Carola P. Friedman, MD, FACC

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Carola P. Friedman, MD, FACC

• Executive Medical Director
• Worldwide Consumer Medicines

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Pravachol 10 OTC Program
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The OTC Population

• Men gt 35 years, women gt 45 years
• Told by physician to lower cholesterol
• Not at desirable cholesterol level despite diet
  and exercise but are not taking Rx therapy
• TC 200 - 240 mg/dl, LDL-C gt 130 mg/dl
• Generally healthy no CHD or DM
• Likely to reach NCEP goal with a moderate
  reduction in LDL-C

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Points to Consider with OTCAvailability of a
Lipid Lowering Medication

• Appropriate use in an OTC setting
• The product will be used by a population who will
  receive benefit
• Physician involvement will be maintained
• Compliance with the OTC product will result in a
  similar profile of biologic activity
• Use in a less supervised environment will result
  in a similar safety profile

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Consumer Use Program

• Label Comprehension (n612)
• Pravachol Experience Documented In a Consumer
  Trial (PREDICT) (n3,872)
• OTC Pravachol Trial In an Observed Naturalistic
  Setting (OPTIONS)(n782)

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Consumer Use Trials Objectives

• Develop Label Consumers can understand and test
  with attention to low literacy
• Consumer Use
• Allow everyone to participate, including those
  who are inappropriate
• Assess behavior by creating natural environments
• Generate data that is
• Generalizable
• Reliable
• Confirm results by utilizing protocols of
  different designs in diverse populations
• PREDICT Create OTC and Rx environments to
  assess comparability
• OPTIONS Capture real-world OTC setting

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Label ComprehensionPeople Understood the Label

• 612 people surveyed 27 read lt 9th grade
• No a priori cholesterol concern required
• People understood key messages lt 9th Grade ³ 9th
  Grade Literacy Literacy
• See MD / Get level checked 95 95
• Do not use if CHD present 94 92
• Do not use if diabetic 79 83
• Follow up with MD for unusual muscle
  pain 93 93

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Comparison of Label Testedand Proposed OTC Label

• Changes primarily reflect Drug Facts Format
  requirements
• Number of See a doctor messages remain constant
• Additional information added to usage section
• LDL-C gt 130mg/dl
• Cholesterol level graphic
• Other changes
• Age for women changed to gt 45 years
• Erythromycin warning eliminated

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PREDICTObjectives

• Allow diverse populations to participate
• Randomize participants to OTC vs Rx environments
  prior to any knowledge of medical history (no
  screening) Rx population served as control group
• Observe behavior for 6 months
• Assess physician consultation for OTC purchasers
• Compare OTC vs Rx participants who qualified for
  Pravachol 10 for
• Physician follow-up
• LDL-C reduction
• Safety

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PREDICTAdvertising Designed to Capture Broad
Spectrum of the Population

• 20 geographically diverse areas
• Demographics of radio, print media mirror
  community
• Augmented by
• Hispanic and Gospel stations
• Minority magazines
• Key communication message of advertisement
• Non prescription medicine to lower cholesterol
• For generally healthy people with TC 200-240
  mg/dl
• No mention of age or specific medical conditions

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PREDICTParticipant Disposition
Responded to Advertisementthrough Call
Center n11,065

• Information providedby Call Center
• Directions to site
• Hours of operation
• No screening conducted (women of childbearing
  potential excluded5 of calls)

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PREDICTRetail Site Characteristics

• Natural
• No medical personnel
• Dissociated from clinics
• No screening performed
• Minimal exclusion criteria

• No contact for 6 months

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Participant Behavior Choices Throughout the
Course of PREDICT
OTC
Rx

Randomized to Environments
n1,948
n1,924
Characterize People Interested
Primary Objective

