> **Joint Meeting of the Nonprescription Drugs Advisory Committee**
>
> **and the Endocrinologic & Metabolic Drugs Advisory Committee**

# January 13-14, 2005

> This is the final report of the Joint Meeting of the Nonprescription
> Drugs Advisory Committee and the Endocrinologic & Metabolic Drugs
> Advisory Committee held on January 13-14, 2005. A verbatim transcript
> will be available in about 2 weeks, sent to the Division and posted on
> the FDA website at
> http://www.fda.gov/ohrms/dockets/ac/cder05.html#NonprescriptionDrugs
>
> All external requests should be submitted to the Freedom of
> Information office.
>
> **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_**
>
> The Nonprescription Drugs Advisory Committee and the Endocrinologic &
> Metabolic Drugs Advisory Committee of the Food and Drug
> Administration, Center for Drug Evaluation and Research, met jointly
> on January 13-14, 2005, at the Versailles Ballrooms, Holiday Inn,
> Bethesda, Maryland.
>
> Alastair Wood, M.D. chaired the meeting.
>
> **Nonprescription Drugs Advisory Committee (voting):**
>
> Alastair Wood, M.D. (Chair), Neal Benowitz, M.D. , Terrence F.
> Blaschke, M.D., Leslie Clapp, M.D.,
>
> Ernest B. Clyburn, M.D., Frank F. Davidoff, M.D., Jack E. Fincham,
> Ph.D., Ruth M. Parker, M.D., Sonia Patten, Ph.D. \[CR\], Wayne R.
> Snodgrass, M.D., Ph.D., Robert E. Taylor, M.D., Ph.D., F.A.C.P.,
> F.C.P., Mary E. Tinetti, M.D.
>
> **Endocrinologic & Metabolic Drugs Advisory Committee (voting):**
>
> Sonia Caprio, Thomas O. Carpenter, M.D., Dean A. Follmann, Ph.D.,
> Michael R. McClung, M.D., David S. Schade, M.D., Morris Schambelan,
> M.D., Nelson B. Watts, M.D., Margaret E. Wierman, M.D., Paul D. Woolf,
> M.D.
>
> **Special Government Employee (SGE) Consultants** **(voting):**
>
> Richard A. Neill, M.D., James Schultz (patient representative)
>
> **Government Employee (voting):**
>
> Susan Makris, Ph.D.
>
> **Industry Representative (non-voting):**
>
> Steven W. Ryder, M.D.
>
> **FDA Speakers**:
>
> Karen Davis-Bruno, Ph.D., Charles Ganley, M.D., Michael Koenig, Ph.D.,
> Mary Parks, M.D., Laura Shay, RN, M.S., C-ANP, Daiva Shetty, M.D.
>
> **FDA Participants:**
>
> Jonca Bull, M.D., Charles Ganley, M.D., John Jenkins, M.D., Robert
> Meyer, M.D., David Orloff, M.D., Mary Parks, M.D., Curtis Rosebraugh,
> M.D.
>
> **Open Public Hearing Speakers (January 14, 2004):**
>
> James McKenney, PharmD - National Lipid Association
>
> Suzanne Hughes MSN RN - Preventive Cardiovascular Nurses Association
>
> Stewart S. Levy, R. Ph. - Impact Health
>
> Robin Edison, M.D., MPH
>
> Dr. Boisey Barnes - Association of Black Cardiologists, Inc.
>
> Sidney M. Wolfe, M.D. - Public Citizen\'s Health Research Group
>
> Alice Rein, M.S. - National Consumer League
>
> Penny M. Kris-Etherton, Ph.D., R.D. - Penn State University
>
> William L. Greene, Pharm.D., BCPS, FASHP - American Society of
> Health-System Pharmacists
>
> Tracy Hankin - WebMD
>
> Bob Dufour - Walmart
>
> Jan Engle, - American Pharmacists Association
>
> Laurie Tansman - Mt Sinai NYU Health
>
> Christopher Maus - Lifestreams Technologies, Inc.
>
> These summary minutes for the January 13 and 14, 2005 of the Joint
> Meeting of the Nonprescription Drugs Advisory Committee and the
> Endocrinologic & Metabolic Drugs Advisory Committee of the Food and
> Drug Administration were approved on February 3, 2005.
>
> I certify that I attended the January 13 and 14, 2005, Joint Meeting
> of the Nonprescription Drugs Advisory Committee and the Endocrinologic
> & Metabolic Drugs Advisory Committee of the Food and Drug
> Administration meeting and that these minutes accurately reflect what
> transpired.
>
> \_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
> \_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Hilda F. Scharen, M.S. Alastair Wood, M.D.
>
> Executive Secretary Chair
>
> On both days, the committees considered the safety and efficacy of new
> drug application (NDA) 21-213, proposing over-the-counter (OTC) use of
> Mevacor 20 mg a day, (lovastatin), Merck & Co., Inc., to help lower
> LDL "bad" cholesterol, which may prevent a first heart attack.
>
> Alastair Wood, M.D. (Committee Chair), called the meeting to order at
> 8:00 a.m. on January 13, 2005. The Committee members, consultants, and
> FDA participants introduced themselves. The conflict of interest
> statement was read into the record by Hilda Scharen, M.S. The agenda
> proceeded as follows:

Introduction Mary Parks, M.D., Deputy Director

Regulatory History and Overview Division of Metabolic and Endocrinologic
Drug Products

of Current Proposed OTC Program Office of Drug Evaluation II

**Sponsor Presentations:**

Introduction Edwin Hemwall, Ph.D., Vice President

> Worldwide Regulatory and Scientific Affairs
>
> Johnson & Johnson / Merck Consumer Pharmaceuticals

Rationale for OTC Lovastatin Richard Pasternak, M.D. -- VP, Clinical
Research

> Merck Research Labs

Mevacor OTC Self Management System Jerry Hansen, RPh - Vice President
Business Development and Consumer Research, Johnson & Johnson / Merck
Consumer Pharmaceuticals

Actual Use Study Results Robert Tipping, M.S.

> Director, Biostatistics
>
> Merck Research Labs

Medical Perspective and Conclusion Jerome D. Cohen, M.D., FACC, FACP

> Professor of Internal Medicine/Cardiology
>
> Director, Preventive Cardiology Programs
>
> St. Louis University Health Sciences Center

**FDA Presentations:**

Reproductive and Fetal Toxicity Karen Davis-Bruno, Ph.D.

Division of Metabolic and Endocrinologic Drug Products

Office of Drug Evaluation II

Label Comprehension Study Laura Shay, RN, M.S., C-ANP

Division of Over-the-Counter (OTC) Drug Products

> Office of Drug Evaluation V

CUSTOM -- Actual Use Study Daiva Shetty, M.D.

Division of Over-the-Counter (OTC) Drug Products

> Office of Drug Evaluation V

Nonprescription Simvastatin Michael Koenig, Ph.D.

in the United Kingdom Division of Over-the-Counter (OTC) Drug Products

> Office of Drug Evaluation V

The meeting was adjourned at approximately 5:20 p.m. on January 13,
2005.

> Alastair Wood, M.D. (Committee Chair), called the meeting to order at
> 8:04 a.m. on January 14, 2005. The conflict of interest statement was
> read into the record by Hilda Scharen, M.S. The agenda proceeded as
> follows:

**Open Public Hearing Presentations**

***[Questions to the Committee]{.underline}**:*

**1. Taking into consideration the efficacy data from the AFCAPS/TexCAPS
and EXCEL studies, plus any additional information provided by the
sponsor, please respond to the following questions:**

a.  **Does the proposed target population merit treatment with a statin
    to lower cholesterol and thereby reduce heart disease risk?**

> Yes: 24
>
> No: 0
>
> Abstain: 0
>
> **Discussion:** The subcommittee agreed the proposed target population
> would benefit from treatment with a statin to lower cholesterol and
> reduce heart disease, along with improved diet and exercise.
>
> **b. Has the sponsor provided adequate rationale for the use of a
> fixed dose of lovastatin 20 mg to lower cholesterol and heart disease
> risk in this population? Is this an effective dose to reduce
> cholesterol in this population?**
>
> Yes: 24
>
> No: 0
>
> Abstain: 0
>
> **Discussion:** The subcommittee discussed that this study assumes
> adherence to the label. In addition, the members emphasized that there
> is not enough data, especially for Over-The-Counter use, of the
> efficacy of a 20mg dose versus usual care.

