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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 z 3 Actual Use Trials y. Self-Selection and Compliance issues (trial 076) y. Compliance issues (trial 079) y. Self-selection and safety (trial 081)
Actual Use Studies Background z Simulate OTC Use of a Product y. Exclusion criteria: The fewer the better! y. Self-selection: Are people choosing product properly based on indications and contraindications? y. Compliance: Are dosing and duration of use according to directions? y. Safety: What are the adverse experiences? z Efficacy information often limited by open-label, uncontrolled design
Actual Use Issues for Lovastatin z Cholesterol: y. Do people know their values? y. Do they understand TC, LDL-C, and HDL-C? y. Do they understand when to treat? y. What is the treatment goal and do consumers understand it?
Actual Use Issues (Continued) z Cholesterol Measurement: y. Can OTC desktop cholesterol screening offer accurate cholesterol measurement? y. What is the appropriate duration of fast prior to measurement? y. How many measurements should be performed to obtain an accurate value? y. If averaging multiple cholesterol values is recommended, can consumers do the math?
Actual Use Issues (Continued) z Self-Selection: y. Can consumers understand what underlying conditions and concomitant medications put them at safety risk if they take lovastatin? y. Do consumers know when they are taking contraindicated drugs? y. Do consumers understand when to seek the counsel of a physician?
Actual Use Issues (Continued) z Compliance: y. Are consumers sufficiently compliant in the OTC setting to derive clinical benefits of lovastatin treatment over the long-term? z Benefit and Risk y. Is monitoring needed to determine if there has been a benefit of use as well as no adverse safety events? y. Can consumers identify symptoms associated with adverse events?
Actual Use Issues (Cont’d) z. Label: y. Can a label adequately convey all necessary information about lovastatin so it can be used properly?
Inclusion Criteria Common to Trials 076, 079, 081 z. TC = 200 -240 mg/dl z. LDL-C 130 mg/dl z. HDL-C was not an inclusion criterion
Exclusion Criteria Common to Trials 076, 077, 081 z. Current or recent (< 2 months) participation in drug study z. Allergy to lovastatin z. Current or Hx liver disease z. Contraindicated drugs z. Other cholesterol medication
Exclusion Criteria Common to 076, 079, 081 (Cont’d) z. Hx heart disease z. FHx MI before age 55 (parents, siblings) z. Pregnant, breast-feeding, childbearing potential z. Inability to read English z. HDL-C was not an exclusion criterion
Sponsor’s Definitions z Persistence = # (%) of subjects who returned for a follow-up visit having taken any of the study tablets z Compliance was calculated in persistent subjects and was defined as: y # tablets taken/# days drug taken during specified time period y Expressed as a percentage
Study Design - 076 z Open-label z Uncontrolled z Multicenter (pharmacies) z 24 -week (4 visits) z “Extension trial” option z To Evaluate: y. LDL-C y. Self-selection y. Compliance y. Adverse experiences
Criteria - 076 z Inclusion (as described) plus: y. Age: x. Men 45; women 55 y. General good health; no disabling disease y. Low-fat diet during previous year z Exclusion (as described) plus: y. Corticosteroid use y. Peripheral vascular disease y 3 alcoholic beverages/day most days
Label - 076 z “Pharmacy” Label: y. Lists Inclusion-Exclusion criteria y. Did not list all interactive medications y 1 tablet qhs y. Retest cholesterol after 8 weeks and contact study doctor if level did not decrease
Study Design - 076 z Cholesterol test ( 2 z Recruitment via ads hr fast) z Review “Pharmacy” label and make selfz Qualified received selection decision study drug z Complete Hx form z Pharmacist triage: potentially qualified or not
Study Design - 076 z. Return visits: ycount returned pills yrecord adverse events ylipid profile ynew drug at visits 2, 3
Results - 076 (Self-Selection) z 722 (12%) of all 6095 study participants qualified to receive drug z 981 (16%) of study participants selfselected to obtain and use the drug y. Only 119 (12%) of this self-selection group actually received drug
Results - 076 (Self-Selection) z 6081 completed self-selection process y 82% needed more than “Pharmacy” label to decide whether to obtain drug y 53% thought they met criteria for TC level, but did not y. No information about how well consumers understood the meaning of the components of the lipid profile
Results - 076 (Self-Selection) z 5% who were likely to buy lovastatin were in “safety risk” group y. Liver disease (72) y. Prohibited medications as per label (44) y. Pregnancy risk (3) y. Allergic to lovastatin (8)
Results - 076 (Compliance) z. Completion, Persistence and Compliance: y 523/722 (72%) completed the study y 504/722 (69%) were persistent at last visit (Visit 4) y 441/722 (61%) were taking 75% of medicine at Visit 4 y. No diary, so precise information about how people actually dosed is unavailable.
