# Presentation: 768025

## Mevacor 20 mg

- Joint Meeting
- Nonprescription Drugs and Endocrinologic and Metabolic Drugs Advisory Committees
- December 13, 2007
- Andrea Leonard-Segal, M.D.
- Director
- Division of Nonprescription Clinical Evaluation

**Center for Drug Evaluation and Research**** **

## Introduction

- History of Development Program for Nonprescription Mevacor
- 2006 NDAC Meeting on Consumer Study Design Issues
- Changes in study design approach
- Regulatory requirements for nonprescription marketing
- Agenda** **

## History of Development Program for Nonprescription Mevacor 20 mg

## Lovastatin(10 mg – 80 mg/day) 

- Marketed by prescription in U.S. since 1987
- Indications:
- Adjunct to diet to reduce elevated total cholesterol (Total-C) and low-density lipoprotein cholesterol (LDL-C)
- adults with 1o hypercholesterolemia
- adolescents with heterozygous familial
- 	hypercholesterolemia
- Slow progression of coronary atherosclerosis in patients with coronary heart disease (CHD)

## Rx to OTC Switch Application

- Today is the 3rd Joint NDAC/EMDAC meeting on this switch application
- Original Submission 1999 – AC 2000
- Re-submission 2004 – AC 2005
- Re-submission 2007
- Proposed labeling for over-the-counter (OTC) Mevacor has changed substantially from one submission to the next, much data has been submitted and reviewed, and progress has been made along the way

## Mevacor Switch History: 2000

- Application for Mevacor 10 mg product for OTC switch based on a Total-C label paradigm was deficient
- Did not establish
- Consumer use in accordance with National Cholesterol Education Program (NCEP) guidelines
- Clinical benefit of 10 mg in proposed OTC population
- That consumers could treat to cholesterol goal
- Consumer comprehension and behavior inadequacies
- Safety concerns not adequately addressed (e.g., liver, muscle, pregnancy)

## Mevacor Switch History: 2005

- Mevacor 20 mg product with a new label
- LDL-C Label Paradigm Target Population
- Males ≥ 45 years / Females ≥ 55 years
- LDC-C 130 – 170 mg/dL
- At least one of these risk factors:
-  Smoking
- HDL-C 1 – 39 mg/dL
- Family Hx in father/brother < 55 or in mother/sister < 65
- Hypertension

## Mevacor Switch History: 2005

- Advisory Committee Agreed:
- Proposed nonprescription LDL-C paradigm target population merits statin treatment to lower cholesterol along with an improved diet
- Adequate rationale for use of fixed dose lovastatin 20 mg to ↓ cholesterol and heart disease risk in the target population assuming adherence to label

## Mevacor Switch History: 2005

- The Mevacor 20 mg label was tested:
- Label Comprehension Study
- Determined if potential consumers could understand the label information
- Consumer Use Study of OTC Mevacor (CUSTOM)
- Determined if consumers could properly self-select to use the product and then use it according to the labeling
- Deficiencies in label comprehension, self-selection, and use led to submission of new data that we will consider today

## 2007

- Merck modified the 2005 label to address deficiencies
- Two new label comprehension studies
- Pivotal and Muscle Warning
- Using two label paradigms LDL-C (same population as in 2005) and a new Total-C paradigm
- New Self-Selection Study: Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment (SELECT) using both label paradigms

## What We Will and Will Not Address Today

- There are issues that have been previously addressed by the committee and subsequently by the Agency that we will not revisit today
- The purpose of today’s meeting is to consider data in the 2007 resubmission that Merck provided to address issues that remained after the 2005 AC meeting

## I’ll Mention Issues for Deliberation Over the Next Few Slides....

- 2 Labels: Cholesterol Treatment Paradigms
- Underlying Liver Disease
- Muscle Warning
- Pregnancy Warning
- Amyotrophic Lateral Sclerosis and Statins
- Self-Selection
- Bridging to Actual Use (CUSTOM)

## LDL-C Paradigm and Total-C Paradigm Target Populations

- Today, we will not ask you to address the merits of the OTC target population defined by the LDL-C label paradigm since the target population is unchanged from 2005 and is considered acceptable
- We do request that the AC consider the merits of the target population defined by the alternative Total-C paradigm label

## Liver Function Test Monitoring

- The 2005 committee:
- Recommended that baseline liver function testing and liver function monitoring for Mevacor 20 mg were not necessary
- Generally found that the risk of liver toxicity with statins was low
- Was not excessively concerned with the use of lovastatin 20 mg by those with undiagnosed liver problems