**2. Lovastatin and other statins cause elevation in hepatic
transaminase serum levels of unknown clinical significance in
individuals with normal baseline hepatic function.**

a.  **Does the Committee think that pretreatment baseline liver function
    tests are required prior to starting lovastatin therapy?**

> Yes: 0
>
> No: 24
>
> Abstain: 0
>
> **b. Are the liver function tests necessary during administration?**
>
> Yes: 0
>
> No: 24
>
> Abstain: 0
>
> **Discussion:** Some members underlined that baseline liver function
> tests (LFT) should be required before administration of lovastatin 20
> mg. Other committee members also felt that LFT should be required
> during therapy, for continued safe use of the drug.
>
> The committee members generally found that the risk of liver toxicity
> with statins seems to be similarly low and were not excessively
> concerned about patients with undiagnosed liver problems taking
> Mevacor Daily.

**3. Statins have been associated with the development of serious muscle
toxicity. Furthermore, drug-drug interactions with lovastatin may
increase the risk of muscle toxicity. Is the risk of muscle toxicity
with lovastatin 20 mg acceptable for an OTC drug; as applied to the
population indicated in the label?**

> Yes: 24
>
> No: 0
>
> Abstain: 0
>
> **Discussion:** The subcommittee argued that the study indicated
> problems in the self-selection of patients for use of lovastatin,
> which may cause some safety concerns.

**4. Lovastatin and other statins are currently labeled as Pregnancy
Category X (the drug should not be used during pregnancy). Have you
heard data that suggests to you that the drug is not so potentially
toxic to the fetus to prevent its marketing OTC under any
circumstance?**

> Yes: 18
>
> No: 5
>
> Abstain: 0
>
> **Is the label adequate for this group?**
>
> Yes: 0
>
> No: 24
>
> Abstain: 0
>
> **Discussion:** The subcommittee discussed that the CUSTOM study is
> not a good representation of the general population, especially for
> women of child-bearing age who might take Mevacor. Some members
> indicated that the drug comparison study included drugs not comparable
> to Mevacor. The members added that some of the drugs used in this
> study are not Over-The-Counter and are used only under Physician's
> care, such as Epinephrine.
>
> The members highlighted that the label advising against use of the
> drug during pregnancy or while trying to become pregnant, should
> include consequences, such as how significant the risk of damage may
> be to the fetus. In addition, the members were concerned that women
> who were unaware that they were pregnant would take Mevacor and
> possibly damage the developing fetus.
>
> The Committee recognized it is difficult to estimate the risks of
> birth defects, as well as be able to correlate animal drug studies to
> humans. The members concluded that the data presented is not
> conclusive enough to extrapolate risk versus benefit to an OTC
> situation.

**Taking into consideration the results from the CUSTOM actual use
study:**

**5. Does the frequency of appropriate self-diagnosis and self selection
support the conclusion that lovastatin 20 mg can be used safely and
effectively in the OTC setting? Please describe which analysis
influenced your decision.**

> Yes: 5
>
> No: 18
>
> Abstain: 0
>
> **Discussion:** The members felt they did not have insight into the
> population that self-selected and used inappropriately; this
> information would be critical as product understanding comes from the
> users. Thus, the committee added that the label comprehension study
> should be made a part of the actual use study.
>
> Some members emphasized that the information needed to self-manage,
> while taking Mevacor, is too complex to reduce to an understandable
> level for the general population. In addition, the members discussed
> that the CUSTOM study literacy level was higher than that of the
> general population.
>
> The committee indicated that there is a need for more organized tests
> to test what is critical information and reduce confusion. The members
> concluded that the self-diagnosis results of the CUSTOM study did not
> support that lovastatin 20 mg can be used safely and effectively in
> the OTC setting.

