aa-3-1 carola p. friedman, md, facc executive medical director worldwide consumer medicines 7asdf
TRANSCRIPT
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Carola P. Friedman, MD, FACCCarola P. Friedman, MD, FACC
Executive Medical DirectorWorldwide Consumer Medicines
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Pravachol 10 Pravachol 10 OTC ProgramOTC Program
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The OTC PopulationThe OTC Population
Men 35 years, women 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 > 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 OTCPoints to Consider with OTCAvailability of a Lipid Lowering MedicationAvailability 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 ProgramConsumer Use Program
Label Comprehension (n=612)
Pravachol Experience Documented In a Consumer Trial (PREDICT) (n=3,872)
OTC Pravachol Trial In an Observed Naturalistic Setting (OPTIONS)(n=782)
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Consumer Use Trials: ObjectivesConsumer 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
environmentsto assess comparability
OPTIONS: Capture real-world OTC setting
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Label Comprehension:Label Comprehension:People Understood the LabelPeople Understood the Label
612 people surveyed; 27% read 9th grade
No a priori cholesterol concern required
People understood key messages 9th Grade 9th
GradeLiteracy 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 TestedComparison of Label Testedand Proposed OTC Labeland 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 130mg/dl
– Cholesterol level graphic
Other changes
– Age for women changed to 45 years
– Erythromycin warning eliminated
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PREDICTPREDICTObjectivesObjectives
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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PREDICTPREDICTAdvertising Designed to Capture Broad Advertising Designed to Capture Broad
Spectrum of the PopulationSpectrum 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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Randomized to OTC Randomized to OTC or Rx Environmentsor Rx Environments
n=3,872n=3,872
Randomized to OTC Randomized to OTC or Rx Environmentsor Rx Environments
n=3,872n=3,872
Information providedby Call Center Directions to site Hours of operation No screening conducted
(women of childbearing potential excluded;5% of calls)
PREDICTPREDICTParticipant DispositionParticipant Disposition
80% responded to advertising80% responded to advertising
20% walk-thru20% walk-thru
Visited Visited Retail SitesRetail Sites
n=3,888n=3,888
Visited Visited Retail SitesRetail Sites
n=3,888n=3,888
Responded to AdvertisementResponded to Advertisementthrough Call Centerthrough Call Center
n=11,065n=11,065
Responded to AdvertisementResponded to Advertisementthrough Call Centerthrough Call Center
n=11,065n=11,065
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Generalizable Neighborhoods accessible to
– Public transportation– Minority populations– Low literacy populations
Randomization to OTC or Rx environments prior to knowledge of medical conditions
PREDICTPREDICTRetail Site CharacteristicsRetail Site Characteristics
No contact for 6 months
Natural No medical personnel Dissociated from clinics No screening performed Minimal exclusion criteria OTC participants could purchase
18 years No research study
participation 30 days Women of childbearing
potential / breastfeeding
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FillFillPrescriptionPrescription
n=352n=352
FillFillPrescriptionPrescription
n=352n=352
Participant Behavior Choices Throughout Participant Behavior Choices Throughout the Course of PREDICTthe Course of PREDICT
OTCOTC RxRx
n=1,306n=1,306n=1,160n=1,160
n=352n=352n=285n=285 Qualified and TreatedQualified and Treated
ConsultConsult
TolerabilityTolerability
SafetySafety
SafetySafety
n=405n=405n=315n=315 QualifiedQualified
Primary Primary ObjectiveObjective
OTC TreatedOTC Treatedn=499n=499
