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UNITED STATES OF AMERICA
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
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FOOD AND DRUG ADMINISTRATION
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CENTER FOR DRUG EVALUATION AND RESEARCH
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NONPRESCRIPTION DRUGS ADVISORY COMMITTEE WITH
CONSULTANTS FROM PULMONARY - ALLERGY AND
DERMATOLOGIC DRUGS ADVISORY COMMITTEES
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MONDAY
APRIL 22, 2002
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The Advisory Committee met in Versaille Room
II in the Holiday Inn, Bethesda, 8120 Wisconsin Avenue,
Bethesda, Maryland, at 8:00 a.m., Louis R. Cantilena,
Jr., M.D., Ph.D., Chairman, presiding.
PRESENT:
Louis R. Cantilena, Jr., M.D., Ph.D., Chairman
Sandra Titus, Ph.D., Executive Secretary
Leslie Clapp, M.D., Member
Frank F. Davidoff, M.D., Member
Edwin E. Gilliam, Ph.D., Member
Julie A. Johnson, Pharm.D., Member
Edward P. Krenzelok, Pharm.D., Member
Y.W. Francis Lam, Pharm.D., Member
Hari C. Sachs, M.D., Member
Donald L. Uden, Pharm.D., Member
PRESENT: (con't.)
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Henry W. Williams, Jr., M.D., Member
Alastair Wood, M.D., Member
Ralph D'Agostino, Ph.D., Nonprescription Drugs SGEs
Mark Dykewicz, M.D., Allergists SGEs
Jesse Joad, M.D., Allergists SGEs
Stan Szefler, M.D., Allergists SGEs
Lloyd King, M.D., Ph.D., Dermatology SGEs
William Rosenberg, M.D., Dermatology SGEs
Michael C. Alfano, D.M.D., Ph.D., Industry Guest
ALSO PRESENT:
Jonca Bull, M.C., FDA
Badrul Chowdhury, M.D., FDA
Charles Ganley, M.D., FDA
Matthew Holman, Ph.D., FDA
Linda Katz, M.D., FDA
Sandy Kweder, M.D., FDA
Charles Lee, FDA
Robert Temple, M.D., FDA
Jonathan Wilkin, M.D., FDA
John Clayton, Ph.D., Schering-Plough
Eugene W. Monroe, M.D. Schering-Plough
Stephen Neuman, Schering-Plough
Patricia Rohane, Schering-Plough
Janet P. Engle, Pharm.D.
Joseph Ferguson, M.D.
Gary Kay, Ph.D.
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A-G-E-N-D-A
page no.
Call to Order, Introductions
Louis Cantilena, M.D., Ph.D., Chair 5
Conflict of Interest Statement
Sandra Titus, Ph.D., Executive Secretary 8
Welcome and introduction to Today's Issues
Charles Ganley, M.D., Director
Over-the-Counter Drugs 10
Schering Plough Presentations:
Overview
John Clayton, Ph.D., Sr., VP
Scientific and Regulatory Affairs 12
Clinical Overview of Urticaria
Eugene W. Monroe, M.D.
Dept. of Dermatology
Medical College of Wisconsin 17
Schering Studies on CIU
Stephen Neuman, Senior Director
Marketing Support Services 29
Risk-Benefit Analysis on CIU
John Clayton, Ph.D. 48
Questions 60
FDA Presentations
Urticaria: An Overview and OTC Considerations
Jonathan Wilkin, M.D.
Director, Dermatologic Drugs 97
Clinical Study Design Issues for the Approved
H1 Antihistamines and CIU Indication
Badrul Chowdhury, M.D., Ph.D., Team Leader
Pulmonary and Allergy Drugs 108
I-N-D-E-X (con't.)
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page no.
OTC Issues: US Regulatory History, Foreign
Marketing and Label Comprehensive Study
Matthew Holman, Ph.D. 121
Interdisciplinary Scientist
Over-the-Counter Drugs
Summary of Issues on Urticaria as an OTC Indication
Charles Ganley, MD. 135
Questions
Open Public Hearing
Dr. Gary Kay 172
Dr. Janet Engle 189
Dr. Joseph Ferguson 184
Questions and Committee Discussion
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1 P-R-O-C-E-E-D-I-N-G-S
2 8:04 a.m.
3 DR. CANTILENA: I'm Doctor Lou Cantilena,
4 head of Clinical Pharmacology at the Uniform Services
5 University and chair of this committee. This is the April
6 22, 2002 meeting of the Nonprescription Drug Advisory
7 Committee.
8 What I'd like to do is start with
9 introductions. I just introduced myself and perhaps
10 there's less empty seats on this side of the table so
11 perhaps we can start here and have everyone sort of say
12 who you are and your affiliation with the committee.
13 DR. ALFANO: My name is Michael Alfano and
14 I'm Dean of the Dental School at New York University
15 College of Dentistry.
16 DR. DYKEWICZ: I'm Mark Dykewicz. I am
17 Director of the training program in allergy and immunology
18 at St. Louis University School of Medicine.
19 DR. JOAD: I'm Jesse Joad. I'm a pediatric
20 pulmonologist and allergist at University of California
21 at Davis.
22 DR. SZEFLER: Stan Szefler at National
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1 Jewish Medical and Research Center.
2 DR. D'AGOSTINO: Ralph D'Agostino from
3 Boston University, biostatistician and consultant to the
4 committee.
5 DR. KRENZELOK: Good morning. I'm Ed
6 Krenzelok. I'm Director of the Pittsburgh Poison Center
7 and a professor of pharmacy and pediatrics at the
8 University of Pittsburgh.
9 DR. UDEN: I'm Don Uden, University of
10 Minnesota College of Pharmacy and NDAC member.
11 DR. JOHNSON: I'm Julie Johnson, Professor
12 of Pharmacy Practice and Medicine at the University of
13 Florida and a member of NDAC.
14 DR. LAM: I'm Francis Lam from the Department
15 of Pharmacology and Medicine at the University of Texas
16 Health Center in San Antonio. I'm also a member of NDAC.
17 DR. DAVIDOFF: I'm Frank Davidoff. I'm the
18 editor emeritus of Annals of Internal Medicine. I'm an
19 internist, and I'm a member of the committee.
20 DR. GILLIAM: I'm Eddie Gilliam. I'm a
21 family nurse practitioner with -- Medical Group in Tucson,
22 Arizona.
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1 DR. TITUS: I'm Sandy Titus. I'm the
2 Executive Secretary and the designated federal official
3 at this meeting.
4 DR. WOOD: I'm Alastair Wood. I'm Assistant
5 Vice Chancellor at Vanderbilt and I'm also a member of
6 the committee.
7 DR. WILLIAMS: I'm Henry Williams, Acting
8 Chair of the Community Health and Family Practice at
9 Howard University and a member of NDAC.
10 DR. CLAPP: I'm Leslie Clapp, pediatrics,
11 Main Pediatrics in Buffalo, New York and clinical
12 associate professor of pediatrics at SUNY Buffalo.
13 DR. KING: I'm Lloyd King, Chief of
14 Dermatology at Vanderbilt University. I'm a
15 dermatologist.
16 DR. ROSENBERG: I'm Bill Rosenberg. I'm a
17 dermatologist and Chairman of Dermatology at the
18 University of Tennessee College of Medicine.
19 DR. CHOWDHURY: I'm Badrul Chowdhury. I am
20 with the U.S. Food and Drug Administration, Division of
21 Pulmonary and Allergy Drug Products.
22 DR. GANLEY: I'm Charlie Ganley, Director
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1 of the Division of Over-the-Counter Drugs at FDA.
2 DR. KWEDER: I'm Sandra Kweder. I'm the
3 Director of the Office of Drug Evaluation II at FDA.
4 DR. CANTILENA: Okay. Thank you, everyone.
5 We'll now ask Doctor Sandy Titus to read the
6 conflict of interest statement.
7 DR. TITUS: The following announcement
8 addresses the issue of conflict of interest with regard
9 to this meeting and is made a part of the record to preclude
10 even the appearance of such at this meeting. Based on
11 the submitted agenda for the meeting and all financial
12 interests reported by the committee participants, it has
13 been determined that all interests in firms regulated
14 by the Center for Drug Evaluation and Research present
15 no potential for an appearance of a conflict of interest
16 at this meeting with the following exceptions.
17 In accordance with 18 USC 208B3, Doctor Ralph
18 D'Agostino has been granted a waiver for his role as a
19 member of the Safety Monitoring Committee and his services
20 as a consultant to a Safety Monitoring Committee for a
21 competitor on an unrelated matter. He receives fees of
22 less than $10,001 for each of these activities.
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1 Doctor Stanley Szefler has been granted a
2 waiver under 18 USC 208B3 for his consulting for a firm
3 that has a financial interest in a competitive product.
4 He receives less than $10,001 a year.
5 In addition, Doctor Harry Sachs has been
6 granted waivers under 18 USC 208B3 and 21 USC 355C4,
7 amendment of Section 505 of the Food and Drug
8 Administration Modernization Act for her ownership of
9 stock in the sponsor and competitors valued between $5,001
10 to $25,000.
11 A copy of the waiver statements may be
12 obtained by submitting a written request to the agency's
13 Freedom of Information Office, Room 12A30 of the Parklawn
14 Building.
15 In addition, we would like to disclose that
16 Doctor Michael Alfano is participating at this meeting
17 as an industry guest acting on behalf of regulated
18 industry. As such, he has reported to the FDA that he
19 has no conflicts of interest in the issues to be discussed
20 at today's meeting.
21 In the event that the discussions involve
22 any other products or firms not already on the agenda
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1 for which an FDA participant has a financial interest,
2 the participants are aware of the need to exclude
3 themselves from such involvement and their exclusion will
4 be noted for the record.
5 With respect to all other participants, we
6 ask in the interest of fairness that they address any
7 current or previous financial involvement with any firm
8 whose products they may wish to comment upon.
9 Thank you.
10 DR. CANTILENA: Okay. Thank you, Doctor
11 Titus. We're almost ready for our first break at this
12 point after the conflict of interest statement. But
13 let's instead move to Doctor Charles Ganley who will
14 introduce us to the issues for discussion.
15 DR. GANLEY: We would just like to thank the
16 members of today's Advisory Committee for taking time
17 from their busy schedules to participate in this meeting.
18 This committee includes members from the Nonprescription
19 Drugs Advisory Committee, selected members from the
20 Pulmonary Allergy Drugs Advisory Committee and the
21 Dermatologic Ophthalmologic Drugs Advisory Committee and
22 some additional FDA consultants.
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1 It was not quite a year ago when the
2 Nonprescription Drugs Advisory Committee and Pulmonary
3 Allergy Drugs Advisory Committee discussed the merits
4 of taking Loratadine Fexofenadine and Cetirizine from
5 prescription to over-the-counter for allergic rhinitis.
6 Today the committee is asked to discuss the merits of
7 taking Loratadine over-the-counter for treatment of
8 chronic idiopathic urticaria. Unlike allergic rhinitis,
9 the indication chronic idiopathic urticaria, urticaria
10 or hives are not approved for any over-the-counter drug
11 products nor is it included in the antihistamine final
12 monograph.
13 So it is important for the committee to
14 understand today that the discussion will not only impact
15 the supplemental application submitted by Schering Plough
16 but it will also impact other antihistamine manufacturers
17 that hope to market their product over-the-counter for
18 urticaria and hives.
19 That concludes my comments right now.
20 DR. CANTILENA: Okay. Thank you, Doctor
21 Ganley, and I would now like to introduce Doctor John
22 Clayton from Schering Plough to start the sponsor
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1 presentation. Doctor Clayton will then introduce his
2 co-presenters and then I believe we'll close the session.
3 DR. CLAYTON: Good morning, Doctor
4 Cantilena, members of the Advisory Committee, consultants
5 and FDA colleagues. I'm John Clayton, Senior Vice
6 President, Scientific and Regulatory Affairs for Schering
7 Plough Health Care Products. On behalf of Schering
8 Corporation, we appreciate this opportunity to present
9 a brief overview of the NDE submissions we made to the
10 FDA for the approval of Claritin tablets and syrup for
11 over-the-counter status for the indication of chronic
12 idiopathic urticaria.
13 The proposed labeling of this indication in
14 consumer terms is that of chronic hives of an unknown
15 source. Discussions with FDA have raised the possibility
16 of a broader hives indication OTC. The research that
17 we are presenting today has been focused on CIU, the
18 current prescription indication. However, we are open
19 to exploring the broader hives indication, as will be
20 discussed by FDA today.
21 Specifically, the products for discussion
22 today are Claritin tablets, Claritin syrup, Claritin
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1 ready tabs rapidly disintegrating tablets, all in 10
2 milligram daily doses.
3 By way of background, as Doctor Ganley
4 mentioned, Loratadine was reviewed by this committee
5 along with the Pulmonary Allergy Advisory Committee on
6 last May 11 for the OTC indication of allergic rhinitis.
7 The majority of the Joint Advisory Committee concluded
8 that Loratadine in 10 milligram daily doses is safe for
9 OTC use in allergic rhinitis.
10 Therefore, the focus of this meeting today
11 is to consider Loratadine for treating the symptoms of
12 chronic idiopathic urticaria as an OTC indication
13 following an initial physician diagnosis.
14 Schering's presentation this morning will
15 follow the outline shown here. Following my overview,
16 Doctor Eugene Monroe, a practicing dermatologist with
17 Advanced Health Care in Milwaukee and Assistant Clinical
18 Professor of Dermatology at Medical College of Wisconsin,
19 will present a brief overview of urticaria including the
20 current standards in the diagnosis and treatment.
21 Mr. Stephen Neuman of Schering will then
22 present the results of four new studies conducted by
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1 Schering which provide strong evidence on the
2 appropriateness of CIU as an OTC indication.
3 This will be followed by a risk benefit
4 analysis of Claritin OTC for this indication and our
5 conclusions and recommendations. At that point, we'll
6 be pleased to respond to any questions you may have.
7 In arriving at the conclusion that CIU is
8 an appropriate OTC indication for Loratadine, Schering
9 has completed several analyses and studies. First, we
10 undertook an in-depth review of the condition and the
11 current standards and practices of management. This
12 included medical literature as well as practice
13 parameters. We've also conducted four new studies to
14 evaluate patient and physician habits and practices in
15 CIU, the ability of consumers to self-recognize recurring
16 episodes of CIU following initial physician diagnosis
17 and a label comprehension study of draft OTC labeling
18 for this indication.
19 We completed an in-depth review of the safety
20 profile of Claritin from clinical trial data as well as
21 the world-wide marketing experience for both allergic
22 rhinitis and CIU and the broad experience with Claritin
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1 OTC for skin allergies. We also reviewed poison center
2 data.
3 And lastly but importantly, we reviewed these
4 findings with a panel of experts in allergy, dermatology
5 and anaphylaxis to gain their insights and
6 recommendations on the appropriateness of the pero
7 switch. This panel included Doctor Randy Jewel, Doctor
8 Ron Simon, Doctor Philip Lieberman, Doctor Richard
9 Aarons, and Doctor Eugene Monroe, who's with us today.
10 I'd like to summarize the most significant
11 findings from these efforts. First, we learned that CIU
12 is a medical condition that is generally not associated
13 or confused with more serious conditions. Secondly, we
14 also learned that through the use of OTC antihistamines
15 and/or multiple prescription refills CIU is currently
16 managed as a self-treated condition.
17 We found that CIU patients and physicians
18 alike are comfortable with consumers' ability to
19 accurately self-recognize recurring outbreaks of CIU
20 which was confirmed through a self-recognition study.
21 As you will hear from our study results, 62
22 percent of CIU sufferers surveyed reported they used OTC
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1 antihistamines for their hives prior to seeking medical
2 diagnosis. So consumers already self-treat their
3 urticaria symptoms with OTC antihistamines without the
4 benefit of labeling for this use.
5 And focusing on the drug Loratadine, through
6 an analysis of our adverse event database as well as poison
7 center data, we confirmed that Claritin has an extremely
8 safe record of use and provides a strong risk benefit
9 and we confirmed that adequate labeling can be developed
10 for Claritin for safe and effective use for OTC following
11 an initial physician diagnosis.
12 I would now like to introduce Doctor Eugene
13 Monroe. Doctor Monroe is a practicing dermatologist at
14 Advanced Health Care and assistant clinical professor
15 of dermatology at the Medical College of Wisconsin.
16 In addition to his medical practice and teaching, Doctor
17 Monroe has a distinguished research career with numerous
18 publications concerning urticaria. Doctor Monroe.
19 DR. MONROE: Thank you and I would like to
20 thank the committee for the opportunity to speak before
21 you today. The presentation I'm going to present today
22 has two major objectives. First, I would like to present
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1 an overview of urticaria or hives with an emphasis on
2 the classification of this condition, the diagnostic
3 evaluation, and the management of urticaria and secondly,
4 I would like to try to answer the question what, if any,
5 potential consequences could arise if a patient or a
6 consumer misdiagnoses or confuses another condition for
7 chronic idiopathic urticaria.