Study Design - 079 z Multicenter z Open-Label z Uncontrolled z Storefront z 8 weeks z “Extension trial” option z To test: y. Mean change in LDL at 8 weeks y. Ability of consumers to remain on lovastatin y. Tolerability of lovastatin as measured by AE incidence
Study Design - 079 z Recruitment via ads z Telephone history screening
Criteria y. Inclusion (as described) plus: xmen 40; women 55 y. Exclusion (as described) plus: x 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 z“Restricted Access” Label y. Designed to reinforce appropriate postpurchase behavior, not to guide self-selection y. Contained trial inclusion and exclusion criteria y. More expansive list of contraindicated medications than “Pharmacy” label y. Recommended seeing doctor at least yearly to discuss cholesterol treatment plan
Study Design - 079 z. Storefront appointment for potentially eligible (Visit 1) y. Lipid profile (6 -hour fast) y. BP y. Weight, Height y. Eligible received drug with “Restricted Access” label and study information card
Study Design - 079 z. Visit 2 (approximately week 8) y. Lipid profile (6 -hour fast) y. Collect remaining drug tablets y. Adverse experience information collected
Results - 079 z 4878 called telephone number y 1312 (27%) potentially eligible and visited storefront x 60% of these were not qualified (cholesterol) y 460 (9%) received study drug
Results - 079 z. Persistence and Compliance y 363 people took some drug (were persistent) y 265 were compliant at least 75% of the time over the 8 -week study y. No diary, so precise information about how people actually dosed is unavailable. z. Trial did not test the ability of consumers to properly self-select
Study Design - 081 z. Open-label z. Uncontrolled z. Multicenter z. Storefront clinical sites z 4 Weeks z“Extension trial” option
Study Design - 081 Objectives z. To test: y. Effectiveness of an enhanced “Red Arrow” label & reinforcement tools (videotape, pamphlet, insert) y. Effectiveness of these in 3 risk subsets: xdrug risk x 1° prevention subjects (cholesterol > 240 mg/dl) xhigh cardiovascular risk group y. Tolerability of lovastation 10 mg as measured by incidence of adverse events.
