1 Introduction Edwin L. Hemwall, PhD Vice President Worldwide Regulatory & Scientific Affairs...

1

Introduction

Edwin L. Hemwall, PhDVice President

Worldwide Regulatory & Scientific AffairsJohnson & Johnson – Merck Consumer Pharmaceuticals

2

NDA: 21-213

Nonprescription lovastatin 20 mg

MEVACOR™ DAILY

Indication: To help lower LDL “bad” cholesterol, which may prevent a first heart attack

3

Background

July 2000: Joint Advisory Committee Review– Benefit of 10 mg dose not established– Statin OTC safety generally accepted– Consumer behavior needs further investigation

August 2000: FDA withdraws official guidance that discouraged development of OTC cholesterol-lowering drugs

4

Background

2000 to Present: New OTC paradigm established and tested with input from FDA and academic experts

– OTC dose increased to 20 mg per day; treatment to LDL-C goal

– Primary prevention target population consistent with NCEP Guidelines (ATP III, May 2001)

– CUSTOM Actual Use Study

• 3000+ consumers evaluated OTC option

• 1000+ used for up to 6 months

• Comprehensive consumer support program

5

Key Topics for Discussion Today

Can an OTC option enable consumers to have a greater role in the prevention of cardiovascular disease?

– OTC target population and label eligibility criteria

– Consumer behavior with regard to label benefit and safety directions

– Role of MEVACOR™ Self-Management System and healthcare professional

– Overall benefit / risk for lovastatin 20 mg OTC

6

Agenda

Introduction Edwin L. Hemwall, PhD

Rationale for MEVACOR™ OTC Richard Pasternak, MD

OTC Label and Self-Management System Jerry Hansen, R.Ph.

Consumer Behavior Robert Tipping, MS

Potential of MEVACOR™ OTC Jerome Cohen, MD

7

Expert Consultants Jeffrey L. Anderson, MD

Professor of Internal MedicineUniversity of Utah

Associate Chief of CardiologyLDS Hospital

Salt Lake City, UT

Herman Gibb, Ph.D.Senior Epidemiologist

Sciences International IncAlexandria, VA

Antonio M. Gotto, Jr., MD, DPhilDean of the Weill Medical College of Cornell University

Cornell University Medical CollegeNew York, NY

Thomas A. Pearson, MD, PhD. MPHAlbert D. Kaiser Professor & Chair

Department of Community & Preventative MedicineUniversity of Rochester Medical Center

Rochester, NY

8

Expert Consultants (Cont’d) David Gray, Ph.D.

Program Director for ToxicologySciences International Inc

Alexandria, VA

Sandra J. Lewis, MDClinical Associate Professor of Medicine

Oregon Health Sciences University Director of Research and Prevention

Portland Cardiovascular InstitutePortland, OR

Thomas A. Pearson, MD, PhD. MPHAlbert D. Kaiser Professor & Chair

Department of Community & Preventative MedicineUniversity of Rochester Medical Center

Rochester, NY

J. Sanford Schwartz, MDProfessor of Medicine, Health Management and Economics

University of Pennsylvania School of MedicinePhiladelphia, PA

9

Expert Consultants (Cont’d) Keith Tolman, MD

Professor of MedicineDirector of Clinical PharmacologyGastroenterology/Liver Division

University of Utah School of MedicineSalt Lake City, UT

Paul Watkins, MDVerne S. Caviness Distinguished Professor of Medicine

Professor of Pharmacotherapy Director, Clinical Research Center

University of North Carolina Chapel Hill, NC

Robert L. Wortmann, MDProfessor & Chair, Department of Internal Medicine

University of Oklahoma Health Sciences Center, Tulsa CampusTulsa, OK

10

Rationale for MEVACOR™ OTC

Richard Pasternak, MDVice President

Clinical Research Cardiovascular & AtherosclerosisMerck Research Laboratories

11


Growing cardiovascular public health problem

Appropriate OTC target and product profile

Opportunity to improve public health

12

Growing Cardiovascular Public Health Problem CVD: The #1 cause of death in the United States*

– Annual events• 1.2 million CHD events

– Economic burden: $133 billion for CHD alone

*AHA Heart Disease and Stroke Update 2004; Foot et al. JACC 2000; 35:5: 66B-80B.

0

10

20

30

40

2001 2010 2020 2030 2040 2050

Estimated CHD Prevalence Growth

Mill

ions

of

Am

eric

ans

13

Importance of Cholesterol in Heart Disease Prevention

LDL-Cholesterol (mg/dL)

Rel

ativ

e R

isk

of C

HD

(Lo

g S

cale

)

40 70 100 130 160 190

3.7

2.9

2.2

1.7

1.3

1.0

ATP III Update Grundy et al. Circulation: 2004.

14

Trends in Cholesterol Management

0

50

100

150

200

250

1988-1994 1999-2002

Tot

al C

hole

ster

ol m

g/dL

NHANES III NHANES

205 203

Healthy People 2000 Goal: <200Healthy People 2010 Goal: <197

Mean Total Cholesterol Among US Adults*

*CDC/NCHS, Health, 2004, Table 68, pgs 239-240.

15

Current Status of Cholesterol Management

Ford et al. Circulation 2003; 107: 2185-89.

TC > 240 mg/dL

TC > 200 mg/dLor receiving Rx

72%

70%

Tested

24%

12%

Treated

NHANES 1999-2000 (N = 4880)

16

Need for Improved Treatment

NHANES 1994, IMS 2003, Ingenix Treatment Gap Data 2003.

