# Presentation: 721677

## Mevacor Daily®MerckNDA 21-213 

- Nonprescription Drugs Advisory Committee and
- Endocrinologic and Metabolic Advisory Committee Meeting
- Silver Spring, Maryland
- December 13, 2007
- Linda Hu, M.D.
- Division of Nonprescription Clinical Evaluation

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

## Self Evaluation of Lovastatin to Enhance Cholesterol Treatment

**(SELECT)**

## Overview 

- Regulatory Background
- SELECT Labeling Paradigms
- SELECT Study Design
- SELECT Results
- Analyses of **Mitigations**
- Analysis Of Eligibility Criteria Subsets (**Hierarchies**)
- Analysis Of **User Population**
- Summary

## Regulatory Background 

- Initial submission 1999
- Response to October 2000 non-approval letter, which included
- CUSTOM actual use study, “A Consumer Use Study of Over-The-Counter MEVACOR”
- Label comprehension study
- Other efficacy data and safety data
- Led to non-approval letter in February, 2005

## CUSTOM Actual-Use Study

- 10% of CUSTOM users correctly self-selected
- Required criteria age, LDL-C, CHD risk factors, absence of certain conditions (conditions = liver disease, high triglycerides, history of statin-induced muscle pain)
- 54% (571/1059) of CUSTOM users considered appropriate by sponsor
- 416 said they talked to their doctor

## Deficiencies in Feb 2005Non Approval Letter

- Concern about inability of consumers, on their own, to make decisions on the appropriateness of statin therapy for their own personal use
- Remaining safety concerns
- Use by pregnant women and women of childbearing potential
- Compliance with muscle pain warning
- Use by patients with asymptomatic liver disease

## Recommendations from Feb 2005 Non Approval Letter

- A self-selection/use study or studies
- Label comprehension studies
- Address the risk in subjects with asymptomatic liver disease

## SELECT Study Label Paradigms

-   **LDL-C Label     **
**  ****Total-C Label**

## LDL-C Label Target Population

- Males ≥ 45 years; females ≥ 55  years
- LDL in range 130 - 170 mg/dL
- One or more additional cardiac risk factors

## Cardiac Risk Factors

- • Cigarette smoking
- • Hypertension or on  BP medication
- • Family history of premature CHD (below age of 55 years in a male parent or sibling or below 65 in female relative)
- • HDL-C < 40 mg/dL
- • Age (men > 45 years, women > 55 years).

## Total-C Label Target Population

- Total-C in range 200-240 mg/dL
- Males
- _>_ 45 years
- Females
- HDL < 60 mg/dL
- _>_ 55  years
- One or more additional cardiac risk factors

## SELECT Label Paradigms

- Label should be consistent with NCEP ATP III guidelines
- LDL-C label conforms better to ATP III than Total-C label
- Focus on results from LDL-C label arm

## NCEP ATP III Guidelines

## (SELECT)

**Self Evaluation of Lovastatin to Enhance Cholesterol Treatment**

**Study Design and Study Population**

## SELECT Self-Selection Study

- How many consumers will decide correctly that Mevacor is OK for them to use (“self-selection”)?
- Study should be naturalistic

*Self-selection: A decision by a consumer whether or not to choose a product for use based on two things: (1) his or her unique medical history and (2) the product labeling.*

## SELECT Self-Selection Study

- Consumers were asked
- Self-assessment (SA) question
- Purchase decision (PD) question
- Reasons why, if incorrect
- Subjects randomized to two labels
- LDL-C
- Total-C

- Focus on LDL-C

## Focus on Self-Assessment

- Purchase Decision is influenced by potentially confounding economic and marketing issues
- cost
- consumer appeal of product
- Our interest is in whether the consumer understands
- who should use
- why should one use
- how to use

## Directions Prior toSelf-Assessment Question

- Participants were told
- The product is not appropriate for everyone
- You will be asked whether the product was appropriate for you
- You will be asked whether you wish to purchase
- Concentrate and to take as much time as needed

## Self-Assessment (SA)  

- “Based on this label, is this product appropriate for you to use right now or not?”* *
- Yes
- No
- Other (unsure or wanted to ask a doctor)

## Purchase Decision (PD)

- “Would you like to pay for this right now for your own use or put it back in the display?”
- If the participant wants to purchase, then ask, “Is there anything you plan to do before you start using it?”

