Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products

Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products Extended Breakout Session 2: Biomarker Strategies Richard C. Ahrens, M.D. Partha Roy, Ph.D. Dale P. Conner, Pharm.D.

Regulatory Issues

Definition of Biomarker "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." ref: BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.

Definition of Bioequivalence Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions

Purpose of BE To confirm therapeutic equivalence (TE) Therapeutically equivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. The most efficient method of confirming TE is to assure that the formulations perform in an equivalent manner.

Topical Corticosteroids Guidance: Topical Dermatologic Corticosteroids: In Vivo Bioequivalence - 2 June 1995 Pharmacodynamic measurement Blanching effect Dose controlled through duration of application (dose-duration) Dose-effect relationship established during each study

Plasma Conc. Plasma Concentration-Dose Dose

Clinical/PD Response Clinical/PD Dose-Response Log Dose

Scientific Issues

What do you do if the innovator s doses are on the top of the dose-response curve?

What do you do if the innovator s doses are on the top of the dose-response curve? You truly are at the top of the DRC by all clinically relevant measures. The traditional clinical study design is on the top of the DRC, but other designs and/or clinically relevant measures may not be - - e.g. albuterol.

RESPONSE Dose-Response to Inhaled Drug 10 B Curve B A Curve A 0 0 1 2 3 DOSE (Actuations)

FEV1 (L) Mean FEV1 Response to Albuterol: Daytime versus Nocturnal Awakening 3.5 MDI ACTUATIONS 3 2.5 0 1 2 4 8 16 DAY 2 NIGHT 1.5 1 0 20 40 60 80 100 TIME (Min)

DOSE (Actuations) Median Dose to Achieve >80% Personal Best FEV1 22 20 18 16 14 12 10 8 6 4 2 0 0.2 DAY NIGHT TREATMENT PERIOD

Potency of Norton MDI Relative to Ventolin Bioequivalence Criteria: 0.67 1.50 PC 20 FEV 1 32 16 8 4 1 puff Norton = 0.95 puff Ventolin (90% C.I. 0.69-1.40) 1 4 DOSE OF ALBUTEROL (Actuations) Norton MDI Ventolin MDI

Choosing a Relevant Biomarker that is NOT on top of DRC Intent of eno Model Asthma Stability Model

What do you do if the innovator s doses are on the top of the dose-response curve? You truly are at the top of the DRC by all clinically relevant measures. The traditional clinical study design is on the top of the DRC, but other designs and/or clinically relevant measures may not be - - e.g. albuterol. Some subjects may be at the top of the DRC, but other subjects are not - - e.g. ICS

Subject Selection for ICS BE Studies Both the Asthma Stability Model and the eno Model require selecting subjects who do exhibit dose-response ( responders ). Justified by Portion of patients for whom dose does make a difference give a signal that can be studied. If a non-equivalent product were marketed, it would most make a difference to this population.

What do you do if the innovator s doses are on the top of the dose-response curve? You truly are at the top of the DRC by all clinically relevant measures. The traditional clinical study design is on the top of the DRC, but other designs and/or addressing may not be - - e.g. albuterol. Some subjects may be at the top of the DRC, but other subjects are not - - e.g. ICS Use lower doses (if possible) OR increase lower doses

Role of Pharmacokinetic Assessments in BE of Inhaled Drugs Comparison of risks for adverse systemic effect Assessment of topical drug delivery to the lung

FAQ If it s so difficult to show a doseresponse relationship, doesn t that mean that dose doesn t really matter?

THE PREDEDENT: Experience With Generic Albuterol 1989 Albuterol off patent 1992 Initial bronchodilitation studies could not identify a significant dose-response for reference inhaler 1992-1995 Search for acceptable, valid methodology 1995 First generic albuterol inhaler approved using bioassay method

THE PRECEDENT: Involves Concepts of Pharmacodynamic response used to bioassay the quantity of drug delivered Comparison along dose-axis rather than response-axis

RESPONSE OVERALL STUDY DESIGN: 2 by 2 Bioassay STANDARD VALIDITY TESTS Highly Significant DRC Parallelism Contrast Preparations Contrast TEST DOSE

THE SOLUTION? Inhaled Beta Agonists: Study under circumstances where a dose-response relationship is present. Protection against bronchoprovocation (methacholine, histamine)

Potency of Norton MDI Relative to Ventolin Bioequivalence Criteria: 0.67 1.50 PC 20 FEV 1 32 16 8 4 1 puff Norton = 0.95 puff Ventolin (90% C.I. 0.69-1.40) 1 4 DOSE OF ALBUTEROL (Actuations) Norton MDI Ventolin MDI

Focused Discussion Response-Scale Or Dose-Scale Analysis?