0

5

10

15

20

25

Moderate RiskPrimary Prevention

11-18 million

24-26 million

High RiskSecondary Prevention/CHD Risk Equivalents

Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

Recommended for drug therapy

17



0

5

10

15

20

25


11-18 million

24-26 million


Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

Rx treated

3-5 million

9-11 million

Gap

Gap


18



0

5

10

15

20

25


11-18 million

24-26 million


Rx focus

Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

Rx treated

3-5 million

9-11 million

Gap

Gap


19



0

5

10

15

20

25


11-18 million

24-26 million


Rx focus

Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

Rx treated

3-5 million

9-11 million

Gap

Gap


OTCOption

20


Appropriate OTC target and product profile – Target population consistent with NCEP Guidelines


21

NCEP-ATP III Treatment Guidelines & 2004 Update Report

Grundy et al. Circulation. 2004;110:227.

Risk CategoryLDL-C Goal

(mg/dL)Initiate TLC

(mg/dL)Consider Drug

Therapy

HighCHD, CHD risk equivalent

(10-y risk >20%)

<100(<70 Optional) ≥100 ≥100

(<100 Optional)

Moderately high≥2 Risk factors

(10-y risk 10%-20%)

<130(<100 Optional) ≥130 ≥130

(100-129 Optional)

Moderate≥2 Risk factors

(10-y risk <10%)<130 ≥130 ≥160

Low0-1 Risk factors <160 ≥160 ≥190

(160-189 Optional)

22

Proposed OTC Target Population

“Moderate risk” per NCEP Guidelines

Label approach– LDL 130-170 mg/dL– Plus 2 risk factors– Treatment to goal: LDL<130 mg/dL

Comprehensive cholesterol management approach– Lifestyle changes - diet and exercise– Self-management system reinforces label– Collaboration with healthcare professional

23


Appropriate OTC target and product profile – Target population consistent with NCEP Guidelines– Proven efficacy and safety of lovastatin 20 mg


24

Statins

2002 ACC/AHA/NHLBI Clinical Advisory

– “Statins have demonstrated a decrease in CHD and total mortality, reductions in myocardial infarctions, revascularization procedures, stroke, and peripheral vascular disease…”

– “Statins have been proved to be extremely safe in the vast majority of patients receiving them…post-marketing reports of adverse events have been very limited when considered in comparison to the very large number of persons safely receiving these drugs.”

Proven Efficacy, Proven Safety

25

2° Prevention / Very High CHD Risk

1° Prevention / Low-Moderate

CHD Risk

Proven Benefit Across Risk GroupsE

stim

ated

Rat

e o

f C

HD

Dea

th a

nd

N

on

-Fat

al M

I in

Pla

ceb

o S

ub

ject

s/10

Yrs

6%

52%

36%

24%

20%

16%

12%

10%

26%

(Lovastatin)AFCAPS/TexCAPS

(Atorvastatin)ASCOT

(Atorvastatin)CARDS

(Pravastatin)WOSCOPS

(Simvastatin)HPS

(Pravastatin)LIPID

(Simvastatin)4S

CARE(Pravastatin)

PROSPER(Pravastatin)

26

2° Prevention / Very High CHD Risk

1° Prevention / Low-Moderate

CHD Risk

Proven Benefit Across Risk GroupsE

stim

ated

Rat

e o

f C

HD

Dea

th a

nd

N

on

-Fat

al M

I in

Pla

ceb

o S

ub

ject

s/10

Yrs

6%

52%

36%

24%

20%

16%

12%

10%

26%

(Lovastatin)AFCAPS/TexCAPS

(Atorvastatin)ASCOT

(Atorvastatin)CARDS

(Pravastatin)WOSCOPS

(Simvastatin)HPS

(Pravastatin)LIPID

(Simvastatin)4S

CARE(Pravastatin)

PROSPER(Pravastatin)

25-50%Relative Risk ReductionRegardless of Baseline

Risk

27

Significant Risk Reduction Across LDL Levels

Grundy et al. Circulation: 2004.

LDL-Cholesterol (mg/dL)

Rel

ativ

e R

isk

of C

HD

(Lo

g S

cale

)

40 70 100 130 160 190

3.7

2.9

2.2

1.7

1.3

1.0

50%

39%Relative Risk Reduction

33%

28

Efficacy of Lovastatin

Megatrials in ~15,000 patients – EXCEL: 20-80 mg/day, 48 weeks– AFCAPS/TexCAPS: 20-40 mg/day, 5 yrs

Lovastatin 20 mg:– Improves Lipid Profile:

• LDL-C -24%, HDL-C +6%, Total-C -17%

Reduces the risk of a first coronary event by 37% in moderate risk individuals (AFCAPS/TexCAPS)

Proven Benefit

29

Potential Benefit in OTC Eligible Population

0.0 0.5 1.0 1.5 2.0

Favors Lovastatin Favors Placebo

All AFCAPS/TexCAPS, 20/40 mgN = 6,605

Relative Risk (95% Confidence Interval)Cox Proportional Hazards Model

30


0.0 0.5 1.0 1.5 2.0

OTC Eligible,Achieved LDL-C < 130, 20/40 mgN = 2,518




31


0.0 0.5 1.0 1.5 2.0

OTC Eligible, 20 mg onlyN = 1,550 (Non-Titrators)

OTC Eligible,Achieved LDL-C < 130, 20/40 mgN = 2,518




32

Safety of Lovastatin

Extensive experience– 17+ years in market– 27+ million patient-treatment years

Strong clinical data – AFCAPS/TexCAPS & EXCEL

• ~15,000 patients• Doses from 20-80mg

– 20-40mg comparable to placebo for potential safety concerns

• Liver, muscle, drug interactions

Proven Safety

33

Lovastatin Safety: Liver

Asymptomatic minor elevations of LFTs are:– Seen with all statins, fibrates, niacin– Dose and potency dependent– Often transient and resolving on therapy – Not associated with clinical liver disease

Liver function testing not proposed for OTC dose

Tolman. Am J Cardiol. 2002;89:1374-80.