## Recruitment

- Recruitment by mass media advertising
- Ads told subjects to know:
- total cholesterol, LDL, HDL, and triglycerides
- Advertising may have recruited more informed subjects who were better prepared for self-selection

## SELECT: Self-Assessment Population

- Number of Calls N=5107

- LDL-C Paradigm N=767

- Number Randomized N=1520

- Total-C Paradigm N=753

- LDL-C Paradigm  after exclusions N=662

- Total-C Paradigm  after exclusions N=664

## SELECT Study Population

- 1520 subjects randomized
-  typically well educated, middle-class
- 90% high school graduates and 60% had some college
- 70% had insurance
- 14% low literate

## Areas Targeted For Improvement in SELECT

- Decrease the proportion of women <55
- Decrease the proportion of women of childbearing potential
- Decrease the proportion of low CHD risk (<5% risk of CHD in 10 years)

## SELECT RESULTS

## Eligibility Assessment Criteria

- Age
- Pregnant or breastfeeding
- May become pregnant
- Heart disease
- Stroke
- Diabetes
- Liver disease
- Listed risk factors

- Allergy to drug
- Lipid-lowering medications
- Interacting drugs
- LDL-C
- HDL-C
- Grapefruit juice
- Fasting lipid profile

## Self-Assessment ResultsLDL-C

- Is it appropriate for you? SA population N=662

## Self-Assessment Results Total-C

- Is it appropriate for you? SA population N=664

## Mitigations for Incorrect Self-Assessment

- Some subjects who incorrectly self-selected to use gave open-ended responses that were acceptable and could be “mitigated”
- Would talk to doctor
- Gave reasonable rationale for treatment
- Gave evidence of not understanding the self-assessment question

## Mitigations

|  Label  
(# Incorrect) | Talk to Doctor | Did Not Understand SA | Other Mitigations | Total Mitigated |
| --- | --- | --- | --- | --- |
| LDL      (n=180) | 46 | 16 | 23* | 85 |
| Total-C (n=176) | 30 | 11 | 32* | 73 |

- Almost half of incorrect subjects were mitigated
- Talk to doctor was most common reason for mitigation
- Cannot verify whether subjects would actually talk to a doctor
- Other Mitigations
- *Reviewers did not agree with 9 mitigations for  LDL and 11 mitigations for Total-C

## Examples of Other MitigationsMade by Sponsor

- Substitution of Mevacor for current lipid medication without talking to doctor
- High risk subject who self-selected to use without talking to doctor
- Self-selected yes when had prior side effects on statins

## Self-Selection Percent Completely Correct, and Correct After Mitigations

| Label | Self Assessment | % Completely Correct | % Correct After Mitigations |
| --- | --- | --- | --- |
| LDL | Yes | 16% | ~50% |
| Total-C | Yes | 27% | ~50% |

## SELECT RESULTS:ANALYSIS OF ELIGIBILITY CRITERIA SUBSETSHIERARCHIES

## Hierarchies

- Many eligibility criteria
- Difficult to get all eligibility criteria correct
- Some criteria of more clinical importance then others
- New analyses where % correct was calculated for subsets of eligibility criteria (“hierarchies”)
- Self-assessment hierarchies will be presented

## Hierarchies for LDL-C Arm

- Self-Selection Results Using **ALL** Label Criteria
- % entirely correct  (16%)
- % correct after mitigation  (~50%)
- Using “hierarchies” or subsets of label criteria
- % correct before mitigation
- % correct after mitigation
- % correct depends on which criteria are used in hierarchy

## Sponsor Safety Hierarchy

- Pregnant/breast feeding
- May become pregnant
- Allergy to lovastatin
- On interacting medications
- On lipid-lowering medications
- Liver problem

## SAFETY Hierarchy SA=Yes (LDL arm)

- N=**214**

**Of 2 Pregnant/breastfeeding**

- N=**0**

- N=**214**

**Of 12 may become pregnant**

- N=**1**

- N=**213**

**Of 4 allergy to lovastatin**

- N=**0**

- N=**213**

**Of 12 on interacting medicine**

- N=**3**

- N=**210**

## SAFETY Hierarchy SA=Yes

- N=**210**

**Of 140 on lipid lowering medicine**

- N=**36**

- N=**174**

**Of 23 liver problem**

- N=**0**

- N=**174**

**Percent Correct   81.3% **

## Sponsor Safety Hierarchy

| Hierarchy | LDL (N=214) |  | Total-C (N=242) |  |
| --- | --- | --- | --- | --- |
|  | % Correct Before Mitigation | % Correct After Mitigation | % Correct Before Mitigation | % Correct After Mitigation |
| Sponsor Safety* | 81.3% | 89.3% | 83.1% | 90.1% |

