Edwin Hemwall, Ph.D. Regulatory Affairs

8/10/99


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Table of Contents

Edwin Hemwall, Ph.D. Regulatory Affairs

Back Problems Are a Common Medical Condition in the U.S.

Nonprescription FLEXERIL® 5 mg NDA 21-070

OTC Availability of Muscle Relaxants

OTC Availability of Muscle Relaxants

Flexeril OTC Development Program

Flexeril OTC Development Program

Flexeril OTC Development Program

Proposed Labeling for FLEXERIL 5 mg Tablets

Flexeril OTC Development Program

Consultants

Consultants

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Program Objectives

Outline of Presentation

Efficacy

Efficacy Questions for Pivotal Trials Studies 006 and 008

Design of Efficacy Studies

Efficacy Ratings Timeline

Efficacy Ratings by Patients Primary Endpoints

Criteria for a Successful Trial

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Primary Efficacy Results Study 006

Primary Efficacy Results Study 008

Mean Relief from Starting Backache

Time to “A Lot of” or “Complete” Relief Protocol 006 (Secondary Endpoint)

Time to “A Lot of” or “Complete” Relief Protocol 008 (Secondary Endpoint)

Magnitude of Effect % Responders - Difference vs. Placebo

Magnitude of Effect % Responders - Difference vs. Placebo

Effect Size

Efficacy Without Sedation Protocols 006 and 008 Combined Clinical Global Impression of Change - Visit 2

Spasm Rating by Physicians

Physician Rating of Muscle Spasm Mean Scores

Muscle Spasm by M.D. vs. Patient Ratings Protocols 006 and 008

Self-Diagnosis of Muscle Spasm

Efficacy Conclusions

Safety

Pharmacologic Effects of Cyclobenzaprine at Therapeutic Plasma Concentrations

Safety

Cyclobenzaprine Pharmacokinetics

Cyclobenzaprine Plasma Concentration by Age

Cyclobenzaprine Metabolism and Excretion Radiolabeled Oral Dose-10 mg

Pharmacokinetic Drug-Drug Interactions

Adverse Experiences

Clinical Adverse Experiences Protocols 006 and 008 Incidence ?2% on CYC 5

Discontinuations for Clinical Adverse Experiences Phase III Studies-Incidence ?0.5% on CYC 5

Adverse Experience Intensity Rating

Maximum Severity of Somnolence Protocols 006 and 008-Cyclobenzaprine 5 mg

First Report of Somnolence by Study Day Cyclobenzaprine 5 mg - Protocols 006 and 008

Adverse Experiences by Age Phase III-Cyclobenzaprine All Doses Reported by 2 or More Patients ?65 Years

Safety Conclusions Phase III Studies

Overview of Psychomotor Studies

Early Psychomotor Studies (001, 002, 003, 012)

Elderly Driving Related Skills Study (014) Design

Rationale for Test Battery

Elderly Driving Related Skills Study (014) Psychomotor Tests

Elderly Driving Related Skills Study (014) Critical Tracking Task: Lambda Score (N=32) Geometric Mean (95% CI)

Elderly Driving Related Skills Study (014) Psychomotor Tests

Elderly Driving Related Skills Study (014) Divided Attention Task: Overall Performance Score (N=32) Geometric Mean (95% CI)

Elderly Driving Related Skills Study (014) Psychomotor Tests

Elderly Driving Related Skills Study (014) Vigilance Task: Response Time (N=32) Geometric Mean (95% CI)

Elderly Driving Related Skills Study (014) Vigilance Task: Number of Errors (N=32) Geometric Mean (95% CI)

Psychomotor Study Conclusions Cyclobenzaprine 5 mg

Postmarketing Surveillance Study

Worldwide Adverse Experience System (WAES)

Spontaneous Reports to Merck - 10 mg

Spontaneous Reports - Fatal Outcomes WAES

Spontaneous Reports - Fatal Outcomes FDA Database

Life-Threatening Dysrhythmias WAES

Life-Threatening Dysrhythmias FDA Database

Spontaneous Reports - Seizures WAES

Spontaneous Reports - Seizures FDA Database

AAPCC Data Other OTC Drugs

Overdose American Association of Poison Control Centers (AAPCC)

AAPCC Summary of Outcomes

Weighted Emergency Department Estimates 1993

Abuse Potential

Safety Conclusions from Marketed Use

Label Development

Proposed Sedation Warnings

Proposed Warnings Ask a Doctor Before Use

Label Development

Concepts Well Understood Label Alone

Comprehension Results Ask a Doctor Before Use

Comprehension Results When Using this Product

Concepts Not Well Understood Label Alone

Label Comprehension Study Works Differently than Pain Relievers

Label Comprehension Study Efficacy on First Day

Revisions After Comprehension Study

Pattern-of-Use Study (009) Design

Pattern-of-Use Study (009) Compliance Data

Concomitant Analgesic Use (Study 009)

Summary Efficacy Results

Summary Safety Results

Summary Label Development

Overall Conclusions

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Pattern-of-Use Study (009) Global Responders by Prior Cyclobenzaprine Use

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Cyclobenzaprine Prescribed Dosing

Muscle Spasm by M.D. vs. Patient Ratings Protocols 006 and 008

Muscle Spasm by M.D. vs. Patient Global Protocol 006 - Visit 3 - CYC 5 mg

Patient-Rated Clinical Global Impression of Change Visit 2 Study 008 (All-Patients-Treated Approach)

Pattern-of-Use Study (009) Concomitant Analgesic Use

Spontaneous Reports - Hallucinations WAES

Spontaneous Reports - Hallucinations FDA Database

Label Comprehension Study Self-Selection: Reasons for Not Being Appropriate

Primary Efficacy Parameters - 006 and 008 Odds Ratios (95% CI) CYC 5 vs. Placebo All Patients Treated

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Reported Congenital Anomalies WAES

Author: Joyce King