34


Liver EnzymesALT Consecutive Elevations 3X Upper Limit of Normal

PlaceboN (%)

20 mgN (%)

40 mgN (%)

EXCEL(1 year) 2/1639 (0.1%) 2/1625 (0.1%) 12/1629 (0.9%)

AFCAPS/TexCAPS(5+ years) 11/3248 (0.3%)

20/40 mg 18/3243 (0.6%)

20 mg 11/1586 (0.7%)

40 mg 7/1657 (0.4%)

Clinical Data

35

Worldwide Adverse Experience System (WAES)

Spontaneous reports of adverse events in postmarketing experience

Voluntary reporting system

Includes all reports independent of perceived causality

Does not provide incidence rate

36


Acute liver failure

– Background rate

• 1-10 cases/million annually

– Reports with lovastatin

• 25 cases

• ~1 report/million patient-treatment-years

WAES reports from health care professionals up to 01-Nov-2003.


37

Lovastatin Safety: Muscle

Muscle toxicity is rare for low-dose statins:

– Occurs with all statins and fibrates

– Dose related

– Self-recognizable muscle symptoms

• Prompt recovery on discontinuation

• Rarely severe (rhabdomyolysis)

Thompson et al. JAMA. 2003;289:1681-90.; Gotto. Arch Intern Med 2003;163:657-9; Bradford et al. Arch Int Med. 1991;151:43-9; Downs et al. Am J Cardiol. 2001;87:1074-79.

38


Muscle EnzymesCPK>10X Upper Limit of Normal

PlaceboN (%)

20 mgN (%)

40 mgN (%)

EXCEL(1 year) 7 (0.4%) 3 (0.2%) 3 (0.2%)

AFCAPS/TexCAPS(5+ years) 21 (0.6%)

20/40 mg: 21 (0.6%)

20 mg: 11 (0.7%) 40 mg: 10 (0.6%)

No significant difference between lovastatin 20-40 mg and placeboNo significant difference between lovastatin 20-40 mg and placebo

Clinical Data

39


Myopathy: Myalgia with CPK>10x ULN

Rhabdomyolysis: Myopathy with end-organ damage

Myopathy

Rhabdomyolysis

AFCAPS/TexCAPS

Lovastatin20-40 mg(N=3304)

0

1

Placebo

(N=3301)

0

2

EXCEL

Lovastatin20 mg

(N=1642)

0

0

Placebo

(N=1663)

0

0

40


Rhabdomyolysis rare

– 336 spontaneous reports

• 1.2 / 100,000 patient-treatment-years

• 158 without potentially interacting drugs†

– 41 reports with lovastatin 20 mg


† Fibrates, niacin, cyclosporine, and/or strong CYP3A4 inhibitors.WAES reports from Health Care Professionals up to 01-Nov-2003.

41

Lovastatin Safety: Drug Interactions

Strong CYP3A4 inhibitors – May increase risk of myopathy with

concomitant administration

OTC label instructs: Ask doctor or pharmacist if taking any prescription medicine

– Package insert and education materials list potentially interacting drugs

42


† Serious, drug-related, or caused discontinuation.‡ Erythromycin, clarithromycin, ketoconazole, itraconazole, nefazodone.

Clinical Experience with Strong CYP3A4 Inhibitors‡AFCAPS/TexCAPS (N=6605)

Musculoskeletaladverse experience

Myalgia

Muscle weakness

Myopathy/rhabdomyolysis

Adverse Experience†

42 (8.0)

3 (1.0)

1 (0.2)

0 (0.0)

Lovastatin20 to 40 mg

(N=535)n (%)

39 (8.0)

4 (1.0)

2 (0.4)

0 (0.0)

Placebo(N=512) n (%)

43


Rhabdomyolysis with Interacting Drugs

– 178 of 336 reports include potentially interacting drugs

• Fibrates (97)

• Cyclosporine (34)

• Niacin (34)

• Strong CYP3A4 Inhibitors (41)

– With strong CYP3A4 inhibitor only (28/41)

• Erythromycin/clarithromycin (16)

• Itraconazole/ketoconazole (5)

• Nefazodone (3)

• Mibefradil (3)

• Protease inhibitor (1)


44

Lovastatin Safety: Pregnancy

Prescription label: pregnancy Category X– Non-specific animal findings at 10-80 times maximum

human dose (80 mg) based on plasma AUC values– No benefit of short-term treatment during pregnancy

Proposed OTC label– “Do NOT use if you are pregnant or breast-feeding”

45

Strong Product Profile for OTC Use

Data demonstrates

– Significant benefit of 20 mg in OTC target population

• Cholesterol lowering efficacy

• Reduction in cardiovascular outcomes

– Safety profile comparable to placebo up to 40 mg

• No apparent risk of liver adverse events

• Low risk of muscle adverse events

• Labeling will further minimize risks

46



Opportunity to improve public health– Consumer interest in an OTC option


47

Consumer Interest in OTC Options National Lipid Association 2004 survey*

– Majority of consumers are making more health decisions on their own

– 72% of cholesterol concerned consumers are interested in learning more about an OTC statin option

National Consumer’s League 2004 survey**– 3 of 4 consumers at moderate risk and not taking

prescription therapy say they prefer OTC for heart health prevention

Consumers spend more than $1 billion per year on heart health OTC and food products***

UK approved non-prescription ZOCOR

*Pearson et al. AJC. 2004;94:16F-21F; **National Consumer League/Harris Interactive 2004 Survey Q#611;***Information Resources Inc.