8 Urticaria or hives is a skin reaction pattern
9 characterized by transient, pruritic, edematous, lightly
10 erythematous papules or wheals that frequently have
11 central clearing. To the patient, urticaria is a very
12 itchy bothersome condition and also embarrassing with
13 raised visible wheals. It has a significant negative
14 impact no quality of life affecting the patients' ability
15 to sleep or their daily activities.
16 Urticaria is basically classified as acute
17 or chronic. Acute urticaria has a duration ranging from
18 a few days to a few weeks. Its incidence is approximately
19 15 to 20 percent of the general population. The ideology
20 of acute urticaria is usually detectable and most cases
21 are mild and are never seen by the physician.
22 Chronic urticaria is arbitrarily defined as
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1 an episode of urticaria whose duration is greater than
2 six weeks. It can range from a continuous problem
3 occurring almost daily to a recurring problem where there
4 may be symptom-free periods from days to many weeks.
5 The course is variable from months to years. The
6 incidence in the general population is up to three
7 percent.
8 The etiology of chronic urticaria, unlike
9 acute urticaria, is not found in 90 to 95 percent of cases
10 and, therefore, most patients with urticaria of a chronic
11 nature have chronic idiopathic urticaria meaning that
12 the cause is unknown or not determined.
13 The potential causes of urticaria or hives
14 is quite extensive. The most common causes, particularly
15 for acute urticaria, are drugs. Some of the common ones
16 would be the penicillins, the NSAIDs, the
17 anti-hypertensives. Foods are another common cause.
18 This may be the food itself or an additive to the food.
19 Infections that are systemic, -- viral, bacterial,
20 fungal can also underlie urticaria.
21 There are multiple other causes that are much
22 less frequent as a source, psychogenic factors, physical
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1 agents, inhalants, contactants, genetic factors and
2 internal diseases. I would mention under internal
3 diseases that some of the potentially more serious
4 conditions such as connective tissue diseases or
5 vasculitis are probably underlying causes in less than
6 one or two percent of the cases.
7 In making a diagnosis of chronic idiopathic
8 urticaria, the most important diagnostic test is a
9 thorough detailed history by the physician. This history
10 would focus on a thorough review of systems and a very
11 thorough review of all the potential causes of urticaria
12 that I listed on the previous slide. A physical
13 examination is also important to detect any underlying
14 problems. Laboratory and diagnostic tests are only
15 ordered based on clues that would be obtained from that
16 thorough history and physical examination. Chronic
17 idiopathic urticaria is a diagnosis of exclusion made
18 by the physician.
19 I would now like to address the current
20 standards of care for managing urticaria. In cases of
21 acute urticaria, the first critical part of the work-up
22 is to eliminate or reduce an underlying cause since in
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1 the vast majority of these cases a cause can be identified.
2
3 Patient education is very important. One
4 wants to review with the patient the natural course of
5 the disease and possible ideologies underlying the
6 condition. It is also important to discuss possible
7 complications and associated conditions and what actions
8 might be appropriate to deal with those situations.
9 The drug therapy for acute urticaria centers
10 around the use of H1 antihistamines, preferably the
11 non-sedating class.
12 The management of chronic idiopathic
13 urticaria assumes that an evaluation has already been
14 made by the physician to rule out an underlying etiology.
15 The first step in the management approach would be to
16 reduce or avoid any of the non-specific aggravating
17 factors that often cause vasal dilatation. These would
18 be things like stress, physical exertion, alcohol,
19 exercise, aspirin, etcetera.
20 Patient education is very important again
21 in alerting the patient to the natural course of the
22 disease and possible underlying etiologies and again the
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1 patient should be thoroughly informed of possible
2 complications and appropriate actions to take.
3 The major maintenance of patients with
4 chronic idiopathic urticaria centers around drug therapy.
5 I would like to briefly summarize what I would consider
6 the treatment algorithm for patients with chronic
7 idiopathic urticaria.
8 The standard of care and the first line of
9 therapy is the use of H1 antihistamines with again the
10 non-sedating class being preferred. Sometimes the
11 monotherapy with an H1 antihistamine is insufficient to
12 control the problem and, therefore, other medications
13 are sometimes added for symptomatic relief of the
14 condition. These would include other H1 antihistamines,
15 H2 receptor blockers, inhibitors of other mediators such
16 as leukotriene antagonists or inhibitors of the
17 inflammatory and cellular reaction which is also part
18 of the urticarial reaction.
19 Urticaria presents a spectrum of patients.
20 The spectrum involves the severity of the condition which
21 ranges from a very mild to a more serious form. Most
22 of the patients with acute urticaria have a mild form
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1 of this disease. Most patients with chronic urticaria
2 have a mild to moderate condition and then a small subset
3 have a much more severe refractory condition.
4 The spectrum of urticaria patients also
5 involves the amount of participation and involvement and
6 interaction that occurs between the patient and the
7 physician. In acute urticaria, as I stated earlier, most
8 of these patients never even consult with a physician.
9 In chronic urticaria, for the majority of cases that
10 are mild to moderate, patients often self-manage this
11 condition after an initial physician diagnosis and have
12 subsequently infrequent physician contact. The smaller
13 subset of more severe refractory chronic urticaria
14 patients require active physician involvement.
15 The treatment of the spectrum of urticaria
16 patients centers around the same common theme, the use
17 of H1 antihistamines.
18 I would now like to turn our attention to
19 the possible question of what would happen in potential
20 situations where a patient or a consumer confuses or
21 misdiagnoses another condition for chronic idiopathic
22 urticaria. What, if any, are the potential consequences
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1 if he or she then self-treats the condition with a
2 non-sedating over-the-counter antihistamine? To put
3 these situations in context, it is important to recognize
4 what occurs in today's health care environment.
5 I want to focus on those conditions that would
6 most likely be confused or misdiagnosed as chronic
7 idiopathic urticaria. That would include acute or
8 chronic urticaria. It would include the category of
9 eczema and dermatitis such as contact dermatitis and it
10 would include the condition of angioedema. There are
11 other conditions where potential misdiagnosis may occur
12 which are rare or much less frequent such as anaphylaxis,
13 and I'll briefly discuss those later as well.
14 Let's look first at the condition of acute
15 urticaria. The vast majority of cases of acute urticaria
16 are mild and self-limiting. An appropriate treatment
17 for acute hives is an antihistamine, as I stated earlier.
18 So the conclusion here is that there are no serious
19 clinical concerns or consequences if a person would take
20 an antihistamine for acute urticaria because that's the
21 appropriate thing to do.
22 Let's look at chronic urticaria. As I stated
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1 earlier, approximately five to 10 percent of patients
2 with chronic urticaria have an identifiable underlying
3 cause. The consequences of confusing chronic urticaria
4 from chronic idiopathic urticaria are that there is a
5 delay in diagnosing the underlying condition which may
6 have alternative treatments. The concern is not serious
7 because these patients will usually be driven to the
8 physician due to the severity and persistence of their
9 itching, the failure of their underlying urticaria to
10 respond to self-treatment, or the presence of other signs
11 and symptoms that might suggest a more serious underlying
12 condition. These might include things such as joint
13 pain, fever, discoloration of the hives, etcetera.
14 There are many itchy rashes which the
15 consumer might confuse with hives. Some of these would
16 include eczema, contact dermatitis, etcetera. The
17 symptoms of itch in these cases might be helped by the
18 antihistamine but other treatment such as the use of
19 topical cortico-steroids might be required to treat the
20 rash. While the potential for delay in diagnosis and
21 initiation of more appropriate therapy exists, this delay
22 will cause no serious clinical concern or consequence
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1 because, again, these patients will usually seek a
2 physician's care when the symptoms or severity of the
3 condition persists and fails to respond to the treatment
4 initiated.
5 Angioedema is another condition that I want
6 to briefly mention. Angioedema and urticaria can
7 co-exist approximately 40 percent of the time and
8 sometimes can be confused with each other. Angioedema
9 would be defined as giant hives or hives involving mucous
10 membranes and tissues around the eyes, lips, or genitalia.
11 There is a subset of individuals who can also develop
12 laryngeal or oral angioedema, but this is a very rare
13 situation in chronic urticaria.
14 Histologically, angioedema involves the
15 deeper layers of the skin than urticaria and very often
16 the angioedema lesions are not pruritic.
17 Although visually more noticeable than
18 urticaria, angioedema presents no additional serious
19 consequences to the patient if the diagnosis of angioedema
20 is confused with urticaria. In general, there are no
21 differences with the clinical treatment of these
22 conditions which often coexist.
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1 An area of potential concern in the acute
2 setting relates to the rare situation in which acute
3 urticaria is the presenting symptom of an anaphylactic
4 reaction. Anaphylaxis would be defined as an immediate
5 systemic allergic reaction produced by the release of
6 mediators from the mass cell or the basophil. This would
7 simultaneously involve skin manifestations, hives being
8 present in about 90 percent of these cases, but it would
9 also involve other systemic manifestations. If the
10 respiratory system is involved, one would have dyspnea
11 and wheezing. If the cardiovascular system is involved,
12 dizziness, syncope and hypotension may be present and
13 if the GI system is involved, nausea, vomiting and
14 diarrhea may occur. The incidents of anaphylaxis is
15 rare.
16 Chronic urticaria is not associated with nor
17 is it a risk factor for the development of anaphylaxis.
18 Acute urticaria is an associated symptom with
19 anaphylaxis but the rapid simultaneous onset of
20 cardiovascular or respiratory symptoms will cause the
21 patient to seek immediate medical attention. The
22 respiratory and cardiovascular symptoms most always occur
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1 within 30 minutes of the presentation of the hives.
2 I'd like to make the following conclusions.
3 The cardinal features of urticaria, whether acute or
4 chronic, are cutaneous wheals, redness and itching. The
5 diagnosis of chronic idiopathic urticaria is a diagnosis
6 of exclusion made by the physician. The consequences
7 of patient misdiagnosis represents a very low safety risk.
8 The availability of an over-the-counter
9 non-sedating H1 antihistamine in chronic idiopathic
10 urticaria would represent a significant benefit to the
11 patient or consumer in two ways. It would provide better
12 safety than exists with the current over-the-counter
13 antihistamines and it would create an opportunity for
14 better care through labeling and patient education.
15 Thank you and at this time I would like to
16 introduce Mr. Stephen Neuman who will present the findings
17 of the Schering chronic idiopathic urticaria studies.
18 MR. NEUMAN: Thank you, Doctor Monroe. Good
19 morning, Doctor Cantilena and members of the committee.
20 My name is Steve Neuman and I'm here today to present
21 the results of four studies that we conducted to better
22 understand both patient and physician habits and
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1 practices around CIU.
2 We sponsored four studies on CIU. Many of
3 these were standard studies which would be used to support
4 the switch of a drug of this safety profile. The first
5 was a study among 388 patients who have received a prior
6 physician diagnosis for CIU. The goals of this study were
7 to really understand the fundamental dynamics of the
8 condition such as duration of suffering, the symptoms
9 that are suffered, patient interaction with their
10 physician, and the modalities and treatment methods that
11 are used to manage the disorder.
12 We also commissioned a study among a
13 representative physician specialties that treat CIU to
14 understand and practice behaviors and perceptions from
15 a physician viewpoint. We conducted a study to determine
16 if consumers that had been diagnosed by a physician as
17 having CIU can accurately self-recognize the condition
18 and the symptoms upon recurrence. And finally, we
19 conducted a label comprehension study.
20 One of the key points that I hope you take
21 away from my presentation this morning is the remarkable
22 consistency and findings from these studies, particularly
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1 with regard to the patient's ability to self-recognize
2 CIU upon recurrence of symptoms.
3 Let's begin with the consumer study.
4 Members of a large Internet panel were sent an email
5 questionnaire to help identify physician-diagnosed CIU
6 sufferers. The question that was posed to them was have
7 you ever been diagnosed by a medical doctor as having
8 chronic or recurrent hives that have no known discernible
9 cause, also known as chronic idiopathic urticaria?
10 A random sample was drawn from among those
11 who responded to the question, and they were sent an email
12 that asked them to log onto a website where they completed
13 a more detailed questionnaire. Importantly, when they
14 logged on, they were rescreened to have
15 physician-diagnosed CIU.
16 A concern might exist that these respondents
17 were not actually CIU sufferers and, in fact, FDA has
18 raised that concern in their briefing book to you. This
19 is unlikely, I think, due to the fact that the literature
20 on consumer research supports that most respondents
21 provide accurate responses to survey questions on
22 personal health unless the topic is a sensitive health
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1 issue. And also, the study remuneration here had a very
2 nominal $8 - $10 value that would be unlikely to attract
3 false claimants in great numbers. And perhaps as
4 important is that the approach to the subject validation
5 used in this study is consistent with what's used in many
6 label comprehension studies.
7 The study population here was representative
8 of the random sample that was drawn from the larger CIU
9 pool. The demographic profile of this group was
10 consistent with that which has been reported in the
11 literature with CIU. That is, being female and age 40
12 to 60. I would also point out that it's consistent with
13 the demographics that are reported in the integrated
14 summary of efficacy section of the CIU clinical study
15 provided by FDA in their briefing book to the committee.
16 I'll speak about the design now. The
17 questions that were asked consisted primarily of a
18 variation of closed end or multiple choice type questions.
19 However, subjects could type in responses whenever list
20 did not meet their needs and all of the questions
21 pertaining to important patient behaviors had this option
22 available to them. To further minimize the impact or
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1 bias in the presentation of these lists, the items in
2 the list were randomly rotated.
3 In their briefing book, FDA took issue with
4 the use of closed ended questions in this study and while
5 certainly open ended questions do have a role, the
6 modified closed ended questions used in a study of this
7 type are commonly employed and they offer a number of
8 advantages to us. The first is that they're a good choice
9 when options are limited and responses can be anticipated
10 for questions such as where did the wheals occur, what
11 was the length of suffering, items like that.
12 They also permit a direct comparison of
13 response from subject to subject. They help address the
14 issue that most respondents will not write elaborate
15 answers, particularly in a self-administered
16 questionnaire. And they avoid issues with having the
17 interviewer not carefully record or misinterpret what
18 the subject is saying and they can avoid the errors that
19 are associated with coding or categorization of responses
20 on the back end as well.
21 What I'd like to do now is move into the
22 findings of the study. The way I'm going to approach
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1 this is for each finding I'm going to show the question
2 that was asked and then I'll report the results as well
3 as draw a conclusion.
4 The first question that was ask is in a
5 typical year, how many episodes of chronic hives do you
6 experience? Two-thirds, 66 percent of sufferers,
7 experienced three or more outbreaks each year and the
8 mean number of outbreaks for the study population is
9 three. This results in a sufferer base who are
10 experienced, frequent sufferers making CIU a recognizable
11 condition, and this ability to self-recognize CIU will
12 be confirmed, as I mentioned earlier, in several of the
13 studies that I'm presenting today.
14 We also asked, please indicate the symptoms
15 you experience when your hives recur. The symptoms
16 of hives are quit discreet with nine in 10 naming itching
17 as a symptom. Hives, wheals, redness, rash also received
18 high level of mentions as key symptoms. There's
19 significant consistency in the symptoms that are
20 described by CIU sufferers and, as Doctor Monroe discussed
21 in his section, the key symptom of itching is quite intense
22 and highly bothersome to patients.
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1 It's also noteworthy that symptoms that could
2 be confused with the most threatening manifestations of
3 anaphylaxis such as breathing problems are rare.
4 An important question that produced key
5 insights for us was thinking about when the hives appeared
6 prior to seeing a physician, what, if anything, did you
7 do to treat or relieve the condition? The question
8 context here is again prior to diagnosis of CIU.
9 While OTC antihistamines in the U.S. are not
10 currently labeled to treat symptoms of CIU, the study
11 subjects often used antihistamines to self-treat hives
12 prior to consulting a physician for diagnosis. Nearly
13 two-thirds, 62 percent of patients who've been diagnosed
14 by a physician as having CIU took an OTC antihistamine
15 for their hives prior to physician diagnosis. I point
16 out also that the use of OTC topicals is also a prevalent
17 first step. So we can conclude from this that
18 self-medication prior to physician diagnosis is common
19 behavior and OTCs are commonly used.
20 One question that we asked regarding
21 physician contact is, in the past year, how often have
22 you seen a physician for this condition? One-third of
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1 patients, 33 percent, have not seen a physician for CIU
2 within the past year and nearly 20 percent have not seen
3 a physician since their initial diagnosis. Thus, many
4 patients are not under the continual care of a physician
5 for CIU.
