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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

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
Outline
  • 3 Actual Use Trials
    • Self-Selection and Compliance issues (trial 076)
    • Compliance issues (trial 079)
    • Self-selection and safety (trial 081)
actual use studies background
Actual Use Studies Background
  • 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
actual use issues for lovastatin
Actual Use Issues for Lovastatin
  • 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?
actual use issues continued
Actual Use Issues (Continued)
  • 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?
actual use issues continued7
Actual Use Issues (Continued)
  • 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?
actual use issues continued8
Actual Use Issues (Continued)
  • 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?
actual use issues cont d
Actual Use Issues (Cont’d)
  • Label:
    • Can a label adequately convey all necessary information about lovastatin so it can be used properly?
inclusion criteria common to trials 076 079 081
Inclusion Criteria Common to Trials 076, 079, 081
  • TC = 200-240 mg/dl
  • LDL-C  130 mg/dl
  • HDL-C was not an inclusion criterion
exclusion criteria common to trials 076 077 081
Exclusion Criteria Common to Trials 076, 077, 081
  • Current or recent (< 2 months) participation in drug study
  • Allergy to lovastatin
  • Current or Hx liver disease
  • Contraindicated drugs
  • Other cholesterol medication
exclusion criteria common to 076 079 081 cont d
Exclusion Criteria Common to 076, 079, 081 (Cont’d)
  • 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
sponsor s definitions
Sponsor’s Definitions
  • 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
Open-label

Uncontrolled

Multicenter (pharmacies)

24-week (4 visits)

“Extension trial” option

To Evaluate:

LDL-C

Self-selection

Compliance

Adverse experiences

Study Design - 076
criteria 076
Criteria - 076
  • 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
label 076
Label - 076
  • “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
study design 07617
Recruitment via ads

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
study design 07618
Study Design - 076
  • Return visits:
    • count returned pills
    • record adverse events
    • lipid profile
    • new drug at visits 2, 3
results 076 self selection
Results - 076 (Self-Selection)
  • 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
results 076 self selection20
Results - 076 (Self-Selection)
  • 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
results 076 self selection21
Results - 076 (Self-Selection)
  • 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)
results 076 compliance
Results - 076 (Compliance)
  • 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
Multicenter

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
study design 07924
Study Design - 079
  • Recruitment via ads
  • Telephone history screening
criteria
Criteria
  • 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
study label 079
Study Label - 079
  • “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
study design 07927
Study Design - 079
  • 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
study design 07928
Study Design - 079
  • Visit 2 (approximately week 8)
    • Lipid profile (6-hour fast)
    • Collect remaining drug tablets
    • Adverse experience information collected
results 079
Results - 079
  • 4878 called telephone number
    • 1312 (27%) potentially eligible and visited storefront
      • 60% of these were not qualified (cholesterol)
    • 460 (9%) received study drug
results 07930
Results - 079
  • 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
study design 081
Study Design - 081
  • Open-label
  • Uncontrolled
  • Multicenter
  • Storefront clinical sites
  • 4 Weeks
  • “Extension trial” option
study design 081 objectives
Study Design - 081Objectives
  • 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
Criteria
  • 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
Label - 081
  • “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
Study Design - 081
  • 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
Study Design - 081
  • 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
Study Design - 081
  • 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
Study Design - 081
  • Eligible Participants
    • Received 4-week supply of open-label lovastatin 10 mg
    • Were told to take drug according to label
study design 08139
Study Design - 081
  • 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
Study Design - 081
  • 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
Results - 081
  • 2416 subjects screened overall
  • 1230 (51%) self-selected, “yes”
  • 1144 (47%) received drug; 86 did not (safety risk)
results 081 completed vs discontinued
Results - 081Completed 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
Results - 081
  • 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
results 081 self selection
Results - 081 (Self-Selection)
  • 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
results 081 safety group self selection errors after label
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
Results - 081: 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
results 081 safety
Results - 081 (Safety)
  • 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
conclusions overall
Conclusions (Overall)
  • 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
Conclusions
  • Treatment goal was a lower cholesterol value (not a clinical endpoint)
    • Appropriateness of that goal and whether consumers understood it was not addressed
conclusions50
Conclusions
  • 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
conclusions51
Conclusions
  • 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
conclusions52
Conclusions
  • 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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