**Joint Meeting of the**

**Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC)**

**and the**

**Drug Safety and Risk Management Advisory Committee (DSaRM)**

# July 12, 2004

**8 am -- 5:30 pm**

**ACS Conference Room, 5630 Fishers Lane, Rockville, MD**

Minutes

**DODAC**

Robert S. Stern, M.D. (Chair)

Roselyn E. Epps, M.D.

Robert Katz, M.D.

Sharon S. Raimer, M.D.

Eileen W. Ringel, M.D.

Jimmy D. Schmidt, M.D.

Michael G. Wilkerson, M.D.

**DODAC Consumer Representative**

Paula Knudson

**DSARM**

Ruth S. Day, Ph.D.

Curt D. Furberg, M.D., Ph.D.

Jacqueline S. Gardner, Ph.D., M.P.H.

Eric S. Holmboe, M.D.

Robyn S. Shapiro, J.D.

**DSARM Consumer Representative**

Arthur A. Levin, M.P.H.

**Industry Representative**

None in Attendance

**Executive Secretary**

Kimberly Littleton Topper, M.S.

**Consultants**

Margaret Honein, Ph.D., M.P.H.

Sarah Sellers, Pharm.D.

**FDA Participants**

Jonca Bull, M.D.

Denise Cook, M.D.

Tapash Ghosh, Ph.D.

Shiowjen Lee, Ph.D.

Jill Lindstrom, M.D.

Marilyn Pitts, Pharm.D.

Anne Trontell, M.D., M.P.H.

Jonathan Wilkin, M.D.

Jiaqin Yao, Ph.D.

I certify that I was at the June 12, 2004, Joint Meeting of the
Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) and the
Drug Safety and Risk Management Advisory Committee (DSaRM) and these
minutes accurately reflect the discussions of the committee.

\_\_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Robert S. Stern, M.D., Kimberly Littleton Topper, M.S.

Chairman, DODAC Executive Secretary, DODAC

**Joint Meeting of the**

**Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC)**

**and the**

**Drug Safety and Risk Management Advisory Committee (DSaRM)**

# July 12, 2004

#  Minutes

The meeting was called to order at 8:00 by Dr. Robert Stern. He welcomed
everyone and had the head table introduce themselves. The conflict of
interest statement was read into the record by Kimberly L. Topper. Dr
Jonca Bull welcomed everyone and thanked the committee for assisting the
FDA in their deliberations. She reminded the committee of the February
04 discussions on fetal exposure and the proposed Risk Management Plan
(RMP) Dr. Jonathan Wilkin also thanked the committee and set the stage
for discussions on (NDA) 21-701, proposed trade name Tazoral (oral
tazarotene 1.5mg and 4.5 mg) capsules, Allergan, Inc., proposed for the
treatment of moderate to severe psoriasis, including risk management
options to prevent fetal exposure. He reminded the committee that no
product is perfect and finding the balance for the risk benefit ratio is
what they need to look for during the day\'s discussions.

Denise Cook, M.D., FDA, provided an \"Introduction to Psoriasis & The
State of the Armamentarium.\" She discussed the prevalence, the genetics
and pathogenesis, and the clinical variants of psoriasis. She presented
the current treatments available and the side effects and
contraindications of each.

**Allergan NDA Presentation**

Patricia Walker, M.D., Ph.D., Vice President, Skin Care Pharmaceuticals,
Allergan, Inc. introduced Tazarotene Capsules in the treatment of
psoriasis. She reminded the committee that Allergan is seeking the
approval of Tazarotene for the treatment of moderate to very severe
plaque psoriasis. She discussed the regulatory history of Tazarotene and
provided a list of the members that were available to answer the
committee questions.

Alan Menter, M.D., Clinical Professor of Dermatology, University of
Texas, Southwestern, presented on Psoriasis: Disease Overview and
Treatment Options. He stated the opportunities to improve care exist and
that psoriasis is a diverse disease and no one drug is suitable for all
patients. Current treatments have therapeutic limitations and a full
range of safe, efficacious and accessible medications are needed for the
psoriatic population.