6 To understand typical behavior upon
7 recurrence we asked, when your chronic hives recur, please
8 indicate what you normally do. Over half, 52 percent
9 of the subjects, indicate use of a prescribed medication
10 already on hand. Just over four in 10, 43 percent, use
11 an OTC medication and 20 percent indicate that they call
12 their doctor.
13 So we see that self-management with both
14 prescription and OTCs are common behavior. Looking at
15 this in more detail, particularly at the 20 percent of
16 subjects who typically don't call or visit their doctor
17 when their hives recur, seven percent do so when their
18 symptoms don't respond and another two percent make
19 contact when more serious symptoms occur.
20 Hence, we would conclude or to summarize,
21 most physician contact comes about when symptoms don't
22 respond or when more serious symptoms occur.
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1 Another important question for us was now
2 that your condition has been diagnosed by a physician,
3 how easy is it for you to identify this condition when
4 it reappears? Once diagnosed by a physician as having
5 CIU, 80 percent of study subjects felt that it was very
6 easy to identify the condition when it recurs and 94
7 percent felt that it was very or somewhat easy. No
8 respondents felt that it was difficult to identify the
9 condition upon recurrence.
10 Finally we asked, what would you do if you
11 experienced other symptoms such as difficulty breathing,
12 fever or trouble swallowing with your hives? Over 95
13 percent of the study subjects indicate that they would
14 seek medical care or call or visit their physician.
15 Importantly, this response is without the benefit of
16 labeling to direct them to an appropriate action.
17 In their briefing book, FDA indicated that
18 it's not clear whether those subjects who would call or
19 visit a physician would act with a sense of urgency and
20 suggested that a follow-up question on timing would have
21 been helpful. I think while this question might have
22 clarified the results here, I would draw attention to
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1 the finding that 55 percent of respondents indicated that
2 they would seek emergency care which implies immediacy.
3 The agency also pointed this out in their discussion
4 of the studies as well.
5 So to draw conclusions from the consumer
6 study. First, consumers appear comfortable that based
7 on the frequency of suffering and the discrete symptoms,
8 recurrent episodes of CIU are easy to recognize. Once
9 diagnosed by a physician, CIU is largely self-managed
10 and most patients are not under continual care.
11 Importantly, treatment with OTC
12 antihistamines prior to physician diagnosis is common
13 behavior today and consumers know to seek medical
14 attention if serious symptoms occur.
15 Now I would like to focus our attention on
16 the study that we conducted among physicians who regularly
17 see patients with CIU to help better understand the
18 practices among those physicians. This sample was drawn
19 from a pool of physicians with Internet access, and the
20 pool was comprised of over 200,000 physicians
21 representing over 40 percent of AMA registered
22 physicians.
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1 The panel was pre-screened as to specialty
2 and treatment of patients suffering CIU and a longer,
3 more detailed survey was conducted among the sample of
4 the screened physicians. The sample was representative
5 of and projectable to the universe of office-based
6 physicians with Internet access, which is 96 percent of
7 the physicians in the specialties that we studied, and
8 the sample reflected the primary CIU treatment groups
9 of PCPs defined here as internists and FP-GPs,
10 dermatologists, allergists and pediatricians which
11 incidentally, according to an independent tracking
12 service of office visits, accounts for 89 percent of the
13 office visits for chronic hives. The ending sample was
14 359.
15 The first question we asked physicians, what
16 terminology do you typically use when explaining the
17 initial diagnosis to your patients? Chronic or recurring
18 hives are the most prevalent descriptors used by nearly
19 75 percent of physicians for CIU. This information was
20 a source of learning that helped us with labeling which
21 we later tested in a label comprehension study and I'll
22 review it with you.
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1 After receiving a diagnosis of chronic
2 idiopathic urticaria from a physician, how likely do you
3 feel that a sufferer is able to self-identify or recognize
4 recurrent episodes of the condition? This question is
5 very similar to the one that was asked of the consumers.
6 Ninety six percent of the physicians believed that it
7 is either very or somewhat likely that their patients
8 can recognize a recurrence. Six in every 10 physicians
9 believed that it's very likely that a recurrence can be
10 recognized. Again, this level is extremely comparable
11 to that which we saw in a similar question in the consumer
12 study.
13 Another question was, thinking of all the
14 patients you have counseled for chronic idiopathic
15 urticaria, what percentage do you recommend keep a
16 medicine on hand in anticipation of a recurrent episode?
17 Counseling at least some CIU patients to keep medications
18 on hand in case of outbreak of hives is nearly universal
19 behavior and interestingly, just under 60 percent of
20 physicians counsel all of their previously diagnosed CIU
21 patients to keep medications on hand in case of an
22 outbreak. Hence, the physician behavior encourages
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1 self-management.
2 So what can we conclude from this
3 representative and projectable study among physicians
4 first? Physicians appear aligned in the terminology they
5 use to describe CIU patients, either chronic hives or
6 recurrent hives. Like the 94 percent of consumers who
7 believe that recurrent episodes of CIU are easily
8 self-recognized, a similar proportion, 96 percent, of
9 physicians believe that once diagnosed, it's likely that
10 patients can self-recognize recurrent outbreaks.
11 Finally, physician prescribing and
12 recommending behavior reinforces CIU patient
13 self-management.
14 Now I'd like to direct our attention to a
15 study of consumers' ability to self-recognize the
16 condition of CIU upon recurrence. This study was
17 conducted in conjunction with a label comprehension
18 study. A key focus of the study was to understand whether
19 consumers who have been diagnosed by a physician as having
20 CIU can accurately self-recognize the condition and the
21 symptoms upon recurrence.
22 The design of this study permitted all
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1 comers, that is anyone who believes they've been diagnosed
2 by a physician with CIU, to come forward and to
3 participate. The ending sample was 196 CIU sufferers.
4 CIU patients were recruited from 21 regionally dispersed
5 cities and the patients were required to bring the name
6 and telephone number of the doctor that diagnosed them.
7 This brings greater credibility to the fact that all
8 the enrollees were CIU sufferers.
9 The subjects that were enrolled in the study,
10 first of all, had a medical history taken along with a
11 photograph of their lesions if they were suffering and
12 willing to be photographed. The patients who were not
13 suffering or refused photographic consent reviewed
14 alternative textbook type photos of lesions and selected
15 the one that looked the most like theirs.
16 These materials were then sent to and
17 reviewed by the investigating physician who asked
18 additional questions via teleconference with the patient
19 and then the physician investigator and overseeing
20 dermatologist reviewed all of the information to
21 determine if the subject had accurately self-recognized
22 their condition as CIU. Nearly all, 94 percent, of the
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1 subjects who believed they had CIU actually did have the
2 condition.
3 So what can we conclude from this?
4 Previously diagnosed CIU patients can accurately
5 self-recognize the symptoms and the condition upon
6 recurrence and this is consistent again with the findings
7 of both the consumer and the physician studies.
8 We also conducted a label comprehension
9 study. This was an all comer study to understand the
10 consumer's ability to comprehend specific communications
11 points on the draft labeling. There were five cohorts
12 in this study. There was a cohort of 196 CIU sufferers.
13 There was a cohort representative of the general
14 population. There was a cohort of individuals screened
15 to read at a maximum 7th - 8th grade level. There was
16 a cohort of patients for whom the labeling for Claritin
17 was contraindicated. That is, those who were either
18 nursing or breast feeding or had liver or kidney disease.
19 And a cohort of acute hive sufferers who, according to
20 the label, should not use the product. Please note that
21 the number of subjects here in each cohort does not add
22 up to 565 as subjects count toward more than one cohort.
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1 The study method here was the CIU cohort was
2 recruited via advertising and the other cohorts were
3 recruited via mall intercepts and intercepts at special
4 locations for the enriched populations. Label
5 comprehension was assessed by asking both direct and
6 scenario-based questions and self-selection was assessed
7 by posing a question to determine if consumers understood
8 that they personally could use Claritin.
9 In response to the scenarios that were
10 presented, consumers in all of the cohorts demonstrated
11 a strong understanding of the general warnings and that
12 Claritin should not be used in situations where serious
13 symptoms are present. Either responses that were correct
14 such as "do not take the product" or those that were
15 acceptable such as "I would ask my doctor before using"
16 were mentioned by between 75 and 96 percent depending
17 on the cohort.
18 Similarly, there was strong understanding
19 of who can and can not use Claritin. The correct and
20 acceptable levels here were in the range of 75 to 99
21 percent.
22 End of condition such as pregnancy or liver
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1 disease under which one must ask a doctor before use.
2 The correct and acceptable levels here are in the range
3 94 to 100 percent and of conditions under which the product
4 should be used correct and acceptable levels, 95 to 100
5 percent. These responses, taken with the information
6 from the consumer study, that 95 percent of subjects will
7 seek medical attention if serious symptoms are present
8 supports the perspective that labeling can be developed
9 to adequately convey the warnings and an understanding
10 not to use the product if serious symptoms occur.
11 Response among the CIU sufferers to the
12 scenarios and to the questions was particularly strong
13 with responses ranging from 91 to 99 percent providing
14 either correct or acceptable responses to these questions
15 and CIU patients also universally demonstrate appropriate
16 self-selection for personal use.
17 A majority of the acute hives cohort, 54
18 percent, correctly de-selected the product for personal
19 use. I'd like to note that the principal display panel
20 of the package labeling that we tested stated that
21 Claritin, quote, "relieves and reduces itching and rash
22 due to chronic and recurring hives." Unquote. We
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1 believe this inclusion of broader symptom descriptors
2 likely led to more acute hive sufferers believing that
3 the product is for their use.
4 In response to a separate scenario question
5 that asked, what should be done in a situation in which
6 an outbreak of acute hives has occurred, 75 percent of
7 the acute hives cohort correctly comprehended that the
8 product should not be used. This level of self-selection
9 and comprehension leads us to believe that labeling can
10 be improved.
11 Turning out attention to the general
12 population, seven in 10 members of the general population
13 cohort provided a correct or an acceptable response, i.e.,
14 do not use, ask a doctor before use, to the personal use
15 question. We believe that this level can be strengthened
16 even more with revised labeling.
17 So our conclusions. Reaction to the
18 scenarios across the cohorts demonstrates understanding
19 of general warning situations in which Claritin should
20 and should not be used and the directions for us.
21 Results of the self-selection and personal
22 use question reveal that the majority of the general
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1 population can appropriately self-select the product for
2 use.
3 Over half, 54 percent, of the acute hives
4 cohort indicated that they would not use the product when
5 asked a question about personal use and the response to
6 the scenarios underscores that this study population
7 understands the warnings.
8 These encouraging results were achieved with
9 draft labeling that would benefit from refinement, and
10 we are committed to work with FDA to refine the labeling
11 and improve comprehension among these consumers.
12 Based on responses to both the self-selection
13 question and to the scenarios, consumers with a physician
14 diagnosis of CIU understand that Claritin is appropriate
15 for their use and are likely to use it correctly. These
16 findings are again aligned with what we have learned in
17 the other studies.
18 I would like to ask Doctor Clayton to return
19 and complete our presentation. Thank you.
20 DR. CLAYTON: I would now like to turn the
21 focus to risk benefit analysis for Claritin for OTC
22 treatment of CIU. As I mentioned at the outset, the
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1 safety of Claritin was reviewed with this committee by
2 FDA last May. FDA's analysis included experience in
3 allergic rhinitis patients as well as CIU patients. This
4 analysis was included in the Schering briefing book that
5 FDA provided to you.
6 This morning I'd like to highlight the
7 significant additional world-wide marketing experience
8 on Loratadine and CIU and other skin allergies which also
9 supports OTC status. We believe that the risk benefit
10 analysis strongly supports a CIU indication for Claritin
11 OTC which is similar to allergic rhinitis.
12 As you're well aware, Claritin is not a new
13 drug. It has enjoyed world-wide marketing experience
14 in just over 14 years since its initial launch in Belgium
15 in 1988. While Claritin has ultimately been approved
16 in a total of 114 countries, it is especially important
17 to today's discussion that it has been approved OTC in
18 some 33 countries including Canada since 1990 and the
19 UK since 1993. It is important also that most of these
20 OTC approvals have included indications beyond chronic
21 idiopathic urticaria including urticaria or skin itching
22 and hives. Hence, our adverse experience database on
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1 these products covers even broader use experience than
2 CIU alone.
3 Claritin has been marketed by prescription
4 for CIU in the U.S. since 1995 following its initial launch
5 for allergic rhinitis in 1993. World-wide patient
6 exposure to Claritin has been substantial totalling
7 approximately 14 billion patients days since its initial
8 commercial launch. Almost half of that exposure has been
9 within the U.S. Based on an average treatment regimen
10 of 30 days, this represents 457 million courses of
11 therapy. With this extensive patient exposure, we
12 believe we have a clear indication of the safety of this
13 drug. Our analysis of our internal database as well as
14 that of poison control centers shows that Claritin has
15 an excellent safety profile with only two adverse event
16 reports per 100,000 courses of treatment.
17 Serious adverse events are rare and important
18 to OTC consideration, Claritin is not a drug of abuse.
19 It is also important to note that adverse event
20 experience in CIU has not shown any event signals
21 different than those reported in allergic rhinitis.
22 As I mentioned, we've also received poison
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1 center data from the toxics exposure surveillance system
2 database for the past five years and confirmed no new
3 adverse event signals in this base and no new medical
4 issues from that in the Claritin database.
5 Further testing to the safety of Claritin
6 for OTC CIU. The Schering database includes significant
7 OTC experience from 33 countries where Claritin has been
8 sold OTC and in most the OTC indications include skin
9 allergies, urticaria, hives, and skin itching.
10 Looking specifically at two of these
11 countries which have had the most significant OTC exposure
12 and where the labeled indications include hives and
13 allergic skin conditions, the marketing experience in
14 Canada and the U.K. include over 38 million patient days
15 of exposure. These data demonstrate that the safety
16 profile of Claritin OTC is very similar to the extensive
17 world-wide prescription experience and the CIU experience
18 is similar to the allergic rhinitis experience.
19 To summarize, the extensive world-wide
20 experience with Claritin supports the appropriateness
21 of this drug for OTC use based on both Rx experience for
22 CIU as well as OTC experience for hives.
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1 In examining the benefits of OTC availability
2 of Claritin with CIU labeling, our research showed that
3 the current practices and standards of care by physicians
4 and patients treats CIU as a self-managed condition
5 following initial physician diagnosis. Through multiple
6 refills of prescription drugs, primarily non-sedating
7 antihistamines, the combination of non-sedating
8 antihistamines and current OTC medications and the lack
9 of continual physician care indicate that with the limited
10 physician oversight that this is a self-managed condition
11 largely.
12 Secondly, consumers already self-treat with
13 sedating OTC antihistamines despite the lack of label
14 indications for this use. A safe OTC product which
15 provides appropriate directions, warnings, and
16 precautions as well as education for proper use including
17 when to see a physician, will provide a significant
18 benefit.
19 CIU patients who physicians and patients
20 alike acknowledge can accurately self-recognize
21 recurrent outbreaks should have ready access to first
22 line non-sedating therapy as needed to relieve their
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1 symptoms.
2 Making a first line, non-sedating
3 antihistamine available OTC with proper labeling and
4 patient education as proposed by Schering will be a
5 benefit to public health. Based on these facts and the
6 current significant use of prescription Claritin for CIU
7 in the U.S., we believe it would be inappropriate to switch
8 Claritin OTC without labeling for this indication.
9 Otherwise, we will continue to facilitate off label use
10 of OTC antihistamines for urticaria.
11 In sum, we conclude the risk of OTC indication
12 of CIU for Claritin is low and the benefit to public health
13 is significant. In addition to easily understandable
14 OTC labeling, Schering is committed to consumer education
15 programs to better educate CIU sufferers as to proper
16 care for their disease. While the specifics of the
17 program have not been finalized, we expect to include
18 education on allergic rhinitis as well as CIU and to focus
19 on educating about the conditions, helping the consumer
20 understand if Claritin is the appropriate drug for their
21 situation, advising when to consult their physician or
22 seek medical care and when emergency care is appropriate.
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1 There are a number of platforms that we expect
2 to utilize in this program including Internet-based
3 information, toll free telephone, print and continuing
4 education for health professionals.
5 In the briefing book that FDA provided to
6 you, FDA has asked the committee to address a number of
7 questions which we believe are appropriate for the
8 decision to switch Claritin for CIU in an OTC setting.
9 We believe that the answers to all of these questions
10 are supported by data presented this morning and are
11 supportive of OTC approval.
12 First, the data support the accurate
13 self-selection of consumers following a physician's
14 diagnosis. Overwhelmingly, physicians and CIU sufferers
15 indicate that they can comfortably and accurately
16 self-recognize recurrent episodes. Although FDA raised
17 some issues about some aspects of certain of these
18 studies, it is clear that the results are remarkably
19 consistent across all studies in confirming
20 self-management.