- For all eligibility criteria 16% correct

- _Sponsor Safety_: Pregnant/breast-feeding, may become pregnant, allergy to lovastatin, interacting medications, lipid lowering medications, and liver problems

## Eligibility Assessment Criteria

- Age
- Pregnant or breastfeeding
- May become pregnant
- Heart disease
- Stroke
- Diabetes
- Liver disease
- Listed risk factors

- Allergy to drug
- Lipid-lowering medications
- Interacting drugs
- LDL-C
- HDL-C
- Grapefruit juice
- Fasting lipid profile

## Sponsor Hierarchies

| Hierarchy | LDL (N=214) |  | Total-C (N=242) |  |
| --- | --- | --- | --- | --- |
|  | % Correct Before Mitigation | % Correct After Mitigation | % Correct Before Mitigation | % Correct After Mitigation |
| Safety* | 81.3% | 89.3% | 83.1% | 90.1% |
| Benefit** | 25.7% | 57.0% | 41.7% | 62.4% |
| Safety & Benefit | 21.0% | 52.8% |  35.1% | 58.3% |

- *  Pregnant/breast-feeding, may become pregnant, allergy to lovastatin, interacting medications, lipid lowering medications, liver problems_ _
- **  Age, lipid values (LDL-C or Total-C), and risk factors

## Other Sponsor Hierarchies

| Hierarchy | LDL (N=214) |  | Total-C (N=242) |  |
| --- | --- | --- | --- | --- |
|  | % Correct Before Mitigation | % Correct After Mitigation | % Correct Before Mitigation | % Correct After Mitigation |
| Benefits w/o Lipid* | 65.4% | 77.1% | 77.3% | 88.4% |
| Expanded Benefit** | 40.7% | 65.9% | 57.4% | 77.3% |

- *   Age and risk factors
- ** Age, risk factors, heart disease, stroke, and diabetes, lipid lowering medications

## FDA Review Team Hierarchies

| Hierarchy | LDL (N=214) |  | Total-C (N=242) |  |
| --- | --- | --- | --- | --- |
|  | % Correct Before Mitigation | % Correct After Mitigation | % Correct Before Mitigation | % Correct After Mitigation |
| #1* | 21.0% | 52.8% | 35.1% | 58.3% |
| #2** | 17.8% | 50.9% | 31.4% | 57.0% |

- *    Age, lipid lowering medications, lipid values, interacting medications, risk factors
- **   Age, lipid lowering medications, lipid values, interacting medications, heart disease, stroke, diabetes, risk factors

## Hierarchies

- None of the hierarchies was defined *a priori *in the study protocol
- Depending on which criteria are included, the percent correct in the hierarchies before mitigations ranged from 20-80%

## SELECT RESULTS:Profiles of User Population

## CHD Risk Profiles SA=Yes LDL-C

| 10-Year CHD 
Risk | Men |  | Women |  | Total
Men + Women |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | n | % | n | % | n | % |
| unknown | 4 | 3.2% | 1 | 1.1% | 5 | 2.4% |
| <5% | 13 | 10.5% | 42 | 46.7% | 55 | 25.7% |
| 5-20% | 51 | 41.1% | 22 | 24.4% | 73 | 34.1% |
| >20% | 13 | 10.4% | 1 | 1.1% | 14 | 6.6% |
| CHD/DM/Stroke | 16 | 12.9% | 12 | 13.3% | 28 | 13.1% |
| Rx Chol. Med. | 27 | 21.8% | 12 | 13.3% | 39 | 18.2% |

## Women Too Young (<55 yo)  LDL arm

- 391 women were asked the self-assessment question in the LDL arm,  220  (56.3%) were too young.
-  13.2% (29/220) self-selected to use
- Of 391 women asked the SA question, 101 women of all ages self-selected to use
- Of these 101 women, ~ 29% were < 55 years old
- Reasons for  their decision were: age is close, lower my cholesterol, family history