**6. A high percentage of study subjects in the CUSTOM actual use study
relied upon a physician for correct self-selection and/or
self-diagnosis.**

**a. Do you expect the general population will have this degree of
health care provider interaction?**

> Yes: 2
>
> No: 16
>
> Abstain: 5 (Those who abstained from voting felt that there was not
> enough information available to answer this questions.)
>
> **b. Do the CUSTOM actual use study results support a conclusion that
> individuals can use lovastatin 20 mg safely and effectively in the OTC
> setting without the guidance of a physician?**
>
> Yes: 3
>
> No: 20
>
> Abstain: 0
>
> **Discussion:** The committee members pointed to the fact that close
> to two-thirds of the patients were not among the intended population
> for treatment with the statin and that a high percentage of patients
> relied upon a physician for correct self-selection and/or
> self-diagnosis to start treatment with lovastatin.
>
> Some members abstained from voting because they did not feel they had
> enough information to extrapolate the degree of interaction of
> subjects with their health care provider to the general population.
>
> Although the committee members criticized the CUSTOM study, they
> praised Merck for its efforts to bring the statin to Over-The-Counter
> and encouraged the company to continue its efforts, as a means to
> address the enormous and growing cardiovascular public health problem
> in the country.
>
> The committee concluded that based on patients' inability to
> self-select for treatment and to comply with long-term use and
> testing, individuals could not safely and effectively use lovastatin
> in the OTC setting.

**7. Do the results regarding self management (i.e. user behavior after
the initiation of treatment) raise any concerns about the safe and
effective use lovastatin 20 mg in the OTC setting? If yes, what are the
concerns? Please consider in your discussion: monitoring LDL-C,
physician interaction, new risk factors or medication after initiation
of therapy.**

> Yes: 23
>
> No: 0
>
> Abstain: 0
>
> **Discussion:** The subcommittee expressed some concerns of potential
> drug interactions with the use of lovastatin. In addition, the members
> the study presented was not conclusive enough to indicate adequate
> self-monitoring of individuals taking 20 mg lovastatin. Some members
> added that patients with low income and no insurance would be unlikely
> to get LDL tests, which would make it difficult to recognize any new
> conditions these individuals may have.

**Based on all the information provided:**

**8. Should Mevacor OTC be marketed OTC for the proposed target
population?**

**a. If no, why not?**

**b. If yes, why?**

> **c. If yes, do you think Mevacor OTC is safe and effective for use in
> the OTC setting without the \"self-management system\"?**

Yes: 3

No: 20

Abstain: 0

> **Discussion:** The members argued that making Mevacor more easily
> available would help get needed treatment to millions of Americans at
> moderate risk of heart disease that needed to lower cholesterol
> levels.
>
> The committee felt that the safety and benefits of Mevacor are
> well-established, but was concerned that the wrong people might take
> it if available in an OTC setting, especially after an aggressive
> advertising campaign.
>
> The members expressed worry that patients will skip necessary doctor
> visits or inaccurately determine the drug is for them, while forgoing
> important advice about changing diet and exercise in order to control
> their elevated level of cholesterol.
>
> The committee concluded that the Health Care System is currently not
> designed for such OTC use of statins and individuals could not operate
> in this system effectively. The concerns expressed by the members
> stemmed that this may set precedence for approval for other "silent"
> diseases drugs, such as anti-diabetic or high blood pressure drugs, to
> go OTC while the infrastructure is not adequate to support this.
>
> Some committee members expressed interest in seeing an in-between
> option in an OTC setting, where patients could buy the drug without a
> prescription but only after speaking with a pharmacist; such an option
> is available in Britain, where a similar drug is being sold
> \"behind-the-counter".
>
> Finally, the committee praised Merck in the efforts to address the
> needs of individuals without health insurance, who should also have
> the right to have treatment with statins. In addition, the members
> felt that FDA and Merck need to work together to bring more effective
> and cost effective drugs to an OTC setting.

The meeting was adjourned at approximately 3:00 p.m. on January 14,
2005.