Patricia Walker, M.D., Ph.D. presented the pharmacology of Tazarotene.
Tazarotene is a prodrug with only one active metabolite, tazarotenic
acid. It is an acetylenic retinoid and has a locked molecule. She then
covered the efficacy data for Tazarotene. The safety and efficacy of
oral tazarotene is based on the results of 12 phase 1 studies in normal
volunteers, 1 dose ranging study in patients with moderate to very
severe plaque psoriasis and 4 phase 3 studies in patients with moderate
to very severe plaque psoriasis. The Overall Lesional Assessment (OLA)
was an integrated clinical assessment of overall psoriasis severity and
it evaluates the signs of psoriasis on a 6 point scale (none, minimal,
mild, moderate, severe and very severe). A photo numeric guideline was
provided for clinical evaluation. She provided examples of clinical
response and the demographic breakdown of the clinical trials. The
efficacy summary showed that \`20% of patients achieved no or minimal
disease, moderate (\>50%) to complete clearing was achieved in the
majority of patients, significant improvements in plaque elevation,
erythema, scaling, purities, and % body surface area (BSA), maintenance
of benefit was observed following discontinuation of drug, there was no
rebounding and a large portion of patients (79%) expressed treatment
satisfaction. She ten discussed the clinical development safety data.
The bone mineral density (BMD) changes were small with individuals with
gains or losses of [\>]{.underline}5% within expected variation and they
were not associated with fractures, osteoporosis, age, gender or
systemic corticosteroids. She stated that they did not recommend routine
laboratory evaluations nor was routine bone monitoring necessary. She
then explained the proposed RiskMap for oral Tazarotene. She stated
their goals as 1) women who are pregnant shall not be prescribed or
dispensed oral tazarotene and 2) women taking oral tazarotene shall not
become pregnant. The primary components of the RiskMap will be mandatory
registration for all patients, targeted education for all patients,
mandatory registration and certification of physicians and pharmacies,
verification of all patients qualified by pharmacist through interaction
with technology-based system, laboratory based pregnancy testing system,
managed access, pregnancy exposure registry, and program effective
metrics.

Alan Menter, M.D. then discussed the Risk Benefit Assessment. He
discussed the important differentiating characteristics of oral
tazarotene and the characteristic safety profile of systemic retinoid
drugs. He stated that the half-life of the drug is very short; it can be
taken when patient drinks alcohol, there is neither change in the lipid
metabolism nor a change in the hepatotoxicity and the alopecia is not
different after 12 weeks and the mucocutaneous reactions are mostly
mild. He concluded that oral tazarotene is safe and effective and they
have shown sustained clinical benefit in patients with moderate to very
severe plaque psoriasis; ongoing therapy with tazarotene capsules
provides extended benefit; there is a high rate of patient acceptance
and a low dropout rate due to adverse events. He concluded that \"Based
on the efficacy and safety profile, tazarotene capsules should be
available as an option for ALL patients, male and female, with moderate
to very severe plaque psoriasis.\" Allergan then answered clarifying
questions from the committee.

The committee took a 15 minute break.

**FDA Presentation**

Jiaqin Yao, Ph.D., FDA, presented the \"Toxicology Studies of
Tazarotene.\" He discussed the toxicity in fertility and early embryonic
development, prenatal and postnatal development, male reproductive
toxicity, the recommended human dose and the lowest teratogenic dose. He
concluded that the human may be the most sensitive species for
teratogenicity of retinoids; tazarotene is a more potent Teratogen than
other retinoids in rats and rabbits on an mg/kg/day basis; and
tazarotene is a probable human teratogen.

Tapash Ghosh, Ph.D. FDA, presented \"Clinical Pharmacology &
Biopharmaceutics\" covering pharmacokinetics of Tazarotene (TAZ) and
Tazarotenic acid (TA) in humans; the potential for drug-drug
interactions and the tazarotenic acid in semen. He concluded that the
no-effect limit for teratogenicity for TAZ/TA is unknown in humans; the
fertilized egg may remain exposed to TA in the semen following repeated
sexual encounters; and the risk to the fetus, if any, while a male
patient is taking the drug or after it is discontinued can not be ruled
out.

Denise Cook, M.D., FDA, discussed the clinical safety of oral
tazarotene. She covered the safety discontinuations, the adverse events
that led to discontinuation in the long term trial, the significant
adverse events to include the bone, metabolic and endocrine events, and
the long term safety trial. She concluded that for the neuropsychiatric
events there was no difference between tazarotene and placebo in the
controlled trials but due to the limitations of the metrics employed and
the statistical power an association cannot be ruled out, given the
existing concerns about other such effects from other retinoids. She
also stated that there was a mean bone mineral density (BMD) decrease
over time for the entire set of patients, with some having decreases
close to 30%.

Shiowjen Lee, Ph.D., FDA, provided the \"Biostatistical Analysis of
Pivotal Studies.\" She stated that oral tazarotene is statistically
superior to placebo regarding treatment success although success rates
are below 20% for both studies; female patients had higher success rates
than males though makes accounted for over 2/3 of study enrollment in
each trial. Treatment success decreases as baseline OLA score increases
and there is insufficient data to evaluate the efficacy claim of \"very
severe\" plaque psoriasis. Oral tazarotene demonstrates short term
efficacy in treating scalp psoriasis but not in treating nail psoriasis.

