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Transcript of Mevacor Daily ® Merck NDA 21-213 Nonprescription Drugs Advisory Committee and Endocrinologic and...
Mevacor DailyMevacor Daily®®
MerckMerckNDA 21-213NDA 21-213
Mevacor DailyMevacor Daily®®
MerckMerckNDA 21-213NDA 21-213
Nonprescription Drugs Advisory Committee andNonprescription Drugs Advisory Committee and
Endocrinologic and Metabolic Advisory Committee MeetingEndocrinologic and Metabolic Advisory Committee Meeting
Silver Spring, MarylandSilver Spring, MarylandDecember 13, 2007December 13, 2007
Linda Hu, M.D. Linda Hu, M.D.
Division of Nonprescription Clinical EvaluationDivision of Nonprescription Clinical Evaluation
Nonprescription Drugs Advisory Committee andNonprescription Drugs Advisory Committee and
Endocrinologic and Metabolic Advisory Committee MeetingEndocrinologic and Metabolic Advisory Committee Meeting
Silver Spring, MarylandSilver Spring, MarylandDecember 13, 2007December 13, 2007
Linda Hu, M.D. Linda Hu, M.D.
Division of Nonprescription Clinical EvaluationDivision of Nonprescription Clinical Evaluation
Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research
NDAC NDAC December 13, 2007December 13, 2007
Self Evaluation of Lovastatin to Self Evaluation of Lovastatin to Enhance Cholesterol TreatmentEnhance Cholesterol TreatmentSelf Evaluation of Lovastatin to Self Evaluation of Lovastatin to Enhance Cholesterol TreatmentEnhance Cholesterol Treatment
(SELECT)(SELECT)
3NDAC NDAC December 13, 2007December 13, 2007
Overview Overview Overview Overview • Regulatory Background
• SELECT Labeling Paradigms
• SELECT Study Design
• SELECT Results
– Analyses of Mitigations
– Analysis Of Eligibility Criteria Subsets (Hierarchies)
– Analysis Of User Population
• Summary
• Regulatory Background
• SELECT Labeling Paradigms
• SELECT Study Design
• SELECT Results
– Analyses of Mitigations
– Analysis Of Eligibility Criteria Subsets (Hierarchies)
– Analysis Of User Population
• Summary
4NDAC NDAC December 13, 2007December 13, 2007
Regulatory Background Regulatory Background Regulatory Background Regulatory Background
• Initial submission 1999
• Response to October 2000 non-approval letter, which
included
– CUSTOM actual use study, “A Consumer Use Study of
Over-The-Counter MEVACOR”
– Label comprehension study
– Other efficacy data and safety data
• Led to non-approval letter in February, 2005
• Initial submission 1999
• Response to October 2000 non-approval letter, which
included
– CUSTOM actual use study, “A Consumer Use Study of
Over-The-Counter MEVACOR”
– Label comprehension study
– Other efficacy data and safety data
• Led to non-approval letter in February, 2005
5NDAC NDAC December 13, 2007December 13, 2007
CUSTOM Actual-Use StudyCUSTOM Actual-Use StudyCUSTOM Actual-Use StudyCUSTOM Actual-Use Study
• 10% of CUSTOM users correctly self-selected– Required criteria age, LDL-C, CHD risk factors, absence of
certain conditions (conditions = liver disease, high
triglycerides, history of statin-induced muscle pain)
• 54% (571/1059) of CUSTOM users considered
appropriate by sponsor– 416 said they talked to their doctor
• 10% of CUSTOM users correctly self-selected– Required criteria age, LDL-C, CHD risk factors, absence of
certain conditions (conditions = liver disease, high
triglycerides, history of statin-induced muscle pain)
• 54% (571/1059) of CUSTOM users considered
appropriate by sponsor– 416 said they talked to their doctor
6NDAC NDAC December 13, 2007December 13, 2007
Deficiencies in Feb 2005Deficiencies in Feb 2005Non Approval LetterNon Approval Letter
Deficiencies in Feb 2005Deficiencies in Feb 2005Non Approval LetterNon Approval Letter
• Concern about inability of consumers, on their own,
to make decisions on the appropriateness of statin
therapy for their own personal use
• Remaining safety concerns
– Use by pregnant women and women of
childbearing potential
– Compliance with muscle pain warning
– Use by patients with asymptomatic liver disease
• Concern about inability of consumers, on their own,