48



Opportunity to improve public health– Consumer interest in OTC option – Public health prevention approach


49

Need for Comprehensive Approach to Cholesterol Management

US Population (>45 Yrs.) by Total Cholesterol (NHANES ‘99-’02)

0

5

10

15

20

25

30

75 100 125 150 175 200 225 250 275 300 >325

Total Cholesterol (mg/dL)

Mill

ions

50

Need for Comprehensive Approach to Cholesterol Management

0

5

10

15

20

25

30

75 100 125 150 175 200 225 250 275 300 >325

Total Cholesterol (mg/dL)

Mill

ions

US Population (>45 Yrs.) by Total Cholesterol (NHANES ‘99-’02)

51




Summary Rationale for MEVACOR™ OTC

52




Demonstrated appropriate consumer behavior


53

MEVACOR™ OTCLabel & Self-Management System

Jerry Hansen, RPhVice President

New Product Development and Consumer ResearchJohnson & Johnson – Merck Consumer Pharmaceuticals

54

Extensive Consumer Research

Consumer understanding (attitude & behavior)

Label development & comprehension

Self-Management System development

Actual use studies (lovastatin 10 & 20 mg)

Total

Research

10,600

8,900

2,700

12,400

34,600

Approximate Numberof Participants

55

People Likely to Take Actionwith OTC Option

Demographics representative of US population

– Older (45+)

– Other factors similar to US averages

• Gender

• Income

• Race

• Education

56


Attitudes and behaviors not representative

– Very active in own healthcare - more likely to:

• Knowledgeable about health issues

• Diet & exercise

• Take aspirin for heart health

• Take vitamins & supplements

57


Attitudes and behaviors not representative

– Very active in own healthcare

• Strong relationship with physician

– 80%+ see doctor at least once a year

– 70%+ had a cholesterol test in past year

– 80% have discussed cholesterol with doctor

• “Motivated health-conscious”

58

Higher Interest in OTC vs. RxUntreated Potential or Known Moderate Risk

N=730

National Consumer League/Harris Interactive 2004 Survey Q#611.

Consider taking

Recommend to family member or friend

Seek more information about

76

76

75

OTC%

24

24

25

Rx%

Please tell us which product you would be more likely to…

59

Why Moderate Risk Untreated Prefer OTC to Rx

Q#606: Please tell us which product you believe would be….Untreated Potential or Known Moderate Risk.National Consumer League/Harris Interactive 2004 Survey.

RxOTC

9%91%Easier to buy at a store where

you shop

27%73%Easier to keep taking every day

84%16%More suitable for someone who is

in poor health

22%78%More suitable for someone who

takes charge of his health

30%70%More suitable for someone with

your health care needs

N=730

60

Label & Self-Management System

Development process

– Consistent with NCEP Guidelines but understandable by consumers

– Incorporated iterative consumer feedback

– Developed language & tools to ensure effective communication

– Comprehensive approach to cholesterol management

• Diet, exercise

61

Label & Self-Management System

Healthcare professional collaboration

– Before using any OTC for the first time, healthcare professionals are frequently consulted*

• Doctor (79%)

• Pharmacist (64%)

– Data is consistent for those likely to use MEVACOR™ OTC**

• 80% claim they will talk to a doctor prior to, or shortly after beginning use

*Prevention Magazine National Survey. **BASES, NLA , NCL.

62

Key Label Messages

OTC target consistent with NCEP Guidelines

– LDL (130-170 mg/dL)

– Male ≥ 45; female ≥ 55

– Plus one additional risk factor

• Family history

• Smoking

• Low HDL

• High blood pressure

63

Key Label Messages (Cont’d) Do not use if:

– Liver disease– Pregnant or breast-feeding– Allergy to lovastatin

Do not use – see doctor about Rx therapy:– CHD– Diabetes– Taking cholesterol medicine– Triglycerides ≥ 200 mg/dL

Clear Safety Warnings– Drug interactions– Muscle pain

64

Key Label Messages (Cont’d)

Encourage lifestyle changes & testing

– Before using you must have:

• Tried diet & exercise to reduce cholesterol

• Had a fasting cholesterol test within the past year

– Test at 6 weeks to see if you got to goal

• If yes, keep taking daily and test yearly

– Continue diet & exercise while taking MEVACOR™ OTC

65

Key Label Messages (Cont’d)

Drives ongoing healthcare professional interaction

– Consult doctor or pharmacist if questions

• If do not reach LDL goal, talk to doctor: “OTC may not be enough for you”

• Talk to doctor if there is a change in your health

• Talk to your doctor or pharmacist if you are taking a new prescription

66

Package Label Comprehension Study

Methodology

– Representative sample tested

• Projectable representative sample: n=696

• Low literacy subgroup: n=203 (REALM)

• Ethnic subgroup: n=207

– Respondents reviewed label & answered questions

• Identical label used in CUSTOM

– “Correct” and “correct/acceptable” scoring

• “Acceptable” often referred to checking with doctor

67

Package Label Comprehension Study

Results 80% correct/acceptable for most measures 90% correct/acceptable for key safety messages

Conclusions– Very effective at communicating key messages in all

groups (low literacy/ethnic) – Consumers understood to ask healthcare

professionals if questions

68

Self-Management System

Goal: To provide additional information & tools to reinforce key label messages

– Incorporated input from external experts

– Multiple methods of delivering information to appeal to different learning styles

– All elements part of proposed NDA labeling

• Required in-market

– Self-Management System tested in CUSTOM

Overview

69

In-StorePre-Purchase Post-Purchase

Healthcare Professional Interaction

MEVACOR™ OTCSelf-Management System

70



In-StorePre-Purchase Post-Purchase

71

Communication & Education– Know your numbers– OTC is not right for everyone,

ask if you're not sure

Eligibility Assistance– Physician & pharmacist– Trained product specialist

• Toll-free & on-line• Questions and related services

Pre-Purchase Assistance

72

Post-Purchase

Pre-Purchase



In-Store

73

In-Store Assistance

Pharmacy Support– “Pharmacy Care OTC”– Pharmacist & staff training

Enhanced Retail Communication– Interactive tools to support label

74

“Pharmacy Care OTC”

New approach developed by American Pharmacists Association (APhA) and other leading pharmacy groups

Features– Distributed voluntarily only in stores with a pharmacy– On open shelf with current OTC products– Does not require pharmacist intervention but strongly

supports it– Expands supportive services

• Cholesterol testing, counseling

75

Store Shelf Communication

Highlights two decision processes Interactive tools Encourages dialogue with pharmacist

76

In-Store


Pre-Purchase


Post-Purchase

77

Post-Purchase Assistance

In-package materials

– Educational brochure

– Package insert & Q&A

– “Quick Start Guide”