Denise Cook, M.D. then presented the clinical wrap-up discussing the
drug use trends, adverse events and the efficacy of both oral and
topical tazarotene.

Jill Lindstrom, M.D., FDA, spoke on the \"Evolution of Risk Management
for Systemic Retinoids.\" She provided an overview of the background of
the retinoids currently approved for use by FDA, their historical
development of risk management for systemic retinoids and in summary she
states that all approved systemic retinoids are known or highly suspect
potent human teratogens, risk management plans should incorporate the
current best practices and current best practices for pregnancy
prevention include, labeling, targeted education, reminder systems and
controlled distribution.

Ann Trontell, M.D., M.P.H. FDA, discussed the \"Potential Risk
Management Tools for Oral Tazarotene: Context, Considerations, and
Experience.\" She described the risk management in the context of the
PDUFA3 Draft Guidance\'s, discussed the advantages and disadvantages of
different tools, described the isotretinoin risk management for
teratogenicity and placed the options proposed by the sponsor for
tazarotene into context. She summarized that the systemic retinoid
teratogenicity risk management plan for isotretinoin has evolved over
time and the tazarotene RiskMAP has proposals for a reminder system for
females of child bearing potential and a registry for physicians and
pharmacists similar to that of the S.M.A.R.T. system.

The committee asked clarifying questions of the FDA presenters and then
adjourned at 12:05 for lunch.

The meeting resumed at 1:00. The Open Public Hearing (OPH) had 3
speakers registered. Mr. White spoke about the National Psoriasis
Foundation, the impact of psoriasis, and his experience as a person
whose son has psoriasis. Ms. Janey Freeman spoke about her experience as
a person with psoriasis and about her positive experience with oral
tazarotene. Mr. Gorre spoke about his experience as a person with
psoriasis and about his positive experience with oral tazarotene. The
Chair asked for any other speakers for the OPH and seeing none the OPH
was closed at 1:25.

The committee continued the discussion with both FDA and Allergan
answering questions on a wide variety of topics. At 2:52 the committee
took a break and returned at 3:00 to start answering the questions.

1.  Based on the information from the clinical studies conducted for
    tazarotene capsules, is there an adequate demonstration of
    effectiveness for moderate to severe psoriasis?

    -   **Efficacy was not shown at the end of the 12 week study**

    -   **It did show that it is more effective than placebo (6
        members)**

    -   **The efficacy shown does not represent a significant benefit
        over what is currently on the market**

    -   **The short half life could be a benefit with other types of
        psoriasis**

    -   **Do not know the reliability of the scoring tool therefore the
        extent of efficacy is an issue**

    -   **The drugs short half life is compelling for patients at risk
        of becoming pregnant and cannot reliably forgo pregnancy for a
        long post treatment as required for oral retinoid approved for
        psoriasis**

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    -   **Concern about off label use for acne given that the topical
        form is widely used for this indication, posters and non peer
        reviewed publications suggesting efficacy have been presented to
        dermatologists , and efficacy of Tazoral including remission
        rate and duration relative to isotretinoin (and hence
        risk/benefit ratio for a high risk drug) has not been
        established.**

Is there an adequate demonstration of efficacy for "very severe"
psoriasis?

-   **There was not enough power (15 patients) to show efficacy**

-   **It is difficult to show progress in 12 weeks**

-   **It showed that it cleared some and the patient may be happy with
    that but it did not meet the point required to pass**

-   **There was no demonstration for efficacy for very severe psoriasis
    (5 members)**

2.  Has the safety profile for this product been adequately assessed?

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A)  Please provide discussion of the clinical and preclinical safety
    data, including comments on bone and liver abnormalities,
    hyperlipidemia, and teratogenicity.

    -   **There is great concern about the pregnancy rate with the
        drug - there needs to be better follow-up**

    -   **The study was inadequately powered to show safety and the
        demographics of the subjects need to be improved (4 members)**

    -   **There was not enough information on the tendency to fracture
        with the bone information**

    -   **Not overly concerned about hyperlipidemia as it can be treated
        but there was not enough data to adequately assess the drugs
        effect**

    -   **The teratogenicity is a grave concern and a risk management
        plan must be implemented**

    -   **The liver abnormalities were well explained in their
        presentation and are controllable**

B)  Please discuss any potential issues, regarding long term safety of
    oral tazarotene with repeated use.

-   **Currently there is not enough long term safety data**

-   **Need long term bone data and pregnancy data if the drug is going
    to be used long term**

-   **Need labeling to address lab abnormalities, liver function tests,
    and alkaline phosphatase and require continuous monitoring**

-   **Concern over the bone and pregnancy issues**

3\. Given the safety and efficacy information, does the Committee find a
favorable

balance of risks and benefits which would support approval of this
product?

