Medical Review

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| NDA #: 19-658/S-018                                                   |
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| Drug Name: Claritin (loratadine)                                      |
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| Sponsor: Schering Corporation                                         |
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| Reviewer: Charles J. Ganley, M.D.                                     |
|                                                                       |
| Correspondence Date: January 25, 2002                                 |
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Date: March 26, 2002

In support of their supplemental NDA for the switch of the Chronic
Idiopathic Urticaria (CIU) indication for Claritin from prescription to
OTC, the sponsor has submitted a consumer survey, a physician survey, an
expert panel report and a labeling comprehension study. This review
summarizes the results of the consumer and physician surveys and
comments on the Expert Panel report. The labeling comprehension study is
reviewed in a separate FDA document.

**Consumer Survey**

*Design*

The consumer survey was conducted through the National Family Opinion
Interactive Panel. This is a website-based group that allows any
Internet user to register for their survey participant list. Registered
users are informed of survey opportunities via e-mail and can decide in
which surveys they choose to participate. Participation in a survey
allows users to accumulate points that can be used for prizes or
cash.[^1] In this case, an e-mail was sent to over 500,000 households
each for two consecutive weeks in October-November 2001. A screening
survey was used to help identify a chronic urticaria population by
asking, \"Have you ever been diagnosed by a medical doctor as having
chronic or recurrent hives that have no known discernable cause (also
known as chronic urticaria).\" Each e-mail mailing yielded approximately
15,000 qualified adult subjects (older than 18 years of age).

A more detailed interactive survey was conducted in 845 subjects
randomly sampled from the pool of subjects. The sample size was chosen
so that 300 chronic idiopathic urticaria sufferers would complete the
survey. This would allow for an error of +/- 6% at a 95% confidence
interval. Questions in the survey were either open ended or multiple
choice.

The objectives of the survey were as follows:

-   To obtain information on the frequency and severity of symptoms from
    a patient perspective;

-   To obtain information on the patient interaction with their
    physician;

-   To obtain information on treatment modalities;

-   To obtain information on a patient's perspective on the ability of
    patients to recognize symptoms and determine what actions should be
    taken during an attack.

*Results*

Of the 845 subjects, 388 subjects completed the survey[^2]. The average
age was 45 years, 66% were female and 84% were white. The majority of
subjects had experienced recurring hives for greater than 3 years (68%).
Thirteen percent had the condition for less than one year. Most were
diagnosed with chronic hives more than three years prior to the survey
(59%). Approximately 39% had episodes \"all of the time\" or at least
every month. A majority of subjects had four or more episodes each year
(58%). The episodes resolve within a week for 66%. Approximately 51%
experienced an episode in the past month.

Itching (81%), hives or wheals (77%) and redness (68%) were the most
common symptoms. Itching (56%) and hives (25%) were listed as the most
prominent symptoms during an attack. Individuals were more likely to
have hives in multiple areas simultaneously (62% had 8 or more hives at
one time). Most did not view the condition as serious (73%). During an
attack, most use a prescription or OTC medication.

Approximately 20% of the subjects contact their physician when they have
an attack (78 of 388). Only 21% of these subjects contacted the
physician immediately and an additional 33% waited a day or less before
contacting the physician.

Most subjects (94%) felt it was easy to identify the condition when it
appeared. Prior to seeing a physician, over 90% used an OTC medication
to treat the condition. The majority of these subjects used an OTC
antihistamine (62%). There was no consensus for the name given the
condition by the physician at the initial visit. Chronic idiopathic
urticaria was used less than 10% of the time.

When asked what they would do if they developed difficulty breathing,
fever or trouble swallowing during an attack, 95% would go to the
emergency room or visit their doctor. Only 5% would use the medicine
already prescribed. This was a multiple-choice question. An open-ended
question in this instance would be more appropriate to decrease the
chance of biasing the respondent.

# Discussion

It is difficult to interpret these surveys for the following reasons:

-   It is difficult to validate whether the subjects who participated
    actually have the underlying condition;

-   Because many of the questions are multiple choice and not
    open-ended, this limits the range of answers that would have been
    provided by the respondents and may influence the respondents
    answer;

-   The results of this survey are not reproduced in another cohort of
    subjects with chronic urticaria; and

-   It assumes that the population who participated are representative
    of the overall population of chronic urticaria sufferers.

If it is assumed that the majority of subjects have the underlying
condition, then there are some interesting observations.

-   It is not surprising that the majority of subjects, after the
    initial diagnosis by a physician, would self-identify the condition
    and not call the doctor. They were given either prescription
    medication or instructed to use OTC medication by the physician for
    the next attack.

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-   It is not surprising that many attempted to treat the symptoms with
    an OTC topical product indicated for itching prior to seeing a
    physician. Itching was the most common symptom (in 81%) and the most
    prominent (in 56%) in this group of respondents. What is surprising
    is that 62% used OTC anti-histamines prior to seeing a physician.
    OTC anti-histamines are not indicated for this condition or for the
    symptoms associated with a rash. It is unclear whether they sought
    the advice of another health provider, pharmacist or used
    alternative resources (e.g. the Internet) in deciding to use an
    anti-histamine before seeking the opinion of a physician.