to make decisions on the appropriateness of statin
therapy for their own personal use
• Remaining safety concerns
– Use by pregnant women and women of
childbearing potential
– Compliance with muscle pain warning
– Use by patients with asymptomatic liver disease
7NDAC NDAC December 13, 2007December 13, 2007
Recommendations from Feb Recommendations from Feb 2005 Non Approval Letter2005 Non Approval Letter
Recommendations from Feb Recommendations from Feb 2005 Non Approval Letter2005 Non Approval Letter
• A self-selection/use study or studies
• Label comprehension studies
• Address the risk in subjects with asymptomatic
liver disease
• A self-selection/use study or studies
• Label comprehension studies
• Address the risk in subjects with asymptomatic
liver disease
NDAC NDAC December 13, 2007December 13, 2007
SELECT Study Label SELECT Study Label ParadigmsParadigms
SELECT Study Label SELECT Study Label ParadigmsParadigms
LDL-C Label LDL-C Label
Total-C LabelTotal-C Label
LDL-C Label LDL-C Label
Total-C LabelTotal-C Label
9NDAC NDAC December 13, 2007December 13, 2007
LDL-C Label Target LDL-C Label Target PopulationPopulation
LDL-C Label Target LDL-C Label Target PopulationPopulation
• Males ≥ 45 years; females ≥ 55 years
• LDL in range 130 - 170 mg/dL
• One or more additional cardiac risk factors
• Males ≥ 45 years; females ≥ 55 years
• LDL in range 130 - 170 mg/dL
• One or more additional cardiac risk factors
10NDAC NDAC December 13, 2007December 13, 2007
Cardiac Risk FactorsCardiac Risk FactorsCardiac Risk FactorsCardiac Risk Factors
• Cigarette smoking
• Hypertension or on BP medication
• Family history of premature CHD (below age of 55
years in a male parent or sibling or below 65 in
female relative)
• HDL-C < 40 mg/dL
• Age (men > 45 years, women > 55 years).
• Cigarette smoking
• Hypertension or on BP medication
• Family history of premature CHD (below age of 55
years in a male parent or sibling or below 65 in
female relative)
• HDL-C < 40 mg/dL
• Age (men > 45 years, women > 55 years).
11NDAC NDAC December 13, 2007December 13, 2007
Total-C Label Target Total-C Label Target PopulationPopulation
Total-C Label Target Total-C Label Target PopulationPopulation
• Total-C in range 200-240 mg/dL
• Males– > 45 years
• Females– HDL < 60 mg/dL
– > 55 years
– One or more additional cardiac risk factors
• Total-C in range 200-240 mg/dL
• Males– > 45 years
• Females– HDL < 60 mg/dL
– > 55 years
– One or more additional cardiac risk factors
12NDAC NDAC December 13, 2007December 13, 2007
SELECT Label ParadigmsSELECT Label ParadigmsSELECT Label ParadigmsSELECT Label Paradigms
• Label should be consistent with NCEP ATP III
guidelines
• LDL-C label conforms better to ATP III than
Total-C label
• Focus on results from LDL-C label arm
• Label should be consistent with NCEP ATP III
guidelines
• LDL-C label conforms better to ATP III than
Total-C label
• Focus on results from LDL-C label arm
13NDAC NDAC December 13, 2007December 13, 2007
NCEP ATP III GuidelinesNCEP ATP III GuidelinesNCEP ATP III GuidelinesNCEP ATP III Guidelines
<
NDAC NDAC December 13, 2007December 13, 2007
(SELECT)(SELECT)(SELECT)(SELECT)
Self Evaluation of Lovastatin to Self Evaluation of Lovastatin to Enhance Cholesterol TreatmentEnhance Cholesterol TreatmentSelf Evaluation of Lovastatin to Self Evaluation of Lovastatin to Enhance Cholesterol TreatmentEnhance Cholesterol Treatment
Study Design and Study PopulationStudy Design and Study Population
15NDAC NDAC December 13, 2007December 13, 2007
SELECT Self-Selection SELECT Self-Selection StudyStudy
SELECT Self-Selection SELECT Self-Selection StudyStudy
• How many consumers will decide correctly
that Mevacor is OK for them to use (“self-
selection”)?
• Study should be naturalistic
• How many consumers will decide correctly
that Mevacor is OK for them to use (“self-
selection”)?
• Study should be naturalistic
Self-selection: A decision by a consumer whether or not to choose a product for use based on two things: (1) his or her unique medical history and (2) the product labeling.
