry Bioanalytical Method Validation. Draft (Revision 1) September 2013.

• European Medicines Agency (EMA). Guideline on Bioanalytical Method Validation. 21 July 2011.

§ EMA. Guideline on the Investigation of Drug Interactions (Revised) 2012.

§ Food and Drug Administration (FDA). Drug Interaction Studies — Study Design, Data Analysis, and Implications for Dosing and Labeling (Draft) 2006.

§ FDA. Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations (Revised Draft) 2012.

• FDA. Safety Testing of Drug Metabolites. 2008

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References• International Conference on Harmonisation (ICH). E14: Clinical Evaluation of QT/QTc Interval

Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. Available from: http://www.ICH.org.

• ICH. E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers. November 2008.

• ICH. E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, Questions and Answers (R1). October 2012.

• ICH. S7B: Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. October 2005.

• ICH. Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. M3(R2) 2010, M3(R2) Q&A (R2) 2013.

• Van Amsterdam, Peter;; The EMA Bioanalytical Method Validation Guideline: process, history, discussions, and evaluation of content. 16 NOV 2012. 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: http://www.pharmoutsourcing.com.

china presentation 07nov2013 finalich guidelines (step 5, fda adoption)! 2010: m3(r2) nonclinical...

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