n1,306
n1,160
Consult

n405
n315
Qualified

Qualified and Treated
n352
n285
Tolerability
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PREDICT Results Baseline Characteristics of
Participants Responding to Advertisement
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PREDICTParticipants Responding to
AdvertisementDemographics(Randomized Population
n3,872)
()
Mean Age (yr. SD)
56 12
Age Group
lt 35
4
35-54
42
55-74
48
? 75
6
Gender
Female
38
Male
62
Race
Caucasian
84
Black
8
Hispanic
5
Other
3
lt 9th Grade Literacy
8
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PREDICTParticipants Responding to
AdvertisementHealth Care Status / Cholesterol
Action(Randomized Population n3,872)
()
Health Care Status
Have a Doctor
85
See MD Yearly
83
Saw MD Specifically for Cholesterol
25
Cholesterol Elevated gt 5 Years
24
Have Prescription Coverage
72
Cholesterol Action
Following AHA Diet (MEDFICTS)
81
Taking Rx Therapy
9
Taking Non-Rx Therapies
18
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PREDICTSubsequent Evaluations
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PREDICT ResultsOTC Consumer Behavior
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PREDICT Disposition of OTC Participants
Randomized to OTC n1,924
Purchase
Yes n720
No n1,204
Wanted to consult MD 47 Recognized label
warning 18 Cost 15 Need more information 9 Not
interested / other 9
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PREDICTCharacteristics of the OTC Purchase
Population
()
Characteristics
96
Free of CHD
98
Free of diabetes mellitus
80
Knew healthy total-C was lt 200mg/dl
Had been told of high cholesterol
91
87
Total cholesterol gt 200 mg/dl
LDL-C above desirable levels
74
Based on purchasers with evaluable data
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PREDICTBehavior to Consult a Physician(OTC
Purchase Population n720)
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PREDICTProfile of Participants Who Took Without
Consulting(n72)

• Health Care Status / Risk Factor Profile
• Discussed cholesterol with MD within 6
  months 88
• Free of CHD 94
• Free of diabetes 94
• 2 people reported adverse events ofmyalgia and
  prostate surgery
• 90 did not repurchase

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PREDICTOTC Availability Did Not Distract from
Physician Involvement(Qualified Population)
OTCn315
Rxn405
Follow-up after Initial Consultation
pNS OTC vs Rx
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PREDICTUtilization of Health Care System
Maintained

• Minimal distraction from Rx therapy
• 183 participants randomized to OTC environment
  were taking prescription therapy at baseline
• Only 2 shifted to OTC therapy

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PREDICTPravachol 10 Did Not Distract From
Dietary Therapy AHA Diet Status at 6 Months
(Qualified Population)
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PREDICT Dialogue Served as Gateway into
Healthcare System

• At entry, 321 people qualified for higher dose
  prescription therapy because of high risk. At 6
  months
• 46 (n147) saw their personal physician
• 29 (n93) were taking Rx lipid lowering medicine
• New medical conditions diagnosed included
  hypertension, diabetes and thyroid disease

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PREDICTSafety Profile Maintained

• No deaths
• 19 serious adverse events unrelatedto Pravachol
• Overall incidence of AEs similar toRx experience
• Most common reason for discontinuationwas
  myalgia (1) and headache (1)no difference OTC
  vs Rx

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PREDICTTolerability of Pravachol 10 mg Is
Similar in OTC and Rx Environments (Qualified
and Treated Population)
n ()
n ()
Reasons for Discontinuing Medication
pNS OTC vs Rx
A subject could have more than 1 reason for
discontinuing study medication
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OTC Pravachol 10 mgPercent Reduction in LDL-C
(mg/dl) SEMaintained in OTC Environment
18
18
22
10
13
83 of OTC subjects reach NCEP goal
p ? 0.001 vs placebo
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Dose Response Studies
Protocol 27201-2 n61 (12 weeks)
Protocol 27201-42 n18 (8 weeks)
Protocol 27201-89 n64 (8 weeks)
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PREDICT ExtensionOTC Compliance Maintained at 1
Year
OTC
Rx
Qualified n315
Qualified n405
On Drug at Week 48 52
On Drug at Week 48 53
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PREDICT ExtensionReduction in LDL-C Maintained
at 1 Year(Extension Population)
0
OTC n186
Rx n244
10
20
30
Week 8
Week 24
Week 48
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PREDICT Behavior to Follow-Up with a Physician
at One Year
(Extension Population)
86
85
OTCn186
1
2
Rxn244
Did Not Consultat 1 Year or Prior to D/C
Discontinued and Consulted at 1 Year
Consulted Priorto D/C
Completed 48 6Weeks and Consultedat 1 Year
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Summary of PREDICT OTC Behavior

• In the OTC Environment
• 1,925 people exposed to OTC Pravachol 10
• 499 (25) bought and took drug
• 414 (83) consulted with MD and adjusted
  behavior correctly
• For people whose doctor recommended OTC
  Pravachol 10
• 52 still on drug at 48 weeks and received
  meaningful LDL-C reduction similar compliance to
  Rx group