16NDAC NDAC December 13, 2007December 13, 2007
SELECT Self-Selection SELECT Self-Selection StudyStudy
SELECT Self-Selection SELECT Self-Selection StudyStudy
• Consumers were asked
– Self-assessment (SA) question
– Purchase decision (PD) question
– Reasons why, if incorrect
• Subjects randomized to two labels
– LDL-C
– Total-C
• Consumers were asked
– Self-assessment (SA) question
– Purchase decision (PD) question
– Reasons why, if incorrect
• Subjects randomized to two labels
– LDL-C
– Total-CFocus on LDL-C
17NDAC NDAC December 13, 2007December 13, 2007
Focus on Self-AssessmentFocus on Self-AssessmentFocus on Self-AssessmentFocus on Self-Assessment
• Purchase Decision is influenced by potentially
confounding economic and marketing issues
– cost
– consumer appeal of product
• Our interest is in whether the consumer
understands
– who should use
– why should one use
– how to use
• Purchase Decision is influenced by potentially
confounding economic and marketing issues
– cost
– consumer appeal of product
• Our interest is in whether the consumer
understands
– who should use
– why should one use
– how to use
18NDAC NDAC December 13, 2007December 13, 2007
Directions Prior toDirections Prior toSelf-Assessment QuestionSelf-Assessment Question
Directions Prior toDirections Prior toSelf-Assessment QuestionSelf-Assessment Question
• Participants were told
– The product is not appropriate for everyone
– You will be asked whether the product was
appropriate for you
– You will be asked whether you wish to purchase
– Concentrate and to take as much time as needed
• Participants were told
– The product is not appropriate for everyone
– You will be asked whether the product was
appropriate for you
– You will be asked whether you wish to purchase
– Concentrate and to take as much time as needed
19NDAC NDAC December 13, 2007December 13, 2007
Self-Assessment (SA) Self-Assessment (SA) Self-Assessment (SA) Self-Assessment (SA)
• “Based on this label, is this product
appropriate for you to use right now or not?”
– Yes
– No
– Other (unsure or wanted to ask a doctor)
• “Based on this label, is this product
appropriate for you to use right now or not?”
– Yes
– No
– Other (unsure or wanted to ask a doctor)
20NDAC NDAC December 13, 2007December 13, 2007
Purchase Decision (PD)Purchase Decision (PD)Purchase Decision (PD)Purchase Decision (PD)
• “Would you like to pay for this right now for
your own use or put it back in the display?”
• If the participant wants to purchase, then ask,
“Is there anything you plan to do before you
start using it?”
• “Would you like to pay for this right now for
your own use or put it back in the display?”
• If the participant wants to purchase, then ask,
“Is there anything you plan to do before you
start using it?”
21NDAC NDAC December 13, 2007December 13, 2007
RecruitmentRecruitmentRecruitmentRecruitment
• Recruitment by mass media advertising
• Ads told subjects to know:
– total cholesterol, LDL, HDL, and triglycerides
• Advertising may have recruited more
informed subjects who were better prepared
for self-selection
• Recruitment by mass media advertising
• Ads told subjects to know:
– total cholesterol, LDL, HDL, and triglycerides
• Advertising may have recruited more
informed subjects who were better prepared
for self-selection
22NDAC NDAC December 13, 2007December 13, 2007
SELECT: Self-Assessment SELECT: Self-Assessment PopulationPopulation
SELECT: Self-Assessment SELECT: Self-Assessment PopulationPopulation
Number of Number of Calls N=5107Calls N=5107
LDL-C LDL-C Paradigm Paradigm
N=767N=767
Number Number Randomized Randomized
N=1520N=1520
Total-C Total-C Paradigm Paradigm
N=753N=753
LDL-C Paradigm LDL-C Paradigm after exclusions after exclusions
N=662N=662
Total-C Paradigm Total-C Paradigm after exclusions after exclusions
N=664N=664
23NDAC NDAC December 13, 2007December 13, 2007
SELECT Study PopulationSELECT Study PopulationSELECT Study PopulationSELECT Study Population
• 1520 subjects randomized
– typically well educated, middle-class
– 90% high school graduates and 60% had some
college
– 70% had insurance
– 14% low literate
• 1520 subjects randomized
– typically well educated, middle-class
– 90% high school graduates and 60% had some
college
– 70% had insurance
– 14% low literate
24NDAC NDAC December 13, 2007December 13, 2007
Areas Targeted For Areas Targeted For Improvement in SELECTImprovement in SELECT
Areas Targeted For Areas Targeted For Improvement in SELECTImprovement in SELECT
• Decrease the proportion of women <55
• Decrease the proportion of women of
childbearing potential
• Decrease the proportion of low CHD risk
(<5% risk of CHD in 10 years)
• Decrease the proportion of women <55
• Decrease the proportion of women of
childbearing potential
• Decrease the proportion of low CHD risk
(<5% risk of CHD in 10 years)
25NDAC NDAC December 13, 2007December 13, 2007
SELECT RESULTSSELECT RESULTSSELECT RESULTSSELECT RESULTS
26NDAC NDAC December 13, 2007December 13, 2007
Eligibility Assessment Eligibility Assessment CriteriaCriteria
Eligibility Assessment Eligibility Assessment CriteriaCriteria
• Age
• Pregnant or breastfeeding
• May become pregnant
• Heart disease
• Stroke
• Diabetes
• Liver disease
• Listed risk factors
• Age
• Pregnant or breastfeeding
• May become pregnant
• Heart disease
• Stroke
• Diabetes
• Liver disease
• Listed risk factors
• Allergy to drug
• Lipid-lowering
medications
• Interacting drugs
• LDL-C
• HDL-C
• Grapefruit juice
• Fasting lipid profile
• Allergy to drug
• Lipid-lowering
medications
• Interacting drugs
• LDL-C
• HDL-C
• Grapefruit juice
• Fasting lipid profile
27NDAC NDAC December 13, 2007December 13, 2007
Self-Assessment ResultsSelf-Assessment ResultsLDL-CLDL-C
Self-Assessment ResultsSelf-Assessment ResultsLDL-CLDL-C
Is it appropriate for Is it appropriate for you?you?
