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DRAFT SLIDES FOR NDA 21-213 ADVISORY COMMITTEE PRESENTATION. Joint Advisory Committee Meeting on OTC Availability of Lovastatin 10 mg. Actual Use Trials Andrea Leonard-Segal, M.D. Division of OTC Drug Products. Outline. 3 Actual Use Trials Self-Selection and Compliance issues (trial 076)

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Joint advisory committee meeting on otc availability of lovastatin 10 mg l.jpg

Joint Advisory Committee Meeting on OTC Availability of Lovastatin 10 mg

Actual Use Trials

Andrea Leonard-Segal, M.D.

Division of OTC Drug Products


Outline l.jpg
Outline Lovastatin 10 mg

  • 3 Actual Use Trials

    • Self-Selection and Compliance issues (trial 076)

    • Compliance issues (trial 079)

    • Self-selection and safety (trial 081)


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Actual Use Studies Lovastatin 10 mgBackground

  • Simulate OTC Use of a Product

    • Exclusion criteria: The fewer the better!

    • Self-selection: Are people choosing product properly based on indications and contraindications?

    • Compliance: Are dosing and duration of use according to directions?

    • Safety: What are the adverse experiences?

  • Efficacy information often limited by open-label, uncontrolled design


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Actual Use Issues for Lovastatin Lovastatin 10 mg

  • Cholesterol:

    • Do people know their values?

    • Do they understand TC, LDL-C, and HDL-C?

    • Do they understand when to treat?

    • What is the treatment goal and do consumers understand it?


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Actual Use Issues (Continued) Lovastatin 10 mg

  • Cholesterol Measurement:

    • Can OTC desktop cholesterol screening offer accurate cholesterol measurement?

    • What is the appropriate duration of fast prior to measurement?

    • How many measurements should be performed to obtain an accurate value?

    • If averaging multiple cholesterol values is recommended, can consumers do the math?


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Actual Use Issues (Continued) Lovastatin 10 mg

  • Self-Selection:

    • Can consumers understand what underlying conditions and concomitant medications put them at safety risk if they take lovastatin?

    • Do consumers know when they are taking contraindicated drugs?

    • Do consumers understand when to seek the counsel of a physician?


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Actual Use Issues (Continued) Lovastatin 10 mg

  • Compliance:

    • Are consumers sufficiently compliant in the OTC setting to derive clinical benefits of lovastatin treatment over the long-term?

  • Benefit and Risk

    • Is monitoring needed to determine if there has been a benefit of use as well as no adverse safety events?

    • Can consumers identify symptoms associated with adverse events?


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Actual Use Issues (Cont’d) Lovastatin 10 mg

  • Label:

    • Can a label adequately convey all necessary information about lovastatin so it can be used properly?


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Inclusion Criteria Common to Trials 076, 079, 081 Lovastatin 10 mg

  • TC = 200-240 mg/dl

  • LDL-C  130 mg/dl

  • HDL-C was not an inclusion criterion


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Exclusion Criteria Common to Trials 076, 077, 081 Lovastatin 10 mg

  • Current or recent (< 2 months) participation in drug study

  • Allergy to lovastatin

  • Current or Hx liver disease

  • Contraindicated drugs

  • Other cholesterol medication


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Exclusion Criteria Common to 076, 079, 081 (Cont’d) Lovastatin 10 mg

  • Hx heart disease

  • FHx MI before age 55 (parents, siblings)

  • Pregnant, breast-feeding, childbearing potential

  • Inability to read English

  • HDL-C was not an exclusion criterion


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Sponsor’s Definitions Lovastatin 10 mg

  • Persistence = # (%) of subjects who returned for a follow-up visit having taken any of the study tablets

  • Compliance was calculated in persistent subjects and was defined as:

    • # tablets taken/# days drug taken during specified time period

    • Expressed as a percentage


Study design 076 l.jpg

Open-label Lovastatin 10 mg

Uncontrolled

Multicenter (pharmacies)

24-week (4 visits)

“Extension trial” option

To Evaluate:

LDL-C

Self-selection

Compliance

Adverse experiences

Study Design - 076


Criteria 076 l.jpg
Criteria - 076 Lovastatin 10 mg

  • Inclusion (as described) plus:

    • Age:

      • Men  45; women  55

    • General good health; no disabling disease

    • Low-fat diet during previous year

  • Exclusion (as described) plus:

    • Corticosteroid use

    • Peripheral vascular disease

    •  3 alcoholic beverages/day most days


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Label - 076 Lovastatin 10 mg

  • “Pharmacy” Label:

    • Lists Inclusion-Exclusion criteria

    • Did not list all interactive medications

    • 1 tablet qhs

    • Retest cholesterol after 8 weeks and contact study doctor if level did not decrease


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Recruitment via ads Lovastatin 10 mg

Review “Pharmacy” label and make self-selection decision

Complete Hx form

Pharmacist triage: potentially qualified or not

Cholesterol test ( 2-hr fast)

Qualified received study drug

Study Design - 076


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Study Design - 076 Lovastatin 10 mg

  • Return visits:

    • count returned pills

    • record adverse events

    • lipid profile

    • new drug at visits 2, 3


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Results - 076 (Self-Selection) Lovastatin 10 mg

  • 722 (12%) of all 6095 study participants qualified to receive drug

  • 981 (16%) of study participants self-selected to obtain and use the drug

    • Only 119 (12%) of this self-selection group actually received drug


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Results - 076 (Self-Selection) Lovastatin 10 mg

  • 6081 completed self-selection process

    • 82% needed more than “Pharmacy” label to decide whether to obtain drug

    • 53% thought they met criteria for TC level, but did not

    • No information about how well consumers understood the meaning of the components of the lipid profile


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Results - 076 (Self-Selection) Lovastatin 10 mg

  • 5% who were likely to buy lovastatin were in “safety risk” group

    • Liver disease (72)

    • Prohibited medications as per label (44)

    • Pregnancy risk (3)

    • Allergic to lovastatin (8)


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Results - 076 (Compliance) Lovastatin 10 mg

  • Completion, Persistence and Compliance:

    • 523/722 (72%) completed the study

    • 504/722 (69%) were persistent at last visit (Visit 4)

    • 441/722 (61%) were taking  75% of medicine at Visit 4

    • No diary, so precise information about how people actually dosed is unavailable.


Study design 079 l.jpg

Multicenter Lovastatin 10 mg

Open-Label

Uncontrolled

Storefront

8 weeks

“Extension trial” option

To test:

Mean change in LDL at 8 weeks

Ability of consumers to remain on lovastatin

Tolerability of lovastatin as measured by AE incidence

Study Design - 079


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Study Design - 079 Lovastatin 10 mg

  • Recruitment via ads

  • Telephone history screening


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Criteria Lovastatin 10 mg

  • Inclusion (as described) plus:

    • men  40; women  55

  • Exclusion (as described) plus:

    •  3 alcoholic beverages most days; diabetes; angina; peripheral vascular disease; TIA; stroke; invasive procedures (PTCA, CABG); taking >1 BP drug; diastolic BP  100 or systolic BP  180 mm/Hg; subjects who knew their TC was < 190 mg/dl or > 250 mg/dl; corticosteroids


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Study Label - 079 Lovastatin 10 mg

  • “Restricted Access” Label

    • Designed to reinforce appropriate post-purchase behavior, not to guide self-selection

    • Contained trial inclusion and exclusion criteria

    • More expansive list of contraindicated medications than “Pharmacy” label

    • Recommended seeing doctor at least yearly to discuss cholesterol treatment plan


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Study Design - 079 Lovastatin 10 mg

  • Storefront appointment for potentially eligible (Visit 1)

    • Lipid profile (6-hour fast)

    • BP

    • Weight, Height

    • Eligible received drug with “Restricted Access” label and study information card


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Study Design - 079 Lovastatin 10 mg

  • Visit 2 (approximately week 8)

    • Lipid profile (6-hour fast)

    • Collect remaining drug tablets

    • Adverse experience information collected


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Results - 079 Lovastatin 10 mg

  • 4878 called telephone number

    • 1312 (27%) potentially eligible and visited storefront

      • 60% of these were not qualified (cholesterol)

    • 460 (9%) received study drug


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Results - 079 Lovastatin 10 mg

  • Persistence and Compliance

    • 363 people took some drug (were persistent)

    • 265 were compliant at least 75% of the time over the 8-week study

    • No diary, so precise information about how people actually dosed is unavailable.

  • Trial did not test the ability of consumers to properly self-select


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Study Design - 081 Lovastatin 10 mg

  • Open-label

  • Uncontrolled

  • Multicenter

  • Storefront clinical sites

  • 4 Weeks

  • “Extension trial” option


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Study Design - 081 Lovastatin 10 mgObjectives

  • To test:

    • Effectiveness of an enhanced “Red Arrow” label & reinforcement tools (videotape, pamphlet, insert)

    • Effectiveness of these in 3 risk subsets:

      • drug risk

      • 1° prevention subjects (cholesterol > 240 mg/dl)

      • high cardiovascular risk group

    • Tolerability of lovastation 10 mg as measured by incidence of adverse events.


Criteria33 l.jpg
Criteria Lovastatin 10 mg

  • Inclusion

    • Men  40; women  1 year post-menopausal

    • Express interest in purchasing lovastatin

  • Exclusion

    • Employed in healthcare

    • Diabetes

    • Stroke

    • Taking > 1 anti-hypertension drug

    • Participated in cholesterol lowering study < 2 years


Label 081 l.jpg
Label - 081 Lovastatin 10 mg

  • “Red Arrow” label

    • Flip-up back panel design

    • Warnings emphasized with red arrows and stop signs

    • Examples of muscle pain, tenderness or weakness added to drug interaction warnings

    • “Warnings” precede “who should use”

    • Boxed warning to “carefully read package before self-selecting and call a product specialist for help understanding the label”


Study design 08135 l.jpg
Study Design - 081 Lovastatin 10 mg

  • Recruitment via ads

  • Visit 1 - Storefront site:

    • Participants read product concept & label; then made self-selection decision

    • If “yes” paid $15 for lovastatin 10 mg and answered specific safety risk questions