21 The self-recognition study demonstrates 94
22 percent accuracy in patient self-recognition of episodes
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1 following initial physician diagnosis. As pointed out
2 in Schering's briefing book to the committee, there is
3 adequate precedent for the proposed approach of requiring
4 an initial physician diagnosis for OTC products including
5 the vaginal antifungals which were introduced OTC in 1991
6 and the most recent example of OTC migraine products.
7 You will note that the label of the OTC
8 migraine products has a statement, "Ask a doctor before
9 use if you've never had migraines diagnosed by a health
10 professional." We would propose similar wording for an
11 OTC hives indication.
12 In light of the common use of OTC
13 antihistamines for hives, OTC labeling for CIU will
14 unquestionably be a positive step forward. We recognize
15 that there may be likely use by some of Claritin OTC by
16 acute hive sufferers. However, we know that this is
17 occurring today with sedating antihistamines OTC without
18 benefit of any labeling to instruct the consumer how to
19 properly use the product or when to see a physician.
20 We also acknowledge that there's a benefit
21 in use of Claritin for symptomatic relief of acute hives
22 and there's likely little increased risk in doing so.
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1 However, we believe it is more appropriate and prudent
2 as a first step to label the product solely for chronic
3 hives of an unknown source and encourage proper diagnosis
4 for all other hives sufferers. We are, however, open
5 to continued discussions with FDA to explore broadening
6 the indication for general gives with appropriate
7 labeling and label comprehension testing.
8 We believe that the OTC labeling for CIU can
9 be improved and we are working to do just that. However,
10 the results to date clearly indicate that this can be
11 achieved. We will work with the agency to refine the
12 labeling to make it even better than the labeling that
13 we tested. We are strongly encouraged by the results
14 of the first study and are confident that we can accomplish
15 this.
16 We are also committed to an unprecedented
17 consumer and health education professional program to
18 better educate both the treatment of allergic rhinitis
19 and CIU.
20 You will be asked in you deliberations to
21 consider a number of questions by FDA. I'd like to share
22 Schering's point of view on those questions. First
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1 question, is urticaria a disease process appropriate for
2 an OTC indication? Based on a careful review of the
3 disease, standards of care and consumer and physician
4 practices and self-management, we believe the answer is
5 yes.
6 The second question. If yes, should the
7 indication be for chronic idiopathic urticaria or hives
8 or should it be broader such that it includes acute
9 urticaria and hives? Our data, as we presented this
10 morning, support the indication of chronic idiopathic
11 urticaria following an initial physician diagnosis.
12 The next question is, if your answer to
13 question one is yes, are there sufficient data to support
14 an OTC switch of Loratadine for CIU or a more general
15 urticaria claim? We believe that the data we presented
16 this morning are sufficient to justify a switch of
17 Loratadine for CIU. The safety and efficacy of
18 Loratadine in this indication along with the OTC
19 international experience are consistent with OTC
20 standards. While we will refine the labeling for this
21 indication, we believe no additional studies beyond that
22 are necessary.
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1 The second part of the question. If not,
2 what other types of data are needed such as clinical
3 trials, safety, efficacy, label comprehension or actual
4 use. As I mentioned, for CIU with an initial physician
5 diagnosis, we believe no additional studies are
6 necessary. But if the committee and FDA determine that
7 a broader hives indication is warranted, we do not believe
8 additional clinical trials are warranted or necessary.
9 It is recognized that acute hives and CIU have common
10 mechanisms. The standard of care is the same for both.
11 Efficacy is acknowledged as the first line therapy for
12 both of these is non-sedating antihistamines.
13 In the case of Loratadine, the safety has
14 clearly been established through international OTC
15 experience in treating hives including acute hives.
16 Further, we do not believe the actual use studies in this
17 condition are either practical to conduct or of value.
18 We believe that any questions could be answered through
19 additional label comprehension testing.
20 The final question reads, if your answer to
21 question two is yes, what are your recommendations for
22 appropriate labeling of Loratadine with regard to
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1 indications, warnings and directions? We have provided
2 draft labeling in our NDA submission which we believe
3 provides the appropriate indications, warnings and
4 directions. Specifically, the use statement, relieves
5 and reduces itching and rash due to recurring or chronic
6 hives of an unknown source. Use only after being told
7 by a doctor that you have recurring or chronic hives of
8 an unknown source.
9 In conclusion, based on the extremely
10 favorable risk benefit analysis and in light of the
11 current consumer/physician practices, we recommend that
12 Claritin be approved as an appropriate safe and effective
13 therapy for treating symptoms of previously diagnosed
14 chronic idiopathic urticaria in an OTC setting following
15 an initial physician diagnosis. Our expert panel review
16 concurred with this recommendation.
17 Although we believe this approach for OTC
18 labeling is conservative and prudent, we remain open to
19 exploring a broader hives indication through additional
20 label development validated through label comprehensive
21 studies if the advisory committee and FDA recommend this
22 approach.
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1 Thank you very much for your attention this
2 morning. My colleagues and I will be pleased to respond
3 to any questions that you may have at this time. Thank
4 you, Doctor Cantilena.
5 DR. CANTILENA: Okay. Thank you, Doctor
6 Clayton and other members of you team. I think we have
7 plenty of time now for questions for the sponsor. I guess
8 you can identify who specifically of the sponsor team
9 that you're asking or just ask in general and it'll be
10 handled by Doctor Clayton. Questions from the committee
11 members. Doctor D'Agostino.
12 DR. D'AGOSTINO: My comments are dealing
13 with the particular consumer studies and the label
14 comprehension. I'm not sure from the way the
15 presentation is made that these questions I think are
16 profound or needed because we keep hearing that even if
17 the consumer doesn't have the CIU but has some other type
18 of hives and what have you, you still should give
19 antihistamines and so I think a question that ultimately
20 we have to or will get to is how do you handle this whole
21 bag of conditions that antihistamines work for.
22 I'd like to have on the record that I don't
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1 think that the consumer study and the label comprehension
2 study are necessarily powerful studies for the
3 comprehension that is being suggested. I think a 70
4 percent comprehension leaves a lot to be desired and I
5 think that we may say it doesn't make a difference whether
6 the consumer understands a particular condition, he or
7 she still should be taking the drug, but 70 percent with
8 a margin of error of 10 percent is not very large so I'd
9 like to ask the company, the sponsor, to comment on why
10 you're suggesting 70 percent is indicating good
11 comprehension.
12 DR. CLAYTON: I think our intention there
13 was to indicate that we are encouraged that we can get
14 there to the level we would like to achieve. As Steve
15 Neuman mentioned, the principal display panel was broader
16 probably in terms of stating what the product use was.
17 The drugs facts box that I showed you in the next to
18 last slide was a lot more specific. We believe that the
19 labeling can be improved and our standard is higher than
20 the 70 percent, too. We would expect to achieve that.
21 DR. D'AGOSTINO: I have just two other
22 questions and I'll move fast because I know that people
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1 have a lot of questions. With the random sample and the
2 consumer study, you took a random sample and they were
3 supposedly a validation procedure where you rescreened
4 the individual. Could you tell us how many individuals
5 were selected for the random sample and how many out of
6 those didn't actually have the CIU condition on the
7 rescreening in terms of the validation. I'm not sure
8 I heard that number.
9 DR. CLAYTON: Steve, would you please come
10 forward and respond. He's checking his notes.
11 DR. D'AGOSTINO: And my last question, while
12 you're fishing that out, it again may sound naive but
13 if we're saying that these potpourri of conditions can
14 be handled by antihistamines and you're focusing on the
15 CIU, I know it's in the Rx, but why aren't we hearing
16 a presentation for the broader condition? You're telling
17 us that people are using it for broader conditions and
18 it appears to me once it goes OTC, if it goes OTC with
19 this label, physicians are going to be telling patients
20 to use it for the broader array of conditions. Why aren't
21 we hearing the sponsor saying something in defense of
22 that as opposed to that's what you do and it's off label?
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1 Those are my three questions.
2 DR. CLAYTON: I can respond to that one while
3 Steve is preparing. The prescription indication is
4 chronic idiopathic urticaria and that's what led us to
5 do the research that we conducted about the
6 appropriateness for OTC use. So that is the basis for
7 our interest in CIU and that is the research that we've
8 conducted. So that is the area where we are most
9 comfortable that the data support OTC use and indication.
10 I mentioned that there is wide-spread
11 international experience OTC with a broader indication
12 and we are open to continuing to pursue that, discuss
13 that with FDA. It's certainly not a closed door but our
14 research today most strongly supports CIU following an
15 initial physician diagnosis.
16 DR. D'AGOSTINO: Thank you.
17 DR. CLAYTON: Steve I think has the response.
18 MR. NEUMAN: There were 81 individuals who
19 did not suffer CIU at the re-qualification phase.
20 DR. D'AGOSTINO: So about 25 percent of the
21 sample --
22 MR. NEUMAN: The outgo was 834. One hundred
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1 ninety two did not log in. One individual was not 18.
2 Eighty one worked in a sensitive occupation such as
3 marketing research, advertising and so forth. Then 81
4 did not suffer CIU at the re-qualification phase and
5 another logged on after the survey period closed.
6 DR. D'AGOSTINO: So 10 - 20 percent said CIU.
7 MR. NEUMAN: About 20 percent.
8 DR. D'AGOSTINO: Thank you.
9 DR. CANTILENA: Okay, Doctor Krenzelok.
10 DR. KRENZELOK: Thank you. This question
11 is for Doctor Monroe. The literature that we received
12 from the sponsor indicated that urticaria is often an
13 expression of a number of very serious diseases,
14 urticarial vasculitis, thyroid conditions, cancer and
15 so on. I just wondered if chronic use of something like
16 Loratadine would mask the diagnosis of some of these more
17 serious diseases and delay their treatment.
18 DR. MONROE: Approximately 90 to 95 percent
19 of the cases of chronic urticaria are idiopathic so the
20 percentage that have an underlying disease would be very
21 small to begin with and the more serious ones that would
22 concern me the most that are systemic in nature such as
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1 a connective tissue disease or vasculitis, I would say
2 the incidents might be less than one to two percent of
3 the total. Those patients also should have other signs
4 and symptoms. So for example, on the connective tissue
5 diseases, one would expect arthralges, fever, fatigue,
6 other systemic signs. There are in urticarial vasculitis
7 signals such as the lesions persist longer. There are
8 some signs and symptoms that I think would lead those
9 patients to go consult the physician.
10 So I think the concern potentially in that
11 small subset is a delay in getting to the physician but
12 I think the persistence of their condition since the
13 underlying cause for the urticaria is there and the
14 possible accompaniment of these other signs and symptoms
15 would eventually leave them with a mild delay to the
16 physician anyway.
17 DR. CANTILENA: Okay. We have Doctor
18 Szefler and then Doctor Sachs.
19 DR. SZEFLER: Two questions for Doctor
20 Monroe. In treating the disease and also looking at all
21 the review articles that were provided, it was a very
22 nice package. I didn't get any indication that
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1 Loratadine had a specific effect on chronic urticaria.
2 In other words, if a physician was choosing an
3 antihistamine, would they choose Loratadine over the
4 other three drugs? Is there any reason to believe that
5 Loratadine confirms unique features in terms of drug
6 selection? And then also the situation a physician runs
7 into is the necessity of using higher doses to treat the
8 disease. How will the package insert or how do you
9 anticipate physicians will handle the use of higher doses
10 potentially for prolonged periods of time and is there
11 any unique feature that the physician should be concerned
12 about in the OTC application?
13 DR. MONROE: Your first question I think
14 centered on did Loratadine have any unique properties
15 versus you said the other three. You mean the other
16 approved for prescription?
17 DR. SZEFLER: Yes.
18 DR. MONROE: Okay. I believe that the
19 currently available second generation H1 antihistamines
20 are all relatively equally efficacious and the difference
21 lies that at least one of them is sedating. So I think
22 that Loratadine doesn't offer any unique property. It
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1 offers an equally excellent property.
2 The second question I think centered around
3 a concern over exceeding the currently recommended dose
4 and my answer to that would be there are anecdotal stories
5 from patients and certainly use by some physicians
6 exceeding the recommended doses of all the second
7 generation antihistamines. I am not aware of any
8 scientific study to show that doses beyond the approved
9 doses are more effective and, as a matter of fact, in
10 the initial Loratadine approval or clinical studies,
11 doses ranged from 10 to 40 in chronic urticaria and there
12 was no added efficacy beyond the 10. So it does occur
13 in practice. I can't support it from any scientific study
14 and I think that I'm not a labeling expert but one would
15 just deal with it in the labeling like they did for the
16 prescription.
17 DR. SZEFLER: So your suggestion might be
18 in labeling that a preferred route of additional treatment
19 might be to use an additional drug rather than increasing
20 dose.
21 DR. MONROE: I'm not a labeling expert. My
22 recommendation, if they came to my office, would be that
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1 they should see the physician at that point. If the
2 standard of care wasn't sufficient, I think that's where
3 the physician should be involved.
4 DR. CANTILENA: Doctor Sachs and then Doctor
5 Davidoff.
6 DR. SACHS: Hi. You guys look like the label
7 indication is going to go down to age six. From the
8 studies presented today, it sounded like most of the
9 studies were people over 18. The study packet we
10 received, I think the lower age limit was 12. So I was
11 just curious about pediatric data. Unfortunately, in
12 my experience, one of the differential diagnoses of
13 chronic urticaria in children is leukemia and granted,
14 the symptoms would persist and cause a parent to seek
15 help for their child, but I was just curious what the
16 studies in kids were.
17 DR. CLAYTON: I'd like to call on my
18 colleague, Doctor Patricia Rohane, a physician in
19 Schering-Plough, to respond to that question.
20 DR. ROHANE: Yes. Thank you. With respect
21 to the safety data that we have in pediatric subjects,
22 we've conducted three placebo-controlled studies. In
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1 these studies there have been enrolled around 350
2 children. The ages have ranged from six months up to
3 12 years and, as I said, the safety events in these
4 children have been compared to placebo and the adverse
5 event profile has not been different. In other words,
6 the events we saw in the children on the active treatment
7 were the same as; those seen in the placebo groups.
8 DR. CLAYTON: I would also like to mention
9 the syrup product is labeled as approved down to age two
10 and our experience in Canada and the U.K. with OTC
11 products, those products are labeled down to age two
12 including skin allergies as well as allergic rhinitis.
13 So our database of experience includes down to that age
14 group.
15 DR. CANTILENA: Okay, Doctor Davidoff.
16 DR. DAVIDOFF: Yes. I think the studies on
17 the population with pretty well defined CIU are at least
18 moderately reassuring but I think the larger or perhaps
19 the more important question lies with the understanding
20 and behavior of everybody else because 97 percent of the
21 population or more doesn't have CIU and yet this
22 medication would be available to them as are now of course
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1 the more sedating antihistamines. Seems to me that your
2 data rather elegantly demonstrate that before the
3 diagnosis is made the great majority or at least the
4 majority of the population either don't read the labels
5 or they don't understand them or don't believe them
6 because they don't follow them. They use sedating
7 antihistamines now for any itchy condition that they don't
8 understand. So I was rather struck by the minimal amount
9 of data on the general population. Perhaps you could
10 give us some thoughts on whether more data really are
11 needed before we go ahead.
12 DR. CLAYTON: Steve, do you want to comment
13 on the label comprehensive studies that relates to the
14 general population?
15 MR. NEUMAN: Yes. The general population
16 in terms of the label comprehension. Label comprehension
17 was sound on all of the general warnings. It was really
18 in the self-selection area that there was probably one
19 of the largest issues with 30 percent inappropriately
20 selecting the products and, as we indicated earlier, we
21 think that that's not as high as it should be and we would
22 definitely recommend continued work on the label to
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1 improve that level.
2 DR. CLAYTON: As you pointed out certainly,
3 the current practice now is that there is significant
4 off-label use and, as we improve the label, we think we
5 will set a higher standard of education for the general
6 population with labeling that specifically advises on
7 the appropriate use and the appropriate precautions and
8 warning statements.
9 DR. DAVIDOFF: Thank you. Could I ask a
10 brief related follow-up question and that is I was curious
11 about the low literacy population because my
12 understanding is it's somewhere in the range of 15 to
13 25 percent of the population is functionally illiterate
14 and particularly when it comes to medical information.
15 I was curious how you were able to get the low literate
16 population to read the labels.
17 DR. CLAYTON: Steve.
18 MR. NEUMAN: The low literate population was
19 recruited from special sites that have been targeted as
20 places where these individuals can be found at higher
21 proportions in the population. The label was presented
22 to them just as they were in a store potentially looking
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1 at it for purchase and the numbers actually were fairly
2 encouraging among that cohort. They were lower than the
3 general population by a few points but across the board
4 there was relatively good understanding of most of the
5 general warnings.