RESPONSE FDAs Dose-Scale Approach (hypothetical data) 10 Reference Curve (Emax Model) Test Dose = 100 mcg 100 mcg Test = 90 mcg Ref Therefore 1 mcg Test = 0.9 mcg Ref. C.I. by "bootstrap" 0 50 100 0 1 2 DOSE (micrograms) 200

Long Acting Beta Agonists: Appropriate Biomarkers?

Lessons Learned From Albuterol Experience STUDY MODEL MUST: Use a clinically relevant outcome (reflect delivery to site of clinical action) Sufficiently steep dose-response => Sufficient statistical power.

Inhibition of Methacholine Challenge PC20FEV1 (mg/ml) as a Biomarker for LABA BE in Asthma 32 5 16 4 8 3 SAL 100 SAL 50 ALB 90 PLAC 42 1 2 1 0 1 0 2 4 6 8 10 12 Time (hrs) Derom et al. JACI 1992

Focused Discussion Biomarkers for LABA Bioequivalence? Candidates Inhibition of Methacholine Challenge Bronchodilation Others? Which to use? How to validate?

Inhaled Corticosteroids: Appropriate Biomarkers?

Focused Discussion Biomarkers for ICS Bioequivalence? Candidates Exhaled nitric oxide Inhibition of Adenosine challenge Asthma stability model Sputum Eosinophilia? Others? Which to use? How to validate?

Focused Discussion Role of Pharmacokinetic Assessments in BE of Inhaled Drugs Comparison of risks for adverse systemic effect Assessment of topical drug delivery to the lung

Open Discussion

Back Ups

Definition of Biomarker "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." ref: BIOMARKERS DEFINITIONS WORKING GROUP: BIOMARKERS AND SURROGATE ENDPOINTS: PREFERRED DEFINITIONS AND CONCEPTUAL FRAMEWORK. CLIN PHARMACOL THER 2001;69:89-95.

Definition of Bioequivalence Pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to patients or subjects at the same molar dose under similar experimental conditions

Purpose of BE To confirm therapeutic equivalence (TE) Therapeutically equivalent products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. The most efficient method of confirming TE is to assure that the formulations perform in an equivalent manner.

Topical Corticosteroids Guidance: Topical Dermatologic Corticosteroids: In Vivo Bioequivalence - 2 June 1995 Pharmacodynamic measurement Blanching effect Dose controlled through duration of application (dose-duration) Dose-effect relationship established during each study

Plasma Conc. Plasma Concentration-Dose Dose

Clinical/PD Response Clinical/PD Dose-Response Log Dose

Model of Nasal Spray Dosage Form Performance Dosage Form Performance (Device and Formulation) Membrane Site of Activity Clinical/PD Measurements Therapeutic Effect Dosage Form Drug in Solution GI Tract Blood Toxic/Ther. Effect Pharmacokinetic Measurement Dose ln Dose

DISCLAIMER The views expressed in this slides/discussion are those of mine and must not be taken to represent policy or guidance on behalf of the Food and Drug Administration.

What is a valid biomarker? A biomarker that is measured in an analytical test system with well established performance characteristics and for which there is an established scientific framework or body of evidence that elucidates the physiologic, toxicologic, pharmacologic, or clinical significance of the test results.