– Cholesterol testing

78

Cholesterol Testing

Cholesterol testing referral system

Coupon for six-week cholesterol test

Options– Doctor’s office/laboratory/hospital– Retail setting– Walk-in clinics– At-home kit

79

Post-Purchase Assistance

Adherence Program

– Toll-free hotline & website

– Video & AHA cookbook

– Newsletters, postcards, e-mail reminders

80

Adherence Program

Customized to start date

First three months focus on– Eligibility– Treatment to goal

Subsequent focus– Diet & exercise– Adherence– Healthcare professional

interaction

81

Post-PurchaseIn-StorePre-Purchase



82

Healthcare Professionals

Encourages ongoing dialogue concerning– OTC questions– Testing & monitoring– Higher CHD risk referral

83

Pre-Purchase In-Store


Post-Purchase


84

Conclusions

Those likely to take action: “Motivated Health Conscious”

85

Conclusions


Self-Management System offers multi-faceted support to reinforce key label messages

– Included as part of proposed NDA labeling and required in-market

– Demonstrated feasibility with key partners• Retail, pharmacy, testing companies

86

Conclusions





Committed to extensive post-marketing surveillance

87

Conclusions





Committed to extensive post-marketing surveillance

Self-Management System fully evaluated in CUSTOM

88

CONSUMER BEHAVIOR

Robert W. Tipping, MSDirector, Clinical BiostatisticsMerck Research Laboratories

89

Key Questions

Will the MEVACOR™ OTC Self-Management System allow consumers to:

1. Make appropriate initial use decisions?

2. Self-manage the potential safety risks over time?

3. Self-manage their cholesterol over time and obtain benefit?

90

The CUSTOM StudyConsumer Use Study of OTC MEVACOR™

Demonstrating Consumer Behavior in an OTC Setting

91

• No specificlabel eligibilitycriteria

• 14 sites in7 geographicareas

• Minority ads

• TV• Print• Radio

OTC-likeRecruitment

CUSTOM Study Design

92



• Minority ads


OTC-likeRecruitment

• Naturalistic retail setting• In-store components of System• All comers accepted

Site Visit Initial Use Decision

CUSTOM Study Design

Self Assessment

• Review of label• Option to leave to obtain information• Purchase cholesterol test (optional)• Pharmacist available to answer

questions if asked• Purchase of drug required

Naturalistic Observation

93



• Minority ads


OTC-likeRecruitment



CUSTOM Study Design

Self Assessment



On-going Use


Self-guided Behavior

& Product Use

• Follow-up test• Treatment to goal• New conditions

6 months

Visits not scheduled

94



• Minority ads


OTC-likeRecruitment



CUSTOM Study Design

Self Assessment



On-going Use



& Product Use


6 months


Pre & post lipid values obtained

95



• Minority ads


OTC-likeRecruitment



CUSTOM Study Design

En

d O

f S

tud

y Q

ues

tio

ns

Self Assessment



On-going Use



& Product Use


6 months



96



• Minority ads


OTC-likeRecruitment

Po

st C

US

TO

M S

urv

ey



CUSTOM Study Design

En

d O

f S

tud

y Q

ues

tio

ns

Self Assessment




& Product Use


6 months

On-going Use




97

Pre-Purchase In-Store


Post-Purchase


98

CUSTOM Study Design

Decisions about product purchase and use– Initial decision to use– Ongoing decisions regarding continued use

Interactions with healthcare professionals– Important factor in determining appropriateness

of product use– Creating and maintaining partnerships

Diet and exercise

Analysis of Behavior

99

CUSTOMActual Use Results

100

CUSTOM ResultsParticipant Flow Through Study

11252 Callers

(Responded to advertising)

3316 Evaluators

(Evaluated MEVACOR™ OTC System at the Site)

2111 Non- purchasers

1205 Purchasers

52Behavior Not Analyzed

50 Missing data2 Protocol violators

1059 Users

398 Post- CUSTOM

Survey

94

Purchaser, Non-Users

11252 Callers


3316 Evaluators


2111 Non- purchasers

1205 Purchasers



1059 Users

398 Post- CUSTOM

Survey

94


101

CUSTOM Results

59% men

Median age – 53 yrs

28% Non-Caucasian

12% Low-literacy

Population ProfileEvaluators(n=3316)

102

CUSTOM Results

1 serious, drug-related AE– 63 year-old female with acute allergic

reaction

1 death, probably not related to drug– 50 year-old male with CVA

No serious, drug-related muscle or liver AEs

No new safety issues identified

MEVACOR™ was generally safe and well tolerated in this OTC population

Safety SummaryUsers

(n=1061)

103

CUSTOM

Benefit Criteria

Initial Use

Benefit Criteria

Ongoing Use

Safety Warnings

Initial Use

Safety Warnings

Ongoing Use

Label

104

CUSTOM

Benefit Criteria

Initial Use

Benefit Criteria

Ongoing Use

Safety Warnings – Initial Use

Pregnant/breast feeding Liver disease Previous muscle pain Interacting meds Rx Lipid-lowering therapy

Safety Warnings - Ongoing Use

New Rx New medical condition Unexplained muscle pain

Label

105

CUSTOM

Benefit Criteria – Initial Use

Age Lipids Risk Factors

Benefit Criteria – Ongoing Use

Follow up Lipid Test LDL-C Goal

Safety Warnings

Initial Use

Safety Warnings

Ongoing Use

Label

106

CUSTOM

Benefit Criteria – Initial Use

Age Lipids Risk Factors

Benefit Criteria – Ongoing Use

Follow up Lipid Test LDL-C Goal

Safety Warnings – Initial Use

Pregnant/breast feeding Liver disease Previous muscle pain Interacting meds Rx Lipid-lowering therapy