SA population N=662 SA population N=662
Not appropriate for Not appropriate for me (SA =No)me (SA =No)
N=448 (68%) N=448 (68%)
Appropriate for me Appropriate for me (SA =Yes)(SA =Yes)
N=214 (32%)N=214 (32%)
Correct439 (98%)
Incorrect9 (2%)
Incorrect180 (84%)
Correct34 (16%)
Correct473 (71.5%)
Incorrect189 (28.5%)
28NDAC NDAC December 13, 2007December 13, 2007
Self-Assessment Results Self-Assessment Results Total-CTotal-C
Self-Assessment Results Self-Assessment Results Total-CTotal-C
Is it appropriate for Is it appropriate for you?you?
SA population N=664 SA population N=664
Not appropriate for Not appropriate for me (SA =No)me (SA =No)
N=422 (64%) N=422 (64%)
Appropriate for me Appropriate for me (SA =Yes)(SA =Yes)
N=242 (36%)N=242 (36%)
Correct414 (98%)
Incorrect176 (73%)
Correct66 (27%)
Incorrect8 (2%)
Correct480 (72%)
Incorrect184 (28%)
29NDAC NDAC December 13, 2007December 13, 2007
Mitigations for Incorrect Mitigations for Incorrect Self-AssessmentSelf-Assessment
Mitigations for Incorrect Mitigations for Incorrect Self-AssessmentSelf-Assessment
• Some subjects who incorrectly self-selected to
use gave open-ended responses that were
acceptable and could be “mitigated”
– Would talk to doctor
– Gave reasonable rationale for treatment
– Gave evidence of not understanding the self-
assessment question
• Some subjects who incorrectly self-selected to
use gave open-ended responses that were
acceptable and could be “mitigated”
– Would talk to doctor
– Gave reasonable rationale for treatment
– Gave evidence of not understanding the self-
assessment question
30NDAC NDAC December 13, 2007December 13, 2007
MitigationsMitigationsMitigationsMitigations
Label
(# Incorrect)
Talk to
Doctor
Did Not
Understand
SA
Other
Mitigations
Total
Mitigated
LDL (n=180) 46 16 23* 85
Total-C (n=176) 30 11 32* 73
• Almost half of incorrect subjects were mitigated– Talk to doctor was most common reason for mitigation
– Cannot verify whether subjects would actually talk to a doctor
• Other Mitigations– *Reviewers did not agree with 9 mitigations for LDL and 11
mitigations for Total-C
• Almost half of incorrect subjects were mitigated– Talk to doctor was most common reason for mitigation
– Cannot verify whether subjects would actually talk to a doctor
• Other Mitigations– *Reviewers did not agree with 9 mitigations for LDL and 11
mitigations for Total-C
31NDAC NDAC December 13, 2007December 13, 2007
Examples of Other Examples of Other MitigationsMitigations
Made by SponsorMade by Sponsor
Examples of Other Examples of Other MitigationsMitigations
Made by SponsorMade by Sponsor
• Substitution of Mevacor for current lipid
medication without talking to doctor
• High risk subject who self-selected to use
without talking to doctor
• Self-selected yes when had prior side effects
on statins
• Substitution of Mevacor for current lipid
medication without talking to doctor
• High risk subject who self-selected to use
without talking to doctor
• Self-selected yes when had prior side effects
on statins
32NDAC NDAC December 13, 2007December 13, 2007
Self-Selection Percent Self-Selection Percent Completely Correct, and Completely Correct, and Correct After MitigationsCorrect After Mitigations
Self-Selection Percent Self-Selection Percent Completely Correct, and Completely Correct, and Correct After MitigationsCorrect After Mitigations
Label Self
Assessment
% Completely
Correct
% Correct After
Mitigations
LDL Yes 16% ~50%
Total-C Yes 27% ~50%
33NDAC NDAC December 13, 2007December 13, 2007
SELECT RESULTS:SELECT RESULTS:ANALYSIS OF ELIGIBILITY ANALYSIS OF ELIGIBILITY