Clinical Relevance Disease type, severity and progression The Question of Switchability for all approved indications and conditions of use Reflect drug delivery to the site of action site of action: a case of moving target Disease specific: Asthma, COPD Drug specific: ICS, LABA, LAMA Requirements for Biomarkers of Inhaled Drugs to demonstrate BE

Non-invasive and Methodology of measurement easy on patient and investigator Capable of dose-response within the clinical dose range mimicking the RLD Reproducible Fast onset and reversibility Requirements for Biomarkers of Inhaled Drugs to demonstrate BE Ref: Dr. Badrul Chowdhury s slides from the morning

Challenges Robust Framework for Dose-Response Acceptable BE Criterion Drug Class Specific Lack of suitable biomarkers across diseases Single-Ingredient vs. Combination Product

Harmonization across different regions Canada: Airway Eosinophils, eno Europe: Not spelled out, biomarkers with sufficient sensitivity US: eno, asthma stability model (FEV1)

a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention Specific Sensitive Reproducible Non-invasive Subject acceptability Measurable What is a biomarker? An ideal one?

Exhaled Nitric Oxide (eno) Relevant marker of asthma Independent of age and gender Dependent on expiratory flow Reproducible Responsive to ICS Suitable for cross-over BE study Measurable Asthma

Induced Sputum Eosinophil number Eosinophil Cationic Protein (ECP) IL-5 Neutrophils TNF-alpha Asthma

Asthma Stability Model Inhaled Corticosteroids Dose Scale Approach: FEV1 Asthma

Induced Sputum Neutrophil number IL-8 BAL and biopsy Exhaled breath eno exhaled ethane Blood C-Reactive protein TNF-alpha COPD disease markers

Experience teaches you to recognize a mistake when you ve made it again. Unknown

Typical ICS Study Design Parallel Treatment Groups 1-12 Months of Treatment Baseline PFTs, Sx, etc. ICS Improvement in PFTs, Sx, PEFR (a) high variability (S) (b) shallow sloped DRC (B) (c) carry-over (prevents cross-over)

Statistical Power Associated with a Bioassay Study Related to: Variability of responses (S) Steepness of dose-response slope (B) S + B do not function independently, but in concert as the ratio of S/B The smaller S/B, the more powerful the study

Computed Sample Size Relationship Between S/B and Computed Sample Size 7000 6000 5000 4000 3000 2000 1000 0 Busse Study (HFA-BDP, QVAR) 0 0.5 1 1.5 2 2.5 3 S/B Ratio Typical Study?? 2 by 2 Study Design

Asthma Stability Following Prednisone Burst 1. 100 and 800 mcg/d HFA-BDP 2. Cross-over Prednisone burst Baseline PFTs, Sx, etc. ICS Deterioration in PFTs, Sx, etc.?? 3. Multiple variables examined (58) 4. Estimate S/B for each 5. The lower S/B, the better

Computed Sample Size Relationship Between S/B and Computed Sample Size 200 PM FEV1 150 PC20 FEV1 (Methacholine) 100 50 AM PEFR AM FEF 25-75 2 by 2 Study Design 0 AM FEV1 0 0.5 1 1.5 S/B Ratio

Computed Sample Size Relationship Between Crossover and Parallel Study Designs 2500 2000 PC20 FEV1 Parallel Design 1500 1000 500 Busse Study (HFA-BDP, QVAR) AM FEF25-75 AM PEFR Crossover Design 0 0 0.5 1 1.5 2 2.5 S/B Ratio

Asthma Stability Following High-Dose Corticosteroid Burst RUN-IN PERIOD 4 weeks LOW-DOSE ICS (CFC-BDP 100 mcg/d) 2 weeks high-dose ICS (Budesonide DPI 1600 mcg/d) ENTRANCE CRITERIA: >7% predicted increase between HIGH and LOW- DOSE ICS

FEV1 (Liters) QVAR versus Flovent Diskus 2.95 2.9 2.85 2.8 2.75 2.7 2.65 2.6 2.55 HFA-BDP FP-Diskus 0 100 200 300 400 Dose (mcg/day) p-value Regress. 0.01 Parallel 0.16 1 mcg QVAR = 0.84 mcg FP (90% CI : 0.35 1.74)

Asthma Stability Following High-Dose Corticosteroid Burst RUN-IN PERIOD Approx. 20% of subjects met this entrance criteria This screening burden => Increased time and cost