New Rx New medical condition Unexplained muscle pain

Label

107

Key Questions





108

Key Questions


1. Make appropriate initial use decisions? 3316 Evaluators

– 2111 Chose not to purchase– 64 Purchased but chose not to use– 659 Chose to use appropriately (safety and

benefit criteria)

109



– 2111– 64 – 659

Key Questions

= 2834 (86%)

110



– 2111– 64 – 659

– 109 (3%) use inconsistent with label safety warnings

Key Questions

= 2834 (86%)

111


11252 Callers


3316 Evaluators


2111 Non-purchasers

1205 Purchasers



1059 Users

398 Post-CUSTOM

Survey

94


11252 Callers


3316 Evaluators


2111 Non-purchasers

1205 Purchasers



1059 Users

398 Post-CUSTOM

Survey

94


112

CUSTOM: Non-Purchaser Behavior

2111 Non-purchasers

21%“Needed More Info”

79%“Not Interested in Buying”

19%Talked to their doctor

63%“Believed Not Right for Them”

18%Other

(Cost, convenience, etc.)

In-Store OTC System DiscouragedInappropriate People from Purchasing

113

CUSTOM: Purchaser, Non-User Behavior

94Purchaser, Non-Users

30 Did not Leave site with MEVACOR™ OTC

64 Left site with MEVACOR™ OTC But Never Used

Majority said either: “Dr. advised against” or

“Learned not right for me”

Post-Purchase OTC System Discouraged Additional Inappropriate People from Using

114


11252 Callers


3316 Evaluators


2111 Non-purchasers

1205 Purchasers



1059 Users

398 Post-CUSTOM

Survey

94


11252 Callers


3316 Evaluators


2111 Non-purchasers

1205 Purchasers



1059 Users

398 Post-CUSTOM

Survey

94


115

CUSTOM Results

80%

Initial Decision to Use(N=1059)

Benefit and Safety Behavioral Assessment

116

CUSTOM Results



Label SafetyWarnings

SupplementalAnalyses

90%

n=1044

80%

117

CUSTOM Results



Label BenefitCriteria



66%

90%

n=1044

80%

118

CUSTOM Results



All LabelCriteria



Pre-SpecifiedAnalysis


55%66%

90%

n=1037n=1044

80%

119

CUSTOM Results

Met Did NotMeet

90%

10%

% o

f U

sers

(n=

1044

)

0

10

20

30

40

50

60

70

80

90

100

Label Safety Criteria

Users who did not talk with doctor (n=109)

Safety Warnings - Initial Use

120

CUSTOM Results

Met Did NotMeet

Pregnant LiverDisease

PreviousMuscle

Pain

On RxLLT

90%

10%

12

80

300

152

609

PotentiallyInteracting

Med

Evaluators


% o

f U

sers

(n=

1044

)

0

10

20

30

40

50

60

70

80

90

100

# of

Ind

ivid

uals

0

100

200

300

400

500

600



121

CUSTOM Results

Met Did NotMeet


PreviousMuscle

Pain

On RxLLT

90%

10%

12

80

3

300

53

152

1052

609


Med

Evaluators


0

% o

f U

sers

(n=

1044

)

0

10

20

30

40

50

60

70

80

90

100

# of

Ind

ivid

uals

0

100

200

300

400

500

600



122

CUSTOM Results

Met Did NotMeet


PreviousMuscle

Pain

On RxLLT

90%

10%

12

80

3

300

53

152

1052

609


Med

Evaluators


OTC System Discourages Inappropriate Purchase

0

% o

f U

sers

(n=

1044

)

0

10

20

30

40

50

60

70

80

90

100

# of

Ind

ivid

uals

0

100

200

300

400

500

600



123

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)

Met or Closely Met Label

Criteria

Did not Meet Label Benefit

Criteria

66%

34%

Benefit Criteria - Initial Use

124

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)


Criteria


Criteria

66%

34%

72% eligible for statin therapy according to NCEP Guidelines


125

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)


Criteria


Criteria

Did not Know Lipid Profile

(n=188)

66%

34%

18%

93% had elevated lipids

51% knew TC

Median LDL-C = 165 mg/dL


126

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)


Criteria


Criteria


(n=188)

Triglycerides >200 mg/dL

(n=170)

66%

34%

18% 16%


Median total-C = 253 mg/dL

Median LDL-C = 146 mg/dL

74% had triglycerides <400 mg/dL


127

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)


Criteria


Criteria


(n=188)


(n=170)

Substituted for Rx

Therapy (n=11)

66%

34%

18% 16%

1%

Out of 609 Evaluators on Rx LLT


128

0

10

20

30

40

50

60

70

80

90

100

CUSTOM Results%

of

Use

rs (

n=

1044

)


Criteria


Criteria


(n=188)


(n=170)

CHD, Stroke, Diabetes

(n=70)

Substituted for Rx

Therapy (n=11)

66%

34%

18% 16%

7%1%


129

0

100

200

300

400

500

600

CUSTOM Results #

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

570Initial Decision to Use

Consumers at Higher Risk (CHD, Stroke, Diabetes)

130

0

100

200

300

400

500

600

CUSTOM Results#

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

Users(n=1059)

at Higher Risk

570

167

Initial Decision to Use


131

0

100

200

300

400

500

600

CUSTOM Results#

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

Users(n=1059)

at Higher Risk

570

167

97


Did speak with doctor before use


132

0

100

200

300

400

500

600

CUSTOM Results#

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

Users(n=1059)

at Higher Risk

Users Who Did Not Speak to

Doctor Before Use

570

167

70

97




133

0

100

200

300

400

500

600

CUSTOM Results#

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

Users(n=1059)

at Higher Risk

570

167

70

97


26

Had doctor interaction during study




Doctor Before Use

134

0

100

200

300

400

500

600

CUSTOM Results#

of I

ndiv

idua

ls

Evaluators(n=3316)

at Higher Risk

Users(n=1059)

at Higher Risk

570

167

70

97


26


66% not on lipid lowering therapy at time of study



Had doctor interaction during study


Doctor Before Use

135

CUSTOM Results

3%

3%

8%

86%

Summary of Initial Use DecisionsN=3316

Consumers Can Select Appropriately

Non-Purchasersn=2111

Purchaser, Non-Usersn=64

Users making appropriate decisionsn=659

Unknown

Safety Warnings

Benefit Criteria

136

Key Questions





137

Key Questions


2. Self-manage the potential safety risks over time? 1059 Users

– 693 No emergent medical condition/situation– 366 With emergent medical condition/situation