OTC TreatedOTC Treatedn=499n=499
OTCOTCPurchasersPurchasers
n=720n=720
OTCOTCPurchasersPurchasers
n=720n=720
n=1,948n=1,948n=1,924n=1,924 Randomized to Randomized to EnvironmentsEnvironments
Characterize People InterestedCharacterize People Interested
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PREDICT Results: PREDICT Results: Baseline Characteristics of Baseline Characteristics of Participants Responding to Participants Responding to
AdvertisementAdvertisement
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PREDICTPREDICTParticipants Responding to AdvertisementParticipants Responding to Advertisement
DemographicsDemographics(Randomized Population n=3,872)
Mean Age (yr.SD) 5612
75 6
Other 3
Age Group35 4
35-54 4255-74 48
Gender
Race
Black 8Hispanic 5
Caucasian 84
Male 62Female 38
(%)
9th Grade Literacy 8
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PREDICTPREDICTParticipants Responding to AdvertisementParticipants Responding to Advertisement
Health Care Status / Cholesterol ActionHealth Care Status / Cholesterol Action(Randomized Population n=3,872)
Have a Doctor 85
(%)
Following AHA Diet (MEDFICTS) 81
Taking Non-Rx Therapies 18
Have Prescription Coverage 72
Taking Rx Therapy 9
See MD Yearly 83
Saw MD Specifically for Cholesterol 25
Cholesterol Elevated 5 Years 24
Health Care Status
Cholesterol Action
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PREDICTPREDICTSubsequent EvaluationsSubsequent Evaluations
Follow-up Week 8
Initial physician consultation Physicians saw both OTC
and Rx participants Mimic typical practice Lipid evaluation Therapy recommendation
according to study guidelines
Week 0(Participant Decision)
6 month extension (Optional) Week 48
Week 24
Completion of Study Cholesterol questionnaire Lipid profile Diet assessment (MEDFICTS)
(All Participants)
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PREDICT Results:PREDICT Results:OTC Consumer BehaviorOTC Consumer Behavior
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PREDICT PREDICT Disposition of OTC ParticipantsDisposition of OTC Participants
Wanted to consult MDWanted to consult MD 47%47%
Recognized label warningRecognized label warning 18%18%
CostCost 15%15%
Need more informationNeed more information 9%9%
Not interested / otherNot interested / other 9%9%
Randomized to OTCRandomized to OTCn=1,924n=1,924
Randomized to OTCRandomized to OTCn=1,924n=1,924
PurchasePurchasePurchasePurchase
YesYesn=720n=720YesYes
n=720n=720NoNo
n=1,204n=1,204NoNo
n=1,204n=1,204
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PREDICTPREDICTCharacteristics of the OTC Purchase PopulationCharacteristics of the OTC Purchase Population
80
(%)Characteristics
Had been told of high cholesterol
87Total cholesterol 200 mg/dl *
91
LDL-C above desirable levels * 74
Knew healthy total-C was 200mg/dl
98Free of diabetes mellitus
96Free of CHD
* Based on purchasers with evaluable data
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PREDICTPREDICTBehavior to Consult a PhysicianBehavior to Consult a Physician
(OTC Purchase Population n=720)(OTC Purchase Population n=720)
0
10
20
30
40
50
60
70
80
90
100
% of Subjects
Consulted 2 Monthsof Product Use
77
Took and Never Consulted
10
Did Not Consultand Did Not Take
8
Consulted 2 Months of
Product Use
5
90%
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PREDICTPREDICTProfile of Participants Who Took Without ConsultingProfile of Participants Who Took Without Consulting
(n=72)
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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85 83
0
20
40
60
80
100
% of Subjects
OTCn=315
Rxn=405
PREDICTPREDICTOTC Availability Did Not Distract from OTC Availability Did Not Distract from
Physician InvolvementPhysician Involvement(Qualified Population)(Qualified Population)
p=NS OTC vs Rx
Follow-up after Initial Consultation
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PREDICTPREDICTUtilization of Health Care System MaintainedUtilization 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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PREDICTPREDICTPravachol 10 Did Not Distract From Dietary Therapy:Pravachol 10 Did Not Distract From Dietary Therapy:
AHA Diet Status at 6 MonthsAHA Diet Status at 6 Months(Qualified Population)
11
75
1511
69
21
0
10
20
30
40
50
60
70
80
90
100
Improved No Change Worsened
% ofSubjects
OTCn=256
Rxn=337
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PREDICTPREDICT Dialogue Served as Gateway into Healthcare SystemDialogue Served as Gateway into Healthcare System
At entry, 321 people qualified for higher dose prescription therapy because of high risk. At 6 months:
– 46% (n=147) saw their personal physician
– 29% (n=93) were taking Rx lipid lowering medicine
New medical conditions diagnosed included hypertension, diabetes and thyroid disease
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PREDICTPREDICTSafety Profile MaintainedSafety 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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PREDICTPREDICTTolerability of Pravachol 10 mg Is Similar Tolerability of Pravachol 10 mg Is Similar
in OTC and Rx Environmentsin OTC and Rx Environments (Qualified and Treated Population)(Qualified and Treated Population)
*A subject could have more than 1 reason for discontinuing study medication
OTC(n=285)
Rx(n=352)
4 (1) 3 (1)MD Discontinued Treatment
7 (2) 5 (2)Unknown
14 (5) 10 (3)Other
22 (8) 16 (5)Adverse Events
13 (5) 12 (3)Withdrew Consent
13 (5) 16 (5)Protocol Violation
10 (4) 7 (2)Lost to follow-up
79 (28) 66 (19)Total Number of Subjects
p=NS OTC vs Rx
n (%) n (%)Reasons for Discontinuing Medication*
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50%
40%
30%
20%
10%
0%
18%18%
10
Protocol 27201-2 n=61 (12 weeks)
22%22%
13
Protocol 27201-42 n=18 (8 weeks)
18%18%
26
Protocol 27201-89 n=64 (8 weeks)
Dose Response Studies
OTC Pravachol 10 mg:OTC Pravachol 10 mg:Percent Reduction in LDL-C (mg/dl) ± SEPercent Reduction in LDL-C (mg/dl) ± SE
Maintained in OTC EnvironmentMaintained in OTC Environment
17%18%
14 16
Consumer Use Studies
8 weeks
24 weeks
PREDICT OTC Subjects (n=253)
83% of OTC subjects reach NCEP goal83% of OTC subjects reach NCEP goalp 0.001 vs placebo
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PREDICT Extension:PREDICT Extension:OTC Compliance Maintained at 1 YearOTC Compliance Maintained at 1 Year
OTC Rx
QualifiedQualifiedn=315n=315
QualifiedQualifiedn=315n=315
On Drug at On Drug at Week 48Week 48
52%52%
On Drug at On Drug at Week 48Week 48
52%52%
QualifiedQualifiedn=405n=405
QualifiedQualifiedn=405n=405
On Drug at On Drug at Week 48Week 48
53%53%
On Drug at On Drug at Week 48Week 48
53%53%
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PREDICT ExtensionPREDICT ExtensionReduction in LDL-C Maintained at 1 YearReduction in LDL-C Maintained at 1 Year
(Extension Population)(Extension Population)
22%23%
22% 22%22%21%
OTCn=186
Rxn=244
Week 8 Week 24 Week 48
0%
10%
20%
30%
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PREDICT PREDICT Behavior to Follow-Up with a Physician at One YearBehavior to Follow-Up with a Physician at One Year
87 7
83
7
85
0
10
20
30
40
50
60
70
80
90
100
% ofSubjects
(Extension Population)
OTCn=186
Rxn=244
Consulted Priorto D/C
Did Not Consultat 1 Year or Prior to D/C
Discontinuedand Consulted
at 1 YearCompleted 48 ± 6Weeks and Consultedat 1 Year
85 86
2 1
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Summary of PREDICT OTC BehaviorSummary 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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OOTCTC PPravacholravachol TTrial rial IIn ann an OObservedbserved
NNaturalisticaturalistic SSetting etting (OPTIONS)(OPTIONS)
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OPTIONSOPTIONSStudy Design and Study Design and ObjectivesObjectives
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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OPTIONSOPTIONS AdvertisingAdvertising and and Pharmacy Site CharacteristicsPharmacy Site Characteristics
Generalizable– Site placement accessible
to diverse populations– Advertisement mailed to
