DRAFT SLIDES FOR NDA 21213 ADVISORY COMMITTEE PRESENTATION

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DRAFT SLIDES FOR NDA 21-213 ADVISORY COMMITTEE
PRESENTATION
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Joint Advisory Committee Meeting on OTC
Availability of Lovastatin 10 mg

• Actual Use Trials
• Andrea Leonard-Segal, M.D.
• Division of OTC Drug Products

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Outline

• 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 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

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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?

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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?

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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?

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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?

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Actual Use Issues (Contd)

• 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

• 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

• Current or recent (lt 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
(Contd)

• 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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Sponsors 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

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Study Design - 076

• Open-label
• Uncontrolled
• Multicenter (pharmacies)
• 24-week (4 visits)
• Extension trial option

• To Evaluate
• LDL-C
• Self-selection
• Compliance
• Adverse experiences

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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

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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

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Study Design - 076

• 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

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Study Design - 076

• Return visits
• count returned pills
• record adverse events
• lipid profile
• new drug at visits 2, 3

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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

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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

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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)

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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.

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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

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Study Design - 079

• Recruitment via ads
• Telephone history screening

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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 gt1 BP
  drug diastolic BP ? 100 or systolic BP ? 180
  mm/Hg subjects who knew their TC was lt 190 mg/dl
  or gt 250 mg/dl corticosteroids

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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

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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

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Study Design - 079

• Visit 2 (approximately week 8)
• Lipid profile (6-hour fast)
• Collect remaining drug tablets
• Adverse experience information collected

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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

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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

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Study Design - 081

• Open-label
• Uncontrolled
• Multicenter
• Storefront clinical sites
• 4 Weeks
• Extension trial option

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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 gt 240 mg/dl)
• high cardiovascular risk group
• Tolerability of lovastation 10 mg as measured by
  incidence of adverse events.

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Criteria

• Inclusion
• Men ? 40 women ? 1 year post-menopausal
• Express interest in purchasing lovastatin
• Exclusion
• Employed in healthcare
• Diabetes
• Stroke
• Taking gt 1 anti-hypertension drug
• Participated in cholesterol lowering study lt 2
  years

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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

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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

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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

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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

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Study Design - 081

• 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

• 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

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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

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Results - 081

• 2416 subjects screened overall
• 1230 (51) self-selected, yes
• 1144 (47) received drug 86 did not (safety
  risk)

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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

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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

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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

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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 lt 1 year postmenopausal
• 50 self-selected incorrectly
• 14 - current liver disease
• 36 self-selected incorrectly
• 8 - allergic
• 13 self-selected incorrectly

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Results - 081 Cardiovascular Self-Selection
Error After Label)

• 381 subjects with cholesterol gt 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)

• 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)

• 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 gt1 blood test
  prior to use

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Conclusions

• 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

• 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

• 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
• 3 iterations used in Actual Use Trials
• Self-selection error in gt1/3 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