• 345 (94%) continued use consistent with label• 21 (6%) continued use inconsistent with label

138

Key Questions


3. Self-manage their cholesterol over time and obtain benefit? 1059 Users

– 74% of users obtained follow-up test or discontinued before 6 weeks

– 75% of users with follow-up test followed label directives regarding LDL-C goal

– 21% reduction in LDL-C

139

CUSTOM Results

75%

Ongoing Decisions about Use(N=1059)


140

CUSTOM Results

75%



94%

n=366



141

CUSTOM Results






53%

94%

n=936n=366

75%

142

CUSTOM Results





Pre-SpecifiedAnalysis


53%

94%

n=936n=366

All LabelCriteria

50%

n=986

75%

143

CUSTOM Results%

of

Use

rs w

ith

New

Con

ditio

n(n

=36

6)

94%

0

20

30

40

50

60

70

80

90

100

10

Met Did NotMeet


6%


144

CUSTOM Results%

of

Use

rs w

ith

New

Con

ditio

n(n

=36

6)

94%

0

50

100

150

200

250

300

350

400

270

New Rx

161

New Medical

Condition

63

UnexplainedMuscle Pain

0

20

30

40

50

60

70

80

90

100

10

Met Did NotMeet


6%

# of

Ind

ivid

uals


145

CUSTOM Results%

of

Use

rs w

ith

New

Con

ditio

n(n

=36

6)

94%

0

50

100

150

200

250

300

350

400

270

New Rx

161

3

New Medical

Condition

63

16

UnexplainedMuscle Pain

0

20

30

40

50

60

70

80

90

100

10

Met Did NotMeet


6%2

# of

Ind

ivid

uals


146

98% 2%

Consumers Can Manage Potential Safety Risks Over Time

CUSTOM Results

No new conditionn=693

Users making appropriate decisionsn=345

Safety Warningsn=21

Summary of Ongoing Use Decisions – Safety WarningsN=1059

147

Key Questions




3. Self-manage their cholesterol over time and obtain benefit? • Follow-up lipid test

148

0

20

40

60

80

100

CUSTOM Results

% ofUsers

(n=1059)

26%

11%

63%74% of users

made appropriate decision to get follow-up test

Got a Test

D/C Before Needing Test

Did Not Get Test

Follow-Up Cholesterol Test

Benefit Criteria - Ongoing Use

149

0

20

40

60

80

100

% ofUsers

(n=1059)

26%

11%

63%

Got a Test

D/C Before Needing Test

Did Not Get Test

75% followed label directivesregarding LDL-C goal

CUSTOM Results

Follow-Up Cholesterol Test


150

Key Questions




3. Self-manage their cholesterol over time and obtain benefit? • Follow-up lipid test• Lipid results

151

CUSTOM ResultsUsers Achieved Beneficial Lipid Lowering

with Lovastatin 20 mg/day

24% 24%

Controlled Clinical Studies

21%25%

CUSTOM Study

AFCAPS/TexCAPS

EXCELFastedFasted

&Non-Fasted

50%

40%

30%

20%

10%

0%n=243 n=811 n=2276 n=1642

152

Key Questions




3. Self-manage their cholesterol over time and obtain benefit? • Follow-up lipid test• Lipid results• Persistence/compliance

153

CUSTOM Results

0

20

40

60

80

100

% ofUsers

(n=1059)

21%

17%

62%79% of users

made appropriatepersistence decision

Persistent for 6 months

Appropriately discontinued

Other discontinued

“Did not reach goal” “Doctor advised me to discontinue” “Learned OTC was not right for me”

Persistence


154

Key Questions




3. Self-manage their cholesterol over time and obtain benefit? • Follow-up lipid test• Lipid results• Persistence/compliance• Diet and exercise

155

Dietary Habits*

0%

20%

40%

60%

80%

100%

Baseline Week 26

CUSTOM Results

* Diet assessed with MEDFICTS.

Step II dietStep I dietNeither

47%59%

36%30%

17% 11%

Heart-Healthy Lifestyle Behaviors Improve

156

CUSTOM Results

74% of users obtained follow-up test or discontinued before 6 weeks

75% of users with follow-up test followed label directives regarding LDL-C goal

21% reduction in LDL-C

CUSTOM ResultsSummary of Ongoing Use Decisions – Benefit Criteria

N=1059

Consumers Can Manage Their Cholesterol Over Time and Obtain Benefit

157

CUSTOM Results

Will the MEVACOR™ OTC Self-Management System promote consumer interactions with

healthcare professionals?

158

CUSTOM Results

0

10

20

30

40

50

60

70

80

90

100

% o

f In

divi

dual

sC

onsu

lting

Doc

tor

22%

57%

74%

Non Users N = 2111

Users N = 1059

High CHD Risk Users

N = 167

MEVACOR™ OTC Self-Management SystemEncourages Consumer Involvement with HCP

159

CUSTOM Conclusions

The Self-Management System discourages inappropriate use

160

CUSTOM Conclusions


The majority of consumers who choose to use MEVACOR™ OTC will

– Be appropriate for self-management– Gain clinical benefit– Be at minimal safety risk

161

CUSTOM Conclusions


The majority of consumers who choose to use MEVACOR™ OTC will

– Be appropriate for self-management– Gain clinical benefit– Be at minimal safety risk

There will be important public health benefits from the Self-Management System including

– Increased healthcare professional interactions– Improved heart health awareness and behavior

162

The Potential of MEVACOR™ OTC

Jerome D. Cohen, MD, FACC, FACP, FAHAProfessor Internal Medicine

Director of Preventive Cardiology ProgramSt. Louis University

163

Key Questions

Is there a need for an OTC option?

