AA-3-1 Carola P. Friedman, MD, FACC Executive Medical Director Worldwide Consumer Medicines 7asdf.

AA-3-1AA-3-1

Carola P. Friedman, MD, FACCCarola P. Friedman, MD, FACC

Executive Medical DirectorWorldwide Consumer Medicines

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AA-3-2AA-3-2

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


18%18%

26


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


On Drug at On Drug at Week 48Week 48

52%52%


52%52%




53%53%


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

AA-3-47AA-3-47

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

AA-3-1 Carola P. Friedman, MD, FACC Executive Medical Director Worldwide Consumer Medicines 7asdf.

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Transcript of AA-3-1 Carola P. Friedman, MD, FACC Executive Medical Director Worldwide Consumer Medicines 7asdf.