-   **Yes - 3 Raimer, Schmidt, Wilkerson**

    -   **With monitoring of Phase IV study**

-   **No - 9 Knudson, Epps, Katz, Ringel, Stern, Gardner, Levin,
    Honein**

    -   **There is too much unknown**

    -   **Not enough data to power the studies**

-   **Abstain - 4 Shapiro, Day, Furberg, Holmboe**

    -   **Needs more data**

    -   **information is missing**

    -   **need to see an outline of a risk management plan to feel
        comfortable approving**

    -   **need Phase IV study information**

4\. Allergan has submitted a risk minimization proposal to the NDA that
is similar to the isotretinoin SMART program. In addition, they have
described in their package to the advisory committee a registry program
that appears to be similar to the emerging isotretinoin risk
minimization program. Both programs exempt males and females not of
childbearing potential from many program requirements, including refill
restrictions.

A)  Please comment on which teratogenic risk management program is
    preferred for tazarotene?

    -   **Want consistent program across the board for all Retinoids /
        Teratogens**

    -   **Include in risk management plan how drugs are used - \"Use
        Data\"**

    -   **Do not use marketing data - use actual \"use data\"**

    -   **Concern over \"use data\" on script due to insurance issues**

    -   **Want a consistent program but have enough flexibility to allow
        sponsors to make changes**

    -   **Collect \"use data\" but be concerned over insurance companies
        denial of coverage**

    -   **Involve patients to increase participation**

    -   **Have some form of a feedback loop to practitioners to help
        change behaviors**

B)  Please comment on the advantages and disadvantages of having
    teratogenicity program requirements applied solely for Female Child
    Bearing Potential.

-   **With males there is exposure at conception and continued exposure
    during pregnancy if not followed**

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-   **A one size fits all Risk Management Program would need to follow
    everyone male & female alike**

-   **There is a current concern about the male semen therefore they
    should be followed**

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-   **See comments for \# 5**

C)  Are the scientific and clinical uncertainties surrounding semen
    levels of tazarotenic acid a factor to be considered in tazarotene
    risk minimization?

-   **It should be considered and more data gathered**

-   **Comfortable with data presented**

-   **Suggest condom use in labeling**

5.  How can FDA best address the potential clinical relevance of high
    tazarotenic acid levels in semen? Options might include:

    -   **Concerns could be alleviated by labeling information
        discussing restrictions**

    -   **This must be discussed in labeling**

    -   **Need to look at effect in subpopulations**

    -   **Animal studies needed to determine effect at dose target**

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A)  further delineation of the potential risks (via consultation with
    teratogenicity experts, additional preclinical studies, etc.)

-   **More studies are needed (8 members)**

-   **Need long term follow up for bone issues and efficacy rate**

B)  informing clinicians and patients of the finding and its uncertain
    clinical relevance

-   **Provide known information and allow the patient to make final
    judgment (6 members)**

C)  recommending precautions (such as the use of condoms) pending
    characterization of the potential risk

-   **Discuss issues with the patient and let them know we do not know
    and let them decide (5 members)**

**The Committees added a part \"D\" to require additional studies - 9
members wanted more studies**

> Please comment on whether further risk assessment should be done and
> whether any cautionary language or recommendations should be made
> while additional risk assessment is pending.

-   **Talk with the patients but don\'t scare them and let them decide**

-   **We can only make recommendations on things we cannot enforce**

6.  What additional studies are needed? Are these studies needed before
    or after approval of the product?

-   **There is a lot that is unknown and we need to know to make a
    decision**

-   **Comprehension testing of the message before it is in full use**

-   **Current data is inadequate for approval**

-   **Need male reproductive studies before approval**

-   **More discussion and movement on Risk Management Plan**

-   **Study to demonstrate a better Risk - Benefit Ratio**

-   **Require mandatory Adverse Event reporting**

-   **More data on fracture and endocrine issues**

-   **More animal (rabbit and mice) tests for low teratogenicity dose**

[General Comments from the committee:]{.underline}

-   **Should have comparison of Accutane and Trazodone for acne
    indication and publication of the results to show if it works thus
    limiting the off label use of the drug since it has been publicized
    as working at a professional meeting**

-   **Concern that the drug is not being approved due to potential off
    label use**

-   **FDA needs to move forward on the Risk Management Plan for
    Retinoids - do what ever it takes to solve outstanding problems.**

-   **Given the teratogenic risk of retinoids, one key element of a risk
    benefit program is being sure that, that among retinoids with likely
    to be equivalent teratogenic risk, the most effective retinoid
    should used for a given indication. This makes the issue of off
    label use particularly important for indications which include
    substantial numbers of patients of child bearing potential.**