non-targeted sample
Natural– Posters and floor stands placed
to attract walk-thru– Commercial looking advertising– Participants could purchase– No contact for 3 months
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OPTIONSOPTIONSExclusion CriteriaExclusion Criteria
< 18 years
Research study participation 30 days
HMO member 6 months
Pregnant or breastfeeding
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OPTIONS Results:OPTIONS Results:Baseline Characteristics of Baseline Characteristics of Participants Responding to Participants Responding to
AdvertisementAdvertisement
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OPTIONSOPTIONSParticipant DispositionParticipant Disposition
Walk-thruWalk-thru (n=414)(n=414)
MailerMailer (n=355)(n=355)
OtherOther (n=13)(n=13)
Walk-thruWalk-thru (n=414)(n=414)
MailerMailer (n=355)(n=355)
OtherOther (n=13)(n=13)
EnrolledEnrolledn=782n=782
EnrolledEnrolledn=782n=782
Received Recruitment MailerReceived Recruitment Mailern=161,322n=161,322
Received Recruitment MailerReceived Recruitment Mailern=161,322n=161,322
Came to PharmaciesCame to Pharmaciesn=2,207n=2,207
Came to PharmaciesCame to Pharmaciesn=2,207n=2,207
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OPTIONSOPTIONSParticipants Responding to Advertisement Participants Responding to Advertisement
DemographicsDemographics(Enrolled Population n=782)
(%)Mean age (yr.SD) 5110
75 1
Age group35 535-54 5855-74 35
Gender
46MaleFemale 54
Race
Black 21Hispanic 5Other 5
68Caucasian
9th Grade Literacy 12
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Visit MD at least yearly 96
OPTIONSOPTIONSParticipants Responding to Advertisement Participants Responding to Advertisement
Health Care Status / Cholesterol ActionHealth Care Status / Cholesterol Action(Enrolled Population n=782)
(%)
See MD specifically for cholesterol 31
Discussed cholesterol with MD within last 6 months
Taking Rx medication
Taking non-prescription therapies
Cholesterol Action
16
26
70
Cholesterol elevated 5 years 23
Health Care Status
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OPTIONSOPTIONSPhysician Office ActivitiesPhysician 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 Results:OPTIONS Results:Consumer BehaviorConsumer Behavior
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OPTIONSOPTIONSPurchase Population was AppropriatePurchase 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 200 mg/dl 79% had LDL-C 130 mg/dl
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0
10
20
30
40
50
60
70
% of Subjects
OPTIONSOPTIONSBehaviors of Purchase PopulationBehaviors of Purchase Population
(n=404)(n=404)
Consulted Within2 Months
44
Did Not Consult / Did Not Appropriately
Self-select
7
Consulted After2 Months
5
12
Did Not Consult / Did Not Take
Did Not Consult / AppropriatelySelf-selected
93%
• No CHD, DM or liver disease• Not pregnant or on Rx medication
32%
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OPTIONSOPTIONSProfile of Participants Who Took Without ConsultingProfile of Participants Who Took Without Consulting
(n=157)
157 participants took without consulting
– 82% were not at high risk
– 75% discussed cholesterol with physician within prior 6 months
– 90% had Total-C 200 mg/dl
Incidence of adverse events similarto those who consulted
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OPTIONSOPTIONSSafetySafety
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 Summary of the Pravachol Consumer Use ProgramPravachol 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 Characteristics of OTC Purchase Population Are Consistent Across StudiesPopulation Are Consistent Across Studies
74
PREDICT(n=720)
(%)
79
OPTIONS(n=404)
(%)
Taking Non-Prescription Therapies
7 12Taking Prescription Therapy
23 25
See MD Yearly 82 97
LDL-C 130 mg/dl *
87 89Total-C 200 mg/dl *
*Based on purchasers with available laboratory data.
91 90Told of High Cholesterol
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Summary of ResultsSummary 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