CRITERIA SUBSETSCRITERIA SUBSETSHIERARCHIESHIERARCHIES
SELECT RESULTS:SELECT RESULTS:ANALYSIS OF ELIGIBILITY ANALYSIS OF ELIGIBILITY
CRITERIA SUBSETSCRITERIA SUBSETSHIERARCHIESHIERARCHIES
34NDAC NDAC December 13, 2007December 13, 2007
HierarchiesHierarchiesHierarchiesHierarchies
• Many eligibility criteria– Difficult to get all eligibility criteria correct– Some criteria of more clinical importance then
others
• New analyses where % correct was calculated for subsets of eligibility criteria (“hierarchies”)
• Self-assessment hierarchies will be presented
• Many eligibility criteria– Difficult to get all eligibility criteria correct– Some criteria of more clinical importance then
others
• New analyses where % correct was calculated for subsets of eligibility criteria (“hierarchies”)
• Self-assessment hierarchies will be presented
35NDAC NDAC December 13, 2007December 13, 2007
Hierarchies for LDL-C ArmHierarchies for LDL-C ArmHierarchies for LDL-C ArmHierarchies for LDL-C Arm
• Self-Selection Results Using ALL Label Criteria
– % entirely correct (16%)
– % correct after mitigation (~50%)
• Using “hierarchies” or subsets of label criteria
– % correct before mitigation
– % correct after mitigation
• % correct depends on which criteria are used in
hierarchy
• Self-Selection Results Using ALL Label Criteria
– % entirely correct (16%)
– % correct after mitigation (~50%)
• Using “hierarchies” or subsets of label criteria
– % correct before mitigation
– % correct after mitigation
• % correct depends on which criteria are used in
hierarchy
36NDAC NDAC December 13, 2007December 13, 2007
Sponsor Safety HierarchySponsor Safety HierarchySponsor Safety HierarchySponsor Safety Hierarchy
• Pregnant/breast feeding
• May become pregnant
• Allergy to lovastatin
• On interacting medications
• On lipid-lowering medications
• Liver problem
• Pregnant/breast feeding
• May become pregnant
• Allergy to lovastatin
• On interacting medications
• On lipid-lowering medications
• Liver problem
37NDAC NDAC December 13, 2007December 13, 2007
SAFETY Hierarchy SA=Yes (LDL arm)
SAFETY Hierarchy SA=Yes (LDL arm)
N=214
Of 2 Pregnant/breastfeedingCorrect
NoN=0
N=214
Of 12 may become pregnantCorrect
NoN=1
N=213
Of 4 allergy to lovastatinCorrect
NoN=0
N=213
Of 12 on interacting medicineCorrect
NoN=3
N=210
38NDAC NDAC December 13, 2007December 13, 2007
SAFETY Hierarchy SA=YesSAFETY Hierarchy SA=Yes
N=210
Of 140 on lipid lowering medicineCorrect
NoN=36
N=174
Of 23 liver problemCorrect
NoN=0
N=174
Percent Correct 81.3%
39NDAC NDAC December 13, 2007December 13, 2007
Sponsor Safety HierarchySponsor Safety HierarchySponsor Safety HierarchySponsor Safety Hierarchy
Hierarchy
LDL (N=214) Total-C (N=242)
% Correct Before
Mitigation
% Correct After
Mitigation
% Correct Before
Mitigation
% Correct After
Mitigation
Sponsor Safety* 81.3% 89.3% 83.1% 90.1%
For all eligibility criteria 16% correct
Sponsor Safety: Pregnant/breast-feeding, may become pregnant, allergy to lovastatin, interacting medications, lipid lowering medications, and liver problems
40NDAC NDAC December 13, 2007December 13, 2007
Eligibility Assessment Eligibility Assessment CriteriaCriteria
Eligibility Assessment Eligibility Assessment CriteriaCriteria
• Age
• Pregnant or breastfeeding
• May become pregnant
• Heart disease
• Stroke
• Diabetes
• Liver disease
• Listed risk factors
• Age
• Pregnant or breastfeeding
• May become pregnant
• Heart disease
• Stroke
• Diabetes
• Liver disease
• Listed risk factors
• Allergy to drug
• Lipid-lowering
medications
• Interacting drugs
