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

Outline3 Actual Use Trials

Self-Selection and Compliance issues (trial 076)

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

Actual Use Studies BackgroundSimulate 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 LovastatinCholesterol:

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/dlLDL-C 130 mg/dl

HDL-C was not an inclusion criterion

Exclusion Criteria Common to Trials 076, 077, 081Current or recent (< 2 months)

participation in drug studyAllergy to lovastatinCurrent or Hx liver diseaseContraindicated drugsOther 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

potentialInability to read English

HDL-C was not an exclusion criterion

Sponsor’s DefinitionsPersistence = # (%) 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 - 076Open-labelUncontrolledMulticenter

(pharmacies)24-week (4 visits)“Extension trial”

option

To Evaluate: LDL-C Self-selection Compliance Adverse

experiences

Criteria - 076Inclusion (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 - 076Recruitment via adsReview “Pharmacy”

label and make self-selection decision

Complete Hx formPharmacist triage:

potentially qualified or not

Cholesterol test ( 2-hr fast)

Qualified received study drug

Study Design - 076Return 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 - 079MulticenterOpen-LabelUncontrolledStorefront8 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 - 079Recruitment via adsTelephone 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 - 079Storefront 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 - 079Visit 2 (approximately week 8)

Lipid profile (6-hour fast) Collect remaining drug tablets Adverse experience information

collected

Results - 0794878 called telephone number

1312 (27%) potentially eligible and visited storefront 60% of these were not qualified

(cholesterol) 460 (9%) received study drug

Results - 079Persistence 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 - 081Open-label Uncontrolled MulticenterStorefront clinical sites4 Weeks“Extension trial” option

Study Design - 081ObjectivesTo 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.

CriteriaInclusion

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 - 081Recruitment via adsVisit 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 questionsContraindicated medsCurrent liver diseaseChildbearing potentialAllergy 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 - 081Cholesterol 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 - 081Eligible 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 - 081Visit 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 - 0812416 subjects screened overall1230 (51%) self-selected, “yes”1144 (47%) received drug; 86 did not

(safety risk)

Results - 081Completed vs Discontinued74% completed the 4-week studyReasons 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 - 081Self-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

labelDecreased to 22% erroneous self-selection after

seeing label + reinforcements61% 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

ConclusionsTreatment goal was a lower

cholesterol value (not a clinical endpoint) Appropriateness of that goal and

whether consumers understood it was not addressed

ConclusionsSelf-Selection:

Self-selection errors were common It was not demonstrated that subjects

know when to involve their physiciansCompliance in the OTC setting is less

than desired over the short-term

ConclusionsBenefit/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

ConclusionsLabel:

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