Is MEVACOR™ 20 mg safe for OTC use?

Can consumers manage cholesterol effectively with OTC?

Will OTC divert consumers from physician care and from heart-healthy lifestyle practices?

What’s the overall benefit/risk of MEVACOR™ OTC?

164

Key Questions


165

Large Treatment Gaps Remain


0

5

10

15

20

25


11-18 million

24-26 million


Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

Rx treated

3-5 million

9-11 million

Gap

Gap


166

Key Questions



167

Proven Safety Profile

17+ years in-market experience

27+ million patient-years of treatment

Safety profile comparable to placebo

168

Key Questions




169

Consumers Are Already Using OTC Productsfor Chronic Asymptomatic Conditions

~35 million use calcium*

~26 million use aspirin for heart health**– 27% self-initiated

~14 million use heart health supplements*** – e.g., Garlic, vitamin E, antioxidants, niacin,

red rice yeast

*Osteoporosis Omnibus Study, 2001.**McNeil Pharmaceutical internal data.***Cholesterol Omnibus Study, 2004.

170

Consistent Data Show Consumers Exhibit Appropriate Behavior

* Made decision to purchase.

OTC Users:

Total Cholesterol >200 mg/dL(Pre-treatment)

Taking Rx lipid therapy

OTC User Behaviors:

Appropriately self-selectSafety

Benefit

n/a

5

97

68

Lovastatin 10 mgActual UseStudy 081N=1229*

%

93

3

95

66

Lovastatin 10 mgActual UseStudy O76N=2662*

%

87

5

90

66

CUSTOMN=1059

%

171

a Pearson et al. Arch Intern Med 2000; 160:459-67. b Frolkis et al. Am J Cardiol 2004; 94:1310-1312.c Benner et al. JAMA 2002;288:455-461. d Grant et al. Arch Intern Med 2004; 164:2343-2348.e AFCAPS data. f EXCEL data.

Key Results of OTC Therapy Consistent with Prescription Experience

Obtained goal

Appropriate persistence (6 months)

Average LDL-C reduction

Current Stateof Rx Care(Statins)

(%)

37a-57b

56c-80d

24e-25f

CUSTOMResults

(%)

62

62-79

21

172

Key Questions





173

MEVACOR™ OTC System Encourages Interaction with Healthcare Professionals

0

10

20

30

40

50

60

70

80

90

100

% o

f In

divi

dual

sC

onsu

lting

Doc

tor

22%

57%

74%

Non UsersN = 2111

UsersN = 1059

Higher Risk Users

N = 167

CUSTOM Results

174

CUSTOM Results

0

20

40

60

80

100

% o

f U

sers

(n=

105

9)

Improved

Maintained

Previously Tried to Lower

Cholesterol with Diet or Exercise

Change in Dietary Patterns

During Study

Change in Exercise

Patterns During Study

40%

58%

24%

70%

80%

Promotes Lifestyle Changes

175

Key Questions





What’s the overall benefit/risk of MEVACOR™ OTC?

176

OTC Can Narrow Treatment Gap

0

5

10

15

20

25

Rx

Elig

ible

Am

eric

ans

(Mill

ions

)

NHANES 1994, IMS 2003, Ingenix Treatment Gap Data 2003. BASES 2002.

Gap


11-18 million

+ 4-5 million

3-5 million

Currently on Rx therapy

OTC users


177


0

5

10

15

20

25

Rx

Elig

ible

Am

eric

ans

(Mill

ions

)


Gap


11-18 million

+ 4-5 million

3-5 million


OTC users


178


0

5

10

15

20

2524-26 million

9-11 million


Rx

Elig

ible

Am

eric

ans

(Mill

ions

)


Gap

Gap

+ 1-2 million


11-18 million

+ 4-5 million

3-5 million


OTC users

Rx therapy due to OTC


179


0

5

10

15

20

2524-26 million

9-11 million


Rx

Elig

ible

Am

eric

ans

(Mill

ions

)


Gap

Gap

+ 1-2 million


11-18 million

+ 4-5 million

3-5 million


OTC users

Rx therapy due to OTC


180

CUSTOM DataUsers Achieved Beneficial Lipid Lowering

OTC Can Help Shift the Curve

0

2

4

6

8

10

12

14

16

% o

f U

sers

LDL-C levels (mg/dL)

Baseline (N=931)

130 170 200100 24070

181

OTC Can Help Shift the Curve

% o

f U

sers

LDL-C levels (mg/dL)

Baseline (N=931)

End of Study (N=878)

130 170 200100 24070

CUSTOM DataUsers Achieved Beneficial Lipid Lowering

0

2

4

6

8

10

12

14

16

182Carleton R.A. et al., Circulation 1991, vol 83. 2154-2232.

100 200 300 4000

2

4

6

8

10Cholesterol distribution in USpopulation NHANES II

Expected shift in populationdistribution of cholesterol valueswith application of ATP guidelines

Pe

rce

nt o

f Po

pul

atio

n

Serum Cholesterol Level (mg/dL)

Expected shift in populationdistribution of cholesterol valuesif recommendations of PopulationPanel results in 10% decrease ofcholesterol

The Additive Effect of a Primary Prevention Strategy

200

183

Overall Benefit of MEVACOR™ OTC

For example:

– 1 million OTC users for 10 years

• Applying CHD risk distribution in CUSTOM population

• Assumed risk reduction ~25%

– Benefit

• 25,000 – 35,000 events prevented

1 Introduction Edwin L. Hemwall, PhD Vice President Worldwide Regulatory & Scientific Affairs...

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Transcript of 1 Introduction Edwin L. Hemwall, PhD Vice President Worldwide Regulatory & Scientific Affairs...