• LDL-C
• HDL-C
• Grapefruit juice
• Fasting lipid profile
• Allergy to drug
• Lipid-lowering
medications
• Interacting drugs
• LDL-C
• HDL-C
• Grapefruit juice
• Fasting lipid profile
41NDAC NDAC December 13, 2007December 13, 2007
Sponsor HierarchiesSponsor HierarchiesSponsor HierarchiesSponsor Hierarchies
Hierarchy
LDL (N=214) Total-C (N=242)
% Correct Before
Mitigation
% Correct After
Mitigation
% Correct Before
Mitigation
% Correct After
Mitigation
Safety* 81.3% 89.3% 83.1% 90.1%
Benefit** 25.7% 57.0% 41.7% 62.4%
Safety & Benefit 21.0% 52.8% 35.1% 58.3%
* Pregnant/breast-feeding, may become pregnant,
allergy to lovastatin, interacting medications, lipid
lowering medications, liver problems
** Age, lipid values (LDL-C or Total-C), and risk factors
42NDAC NDAC December 13, 2007December 13, 2007
Other Sponsor HierarchiesOther Sponsor HierarchiesOther Sponsor HierarchiesOther Sponsor Hierarchies
Hierarchy
LDL (N=214) Total-C (N=242)
% Correct Before
Mitigation
% Correct After
Mitigation
% Correct Before
Mitigation
% Correct After
Mitigation
Benefits w/o Lipid* 65.4% 77.1% 77.3% 88.4%
Expanded Benefit** 40.7% 65.9% 57.4% 77.3%
* Age and risk factors** Age, risk factors, heart disease, stroke, and diabetes,
lipid lowering medications
43NDAC NDAC December 13, 2007December 13, 2007
FDA Review Team FDA Review Team HierarchiesHierarchies
FDA Review Team FDA Review Team HierarchiesHierarchies
Hierarchy
LDL (N=214) Total-C (N=242)
% Correct Before
Mitigation
% Correct After
Mitigation
% Correct Before
Mitigation
% Correct After
Mitigation
#1* 21.0% 52.8% 35.1% 58.3%
#2** 17.8% 50.9% 31.4% 57.0%
* Age, lipid lowering medications, lipid values, interacting medications, risk factors
** Age, lipid lowering medications, lipid values, interacting medications, heart disease, stroke, diabetes, risk factors
44NDAC NDAC December 13, 2007December 13, 2007
HierarchiesHierarchiesHierarchiesHierarchies
• None of the hierarchies was defined a
priori in the study protocol
• Depending on which criteria are
included, the percent correct in the
hierarchies before mitigations ranged
from 20-80%
• None of the hierarchies was defined a
priori in the study protocol
• Depending on which criteria are
included, the percent correct in the
hierarchies before mitigations ranged
from 20-80%
45NDAC NDAC December 13, 2007December 13, 2007
SELECT RESULTS:SELECT RESULTS:Profiles of User Profiles of User
PopulationPopulation
SELECT RESULTS:SELECT RESULTS:Profiles of User Profiles of User
PopulationPopulation
46NDAC NDAC December 13, 2007December 13, 2007
CHD Risk Profiles SA=Yes LDL-CCHD Risk Profiles SA=Yes LDL-CCHD Risk Profiles SA=Yes LDL-CCHD Risk Profiles SA=Yes LDL-C
10-Year CHD Risk
Men WomenTotal
Men + Women
n % n % n %
unknown 4 3.2% 1 1.1% 5 2.4%
<5% 13 10.5% 42 46.7% 55 25.7%
5-20% 51 41.1% 22 24.4% 73 34.1%
>20% 13 10.4% 1 1.1% 14 6.6%
CHD/DM/Stroke 16 12.9% 12 13.3% 28 13.1%
Rx Chol. Med. 27 21.8% 12 13.3% 39 18.2%
47NDAC NDAC December 13, 2007December 13, 2007
Women Too Young (<55 yo) LDL Women Too Young (<55 yo) LDL armarm
Women Too Young (<55 yo) LDL Women Too Young (<55 yo) LDL armarm
• 391 women were asked the self-assessment question in
the LDL arm, 220 (56.3%) were too young.
– 13.2% (29/220) self-selected to use
• Of 391 women asked the SA question, 101 women of all
ages self-selected to use
– Of these 101 women, ~ 29% were < 55 years old
• Reasons for their decision were: age is close, lower my
cholesterol, family history
• 391 women were asked the self-assessment question in
the LDL arm, 220 (56.3%) were too young.