6 DR. CANTILENA: Okay. Doctor Dykewicz,
7 please.
8 DR. DYKEWICZ: I have several questions and
9 comments. The first would be about the consumer study.
10 As Doctor Monroe has pointed out, one of the concerns
11 historically that would identify potentially a more
12 serious underlying problem might be the symptom of joint
13 complaint. In the consumer study, was there any question
14 that addressed that particular issue?
15 DR. CLAYTON: Steve.
16 As he's coming to the microphone, I would
17 point out that the draft labeling did include a
18 precautionary statement on joint pain to not use the
19 product but seek medical care as far. As the testing
20 is concerned, Steve can respond to that.
21 DR. DYKEWICZ: And as he's approaching the
22 microphone, besides the joint ache question, it would
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1 be how representative the study group was in terms of
2 education versus the general population.
3 DR. CLAYTON: Okay.
4 MR. NEUMAN: I can address both of those
5 questions. There was a question that was asked regarding
6 symptoms that have been experienced and joint pain was
7 experienced by 14 percent of the sample CIU population.
8 There's not a lot of specificity beyond that as to what
9 type of joint pain or the characteristics of that joint
10 pain but 14 percent did experience that.
11 With regard to the Internet and less educated
12 populations, the Internet does under-represent less
13 educated populations to some degree but what we did was
14 we did an analysis where we looked at those who were less
15 educated among our consumer population which was high
16 school and less and compared that to those with a
17 bachelor's degree and higher. What we saw across most
18 of the key questions was that there was really no
19 difference in response.
20 DR. DYKEWICZ: Okay. I guess it still
21 raises the issue in my mind though relative to the joint
22 complaints that that was not something that was focused
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1 on relative to whether this would be a cause for seeking
2 attention of a medical provider.
3 Another question about the label
4 comprehension study. I guess I'm a bit perplexed. On
5 one hand, we see that 30 percent of the respondents gave
6 incorrect answers for self-selection and sponsor I think
7 appropriately is saying that some improvement of the draft
8 labeling would be required. But it also is the position
9 of the sponsor that no additional label comprehension
10 studies would be required in that vein?
11 DR. CLAYTON: No. If that has been the
12 message we've delivered, that is not the correct message.
13 We believe the labeling can be improved and we would
14 test the labeling that we believe would be more
15 appropriate for the market place.
16 DR. DYKEWICZ: Okay. Thank you. And one
17 last comment. The statement which I think is generally
18 correct that chronic urticaria is not associated nor is
19 it a risk factor for anaphylaxis is mostly valid but I
20 would point out I was involved with Northwestern
21 University's series of patients with idiopathic
22 anaphylaxis who did have life-threatening manifestations
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1 at anaphylaxis and looking back historically, about 50
2 percent of the patients in that series did have a
3 pre-existing history of idiopathic urticaria and
4 angioedema. So while I agree that in general for the
5 population the presence of urticaria probably does not
6 identify a significant major risk for development of more
7 severe manifestations including anaphylaxis, there may
8 be certain notable exceptions to that.
9 DR. CANTILENA: Other questions from the
10 committee? Doctor Rosenberg.
11 DR. ROSENBERG: I have questions, not about
12 the presentation we heard but about the written submission
13 from Schering and specifically under Tab 7, confidential
14 physician habits and practices study and specifically
15 on page 24 which is your slide for question 15b. I'd
16 like to ask, I suppose, Doctor Monroe, to comment on it.
17 What this addresses is, of course, if it's not OTC, it's
18 in the hands of the profession and I think I don't know
19 if this is the only time, maybe this afternoon, but we
20 ought to look at what the profession does.
21 A couple of points I wanted to make. One,
22 under primary care practitioners, it's a mix of family
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1 doctors and internists and our experience in a medium
2 size city and a disease that's not so serious and where
3 it's hard to get an appointment with a doctor,
4 particularly a specialist, that much of the urticaria
5 patient population we see have come from a walk-in clinic,
6 a minor, open late hours type store front clinics which
7 some of them are under hospital ownership but which are
8 a feature of medical care in our community and I think
9 were they to have been included, 100 percent of those
10 people got prednisone. They all get prednisone.
11 The line I want to talk about is where
12 systemic steroids are, as I understand the question, the
13 medication most often prescribed by the treating
14 physician and it shows that these primary care internists,
15 pediatricians -- I mean pediatricians, 28 percent choose
16 systemic steroids first . The allergists in my opinion
17 do somewhat better at 22 percent.The primary care people,
18 as I say, 41 percent and if you include the walk-in clinics
19 and emergency rooms, it's 100 percent, and the
20 dermatologists, only 12 percent which I think is certainly
21 the best of those and I want to ask Doctor Monroe, A)
22 which he thinks would be more likely to mask some serious
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1 underlying disease. The use of Loratadine or prednisone.
2 And B) would he comment on the appropriateness of
3 prednisone under most circumstances as a first treatment
4 and would he be more comfortable prescribing prednisone
5 if the patient had first treated themselves with, when
6 available, OTC antihistamine and came in and said I can't
7 sleep despite I take all that stuff. Can you help me?
8 DR. MONROE: Okay. I am not familiar with
9 the section that you're referring to but I think I
10 understand your question and I appreciate the compliment
11 that the dermatologist had the best percentage of not
12 using systemic steroids.
13 I think there is a concern that primary care
14 physicians as well as ER or urgent care physicians tend
15 to turn more, particularly in acute urticaria, to the
16 use of systemic steroids. In a treatment algorithm of
17 what I believe is appropriate therapy, in acute urticaria,
18 I believe that the first choice is the use of the H1
19 antihistamines and the second choice for a severe case
20 would be the use of systemic steroids because you assume
21 you've got a fairly self-limited condition.
22 I'm very reluctant to suggest that systemic
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1 steroids should play a regular part in the treatment of
2 chronic urticaria where I think you have more risk of
3 introducing more serious problems from the treatment than
4 you do from the condition that you're treating.
5 I think systemic steroids have a very
6 possible likelihood of masking the underlying problem
7 but if the underlying problem is there, I'm assuming we're
8 talking about a short course of let's say oral steroids.
9 The steroids will wear off and I think you're again back
10 to the baseline that if you have a persistence of the
11 signs or symptoms of the urticaria or of some other
12 systemic symptoms, the patient should see their
13 physician. I think if a physician gave systemic steroids
14 in an IM form, something which I don't recommend, you
15 might mask it for a longer period but I think you're again
16 back to the situation that if there's an underlying
17 problem, whether it's the antihistamine or the steroid,
18 masking will be very temporary and you're back to
19 hopefully seeing a physician for further evaluation.
20 I hope that answered your question.
21 DR. CLAYTON: Perhaps we're on target with
22 our commitment to an educational campaign that includes
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1 health professionals if we go forward here.
2 Doctor Joad.
3 DR. JOAD: Yes, I have a question follow-up
4 to Doctor Sachs' question which is it's not clear to
5 me that we have a study that shows how well people
6 recognize hives versus non-hives. For instance, how able
7 are people to recognize hives as compared to purpura or
8 something that would be not even hives. So the
9 differential that we've been talking about is a high
10 differential but what about all other ashes that might
11 also be really important to look into? Are there studies
12 like that or is your company considering doing or should
13 your company do it?
14 DR. CLAYTON: I'm not aware -- I don't know
15 whether Doctor Monroe is aware -- of studies that are
16 as you describe. Certainly our experience in the
17 self-recognition study showed a very good correlation
18 of patient and physician recognition or diagnosis, if
19 you will, in this case, of chronic idiopathic urticaria.
20 Doctor Monroe.
21 DR. JOAD: But those patients had that
22 condition.
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1 DR. CLAYTON: That is correct.
2 DR. JOAD: That is not the general
3 population.
4 DR. CLAYTON: That is correct.
5 DR. MONROE: And I think that's one of the
6 reasons why there's a higher comfort level for the chronic
7 idiopathic urticaria indication because those people by
8 definition have usually consulted a physician, understand
9 what they have whereas what you're saying, there could
10 easily be a broader array of confusing dermatologic
11 problems that the layperson might not be able to
12 accurately diagnose. I think that can be addressed, but
13 the comfort level in CIU is that there is a significantly
14 high recognition level. In the broader population, I
15 think that presents more of an issue. I think the point
16 I tried to stress was the situations where that confusion
17 would occur would most likely not result in a serious
18 problem but if somebody had, for example, purpura that
19 you alluded to, I consider that a much more significant
20 issue that would require seeing a physician. Whether
21 the patient or consumer would be comfortable in making
22 that distinction is very debatable.
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1 DR. CLAYTON: On additional point is as we
2 are evolving our labeling, the labeling that was tested,
3 we've tried to put precautionary statements that would
4 steer a consumer to a physician if in fact they don't
5 experience relief within a matter of a few days and, again,
6 as we move forward in refining that labeling, that will
7 be a consideration that we would certainly take.
8 DR. CANTILENA: Doctor Johnson.
9 DR. JOHNSON: I'm wondering if Doctor Monroe
10 can educate me a little bit about angioedema since this
11 might be one of the conditions confused. I guess my
12 confusion is based in part on my general impression of
13 angioedema and there's also a drug under review by
14 cardio-renal that has angioedema as a side effect.
15 There's apparently very, very significant concern,
16 certainly in the community that would use it, if that
17 drug is approved. My understanding is that in most cases
18 the angioedema was not serious and so I guess the
19 presentation here presented angioedema as something that
20 is not serious and yet in other settings it seems to be
21 something that's taken very seriously. So I'm wondering
22 if you can sort of clarify.
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1 DR. MONROE: The vast majority of people who
2 have angioedema who have it in soft tissue areas, let's
3 take the non-laryngio, non-oral, which is the vast
4 majority, I view that as a more visually upsetting but
5 similar process to urticaria. I think the issue with
6 maybe the drug you're alluding to and the medical concern
7 would be angioedema affecting the oral cavity, the larynx
8 so that you might then develop the respiratory compromise
9 and that kind of concern and that I do consider a serious
10 issue. It's a much, much less frequent issue than the
11 general angioedema because I think the studies would
12 indicate that about 40 percent of the patients who have
13 urticaria have concomitant angioedema and maybe another
14 20 percent have urticaria alone and another 20 percent
15 have angioedema alone.
16 So angioedema is not that uncommon of a
17 problem. It's that rare situation when you have, for
18 example, the lorengio edema that causes us concern and
19 that causes me concern as well and that's why I think
20 there was an attempt to state that any symptoms of
21 respiratory distress, wheezing, difficulty of that
22 nature, would have to be appropriately labeled and
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1 patients educated as to the seriousness of that potential.
2 So I think what the concern is on that very
3 small percentage who have angioedema in that anatomical
4 region.
5 DR. JOHNSON: So those people, the 40 or 60
6 percent that have angioedema but not lorengio, they're
7 not at risk for lorengio angioedema?
8 DR. MONROE: The vast majority of people who
9 have angioedema have it in other soft tissue areas that
10 would not be of medical significance and, again, we're
11 not talking about the exceptions like the hereditary
12 angioedema in that either. So the vast majority, I
13 believe it's just concomitant as part of their general
14 urticaria and the treatment would be the same as the
15 general urticaria.
16 DR. CLAYTON: I'd just like to underscore
17 Doctor Monroe's comment about labeling because we do have
18 in our graph labeling any respiratory difficulties as
19 seek emergency medical care. We're certainly sensitive
20 to that possibility.
21 DR. CANTILENA: Doctor Uden, then Doctor
22 Szefler.
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1 DR. UDEN: I'd like to know the incidents
2 of chronic idiopathic urticaria across races and I didn't
3 see any information presented in your documentation about
4 the demographics, racial demographics of your
5 self-recognition study and your label comprehension
6 study. Do you have that information?
7 DR. CLAYTON: Yes. Steve.
8 MR. NEUMAN: As for race and CIU, in the
9 literature that's been reviewed, there is no proclivity
10 for any one race to have or any sort of racial skew toward
11 any group to have CIU.
12 With regard to our studies, the profile of
13 the consumer study did somewhat under-represent
14 non-whites, particularly blacks, but there was a bit of
15 a confusion here in that some of those subjects indicated
16 that they would not respond to the question. So it's
17 a little difficult to determine in that study exactly
18 what the African-American population was.
19 And the label comprehension study, I'll have
20 to look that one up.
21 DR. UDEN: While you're looking that up,
22 could you clarify what you just said about the
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1 African-American population. I didn't understand that.
2 MR. NEUMAN: I'm sorry. About the effort
3 in the Internet study or in --
4 DR. UDEN: You just made a comment about the
5 African American population, that they didn't respond
6 and what study was that?
7 DR. CLAYTON: Oh, that was the consumer
8 study. In the consumer study, there was a relatively
9 low proportion of blacks who were indicated in the
10 demographic profile. However, it was a little confusing
11 because it was like in the four percent range. But there
12 was about six percent, as I recall, who just did not
13 respond to the question at all. So it's difficult to
14 determine what the racial profile of those individuals
15 might have been. So it's hard to say how
16 under-represented it is. Is that clear?
17 DR. UDEN: I'm a little closer but not there
18 yet.
19 MR. NEUMAN: It's not definitive. We have
20 four percent that actually signified African-American.
21 There were six percent that didn't declare. So we can
22 confirm that four percent did say they're
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1 African-American. The other six percent we don't know
2 how it's made up according to race.
3 In the label comprehension study, the white
4 population was 84 percent, black African-American two
5 percent.
6 DR. CANTILENA: Okay. Doctor Szefler and
7 then Doctor Joad.
8 DR. SZEFLER: I'll speak to Doctor Clayton.
9 Much of the discussion this morning and much of the
10 literature that came to us was centered around the product
11 information or the labeling, but another big area of
12 contact with patients is direct patient advertising
13 through television, through magazines. When I looked
14 at your list of consumer health profession education
15 programs, I didn't see this included. I wondered what
16 your thoughts were. Was it intentional not to put these
17 sources and what's your plans for the future in terms
18 of advertising since this is such a confusing issue and
19 since the chronic urticaria is a minor population in terms
20 of the urticaria presentation. How do you plan to
21 interact with the public in terms of these media?
22 DR. CLAYTON: Obviously advertising is not
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1 set so I really can't comment on the composition.
2 Hopefully our advertising would be educational also to
3 help patients clearly understand the appropriate product
4 or if this is an appropriate product for their condition.
5 We think that there's very limited, certainly in the
6 media, the non-print media, it's very limited time element
7 to provide that kind of education. Our better hope would
8 be through print. In the draft, the outline of our
9 educational program that included a number of different
10 vehicles including print along with Internet and other
11 forms or other platforms of communication.
12 But the answer is we have not established
13 that but we certainly understand the importance and value
14 of educating the consumer about this drug and its uses,
15 not just urticaria but also allergic rhinitis.
16 DR. CANTILENA: Doctor Joad.
17 DR. JOAD: For Doctor Monroe. What percent
18 of the patients with chronic idiopathic urticaria are
19 children? I think some of the articles said it was a
20 middle age disease primarily. I'm just trying to get
21 a sense.
22 DR. MONROE: I don't know the answer. The
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1 highest incidents of chronic idiopathic urticaria is in
2 middle aged women and definitely the urticaria we see
3 in the pediatric age group is more commonly the acute,
4 but I don't know the exact number for chronic idiopathic
5 urticaria. It would be small.
6 DR. CANTILENA: Doctor Davidoff.
7 DR. DAVIDOFF: Also a question for Doctor
8 Monroe. It gets back to the issue of potential
9 difficulties or harms that might come from delay in
10 diagnosis because you pointed out that if there is a
11 negative effect of release as over-the-counter drug, it's
12 not likely to be negative in the sense of direct harm
13 from the drug but rather from delay or some non-optimal
14 care pathway.
15 On the other hand, it's also pointed out that
16 there's been no reporting of signals of events that might
17 be red flags that there might be some such problems
18 occurring. On the other hand, it's also known that the
19 under-reporting problem is enormous, even for direct
20 harms from drugs. So what I'd like to ask you to do is
21 to give us your best estimate. What would be found if
22 reporting of delays and the potential harms that came
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1 from them were perfect? What would you speculate would
2 be the kinds of harms and less than optimal care that
3 might result from such delays, both in the CIU population
4 and perhaps in the more general population?
5 DR. MONROE: In the CIU population, I'm
6 making the assumption that they have seen a physician
7 to get that diagnosis, so I don't see any added harm.
8 Obviously there are some people that we would diagnose
9 as CIU that as time evolves maybe we come up with an answer
10 for an underlying reason. So I don't think that changes
11 the CIU scenario.
12 In the general population, I tried to give
13 a quick overview. I think there are situations with some
14 very common conditions. The acute urticaria that may
15 be confused. I think that in that situation the treatment
16 is what the physician would have prescribed anyway except
17 that we're introducing a safer treatment than the OTC.