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OTC Pravachol Trial In an Observed Naturalistic
Setting (OPTIONS)
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OPTIONSStudy Design and Objectives

• Conducted in 20 communities in 6 states
• Participants able to purchase Pravachol 10 in
  theirown pharmacies
• Observe behavior for 3 months
• HMO populations allowed access to patient charts
  for verification of data in a real world setting
• Assess
• Physician consultation within 2 months of product
  use
• Appropriate self-selection
• No CHD, DM, liver disease or pregnancy
• Not currently taking Rx lipid lowering medication
• Safety

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OPTIONS Advertising and Pharmacy Site
Characteristics

• Generalizable
• Site placement accessible to diverse populations
• Advertisement mailed to non-targeted sample

• Natural
• Posters and floor stands placedto attract
  walk-thru
• Commercial looking advertising
• Participants could purchase
• No contact for 3 months

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OPTIONSExclusion Criteria

• lt 18 years
• Research study participation lt 30 days
• HMO member lt 6 months
• Pregnant or breastfeeding

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OPTIONS ResultsBaseline Characteristics of
Participants Responding to Advertisement
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OPTIONSParticipant Disposition
Received Recruitment Mailer n161,322
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OPTIONSParticipants Responding to Advertisement
Demographics(Enrolled Population n782)
()
Mean age (yr. SD)
51 10
Age group
lt 35
5
35-54
58
55-74
35
? 75
1
Gender
Female
54
46
Male
Race
68
Caucasian
Black
21
Hispanic
5
Other
5
lt 9th Grade Literacy
12
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OPTIONSParticipants Responding to Advertisement
Health Care Status / Cholesterol
Action(Enrolled Population n782)
()
Health Care Status
Visit MD at least yearly
96
See MD specifically for cholesterol
31
Discussed cholesterol with MD within last 6 months
70
Cholesterol elevated gt 5 years
23
Cholesterol Action
Taking Rx medication
16
Taking non-prescription therapies
26
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OPTIONSPhysician Office Activities

• Participant decision to make appointment
• Participants saw their own primary care
  physicians
• HMO setting enabled physician verification of
• CHD risk factors
• Consultation

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OPTIONS ResultsConsumer Behavior
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OPTIONSPurchase Population was Appropriate

• Of 782 enrolled participants, 404 purchased
• Reasons for non-purchase
• 47 wanted to consult MD
• 20 recognized label warnings
• Of those who purchased
• 95 free of CHD, 90 free of diabetes
• Of subjects with lab values in chart
• 89 had total cholesterol gt 200 mg/dl
• 79 had LDL-C ³ 130 mg/dl

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OPTIONSBehaviors of Purchase Population(n404)
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OPTIONSProfile of Participants Who Took Without
Consulting(n157)

• 157 participants took without consulting
• 82 were not at high risk
• 75 discussed cholesterol with physician within
  prior 6 months
• 90 had Total-C gt 200 mg/dl
• Incidence of adverse events similarto those who
  consulted

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OPTIONSSafety

• Safety Profile Maintained
• No deaths reported
• No serious adverse events related to Pravachol
• No transaminase abnormalities
• Most common reason for discontinuation was
  nausea and dizziness in 1 of participants
• Safety of OTC environment demonstrated
• 99 participants enrolled were taking prescription
  therapy at baseline 11 shifted to OTC

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Summary of the Pravachol Consumer Use Program

• Comprehension of the OTC label was evaluated with
  special attention to thelow literacy population
• Identification of the OTC consumer and
  evaluation of OTC behavior has been assessed in
  large and varied populationsby different study
  designs that allowedreal world behavior
• Monitoring will continue after approval

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Characteristics of OTC Purchase Population Are
Consistent Across Studies
PREDICT(n720)()
OPTIONS(n404)()
91
90
Told of High Cholesterol
87
89
Total-C gt 200 mg/dl
74
79
LDL-C ³ 130 mg/dl
Taking Non-Prescription Therapies
23
25
7
12
Taking Prescription Therapy
See MD Yearly
82
97
Based on purchasers with available laboratory
data.
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Summary of Results

• Pravachol 10 mg can be used appropriately in an
  OTC environment
• Consumers understand label communications
• The physician remains involved initially andover
  time
• The profile of safety and biologic activity is
  maintained
• OTC availability does not significantly shift
  people from prescription therapy
• OTC availability can serve as a gateway for
  increased utilization of appropriate therapy