– 13.2% (29/220) self-selected to use
• Of 391 women asked the SA question, 101 women of all
ages self-selected to use
– Of these 101 women, ~ 29% were < 55 years old
• Reasons for their decision were: age is close, lower my
cholesterol, family history
48NDAC NDAC December 13, 2007December 13, 2007
Pregnant/May Become Pregnant/May Become PregnantPregnant
Pregnant/May Become Pregnant/May Become PregnantPregnant
• Pregnant (n=4)– 1 out of 4: SA=Yes,
– sponsor mitigated
– reviewers agreed
• May become pregnant (n=22)– 9% (2/22) chose SA=Yes,
– sponsor mitigated
– reviewers did not agree
• Pregnant (n=4)– 1 out of 4: SA=Yes,
– sponsor mitigated
– reviewers agreed
• May become pregnant (n=22)– 9% (2/22) chose SA=Yes,
– sponsor mitigated
– reviewers did not agree
49NDAC NDAC December 13, 2007December 13, 2007
Heart Disease (LDL Arm)Heart Disease (LDL Arm)Heart Disease (LDL Arm)Heart Disease (LDL Arm)
• 48.5% (33/68) with heart disease
self-selected yes
• Subjects at high CHD risk might be
undertreated by 20 mg of lovastatin
• 48.5% (33/68) with heart disease
self-selected yes
• Subjects at high CHD risk might be
undertreated by 20 mg of lovastatin
50NDAC NDAC December 13, 2007December 13, 2007
Already on Lipid Medications Already on Lipid Medications
(LDL arm)(LDL arm)
Already on Lipid Medications Already on Lipid Medications
(LDL arm)(LDL arm)
• 140/750 (18.7%) in the self-selection
population were already taking lipid-
lowering medication
• 44/140 (31.4%) of these participants
self-selected yes
• 140/750 (18.7%) in the self-selection
population were already taking lipid-
lowering medication
• 44/140 (31.4%) of these participants
self-selected yes
51NDAC NDAC December 13, 2007December 13, 2007
Reasons Why Subjects on Reasons Why Subjects on Rx Selected IncorrectlyRx Selected Incorrectly
Reasons Why Subjects on Reasons Why Subjects on Rx Selected IncorrectlyRx Selected Incorrectly
• The most frequent reasons for choosing to
use or purchasing, when the subject was
already taking lipid-lowering medication
– to replace the prescription medication
– specifically to replace it because of lower cost
• The most frequent reasons for choosing to
use or purchasing, when the subject was
already taking lipid-lowering medication
– to replace the prescription medication
– specifically to replace it because of lower cost
52NDAC NDAC December 13, 2007December 13, 2007
Substitution Rate of OTC for Rx Substitution Rate of OTC for Rx Medications CHDMedications CHD
Substitution Rate of OTC for Rx Substitution Rate of OTC for Rx Medications CHDMedications CHD
Reported Action
LDL-C(N=27)N(%)
Take along with it 8 (29.6%)
Take in place 14 (51.9%)
Don’t know 1 (3.7%)
Other 3 (11.1%)
Missing 1 (3.7%)
53NDAC NDAC December 13, 2007December 13, 2007
Reasons for Preferring OTC Reasons for Preferring OTC Med Rather than Rx Med for Med Rather than Rx Med for
CholesterolCholesterol
Reasons for Preferring OTC Reasons for Preferring OTC Med Rather than Rx Med for Med Rather than Rx Med for
CholesterolCholesterol• The most frequent reasons for preferring OTC
medications, for those who self-selected yes : – less expensive (50%)
– convenience (29%)
– don’t have to see the doctor (15%)
– feels safer/less side effects (11.3%)
• The most frequent reasons for preferring OTC
medications, for those who self-selected yes : – less expensive (50%)
– convenience (29%)
– don’t have to see the doctor (15%)
– feels safer/less side effects (11.3%)
54NDAC NDAC December 13, 2007December 13, 2007
High Risk, CHD, Diabetes, High Risk, CHD, Diabetes, Stroke: LDL-C armStroke: LDL-C arm
High Risk, CHD, Diabetes, High Risk, CHD, Diabetes, Stroke: LDL-C armStroke: LDL-C arm
• On average, ~30% of subjects with CHD,
DM or stroke wanted to buy
• 2/3 of these subjects were not on any lipid-
lowering medications
• On average, ~30% of subjects with CHD,
DM or stroke wanted to buy
• 2/3 of these subjects were not on any lipid-
lowering medications
55NDAC NDAC December 13, 2007December 13, 2007
What Medications Would Be What Medications Would Be Substituted: LDL armSubstituted: LDL arm
What Medications Would Be What Medications Would Be Substituted: LDL armSubstituted: LDL arm
56NDAC NDAC December 13, 2007December 13, 2007
Knowing LDL-C versus Knowing LDL-C versus Total-CTotal-C
Knowing LDL-C versus Knowing LDL-C versus Total-CTotal-C
• In the LDL-C arm, 37.5% (268/714) did not know their
LDL-C, whereas in the Total-C arm, 21% (149/708)
did not know their Total-C.
• Of those who did not know their cholesterol numbers– LDL-C: 22.4% ( 60/268) self-selected yes
– Total-C: 17.4% (26/149) self- selected yes
• In the LDL-C arm, 37.5% (268/714) did not know their
LDL-C, whereas in the Total-C arm, 21% (149/708)
did not know their Total-C.