18 I think in the common dermatologic conditions that are
19 not urticaria, the dermatoses, I think the patient is
20 not necessarily capable of distinguishing an itchy rash.
21 For physicians in the room, we often get calls, I have
22 a rash, what can you prescribe? And I say there are a
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1 million different rashes. So I think that's a problem.
2 Fortunately, I believe most of those rashes don't present
3 a serious consequence if there's a delay. There may be
4 a quality of life consequence that they have a few extra
5 days or weeks of less than the appropriate therapy.
6 I think there would be the rare rash, if
7 there's purpura or some severe vesicular bullous disease
8 that the patient would not be able to identify, but I
9 think those would be extremely infrequent. So I think
10 in general my message would be that there would be delays
11 of inappropriate diagnosis and treatment but I don't think
12 they would be causing harm.
13 DR. CANTILENA: Any other questions?
14 Doctor Wood.
15 DR. WOOD: It seems to me that we heard a
16 fair amount of data that patients with CIU can diagnose
17 it probably and treat the condition on their own. The
18 issue though that's still unclear to me at least whether
19 patients who don't have CIU and might be using
20 antihistamines even now incorrectly and I'm surprised
21 there's no data to really address that because you've
22 really sort of addressed, kind of answered the question
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1 before you've done the study almost the way it's designed
2 right now, it seems to me. I was pondering here about
3 how one would do that study.
4 I guess one way to address that would be to
5 look at patients who are using currently over-the-counter
6 antihistamines and see what the conditions they're
7 treating are with them. I'm not sure what conclusion
8 you'd necessarily draw from that but that would certainly
9 be educational in terms of trying to more appropriately
10 steer patients to the right therapy.
11 DR. CLAYTON: The only comment I could offer
12 is to your point. I think there is widespread use of
13 over-the-counter antihistamines for those conditions now
14 and, as we've learned in our research, particularly with
15 acute urticaria, most patients don't seek physician care
16 anyway. So it's not a good answer. I don't think that
17 the data exists. Just observations.
18 DR. CANTILENA: Okay. Thank you. Any
19 other questions from the committee for the sponsor?
20 Doctor D'Agostino.
21 DR. D'AGOSTINO: The consumer study and the
22 physician was done by the Internet. Is this sort of a
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1 wave to do them by Internet? I mean you leave out a whole
2 class of individuals who can't participate because
3 they're still illiterate computer-wise.
4 MR. NEUMAN: Yes, it is actually a wave and,
5 in fact, most of the major purveyors of research services
6 have instituted Internet divisions. About 60 percent
7 of the population is on the Internet now and I think that
8 there is an opportunity to see that grow over the next
9 several years.
10 DR. D'AGOSTINO: We all have personal
11 experiences. I have a few experiences where the Internet
12 connection collapsed so I'm not so sure that it's a wave
13 of the future that is completely solid. Aren't you
14 concerned that you're leaving out whole segments of the
15 population, there's still a 40 percent, who take drugs?
16 MR. NEUMAN: Well, actually, there are --
17 as you well may know -- there are issues with nearly every
18 research method. Telephone studies have their issues
19 of non-response and mall intercepts have issues of
20 socio-economic skews, the Internet has some issues as
21 well. So it's, I guess, a little bit of pick your poison.
22
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1 DR. D'AGOSTINO: The label comprehension was
2 an all comer study. Could you just remind me how you
3 recruited that sample.
4 MR. NEUMAN: Yes. It was recruited through
5 malls.
6 DR. D'AGOSTINO: Through malls. Thank you.
7 DR. CLAYTON: And to your point, Doctor
8 D'Agostino, obviously the most critical study, the label
9 comprehension study, is the old fashioned way.
10 Individual contact, not through Internet.
11 DR. D'AGOSTINO: Not necessarily the best
12 but at least --
13 DR. CLAYTON: Accepted.
14 DR. D'AGOSTINO: -- you hope to see
15 everybody.
16 MR. NEUMAN: One other point though. The
17 CIU population was recruited through advertising in the
18 papers.
19 DR. CANTILENA: Okay. And our final
20 question from Doctor Gilliam.
21 DR. GILLIAM: Getting back to Doctor Uden's
22 question about other populations that were surveyed for
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1 the label comprehension. How about Hispanic
2 populations? Spanish labeling. Anything done in that
3 area?
4 DR. CLAYTON: No. Nothing has been done to
5 this point in that area.
6 DR. CANTILENA: Okay. I wish to thank the
7 sponsor and the committee for their questions. We will
8 now take a 30 minute break and report back at 10:30 for
9 the FDA presentation.
10 (Off the record at 9:57 for a 33 minute
11 break.)
12 DR. CANTILENA: The next section of the
13 agenda deals with the presentation by the Food and Drug
14 Administration. The lead-off speaker for the FDA will
15 be Doctor Jonathan Wilkin and then he will introduce the
16 subsequent FDA speakers. Doctor Wilkin.
17 DR. WILKIN: Thank you, Doctor Cantilena.
18 Members of the Advisory Committee, I will
19 give some brief comments, much briefer than what I had
20 originally planned after the very nice presentation of
21 Doctor Monroe and his colleagues.
22 Doctor Monroe has seen this slide before.
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1 I've nominally plagiarized it for today but actually he
2 published this in 1977 with Earl Jones, and I've used
3 it since 1978 to the present at least 15 times to give
4 the conceptual architecture of urticaria to sophomore
5 medical students and, of course, the residents in our
6 training program. Basically, the very nice piece is
7 we've got the immunologic factors that act on the mast
8 cell or basophil and the non-immunologic factors that
9 connect on the mast cell or basophil. So a wide variety
10 of etiologies, different causes that can act on the mast
11 cell. And then there are some modulating factors, those
12 things which can either act on the mast cell itself or
13 can act on the small blood vessels to increase the diameter
14 and potentiate the effect of the released mediators.
15 But at any rate, the mast cell has only one
16 basic trick. It releases this vesicle exocytotically,
17 release mediators, histamine is the principal one, and
18 it acts on the small blood vessels and the upper skin
19 to produce urticaria.
20 This is another slide plagiarized from Doctor
21 Monroe. What I did in the medical school classes was
22 I started out with just the membrane receptors and then
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1 I added the intracellular cyclic nucleotide story and
2 I kept adding different intracellular processes until
3 finally at the end the microtubials and the microfilaments
4 steered these vesicles containing hepron and the
5 histamine and all of the other vaso goodies to the surface
6 and then the exocytotic release into the extracellular
7 area.
8 Where this happens in the skin -- this is
9 Frank Netter's nice drawing of the skin and up here at
10 the top you can see arranged in layers like baklava the
11 epidermis and then from here down to here is the dermis.
12 Here's the subcutaneous fat, the butter, and it's in
13 this very upper layer here where there's a superficial
14 vascular plexus and that's where the mast cells release
15 the histamine that leads to the urticaria.
16 We'll see the two plexus because there's
17 another plexus that's down deep in the next slide so that
18 for the typical urticarial kind of lesion, it's going
19 to be leakage in the superficial vascular plexus. That's
20 where the histamine is released and acts on these vessels.
21 For angioedema it's going to be the vasculature that
22 is in the superficial subcutaneous tissue and the very
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1 lower dermis at that interface. But they are very similar
2 processes. One of the key differences is that the nerve
3 endings, the C fibers, the itch fibers, are predominantly
4 located up in these finger-like extensions up into the
5 epidermis, the dermal papillae. So hives itch a lot more
6 than the angioedema kind of lesions that will form deeper.
7 This is looking at one of those finger-like
8 projections up into the epidermis. Here's the arteriolar
9 part of the superficial vascular plexus and it goes up
10 through the arteriolar side of this capillary loop and
11 finally back down on the venular side of the capillary
12 loops to the post-capillary venial and this is the site
13 right here that really is where histamine acts and the
14 endothelial cells pull apart and the fluid leaks out.
15 That is where the urticarial lesion really occurs. And
16 so it's a very superficial kind of leakage of fluid, so
17 superficial that it puffs up and you can actually run
18 your finger over lesions of urticaria and at the edge
19 you can find that it'll actually lift up to this flat
20 kind of surface.
21 Over a few hours time, the edges of the
22 typical urticarial lesion will migrate and so they're
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1 not fixed kind of lesions.
2 These are the smaller, average size
3 urticarial lesions. Sometimes they can be really large.
4 They're not necessarily angioedema. Angioedema, when
5 you put your hand on the skin, it feels like wood. I
6 mean it's really got a thick indurated kind of quality
7 to it.
8 So the key piece is that there are literally
9 hundreds of causes of urticaria and they either act
10 directly or through the immune system to cause mast cell
11 mediator release which then these mediators are released
12 in the area of the small blood vessels and principally
13 histamine leads to the itching and the edema, the fluid
14 leakage.
15 But there's also another way of looking at
16 urticaria, the heuristic or clinical ways of looking at
17 it. This is very similar to the industry's presentation
18 because I think most physicians use the same system.
19 Acute urticaria is less than six weeks in duration, has
20 an incredibly good prognosis. Most of it is actually
21 gone by six weeks. It's only down in the five percent
22 range that extends beyond. History implicates the cause
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1 in approximately half of the patients. If they come to
2 the emergency room or to the dermatology clinic, they're
3 seeking symptomatic care but very often they know what
4 the inciting event was.
5 I think it would be very difficult to study
6 acute urticaria in clinical trials just because you would
7 almost have to know who's at risk for developing acute
8 urticaria before they actually developed it and since
9 it has such a great prognosis and may only last a week
10 or two, it would be hard to get these people in in time
11 to actually give them medication and monitor them for
12 any length of time to get a signal. So very difficult
13 to study in clinical trials.
14 There's a distinction between chronic
15 urticaria and chronic idiopathic urticaria. Chronic
16 urticaria means greater than six weeks. A work-up is
17 indicated because perhaps five to 10 percent of those
18 patients will have a definable cause that can be detected
19 in the office of the allergist or the dermatologist.
20 These would be much easier to study in clinical studies
21 because often they are persistent. So you can give them
22 medication for a period of time and they're not likely
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1 to have a spontaneous remission.
2 The distinction between chronic urticaria
3 and chronic idiopathic urticaria means that someone
4 really looked in a sensible way to see if there is a cause
5 and they couldn't find it and so then you can add the
6 word idiopathic. But it's the subset of chronic
7 urticaria in which a good work-up fails to pinpoint the
8 cause. It's a diagnosis by exclusion and obviously it's
9 not homogeneous. There's still a lot of different types
10 of causes. Some of them are going to be direct mast cell
11 mediators. Some are going to be through the immune system
12 of causes of chronic idiopathic urticaria.
13 Again I borrowed this one from Doctor Monroe.
14 This is his schema for treating and managing acute
15 urticaria. For the mild and moderate types, he
16 recommends non-sedating H1 antihistamines. I think
17 generally that's the approach most physicians take. So
18 the kind of medication we're talking about today is
19 actually the first choice for most patients who have acute
20 urticaria.
21 So observations. Urticaria really is not
22 a single disease. It's a reaction pattern mediated by
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1 histamine release in the superficial skin. Acute
2 urticaria and chronic urticaria are not single diseases.
3 They're useful for clinical decision making. Most
4 urticaria will respond to an antihistamine which is found
5 safe and effective in patients in chronic idiopathic
6 urticaria.
7 There are some caveats when thinking about
8 what an OTC label might look like. I think that some
9 of the things that we've already heard discussed. The
10 OTC consumer could be informed. I think there are some
11 varieties of urticaria that are more likely to get
12 patients into trouble, not because they might be taking
13 this medication but because they might not be seeking
14 the intervention of a physician early on. In fact, for
15 all of these conditions, I'm not sure but what they might
16 actually get a medication like this as part of the therapy.
17 It's just that they need some additional evaluations.
18 The first kind of urticaria. I think if the
19 patient believes that it's possibly related to peanut
20 or latex allergy because that can ultimately -- the second
21 time around, there may be anaphylaxis. I think that would
22 be a subset that they ought to go and see a physician
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1 early on. Persisting beyond six weeks. Again, that's
2 the group where the work-up is indicated and where perhaps
3 up to 10 percent of patients you can actually find an
4 identifiable cause. Often it's something that they can
5 eliminate so that they will not have the continuing
6 urticaria. Or they may have some underlying disease
7 that's leading to the urticaria and the work-up will
8 detect that.
9 There is a condition called urticarial
10 vasculitis. One of the features in urticarial vasculitis
11 is the lesion. Unlike usual urticaria, it doesn't really
12 migrate. The edges stay in the same place. You could
13 take a skin marker or a fountain pen or something and
14 draw a ring around where the urticarial lesion is and
15 it will be there 24 hours later. That's not what
16 urticaria usually does. I don't think that point
17 probably would translate in an OTC labeling but because
18 these generally leave a bruising or pigmentation
19 post-inflammatory pigmentary changes, I think that might
20 be something that would get these patients alerted that
21 they need medical help.
22 Also, when there's something beyond the
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1 urticaria that also involves the skin. Blistering is
2 one or again the bruising part. It could be part of the
3 vasculitis or bullous penfogoid.
4 Serum sickness. Like reactions can have
5 urticaria as some of the features and the connective
6 tissue diseases. But if we had something on labeling
7 that would say something about fever, joint pain, just
8 feeling unwell, systemic features in general, that if
9 that accompanies the urticaria, then it's important to
10 seek medical help. Any urticaria that's poorly
11 responsive to oral antihistamines also ought to be checked
12 out by a physician and then that variety of angioedema,
13 not the kind that occurs on the arms and the legs and
14 perhaps the skin over the trunk. But if there's swelling
15 of the lips, tongue or throat, again that can be a very
16 worrisome prognostic feature and they should be also seen
17 by a physician.
18 And then the urticaria which looks like
19 urticaria but it doesn't itch and those may be the
20 infiltrates into the skin of a leukemic process or there
21 are some varieties of urticaria that don't itch so much,
22 the delayed physical kinds of urticaria, and
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1 antihistamines don't work really great and so that really
2 means that if it doesn't itch, patient really should see
3 a physician.
4 Some of these statements I've taken from the
5 sponsor's briefing package, modified them a little.
6 Urticarial lesions are generally easy to recognize since
7 they typically occur in visible locations and are
8 associated with intense itching. That's on page seven
9 of sponsor's briefing document. I think that's true.
10 I've seen a lot of patients with urticaria and they
11 generally come in and say I've got hives, doc. What can
12 we do?
13 I would also agree with a second point that
14 they made and this is found on page 18 in the sponsor's
15 briefing document except I added the word sedating in
16 here because I think that's part of the context in which
17 one must think about this. It is likely that acute hive
18 sufferers are already using sedating OTC antihistamines.
19 And so I think this is an opportunity, if this goes
20 over-the-counter for hives, it's an opportunity to put
21 some things in labeling that will direct patients to
22 physicians for some conditions that might be confused
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1 with or associated with hives and actually it could be
2 better than the current situation which is they're just
3 using it but they're not getting that message.
4 And then I think the core piece in Doctor
5 Monroe's message and I think throughout the literature
6 is that the hive and the associated itching of almost
7 all urticaria is mediated by histamine and so one would
8 anticipate that for almost all varieties of urticaria,
9 an H1 non-sedating antihistamine is going to provide
10 patient relief. And so I think that it would be possible
11 with proper labeling but I think that's really the key
12 thing is how does one get some of these extra conditions
13 in there and explain them to an OTC consumer. It just
14 may be that the hives could be the preferable OTC
15 indication.
16 The next speaker is Doctor Chowdhury.
17 DR. CHOWDHURY: Thank you. Good morning,
18 members of the Advisory Committee. I will be talking
19 about the clinical development program that the various
20 companies have done that has resulted in the indication
21 for H1 antihistamines for chronic idiopathic urticaria.
22 The antihistamines that I'll be covering are the newer
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1 ones which includes Loratadine, Desloratadine,
2 Cetirizine and Fexofenadine.
3 In your briefing package you have
4 Desloratadine medical officer review as an example, an
5 example only, of a recent development program for an
6 antihistamine that has the CIU indication.
7 I will be talking initially very briefly
8 about urticaria in general and then in a very global sense
9 about the clinical development program for antihistamines
10 for urticaria. Then I'll be talking about specifically
11 clinical programs for antihistamines elaborating more
12 on Loratadine which is a point of discussion and touching
13 on the other antihistamines. And then I'll have some
14 summary remarks.
15 As we heard before, urticaria is classified
16 as acute and chronic -- duration, the cut-off being six
17 weeks. One thing to keep in consideration which we also
18 heard before that acute urticaria can occur as an early
19 manifestation of anaphylaxis. Urticaria, in addition,
20 can also be intermittent which is in between acute and
21 chronic. Patients have urticaria lasting for days and
22 weeks with intervals which is pretty long in terms of
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1 days, weeks or months.