Criteria z. Inclusion y. Men 40; women 1 year post-menopausal y. Express interest in purchasing lovastatin z. Exclusion y. Employed in healthcare y. Diabetes y. Stroke y. Taking > 1 anti-hypertension drug y. Participated in cholesterol lowering study < 2 years
Label - 081 z“Red Arrow” label y. Flip-up back panel design y. Warnings emphasized with red arrows and stop signs y. Examples of muscle pain, tenderness or weakness added to drug interaction warnings y“Warnings” precede “who should use” y. Boxed warning to “carefully read package before selfselecting and call a product specialist for help understanding the label”
Study Design - 081 z. Recruitment via ads z. Visit 1 - Storefront site: y. Participants read product concept & label; then made self-selection decision y. If “yes” paid $15 for lovastatin 10 mg and answered specific safety risk questions x. Contraindicated meds x. Current liver disease x. Childbearing potential x. Allergy to lovastatin
Study Design - 081 z. If participant self-selected, “yes, ” but was excluded for safety risk: y 2 nd chance to review label and reinforcements and to make self-selection decision x. No drug was provided
Study Design - 081 z. Cholesterol test offered to those who needed before could self-select, then: y. Repeat self-selection decision y. Answered safety risk questions z. Medical Hx performed on all who left storefront site without drug: y. Self-selected “no” y. Failed safety risk exclusion questions y. Did not want to purchase
Study Design - 081 z. Eligible Participants y. Received 4 -week supply of open-label lovastatin 10 mg y. Were told to take drug according to label
Study Design - 081 y. Were given incentive to call toll-free # x. Those who did were asked medical Hx using screening script (incl-excl criteria) x. If deemed inappropriate for drug, were told to: • D/C • return remaining drug and packaging
Study Design - 081 z. Visit 2 (Week 4) y. Returned packaging and unused drug y. For those who had not called toll-free #, nurse administered medical Hx and determined appropriateness of Rx y. Lipid testing for those interested in extension
Results - 081 z 2416 subjects screened overall z 1230 (51%) self-selected, “yes” z 1144 (47%) received drug; 86 did not (safety risk)
Results - 081 Completed vs Discontinued z 74% completed the 4 -week study z Reasons the rest discontinued: y 10% not appropriate (as per medical Hx) y 6% adverse experience y 4% lost to follow-up y 3% returned drug by mail y 2% withdrew consent
Results - 081 z. Self-selection errors among the 1144: y. Heart disease - 22 y. Stroke/TIA - 14 y. Other cholesterol treatment - 45 y. Hypertension 211 (147 on medication) y. Hx hepatitis or liver disease - 35 y. Alcohol 3/day - 26 y. Diabetes - 23
Results - 081 (Self-Selection) z 1112/2264 consumers with known medical history said they would purchase y 39% self-selected erroneously after seeing label x. Decreased to 22% erroneous self-selection after seeing label + reinforcements z 61% of subjects with known medical eligibility status did not call toll-free # y 36% were ineligible to take lovastatin
Results - 081: Safety Group Self. Selection Errors After Label z. Safety risk group = 120 participants y 83 took interacting medication x 30% self-selected incorrectly to take lovastatin y 16 < 1 year postmenopausal x 50% self-selected incorrectly y 14 - current liver disease x 36% self-selected incorrectly y 8 - allergic x 13% self-selected incorrectly
Results - 081: Cardiovascular Self-Selection Error After Label) z 381 subjects with cholesterol > 240 mg/dl as only contraindication y 46% self-selected incorrectly z 262 participants were in high cardiovascular risk categories y 32% self-selected incorrectly to take lovastatin
Results - 081 (Safety) y 15% people who received drug had an adverse experience (AE) likely related to lovastatin y 4% discontinued due to drug-related AE y. None of 6 serious AE likely to have been study-drug related y. Incomplete information because LFTs and CPKs were not done & short duration Rx
Conclusions (Overall) z. Cholesterol: y. Many lack accurate knowledge of their cholesterol values y. Trials do not assess if consumers understand LDL-C and HDL-C levels y. NCEP guidelines were not used to determine cholesterol values. x. Not known if OTC consumers would comply with standard fasting recommendations & >1 blood test prior to use
Conclusions z. Treatment goal was a lower cholesterol value (not a clinical endpoint) y. Appropriateness of that goal and whether consumers understood it was not addressed
Conclusions z. Self-Selection: y. Self-selection errors were common y. It was not demonstrated that subjects know when to involve their physicians z. Compliance in the OTC setting is less than desired over the short-term
Conclusions z. Benefit/Risk: y. 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 y. Studies do not answer whether monitoring is needed to determine if there has been: xbenefit of use xadverse events
Conclusions z. Label: y 3 iterations used in Actual Use Trials y. Self-selection error in >1/3 of people y 4 -Step label (proposed for OTC market) not tested in Actual Use y. Necessary inclusions and exclusions may be too complex for the unmonitored OTC population to understand