• Of those who did not know their cholesterol numbers– LDL-C: 22.4% ( 60/268) self-selected yes
– Total-C: 17.4% (26/149) self- selected yes
57NDAC NDAC December 13, 2007December 13, 2007
Ineligible Subjects for Lipid Ineligible Subjects for Lipid ValuesValues
Ineligible Subjects for Lipid Ineligible Subjects for Lipid ValuesValues
• Many of the subjects who had LDL outside
the eligible range nevertheless selected yes
in the LDL-C arm – 43% (52/122) of subjects w/ LDL-C too high
(above 170) self-selected yes
– 17% (26/153) of subject whose LDL-C too low
(below 130) self-selected yes
• Many of the subjects who had LDL outside
the eligible range nevertheless selected yes
in the LDL-C arm – 43% (52/122) of subjects w/ LDL-C too high
(above 170) self-selected yes
– 17% (26/153) of subject whose LDL-C too low
(below 130) self-selected yes
58NDAC NDAC December 13, 2007December 13, 2007
SELECT Summary SELECT Summary SELECT Summary SELECT Summary
• ~20% self-selected yes entirely correctly
– With mitigations, % correct ~ 50%
• Only 4 pregnant women in the study
• Of those who may become pregnant
– 2/22 (9%) were incorrect (SA=Yes)
• ~ 30% of participants with CHD, diabetes mellitus, or
stroke wanted to buy
– 2/3 were not on cholesterol medications
• ~20% self-selected yes entirely correctly
– With mitigations, % correct ~ 50%
• Only 4 pregnant women in the study
• Of those who may become pregnant
– 2/22 (9%) were incorrect (SA=Yes)
• ~ 30% of participants with CHD, diabetes mellitus, or
stroke wanted to buy
– 2/3 were not on cholesterol medications
59NDAC NDAC December 13, 2007December 13, 2007
SELECT Summary (LDL SELECT Summary (LDL paradigm)paradigm)
SELECT Summary (LDL SELECT Summary (LDL paradigm)paradigm)
• ~ 30% of subjects on lipid-lowering medication self-
selected to use
• Of those who would purchase and were on lipid-lowering
medication
– 50% would take Mevacor “in place of” Rx med
– 30% would take Mevacor along with their Rx Med
– The most commonly taken lipid-lowering medications
were atorvastatin, simvastatin, rosuvastatin, and
lovastatin
• ~ 30% of subjects on lipid-lowering medication self-
selected to use
• Of those who would purchase and were on lipid-lowering
medication
– 50% would take Mevacor “in place of” Rx med
– 30% would take Mevacor along with their Rx Med
– The most commonly taken lipid-lowering medications
were atorvastatin, simvastatin, rosuvastatin, and
lovastatin
60NDAC NDAC December 13, 2007December 13, 2007
SELECT Summary (LDL SELECT Summary (LDL paradigm)paradigm)
SELECT Summary (LDL SELECT Summary (LDL paradigm)paradigm)
Those who self-selected to use in the LDL arm included:
• 101 of 391 women who were asked the SA question
– 29% were < 55 years old
• 13.2% of women < 55 years old
• 22% of the participants who did not know their LDL-C
value
• 43% of subjects who had LDL too high (above 170)
• 17% of subject whose LDL was too low (below 130)
Those who self-selected to use in the LDL arm included:
• 101 of 391 women who were asked the SA question
– 29% were < 55 years old
• 13.2% of women < 55 years old
• 22% of the participants who did not know their LDL-C
value
• 43% of subjects who had LDL too high (above 170)
• 17% of subject whose LDL was too low (below 130)
61NDAC NDAC December 13, 2007December 13, 2007
SELECT SummarySELECT SummarySELECT SummarySELECT Summary
10 -Year CHD risk: LDL-C Label (SA=Yes)
• 41.1% men were in the targeted CHD risk range – Most men outside the target range were of high risk, CHD
equivalent or on lipid lowering meds
• 24.4% of women were in the targeted range– Most women outside this range were low risk
• ~11% of men and over 45% of women were of low
CHD risk (<5% risk of CHD in 10 years)
10 -Year CHD risk: LDL-C Label (SA=Yes)
• 41.1% men were in the targeted CHD risk range – Most men outside the target range were of high risk, CHD
equivalent or on lipid lowering meds
• 24.4% of women were in the targeted range– Most women outside this range were low risk
• ~11% of men and over 45% of women were of low
CHD risk (<5% risk of CHD in 10 years)
62NDAC NDAC December 13, 2007December 13, 2007
AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements
• Division of Nonprescription Clinical Evaluation Review Team
– Daiva Shetty, M.D.
– Joel Schiffenbauer, M.D.
– Andrea Leonard Segal, M.D.
– Laura Shay, CNP
– Stan Lin, Ph.D.
– Michael Koenig, Ph.D.
– Matthew Holman, Ph.D.
– Mary Lewis, PM
• Division of Nonprescription Clinical Evaluation Review Team
– Daiva Shetty, M.D.
– Joel Schiffenbauer, M.D.
– Andrea Leonard Segal, M.D.
– Laura Shay, CNP
– Stan Lin, Ph.D.
– Michael Koenig, Ph.D.
– Matthew Holman, Ph.D.
– Mary Lewis, PM