DRAFT SLIDES FOR NDA 21-198 ADVISORY COMMITTEE PRESENATIONS

Pravachol 10 mg Tablets Rx to OTC Switch

Daiva Shetty, M.D.

Division of Over-the-Counter

Drug Products (HFD-560)

Food and Drug Administration

Friday, July 14, 2000

Actual Use Studies Background

Simulate OTC Use Have few exclusion criteria Objectives depend on the specific product

and concerns related to that product such as: compliance, dosing, duration of use off-label use safety and efficacy in OTC population

Actual Use Issues for Pravachol

Are consumers able to: self-diagnose

know their own cholesterol values understand serum cholesterol values

self-select identify risk factors for CHD

Actual Use Issues for Pravachol

Are consumers able to: self-treat hypercholesterolemia

when to start treatment are they able to follow label directions for

dosing and duration of use do they understand the treatment goal

Review of Pravachol Actual Use Trials

PREDICT, Protocol # 800-01-97 OPTIONS, Protocol # 800-03-97

Actual Use Trials

PREDICT

The Pravachol Experience Documented In a Consumer Trial

Study PREDICT

Study design: multi-center randomized parallel open-label 6 months duration

To test: behavior efficacy tolerability

Study PREDICT

Study design (cont.) recruitment done via advertising

(newspapers, radio, pharmacies) the call center directed interested subjects

to the enrollment site the call center also served as a screening

site for premenopausal or childbearing potential women

Study PREDICT

Study design (cont.)

Inclusion criteria:> 18 years

Study PREDICT

Study design (cont.)

Exclusion criteria: less than 18 years old females of childbearing potentialbreast feeding femalesparticipation in a research study

within the last 30 days

Study PREDICT

Criteria for treatment on the label: Total cholesterol 200-240 mg/dl LDL cholesterol > 130 mg/dl

Study PREDICT

Primary Objective:

Proportion of OTC randomized subjects, who having purchased OTC Pravachol 10 mg, consult a physician within two months of using medication

PREDICT Results

80%Learned throughadvertisem ents

20%W alk through

O TC1,924

Rx1,948

Random ized3,872

Screened at the Screening Site3,888

Called the Call Center11,065

PREDICT Results

119 subjects were ineligible to participate 61 (2%) women of childbearing age

Of the 11,065 who called, unknown how many were women of childbearing potential

Behavior of OTC Population(n=1,924)

720

553499

266

0

100

200

300

400

500

600

700

800

Purchased Consulted aphysician

Treated Did notqualify

Treatment Guidelines

Initiate Treatment/LDL-C Goal/LDL-C

No CHD or diabetes & 2 risk factors

>130 mg/dl, < 190 mg/dl < 130 mg/dl

No CHD or diabetes, <1 risk factor

>160 mg/dl, < 190 mg/dl < 160 mg/dl

PREDICT Results

• Lipid Profile at Baseline in Qualified and Treated Population

• LDL-C:• Mean 162 mg/dl + 17• Median 163 mg/dl

• TC:• Mean 245 mg/dl + 21• Median 245 mg/dl

Behavior of OTC Treated Population

290 (58%) withdrew from the study 123 were withdrawn from the study by a

physician Discontinuation due to adverse events

8% OTC vs. 5% Rx 53 subjects were titrated to a higher dose

PREDICT Results

Compliance Assessed by pill count and self-report, and

defined by 80-120%: 54% OTC vs. 65% Rx CI -19%,-3.7%

Mean duration of treatment: 109.4 days OTC vs. 152.5 days RX

Are consumers able to

self-diagnose hypercholesterolemia?

Knowledge about Cholesterol values Randomized Population (n=3,872)

• Healthy level TC:• < 200 74%• Unknown 21%

• Healthy level LDL-C:• < 130 12%• Unknown 80%

• Knowledge of HDL-C was not tested

Actual Use Trials

OPTIONS

OTC Pravachol Trial In an Observed Naturalistic Setting

Study OPTIONS

Study design: multi-center open-label pharmacy based 3 months duration

To assess: behavior compliance safety

Study OPTIONS

Study design (cont.)

Inclusion criteria: > 18 years member of a participating HMO for at least

6 months

Study OPTIONS

Study design (cont.)

Exclusion criteria:pregnancy or lactationparticipation in a research study

within the last 30 days less than 18 years old

Study OPTIONS

Study design (cont.)

Recruitment was done via: mailing the study brochure to the HMO

members walk through traffic in the participating

pharmacies radio newspaper

Study OPTIONS

Population was not representative of overall U.S. OTC population: restricted to certain geographical areas all participants had health care

insurance and prescription drug coverage

Study OPTIONS

Study design (cont.)

Criteria for treatment on the label Total serum cholesterol 200-240 mg/dl > 35 years for men > 55 years for women

Study OPTIONS

Primary Objective

To determine the proportion of subjects, who having purchased Pravachol 10 mg, contact their health care provider within 2 months of using the medication

OPTIONS Results

45% Responded to the m a ile r53% W alk through2% Responded to the new spaper or radio

782E nrol led

2 ,207Responded to the S tudy Recruitm ent M ate r ia l

161 ,322+T arge ted for enrol lm ent

OPTIONS Results

782

404321

178

0

100

200

300

400

500

600

700

Enrolled Purchased Treated Consulted

OPTIONS Results

Behavior of Treated Population

156 (49%)C ontinued on trea tm ent for > 56 days

165 (51%)W ithdrew from the s tudy

321T rea ted Popula tion

OPTIONS Results

95 (24%) purchase population were not recommended Pravachol by their health care provider

Median total-C level 235 mg/dl

Median LDL-C level 151 mg/dl

59.8% women were <55 years old

Proposed Label

• Total cholesterol 200-240 mg/dl

• “Bad” cholesterol (LDL) > 130 mg/dl

• Do not use• if you are under 18 years• if you have liver disease or drink >3 alcoholic

beverages daily• if you are allergic to pravastatin

Latest Proposed Label

• Total cholesterol 200-240 mg/dl

• “Bad” cholesterol (LDL) > 130 mg/dl

• For men over 35 years of age

• For women over 45 years of age

Overall Conclusions

Low consumer understanding of specific serum cholesterol values

Substantial number of self-selection errors

High withdrawal rate Poor adherence

Overall Conclusions

Behavior of childbearing age women was not addressed in these 2 trials

Consumer understanding was not assessed about: the goal (to lower cholesterol) the length of the therapy titration to a higher dose

Targeted OTC population on the current proposed label has not been studied