2 In addition, there can be urticaria where
3 the causes are known, some of the examples being physical
4 urticarias, cholinergic urticarias and so on. As you
5 heard before, the clinical development program the
6 companies have focused on CIU because these patients have
7 recurrent hives and are expected to have recurrent hives
8 during the clinical trials, therefore, can be studied.
9 The patients with clinical hives have
10 repeated dermal mast cell degeneration -- antihistamine
11 and other mediators and these cause the typical wheals
12 or the -- lesions. It can occur anywhere on the skin.
13 There are varieties of sizes and shapes and they're paler
14 in the center with redness in the surrounding area and
15 the individual wheals last for a short duration and
16 there's entrance itching around the wheals and there is
17 often -- redness of the skin. These are the features
18 that are used in evaluating efficacy end points for
19 patient evaluation in the clinical urticaria trials which
20 I'll go into later on.
21 For the CIU indication, the FDA requires
22 evidence of efficacy from at least two clinical studies
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1 including exploration of the proper dose and
2 demonstration of the safety of the proposed dose. The
3 pivotal efficacy studies are randomized, multi-center,
4 double-blinded, placebo-controlled and often they are
5 active-controlled. Most of the pivotal efficacy studies
6 are four to six weeks in duration. In addition, the
7 safety of the proposed dose must be demonstrated.
8 In addition to the pivotal efficacy studies,
9 the companies often does what is called a wheal and flare
10 study. These are pharmacodynamic studies where small
11 amount of antihistamine is injected under the skin to
12 cause an artificial urticarial-like lesion and histaminic
13 effect is tested on those lesions. These are peer
14 pharmacodynamic studies and are not taken as reflective
15 of evidence for an antihistamine effect or for an evidence
16 of efficacy for urticaria.
17 The patients enrolled in the CIU studies are
18 generally adults. In various studies, they have been
19 12 years or older. In others, 18 years and older. And
20 they're free of clinically significant diseases.
21 Pediatric indications for urticaria are usually given
22 by -- based on pharmacodynamic program. The diagnosis
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1 of CIU is based clinically and patients with other causes
2 of urticaria, which we have heard about before such as
3 the physical urticarias, urticarias from known causes
4 like insect sting, drugs and so on, urticarias associated
5 with underlying disease or patients with angioedema are
6 excluded from all of the studies.
7 Also important differentials which are
8 listed in the slides are also looked at by the physician
9 and those patients are excluded.
10 On entry, the patients are expected to be
11 symptomatic so that an efficacy can be seen during the
12 clinical trials. Typically in various studies, that has
13 meant the patients should have a flare lasting for at
14 least three weeks in some studies or six weeks in other
15 studies and on entry they have symptoms lasting for two
16 days per week or three days per week or approximately
17 50 percent of the days.
18 The patients on entry were required to have
19 some response to antihistamine in the past and on entry
20 they were required to have high symptoms cause.
21 Typically, two or above on a scale of zero to three, three
22 being higher. Medications that can confound the disease
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1 or evaluation of the efficacy end points were excluded.
2 The primary efficacy variables for these
3 urticarial studies are based on patient symptoms which
4 are basically pruritus and hives. The symptoms in the
5 older studies were recorded by physicians. Currently
6 we prefer patient recording. The recordings are done
7 either instantaneously which means how the patient felt
8 at the time of recording or reflective which means how
9 they felt for the previous 12 hours or so. The recordings
10 were done either once a day or twice a day.
11 The typical efficacy end points has been
12 pruritus severity, number of hives, size of largest hives
13 on a scale of zero to three which are explained here,
14 typically zero being less symptomatic, three being more
15 symptomatic.
16 In the studies, -- secondary end points.
17 For example, arrhythmic severity, overall condition,
18 overall therapeutic response and so on.
19 A safety assessment for the antihistamines
20 for CIU indication usually has not been a question because
21 the urticarial indications were secondary after the
22 antihistamines has been studied for allergic rhinitis
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1 and the dose for allergic rhinitis and the dose for
2 urticaria for the currently marketed newer antihistamines
3 are the same. However, to look for disease/drug
4 interactions in these pivotal studies, adverse events,
5 clinical laboratory and ECGs were looked at and all the
6 antihistamines, the newer ones on the market, are safe
7 and effective for urticaria.
8 Now I would like to spend the rest of my talk
9 talking about clinical programs. My focus again will
10 be on Loratadine which is the point of discussion today.
11 I will show the clinical studies and some of the results
12 that we have. I'll very briefly touch on the design
13 issues on the other three antihistamines and I will not
14 show any data on these.
15 The Loratadine clinical program had two
16 pivotal studies, 67 and 44. Both were placebo-controlled
17 and one study was active-controlled. In addition, there
18 were a couple of supporting studies. One study, 56, was
19 a small dose-ranging study. I showed the design and
20 results of Studies 56, 44 and 67.
21 The dose-ranging study, Study 56, was a small
22 study conducted in adult patients with CIU. The study
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1 was placebo-controlled and active-controlled with one
2 day of baseline followed by seven days of double blind
3 treatment. The treatment arms were Loratadine 10 mg,
4 20 mg or 40 mg. The active treatment was hydroxyzine
5 and there was also placebo arm.
6 On entry, the patients were quite
7 symptomatic. For example, the scores for pruritus,
8 erythema, number of hives and size of largest hives were
9 all around two in a scale of zero to three. Here are
10 the results for pruritus, erythema, number of hives, and
11 size of largest hive scores. On the vertical axis, it
12 is percentage change from baseline for all the variables.
13 In the horizontal axis, the first three bars are the
14 three doses of Loratadine 10 mg, 20 mg, 40 mg. The fourth
15 bar is the active control hydroxyzine and the last bar
16 is placebo.
17 As is seen from the slides, for all the
18 efficacy end points, all doses of Loratadine were
19 numerically -- to placebo, was also comparable to
20 hydroxyzine and there was no definite dose response.
21 The company took Loratadine 10 mg dose for further
22 development through two pivotal studies. One of the
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1 pivotal studies was Study 44. This was a seven-center
2 U.S. study, again conducted on adult CIU patients. It
3 was placebo-controlled with one day baseline and 28 days
4 double-blind treatment.
5 On entry, the patients were again quite
6 symptomatic with the scores being two or around two for
7 all the end points on a scale of zero to three. The
8 treatment was Loratadine 10 mg compared to placebo and
9 the symptoms here were scored by investigators and a
10 primary efficacy end point was not defined.
11 The four end points which I showed earlier
12 are shown here again and on the horizontal axis now it
13 is the weeks, weeks one, two, three and four. The small
14 asterisks here denote significance versus placebo at a
15 level of P4, 5 or less.
16 For pruritus and other scores, the active
17 treatment, which is Loratadine 10 mg, was numerically
18 and for most of the time statistically superior to
19 placebo.
20 The second study, Study 67, was again a
21 seven-center study conducted in adult patients. Again,
22 on entry the patients were symptomatic. The study had
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1 one day baseline followed by 28 days of double-blind
2 treatment and this was an active control study. The
3 comparator was hydroxyzine 25 mg three times a day. The
4 primary efficacy end point in this study was measured
5 or assessed by patients and the end point was defined
6 as day seven change compared to baseline. This is the
7 primary end point which is the pruritus curve. I'm
8 showing here day seven which is week one and other time
9 points. At the primary end point, which is the day seven,
10 both the drugs were almost super-imposable and they were
11 both secreted to placebo. Over time, the separation of
12 placebo was maintained. However, hydroxyzine
13 numerically tended to be better than Loratadine.
14 An important secondary end point is change
15 in the number of hives and, again, the active treatments
16 were -- placebo although there was no -- significant
17 differences here.
18 The Loratadine clinical program that you have
19 the medical officer review in your briefing book had two
20 pivotal studies. The designs were very similar to the
21 Loratadine program except that these studies lasted a
22 bit longer, for six weeks. These two studies were
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1 adequate to support approval for these drugs for
2 Loratadine for CIU indication. Also, there was a -- study
3 which was pharmacodynamic study.
4 The Cetirizine program also had two pivotal
5 studies. They were both placebo-controlled. One study
6 was a fixed dose ranging study where multiple doses of
7 Cetirizine were compared to placebo. The second study
8 allowed for dose titration where patients were allowed
9 to increase the dose based on physician's supervision.
10 In addition, the two supporting studies which looked
11 at patients who had idiopathic dry skin pruritus which
12 was meant to indicate the patients did not necessarily
13 have an allergic -- and these studies were not generally
14 supportive of efficacy so Cetirizine currently has the
15 indication of CIU like other antihistamines.
16 The Fexofenadine program also had two pivotal
17 studies. They were both four week studies and in both
18 the studies dose effects of Fexofenadine ranging from
19 20 mg to 240 mg twice a day was explored. All the doses
20 of Fexofenadine were -- to placebo and there was no dose
21 response beyond 60 mg bid doses. Based on these two
22 studies, Fexofenadine is currently approved for CIU.
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1 In the prescription world right now, the
2 newer antihistamines that have the indication for CIU
3 symptom control are the four that I went through very
4 briefly. These are Cetirizine, Desloratadine,
5 Fexofenadine, and Loratadine. The indication states
6 treatment of CIU symptoms.
7 The older antihistamines, which are often
8 called first generation, also has some approvals for
9 urticaria or urticaria-like symptoms. For example, the
10 combination product which is antihistamines and Extendryl
11 hydroxyzine, cyproheptadine and promethazine has
12 indications which states, might complicate uncomplicated
13 allergic manifestations of urticaria or angioedema or
14 both. Specific language varies slightly for the
15 different drugs.
16 Currently in the over-the-counter situation,
17 there are no drug products that are approved for the
18 treatment of CIU, urticaria of other forms or itching
19 due to hives.
20 Based on the clinical studies submitted to
21 the FDA for the NDA and subsequent post-marketing -- the
22 currently available newer antihistamines are safe and
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1 effective for treatment of CIU symptoms. Of the various
2 types of CIUs or urticaria I should call it myself, are
3 the various types of urticaria. In the clinical trials,
4 CIU was studied because, for reasons we explained earlier
5 on, CIU is amenable because the patients are symptomatic
6 and the disease -- to be studied in -- clinical trials.
7 Generally, if antihistamine is found to be efficacious
8 for CIU, it is possibly reflective of efficacy in
9 urticaria for the times and in clinical practice, actually
10 that's the way the antihistamines are used, not
11 necessarily limited for CIU.
12 One has to keep in mind if H1 antihistamines
13 are marketed OTC, they're likely to be used for all types
14 of urticaria including acute urticaria which may or may
15 not be often a manifestation of anaphylactic reactions.
16 Thank you.
17 The next speaker is Doctor Ganley.
18 DR. CANTILENA: Actually, I think it's
19 Doctor Holman.
20 DR. HOLMAN: Good morning. My name is
21 Matthew Holman and I'm an interdisciplinary scientist
22 in the Division of Over-the-Counter Drug Products at the
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1 FDA. Today I'll be talking about U.S. regulations,
2 foreign marketing, and label comprehension studies
3 conducted by the sponsor.
4 As indicated by the title of my talk, my talk
5 will be divided into three sections. First, I'll talk
6 about U.S. regulations regarding OTC antihistamines and
7 specifically with regard to the CIU or hives indication.
8 I will then look at a specific antihistamine, that is
9 Loratadine, and look at its marketing around the world
10 and then lastly I will just briefly highlight some key
11 points to the label comprehension study conducted by the
12 sponsor followed by a summary of my presentation.
13 As Doctor Chowdhury mentioned, there are two
14 routes that a drug going OTC can go by. The first is an
15 NDA which is product-specific and sponsor-specific. The
16 second route is the monograph which is
17 ingredient-specific. As Doctor Chowdhury mentioned,
18 there are currently no approved OTC oral antihistamines
19 with a CIU or hives indication. Therefore, I'm not going
20 to discuss the NDA route but rather I'm going to focus
21 on the monograph system.
22 The monograph system is a three step process
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1 open to the public. The first step is the advance notice
2 of proposed rule making or the ANPR. This contains the
3 Advisory Panel report and this is published to notify
4 the public of the agency's intentions regarding specific
5 ingredients and indications and is to request comments
6 from the public.
7 The second step is a tentative final
8 monograph. Based upon comments received from the ANPR,
9 the agency publishes a TFM containing a proposed rule
10 making and it requests comments from the public.
11 The last step is the final monograph. This
12 is again based on comments from the TFM. The agency
13 develops final regulations regarding specific products
14 and ingredients and publishes these. Once the final
15 monograph is effective, any ingredient within that final
16 monograph can be marketed without prior approval from
17 the FDA as long as regulations are followed.
18 Now that I've given you a general description
19 of the monograph process, let's look specifically at how
20 this has to do with OTC or antihistamines. About 25 years
21 ago, the ANPR was published and this was published for
22 a pretty broad category of cold, cough, allergy,
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1 bronchodilator and anti-asthmatic drug products of which
2 antihistamines were part of. Again, the Advisory Panel
3 report was published. In that report, which again covers
4 this entire drug category, there was no mention of CIU
5 or hives.
6 A few years later, the Tentative Final
7 Monograph was issued and, rather than describe this whole
8 entire drug category, the Tentative Final Monograph in
9 this case referred specifically to OTC antihistamine drug
10 products. In the TFM there was one comment referring
11 to hives that requested indication of hives. However,
12 there is no data submitted and, as I mentioned, the panel
13 did not report on hives. Therefore, the agency declined
14 this request.
15 There was a final monograph issued shortly
16 after TFM and, again, the final monograph was specific
17 for the OTC antihistamines. In this, there were two
18 comments relating to CIU or hives. The first comment
19 requested symptomatic treatment of allergic itching.
20 This comment was subsequently withdrawn, so the agency
21 did not respond.
22 The second comment referenced the
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1 literature, data in the literature that supported relief
2 of itching skin caused by, among other things, hives.
3 The agency did not agree with this comment based upon
4 primarily three points. The first is that hives are a
5 component of anaphylactic reaction. The second and
6 related point is that the average person can not
7 distinguish between mild and life threatening conditions
8 with similar symptoms, i.e., hives.
9 And the last point was that one of the
10 references cited by this comment stated that the ideal
11 treatment for urticaria was identification and removal
12 of the cause. The agency agreed with this comment and,
13 therefore, did not allow this indication.
14 Now that we've discussed a little bit about
15 the marketing of OTC oral antihistamines within the U.S.,
16 I'd like to focus our attention outside the U.S. by
17 focusing on the marketing of Loratadine. I'll give you
18 a brief picture of the marketing of this drug outside
19 the U.S. It is prescription medication in approximately
20 80 countries. It's prescription-free in 33 countries.
21 However, of those 33 countries, only 29 of those
22 countries allow a hives or CIU indication.
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1 I'll further define this by letting you know
2 that of those 29 countries, 22 of the countries sell this
3 product behind the counter. That is, it has to be
4 purchased at a pharmacy through a pharmacist. However,
5 no prescription is required.
6 The other seven countries sell this drug,
7 market this drug over the counter. Again, similar to
8 the U.S., Loratadine can be purchased in these seven
9 countries without a prescription, without a pharmacist
10 intervention from a variety of sources such as gas
11 stations, convenience stores.
12 Rather than talk about all these countries,
13 I'm going to focus just on two of those and those are
14 Canada and the United Kingdom and hopefully give you a
15 flavor for how this drug is marketed in these two countries
16 and around the world.
17 First, let's take a look at Canada.
18 Loratadine has been marketed in Canada since about 1990.
19 It has always been marketed over the counter in this
20 country, never behind the counter, and it's never required
21 a prescription. In Canada, it's allowed two indications
22 and those are allergic rhinitis and hives.
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1 Now let's just take a look at again just one
2 example of the labeling used in Canada for Loratadine.
3 The labels I've shown here are for a 10 mg tablet. You
4 can see on the left there's a product labeled for allergy.
5 Again, 10 mg tablet. There's no mention on the front
6 panel or the rear back panel of CIU or hives. However,
7 on the right you can see that there's again, the 10 mg
8 tablet labeled for skin itch. In this case, the front
9 label reads, fast relief from skin allergic conditions,
10 bullet, skin itch, bullet, hives.
11 Now let's take a look at United Kingdom.
12 In the United Kingdom, Loratadine was initially marketed
13 in the pharmacy class. This corresponds to behind the
14 counter meaning a prescription was not required but it
15 had to be purchased through the pharmacist. However,
16 about four months ago in December, Loratadine was switched
17 to general sales list. This again equates to OTC meaning
18 that it can now be purchased directly by consumers without
19 a pharmacist intervention.
20 Just an interesting note that in the United
21 Kingdom, once the switch to GSL was made, the packaging
22 was limited to seven tablets or a seven day supply.
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1 Again, like Canada, the two indications are allergic
2 rhinitis and hives.