## Liver and Statins

- Today we will not ask you to discuss the need for LFT monitoring in those with normal liver function because we are comfortable with the previous committee advice
- At Agency request, Merck provided additional data on use in those with asymptomatic liver disease.
- We request the AC views as to whether those with asymptomatic liver disease can safely use lovastatin 20 mg without LFT monitoring
- If not, whether labeling could minimize the risk to this population

## Muscle Warning

- In the CUSTOM study, 75% of subjects who developed unexplained muscle pain made a correct decision about stopping Mevacor use
- FDA requested that labeling be developed to accomplish a higher rate of adherence with the muscle warning and that label comprehension testing should document this improvement
- Today we would like your views on the comprehension of the new label muscle pain warning

## Lovastatin and Pregnancy

- Rodents
- Fetal skeletal abnormalities occurred at high lovastatin exposures (40 and 80 X human exposure)
- Reports of congenital anomalies with human use exist, but no causal inference, trend, pattern, or association with lovastatin has been established
- Category X
- Safety has not been established in pregnant women and there is no apparent benefit to therapy during pregnancy
- Rx labeling recommends counseling adolescent patients about contraception

## Pregnancy Warning

- 2005 Committee
- Majority (18/23) thought that lovastatin is not so potentially toxic to the fetus as to prevent nonprescription marketing
- All recommended that the pregnancy warning should be improved
- Today we request your views on the adequacy of the new label pregnancy warning

## Amyotrophic Lateral Sclerosisand Statins?

- Today you will hear what is known and not known about whether there is a connection between statin use and ALS
- We will be interested in your thoughts on what role the state of our knowledge about this issue should have in making a decision about OTC statin availability

## Self-Selection (SS)

- 2005 Committee
- Majority felt SS data were insufficient to show that OTC consumers can use lovastatin 20 mg safely and effectively without physician guidance
- Expressed concerns about the ability consumers to self-manage their cholesterol with regard to self-monitoring and drug interactions

## Self-Selection

- Today we request your views as to whether new data demonstrate that consumers could make an appropriate SS decision giving consideration to:
- NCEP Adult Treatment Panel III Guidelines
- Framingham CHD risk profile
- Those already taking a statin
- And as a related issue, whether data support adequate comprehension of the muscle pain warning

## Actual Use

- There are differences between the CUSTOM actual use study label and the two labels used in the SELECT self-selection study
- We seek your advice as to whether the CUSTOM results on
- behavior related to LDL follow up testing
- behavior when muscle pain develops
- remain meaningful considering the
- labeling differences

## 2006 NDAC Meeting on Consumer Study Design Issues

- Led to Change in SS Analysis Approach

## SS Analysis Approach to CUSTOM In  2005

- For CUSTOM we applied strict label eligibility criteria to define correct self-selection decision making considering
- Each component of the lipid panel
- Risk factors for CHD
- Contraindications to use
- 10% correctly self-selected “yes” based upon these criteria
- After listening to committee member discussion, we wondered if this had been too stringent an analytical approach

## NDAC 2006: Prioritize Label Elements  - Create Hierarchy

- NDAC discussed that it would be reasonable to change SS analyses approach
- Pre-define hierarchy of critical label elements based upon risk/benefit....“deal breakers”
- Consumer must correctly decide whether, based upon these “deal breaker” elements, it is okay for him/her to use the product
- Correctness for other label elements is optional
- Prioritizing the label elements can be very difficult
- Since the NDAC 2006 meeting we have been recommending the hierarchy approach to sponsors of a variety of different types of products

## Mevacor Hierarchies

- 2006...Mevacor SELECT and LC studies in progress
- Today you will see several post-hoc SS hierarchy analyses
- Consider what elements could constitute an appropriate hierarchy for statin self-selection

## Issue for Today

- Does lovastatin 20 mg meet the regulatory requirements for nonprescription marketing?

## Regulatory Requirements for Nonprescription Marketing

## 1951 Durham Humphrey Amendment to the Food, Drug and Cosmetic Act

- Formally differentiates Prescription from Nonprescription Drugs
- Criteria carve niche for Prescription Drugs:
- Drug can be used safely only under supervision because of:
- drug's toxicity or
- other potentiality for harmful effect, or
- method of its use, or
- collateral measures necessary to its use
- Otherwise, the drug should be available without a prescription

## Prescription to Nonprescription Switch Considerations

- Does the product have:
- Acceptable safety profile?
- Low potential for misuse and abuse?
- Reasonable therapeutic index of safety?
- Can the condition to be treated be self-recognized?
- When used under OTC conditions is the product safe and effective?
- Do the benefits outweigh risks in OTC setting?

## Agenda

- Merck
- Break
- FDA
- Lunch
- Open Public Hearing
- Discussion/Questions