-   The screening question for continuing in the survey used the
    descriptor "chronic or recurrent hives that have no
    known/discernable cause (also know as chronic urticaria)." The
    responses to subsequent questions on how the physician described the
    condition at the initial visit (page 25 of the report) may have been
    influenced by this screening question. In any event, there was no
    consensus descriptor for this condition. Chronic Idiopathic
    Urticaria was used infrequently. The most common descriptors
    included the word hives. Clearly, the most important descriptor on
    any label would have to include the word hives. It is unclear what
    other defining terms should be included.

-   The answers to the question regarding what the consumer would do if
    they experienced symptoms such as difficulty breathing, fever or
    trouble swallowing is difficult to interpret because multiple
    choices were given. It is not clear how they would have responded
    had it been an open-ended question. Aside from the answer regarding
    a visit to the emergency room, the sense of urgency is not
    discernable. For those who responded that they would call or visit a
    physician, the timing of this call or visit was not elicited.

## Physician Survey

The physician survey used Internet based databases as their source of
respondents [^3]. The survey was conducted between November 13, 2001 to
November 15, 2001 by Marketing Measures, Inc. Physicians were
pre-screened for their specialty and whether they treated patients with
CIU. The survey included 359 qualified Internet interviews from
physicians with backgrounds in Primary Care (151), Dermatology (75),
Allergy (55) and Pediatrics (78)[^4].

The survey collected information on the practice patterns of these
physicians regarding the diagnosis and treatment of patients with hives.
The deficiencies of the survey are similar to those described in the
consumer use study. The information is anecdotal and is generally not
helpful in assessing the use of loratadine in the OTC setting.

## Expert Panel Report

The sponsor organized a panel of expert consultants to address two
questions:

1)  Can a patient self-recognize and safely self-treat a recurring
    episode of chronic idiopathic urticaria with OTC loratadine after
    initial diagnosis by a physician?

2)  Are there serious medical consequences from a patient self-treating
    hives with OTC loratadine without prior consultation with a
    physician? If so, can these consequences be mitigated with labeling?

Based on personal experience, the panel believed that patients diagnosed
with chronic idiopathic urticaria could self treat their condition
because most already do it after the initial diagnosis by a physician.
Although they provided no data to support this position, it certainly is
not unrealistic if one can be assured that the patient would get the
diagnosis in the first place.

The panel also felt that this population was not at greater risk than
the general population for more serious conditions (e.g. anaphylaxis).
Despite this, they recommend labeling instructing subjects to seek
immediate medical help for symptoms such as "difficulty breathing,
faintness, swelling of the tongue or in the throat, or gastrointestinal
distress". This is somewhat contradictory unless the purpose is to
reinforce what is already told to them by a physician at the time of
diagnosis.

They also recommend that the indication be limited to the CIU population
because 1) patients with recurring hives should have an evaluation by a
physician; and 2) "data are not now available for a broader urticaria
indication". This position and recommendation are perplexing in view of
the information available from the consumer survey of patients with
"chronic urticaria" and the label comprehension study. Presumably, the
sponsor made this information available to them. If the consumer survey
is to be believed, consumers are already using OTC anti-histamines for
the treatment of hives and physicians are not adequately evaluating them
for other conditions[^5]. The broader use of anti-histamines for hives
already appears to be prevalent in the general population based on the
consumer survey. It would be very difficult to reverse that practice if
it is accurate.

One of the major deficiencies of the report is that it fails to address
the issue of accurate self-selection in the general population. Although
this was not one of the questions they were asked to answer, it should
have come up in the course of discussion. Because of the failure to
address the accuracy of self-selection, there is an underlying
assumption that whatever is written on a package will be adhered to by
consumers. The data in the sponsor's database do not support this.

**Summary**

The sponsor notes that \"urticaria is a rather common condition with an
estimated incidence of 10 - 20 percent of the U.S. population\". \"About
one-fifth of the urticaria cases are chronic- - persisting more than six
weeks and the vast majority of chronic sufferers have an idiopathic
disorder.\" Based on this information, the majority of consumers who
experience urticaria will not have chronic hives. One of the important
issues to be addressed for this indication is accurate self-selection,
de-selection and use by all consumers likely to use this product. The
consumer survey and physician surveys do not provide sufficient
information on the ability of consumers to accurately select and use
this product.

The Expert Panel Report is also deficient in providing supporting
information for the accurate self-selection and use of the product.
There appears to be an underlying assumption in their recommendation
that simply writing instructions on the label limiting use to the CIU
population will lead to consumer compliance. Contrary to the
recommendation of the panel, the Agency should also consider a more
general hives indication in the general population and determine what
information should be provided to support this claim.

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Charles J. Ganley, M.D.

[^1]: 1000 points is equivalent to approximately \$10. Up to 1500 points
    can be obtained for taking a survey.

[^2]: 457 subjects did not complete the survey for the following
    reasons: 192 did not respond, 95 logged on after the survey closed,
    81 did not suffer from CIU on requalification, 81 worked in
    sensitive occupations (e.g. advertising, pharmaceuticals), 1 was not
    \> 18 years old, 7 did not want to take the survey

[^3]: databases: Medical Marketing Conference, Medscape or ePocrates

[^4]: \"Qualified \" interview was not defined

[^5]: In the consumer survey, 7% had skin testing and 39% had blood
    testing.