      • Contraindicated meds

      • Current liver disease

      • Childbearing potential

      • Allergy to lovastatin


Study design 08136 l.jpg
Study Design - 081 Lovastatin 10 mg

  • If participant self-selected, “yes,” but was excluded for safety risk:

    • 2nd chance to review label and reinforcements and to make self-selection decision

      • No drug was provided


Study design 08137 l.jpg
Study Design - 081 Lovastatin 10 mg

  • Cholesterol test offered to those who needed before could self-select, then:

    • Repeat self-selection decision

    • Answered safety risk questions

  • Medical Hx performed on all who left storefront site without drug:

    • Self-selected “no”

    • Failed safety risk exclusion questions

    • Did not want to purchase


Study design 08138 l.jpg
Study Design - 081 Lovastatin 10 mg

  • Eligible Participants

    • Received 4-week supply of open-label lovastatin 10 mg

    • Were told to take drug according to label


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Study Design - 081 Lovastatin 10 mg

  • Were given incentive to call toll-free #

    • Those who did were asked medical Hx using screening script (incl-excl criteria)

    • If deemed inappropriate for drug, were told to:

      • D/C

      • return remaining drug and packaging


Study design 08140 l.jpg
Study Design - 081 Lovastatin 10 mg

  • Visit 2 (Week 4)

    • Returned packaging and unused drug

    • For those who had not called toll-free #, nurse administered medical Hx and determined appropriateness of Rx

    • Lipid testing for those interested in extension


Results 081 l.jpg
Results - 081 Lovastatin 10 mg

  • 2416 subjects screened overall

  • 1230 (51%) self-selected, “yes”

  • 1144 (47%) received drug; 86 did not (safety risk)


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Results - 081 Lovastatin 10 mgCompleted vs Discontinued

  • 74% completed the 4-week study

  • Reasons the rest discontinued:

    • 10% not appropriate (as per medical Hx)

    • 6% adverse experience

    • 4% lost to follow-up

    • 3% returned drug by mail

    • 2% withdrew consent


Results 08143 l.jpg
Results - 081 Lovastatin 10 mg

  • Self-selection errors among the 1144:

    • Heart disease - 22

    • Stroke/TIA - 14

    • Other cholesterol treatment - 45

    • Hypertension 211 (147 on medication)

    • Hx hepatitis or liver disease - 35

    • Alcohol  3/day - 26

    • Diabetes - 23


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Results - 081 (Self-Selection) Lovastatin 10 mg

  • 1112/2264 consumers with known medical history said they would purchase

    • 39% self-selected erroneously after seeing label

      • Decreased to 22% erroneous self-selection after seeing label + reinforcements

  • 61% of subjects with known medical eligibility status did not call toll-free #

    • 36% were ineligible to take lovastatin


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Results - 081: Safety Group Self-Selection Errors After Label

  • Safety risk group = 120 participants

    • 83 took interacting medication

      • 30% self-selected incorrectly to take lovastatin

    • 16 < 1 year postmenopausal

      • 50% self-selected incorrectly

    • 14 - current liver disease

      • 36% self-selected incorrectly

    • 8 - allergic

      • 13% self-selected incorrectly


Results 081 cardiovascular self selection error after label l.jpg
Results - 081: Label Cardiovascular Self-Selection Error After Label)

  • 381 subjects with cholesterol > 240 mg/dl as only contraindication

    • 46% self-selected incorrectly

  • 262 participants were in high cardiovascular risk categories

    • 32% self-selected incorrectly to take lovastatin


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Results - 081 (Safety) Label

  • 15% people who received drug had an adverse experience (AE) likely related to lovastatin

  • 4% discontinued due to drug-related AE

  • None of 6 serious AE likely to have been study-drug related

  • Incomplete information because LFTs and CPKs were not done & short duration Rx


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Conclusions (Overall) Label

  • Cholesterol:

    • Many lack accurate knowledge of their cholesterol values

    • Trials do not assess if consumers understand LDL-C and HDL-C levels

    • NCEP guidelines were not used to determine cholesterol values.

      • Not known if OTC consumers would comply with standard fasting recommendations & >1 blood test prior to use


Conclusions l.jpg
Conclusions Label

  • Treatment goal was a lower cholesterol value (not a clinical endpoint)

    • Appropriateness of that goal and whether consumers understood it was not addressed


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Conclusions Label

  • Self-Selection:

    • Self-selection errors were common

    • It was not demonstrated that subjects know when to involve their physicians

  • Compliance in the OTC setting is less than desired over the short-term


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Conclusions Label

  • Benefit/Risk:

    • Because of exclusion criteria, lack of blood tests, and short duration, these studies could not demonstrate that lovastatin is safe in conditions of actual use

    • Studies do not answer whether monitoring is needed to determine if there has been:

      • benefit of use

      • adverse events


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Conclusions Label

  • Label:

    • 3 iterations used in Actual Use Trials

    • Self-selection error in >1/3 of people

    • 4-Step label (proposed for OTC market) not tested in Actual Use

    • Necessary inclusions and exclusions may be too complex for the unmonitored OTC population to understand


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