# Presentation: 764518

## 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)
- Compliance issues (trial 079)
- Self-selection and safety (trial 081)

## 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

- 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)

- 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 (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 (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)

- 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 

- 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

- 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)

- 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

- _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

## 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

- “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 - 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

## Study Design - 076

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

## 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-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-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)

- 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

- Recruitment via ads
- Telephone history screening

## 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

- “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 - 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 - 079

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

## 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 - 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

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

## Study Design - 081Objectives

- 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.

## 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

- “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 - 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 - 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 - 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 - 081

- Eligible Participants
- Received 4-week supply of open-label lovastatin 10 mg
- Were told to take drug according to label

## 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 - 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

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

## Results - 081Completed 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 - 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)

- 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

- 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)

- 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)

- 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)

- 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

- Treatment goal was a lower cholesterol value (not a clinical endpoint)
- Appropriateness of that goal and whether consumers understood it was not addressed

## 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

## 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

## 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