## Pregnant/May Become Pregnant

- Pregnant (n=4)
- 1 out of 4: SA=Yes,
- sponsor mitigated
- reviewers agreed
- May become pregnant (n=22)
- 9% (2/22) chose SA=Yes,
- sponsor mitigated
- reviewers did not agree

## Heart Disease (LDL Arm)

- 48.5% (33/68) with heart disease self-selected yes
- Subjects at high CHD risk might be undertreated by 20 mg of lovastatin

## Already on Lipid Medications (LDL arm)

- 140/750 (18.7%) in the self-selection population were already taking lipid-lowering medication
- 44/140 (31.4%) of these participants self-selected yes

## Reasons Why Subjects on Rx Selected Incorrectly

- The most frequent reasons for choosing to use or purchasing, when the subject was already taking lipid-lowering medication
-  to replace the prescription medication
- specifically to replace it because of lower cost

## Substitution Rate of OTC for Rx Medications CHD

| Reported Action | LDL-C
(N=27)
N(%) |
| --- | --- |
| Take along with it | 8 (29.6%) |
| Take in place | 14 (51.9%) |
| Don’t know | 1 (3.7%) |
| Other | 3 (11.1%) |
| Missing | 1 (3.7%) |

## Reasons for Preferring OTC Med Rather than Rx Med for Cholesterol

- The most frequent reasons for preferring OTC medications, for those who self-selected yes :
- less expensive (50%)
- convenience (29%)
- don’t have to see the doctor (15%)
- feels safer/less side effects (11.3%)

## High Risk, CHD, Diabetes, Stroke: LDL-C arm

- On average, ~30% of subjects with CHD, DM  or stroke wanted to buy
- 2/3 of these subjects were not on any lipid-lowering medications

## What Medications Would Be Substituted: LDL arm

## Knowing LDL-C versus Total-C

- In the LDL-C arm, 37.5% (268/714) did not know their LDL-C, whereas in the Total-C arm, 21% (149/708) did not know their Total-C.
- Of those who did not know their cholesterol numbers
- LDL-C: 22.4% ( 60/268)  self-selected yes
- Total-C: 17.4% (26/149) self- selected yes

## Ineligible Subjects for Lipid Values

- Many of the subjects who had LDL outside the eligible range nevertheless selected yes in the LDL-C arm
- 43% (52/122) of subjects w/ LDL-C too high (above 170) self-selected yes
- 17% (26/153) of subject whose LDL-C too low (below 130) self-selected yes

## SELECT Summary  

- ~20% self-selected yes entirely correctly
- With mitigations, % correct ~ 50%
- Only 4 pregnant women in the study
- Of those who may become pregnant
- 2/22 (9%) were incorrect (SA=Yes)
- ~ 30% of participants with CHD, diabetes mellitus, or stroke wanted to buy
- 2/3 were not on cholesterol medications

## SELECT Summary (LDL paradigm)

- ~ 30% of subjects on lipid-lowering medication self-selected to use
- Of those who would purchase and were on lipid-lowering medication
- 50% would take Mevacor “in place of” Rx med
- 30% would take Mevacor along with their Rx Med
- The  most commonly taken lipid-lowering medications were atorvastatin, simvastatin, rosuvastatin, and lovastatin

## SELECT Summary (LDL paradigm)

- Those who self-selected to use in the LDL arm included:
-  101 of 391 women who were asked the SA question
-  29% were < 55 years old
- 13.2% of women < 55 years old
- 22% of the participants who did not know their LDL-C value
- 43% of subjects who had LDL too high (above 170)
- 17% of subject whose LDL was too low (below 130)

## SELECT Summary

- 10 -Year CHD risk:  LDL-C Label (SA=Yes)
- 41.1% men were in the targeted CHD risk range
- Most men outside the target range were of high risk, CHD equivalent or on lipid lowering meds
- 24.4% of women were in the targeted range
- Most women outside this range were low risk
- ~11% of men and over 45% of women were of low CHD risk (<5% risk of CHD in 10 years)

## Acknowledgements

- Division of Nonprescription Clinical Evaluation Review Team
- Daiva Shetty, M.D.
- Joel Schiffenbauer, M.D.
- Andrea Leonard Segal, M.D.
- Laura Shay, CNP
- Stan Lin, Ph.D.
- Michael Koenig, Ph.D.
- Matthew Holman, Ph.D.
- Mary Lewis, PM