3 The last point I'd like to make is that in
4 the United Kingdom there's only one other oral
5 antihistamine which is on the GSL list and that is
6 Ceterizine and, again, this was switched back in December.
7 Again, I'd like to just show you an example of some of
8 the labeling in United Kingdom. This label here is
9 labeled allergy tablets for hay fever or other allergies.
10 I've blown up a statement on the back panel that refers
11 to hives or CIU and that reads, "Claritin Allergy may
12 also be taken for allergic skin conditions including rash,
13 itching and urticaria (hives)."
14 Now that I've talked a little bit about these
15 two countries, I'd like to step back and sort of summarize
16 the labeling around the world. Rather than look at all
17 29 prescription-free countries, we reviewed labelings
18 from 19 of these countries including six of the seven
19 OTC countries. I've sort of just summarized the labeling
20 and references to CIU or hives in these countries.
21 Only one of the 19 countries was CIU
22 completely indicated on the label and that label read,
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1 "Chronic urticaria of an unknown source." However, in
2 12 countries the label read simply "Chronic urticaria
3 or chronic hives." It did not mention the source of the
4 hives." Further, there were three more countries that
5 simply listed urticaria or hives and another three
6 countries which combined urticaria with a broader term
7 of allergic skin condition.
8 I'd like to make one last point and that is
9 that of these 19 countries, not a single country indicated
10 that the consumer should be diagnosed by a physician prior
11 to using this product. Actually, I'd like to pause just
12 one more minute to sort of put this into context by telling
13 you that of all these statements that I just described,
14 less than half of those statements were on the carton
15 labeling. Rather, the majority of these statements were
16 on the package insert meaning that consumers could not
17 read these indications at the time of purchase.
18 And now let's just take a look at the label
19 proposed by the sponsor. Again, I'm just looking here
20 at the 10 mg tablet. You can see that this package is
21 labeled on the front for recurring hives. It says it
22 "relieves and reduces itching and rash due to recurring
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1 or chronic hives." Again, I've blown up a statement on
2 the back panel from the uses section of the drug facts
3 label. There's two bullets. The first bullet refers
4 to CIU and it reads "relieves and reduces itching and
5 rash due to recurring or chronic hives of an unknown
6 source."
7 The second bullet, which is in bold font,
8 indicates that the consumer should be diagnosed by a
9 physician and it reads "Use only after being told by a
10 doctor that you have recurring or chronic hives (chronic
11 idiopathic urticaria).
12 And similar to Canada, the 10 mg tablet also
13 has a second carton labeling. This time it is labeled
14 for allergy. However, it does refer to CIUs. It says
15 "Non-sedating relief of itching and rash due to recurring
16 or chronic hives." And again on the rear panel, the same
17 two statements, just this time combined into one bullet
18 and again the second statement referring consumers to
19 be diagnosed by a doctor is in bold font.
20 And now I'll just briefly summarize just a
21 few points from the label comprehension study conducted
22 by the sponsor. The label comprehension study consisted
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1 of 565 subjects divided into five cohorts. The first
2 cohort was self-recognized CIU sufferers. These were
3 participants who had claimed to be diagnosed previously
4 by a physician as having CIU. The second and third cohort
5 were the general population and the low literacy group.
6
7 The fourth cohort was that they had a
8 contraindication on the labeling. These were subjects
9 who were pregnant or nursing or who had liver or kidney
10 disease. And then fifth cohort were the acute hive
11 sufferers. These were subjects who had previously had
12 hives or currently had hives but had never been diagnosed
13 by a physician as having CIU.
14 For the label comprehension study, all those
15 subjects were allowed to look at labeling similar to that
16 which I have just shown you proposed by the sponsor and
17 then respond to a series of questions. I'm just going
18 to highlight a few of the questions and the responses,
19 again to try to give you a flavor for the type of responses
20 we saw in the label comprehension study.
21 The first question was an open-ended question
22 that read, "Based on the label, what is this product used
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1 for?" Approximately two-thirds of the participants
2 answered this question correctly or acceptably. To
3 answer this correctly or acceptably, the respondents had
4 to say that the product was used for CIU. However, they
5 could also say that it was used for another appropriate
6 indication such as allergic rhinitis.
7 Of the third of the respondents who got this
8 answer incorrect, nearly all of them simply mentioned
9 hives as the indication, did not mention the chronic
10 nature of the hives or the source of the hives.
11 I'd also like to just point out a couple of
12 other potentially concerning responses that were seen,
13 and that is that some subjects believed that this product
14 could be used if you had trouble speaking or swallowing,
15 drooling, food or medication allergy, had a fever or had
16 breathing problems.
17 The second and final question which I'm going
18 to discuss from the label comprehension study was a
19 close-ended question similar to the first. It read, "Is
20 this product intended to be used for the following
21 conditions?" with a list of 10 indications following this
22 question. I'm not going to talk about all 10 indications
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1 but instead going to focus on just three. In this table,
2 the columns here represent the five cohorts and then this
3 far left column here represents the total of all five
4 cohorts combined. These percentages, I should point out,
5 represent the percentage of respondents who believe this
6 was a correct indication for the product.
7 The first indication or recurring or chronic
8 hives of an unknown source. That is, CIU. And you can
9 see that nearly all the respondents correctly identified
10 this as an indication for the product. However, the
11 second indication, food allergies which is incorrect,
12 a little over 10 percent of the respondents believed this
13 was an appropriate indication for the product. Moreover,
14 if you focus on the acute hives sufferers here at the
15 far right of the table, you can see that number is almost
16 double.
17 And then lastly, a one time outbreak of hives,
18 i.e., acute hives. You can see that about a third of
19 the respondents believe this product could be used for
20 a one time outbreak of hives. Moreover, if you ignore
21 the first cohort of CIU sufferers who have been diagnosed
22 by a physician as having CIU, that number is basically
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1 double. Excuse me, not double. But about 40 percent
2 of the respondents in the other four cohorts believe they
3 could use this product for a one time outbreak of hives.
4 And then lastly I'd just like to mention the
5 self-selection portion of this study and that consisted
6 of the following question. "Considering everything on
7 the package label, is this product intended for you
8 personally to take home and start using?" There were
9 three possible responses that the participants could give
10 to this question. The first is yes, I can take this
11 product. The second is I can only take this product after
12 asking a doctor and third, no, I should not use this
13 product.
14 Again, I've summarized the results in a table
15 here and you can see in the first cohort the CIU sufferers,
16 100 percent of that cohort got this answer correct and
17 that is because all three responses were considered
18 correct or acceptable for this cohort. However, if you
19 look to the far right, the acute hives sufferer, you can
20 see that just over 50 percent of the respondents got this
21 correct meaning that nearly 50 percent of acute hives
22 sufferers believed they could use this product without
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1 asking a physician first.
2 And then lastly, I'd just like to provide
3 you with the take-home points and those are this. OTC
4 or antihistamines can not be marketed currently for CIU
5 or hives under the monograph system. The second.
6 Chronic hives was the most common indication on the
7 labeling from around the world and also Loratadine
8 typically is marketed prescription or behind the counter.
9 That is, it's not typically marketed as over-the-counter
10 outside the U.S.
11 And then lastly, it seems obvious from the
12 consumer study conducted by the sponsor that consumers
13 will use this product for all types of hives.
14 Now I'd like to introduce Doctor Ganley.
15 DR. GANLEY: Okay. What I'm going to just
16 do in the next five minutes or so is just give a quick
17 overview to highlight some of the issues. I think that
18 just hearing the questions after the sponsors'
19 presentations, you sort of get the idea where the issues
20 are. So this may be somewhat redundant.
21 What I've listed here are safety criteria
22 for OTC drugs, and these are actually taken from our
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1 regulations. There's probably additional thoughts that
2 could be captured in these, but there should be a low
3 incidence of adverse reactions or significant side
4 effects under adequate directions for use. The key words
5 here are "adequate directions for use and the incidence
6 of adverse reactions." There should also be warnings
7 against unsafe use and there should be low potential for
8 harm which may result from abuse under conditions of
9 wide-spread availability.
10 I think inherent in this is that a product
11 in the over-the-counter market can be accurately selected
12 and deselected by the general population and not just
13 a subset or a cohort of that population. I don't include
14 a slide regarding the efficacy of this product and I'm
15 somewhat remiss in that after hearing Doctor Chowdhury's
16 talk where we talked about efficacy. One of the reasons
17 for doing that is that if the committee decides that
18 urticaria or hives is an acceptable OTC indication but
19 it should be for the general population, that would
20 include a population that would include acute hives, does
21 the efficacy data that sponsor have on hand support the
22 treatment of acute hives? So that would be one of the
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1 issues that you would have to also address.
2 These are just some observations that I just
3 want to make clear. First with regard to the FDA position
4 on urticaria as an OT indication. We don't really have
5 a position. Many of our reviews, although somewhat
6 critical of some of the things the sponsor has done, is
7 not an indication of our position on this. We really
8 are depending on the committee providing some insight
9 on whether this should be an OTC claim and also
10 specifically whether the application at hand is
11 acceptable.
12 The other thing, which has been recounted
13 earlier, is urticaria or hives as an OTC indication in
14 other countries. We also have to recognize that
15 pharmaceutical marketing in other countries is different.
16 Consumer behavior is somewhat different in some cases
17 and pharmacy practices vary among countries. Clearly,
18 the fact that the OTC-ness of this in other countries
19 is based on having some type of health care provider or
20 pharmacist be the one distributing the medication.
21 The last thing that we really I think are
22 in agreement with the sponsor is consumers may be already
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1 using OTC antihistamines for urticaria. Some of the data
2 they provide actually indicates that. It would be
3 interesting to understand how does that happen? Why is
4 that so? Consumers can be influenced by various
5 information resources. The Internet is a prime example.
6 You could go into the Internet and do a search for
7 urticaria and it quickly takes you to resources where
8 it tells you how to treat urticaria.
9 The other thing that we don't really have
10 a good understanding of is how these products are
11 marketed. One example would be the brand names. There's
12 many brand names out there that include the term allergy.
13 How do consumers interpret that? Do they extrapolate
14 a lot of different diseases and illnesses?
15 As far as urticaria or hives as an OTC use,
16 one of the important things to understand is for acute
17 or chronic hives, what is the frequency and significance
18 of associated conditions? Some of those were touched
19 on this morning as far as angioedema and anaphylaxis.
20 I've heard the term rare and infrequent. It's hard to
21 really get an understanding of what that actually means,
22 especially when you have a product that would go OTC and
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1 be available to tens of millions or hundreds of millions
2 of people. Things that are rare in one setting may become
3 a little more common in another setting in terms of the
4 distribution.
5 Clearly, the consequences leading to serious
6 adverse outcomes are important to understand here. I
7 think, just hearing the discussion of the committee with
8 the sponsor's presentation, they touched on some of those
9 issues.
10 Also, what's important is the condition is
11 misdiagnosed by the consumer as urticaria. They were
12 discussed also earlier. Physician intervention. When
13 is it necessary? Delay in seeking physician advice are
14 important issues that need to be better understood or
15 discussed, I guess. Consumer behavior. Will the OTC
16 availability encourage self-treatment without diagnosis
17 for chronic urticaria? Now if you have a product out
18 there that is marketed for that, will consumers have less
19 of a tendency to go see a health provider and, if they
20 do, was there a negative consequence to that?
21 Consumer self-diagnosis condition.
22 Clearly, I think a chronic idiopathic urticaria
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1 population who goes to a physician and is given that
2 diagnosis, I could believe that they would be able to
3 diagnose that condition should it occur again. I'm not
4 sure I need a study to tel me that. But I guess the issue
5 comes down to what will the general population do with
6 that and what things can we do to influence behavior
7 because the bottom line here really is to reduce risk
8 and how can we manage risk here in a prospective way?
9 As far as the sponsor's proposal, as you've
10 heard, they've wanted to limit the indication to chronic
11 idiopathic urticaria by a physician. In support of that,
12 they've submitted surveys and label comprehension. I
13 reviewed the surveys and wrote the review and I'm not
14 going to go over all the details again. The important
15 things were, in my view, that I'm not surprised by the
16 results of the study. If you go to any population that
17 has a disease that has intermittent symptoms and they've
18 gone to a health care provider who is treating them with
19 some medication and ask them to take that medication when
20 the symptoms recur, I think most people are capable of
21 doing that. So the outcome that a CIU population could
22 actually use this medication is just not really that
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1 surprising.
2 As far as the consumer survey, I had some
3 critique about the multiple choice questions being used
4 and open-ended. The sponsor addressed that. I don't
5 see a need for me to address that again. Most of those
6 individuals in that survey had used oral antihistamines
7 prior to getting a physician's diagnosis and I think
8 that's likely to continue in the future.
9 One other thing is that chronic idiopathic
10 urticaria is not a commonly used term, particularly in
11 telling an individual what the diagnosis is.
12 The sponsor proposed to limit this indication
13 by simply having labeling that states, use only after
14 being told by a doctor that you have recurring or chronic
15 hives of an unknown source, chronic idiopathic urticaria.
16 As I mentioned, we have had some experience with that.
17 Not all of it has been great. The vaginal anti-fungal
18 products have a warning that says do not use if you have
19 never had a vaginal yeast infection diagnosed by a doctor.
20 Subsequent studies have suggested that as many as 40
21 percent of individuals that use those products have never
22 had that diagnosis.
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1 So the problems with the sponsor's approach
2 is that the product is likely to be used for any type
3 of urticaria. Twenty to 25 percent of subjects who
4 experience hives have chronic hives. That means 75 to
5 80 percent of a population would have-- there'd be more
6 people that use that have acute hives than would have
7 chronic hives that would have access to this product.
8 There was no data provided to demonstrate
9 accurate self-selection and de-selection in a general
10 population, not just a CIU population. There is no
11 consensus for consumers on the name CIU. Hives is likely
12 to be translated broadly by the consumer. The labeling
13 restriction proposed by the sponsor will not likely limit
14 use to CIU subjects.
15 So the issue for the committee is whether
16 urticaria should be an OTC claim in any form. If the
17 committee decides that the answer is no to that, that
18 means there is just no studies or anything that the sponsor
19 can do that would ever provide sufficient information
20 for that to be an OTC claim. So if you come to that
21 conclusion, the meeting is going to end early today.
22 The second part would be if you believe that
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1 it's a possible claim, whether the data submitted by the
2 sponsor is adequate or whether there is other data that
3 they need to collect and provide.
4 With that, I'll conclude my discussion.
5 DR. CANTILENA: Okay. Thank you, Doctor
6 Ganley and other members of the FDA team for their
7 presentations.
8 We now have time slotted for questions to
9 the FDA presenters. We'll just sort of use our open
10 format that we used earlier. Doctor D'Agostino.
11 DR. D'AGOSTINO: The question is probably
12 to Doctor Holman but maybe Chowdhury would also be
13 appropriate. You presented that the drug is used in a
14 number of non-U.S.A. countries and the actual indication
15 does say hives. Is there a body of data? I mean I realize
16 that the FDA does its own reviews and so forth, but is
17 there a body of data, publications and what have you,
18 where the drug has been effective, proven to be effective
19 or substantial evidence that it is effective? Also, we
20 keep hearing over and over again that the field thinks
21 it is. What are they basing this decision that it is
22 appropriate on? What database do we actually have? I'm
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1 not talking about the Rx. I'm talking about the OTC
2 aspect of it.
3 DR. CHOWDHURY: Yes. Let me give you the
4 answer from the prescription standpoint and then I'll
5 ask Doctor Holman to answer the question, too. In
6 response to your question, the studies in-house that we
7 have reviewed for the antihistamines are for t CIU
8 indication and I'm not aware of any data that we have
9 that looks at the efficacy for other types of urticaria.
10 DR. D'AGOSTINO: There are a substantial
11 number of countries where the indication is high. You
12 said it's OTC. What's the database?
13 DR. HOLMAN: I'm not really sure exactly what
14 the database is. I talked to some of my counterparts
15 in Canada and the U.K. and there are regulatory bodies
16 there. We never really discussed the database. I think
17 it was just sort of assumed that because they were
18 effective for CIU, they would be effective for hives.
19 All they indicated when I specifically addressed the
20 question, is this a hives indication or is this a CIU
21 indication, they indicated that it was a hives indication
22 because they did not feel the consumers would understand
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1 the term CIU or any statement referring to CIU.
2 DR. D'AGOSTINO: Why is the field so
3 convinced that it is appropriate treatment?
4 DR. HOLMAN: I think, as Doctor Wilkin and
5 Doctor Monroe mentioned, the pathway seems to be common
6 between whether it's chronic or acute urticaria, seems
7 to be a common pathway, and that is the release of
8 histamines. Therefore, antihistamines are effective in
9 preventing CIU or treating CIU would be effective at
10 treating really a more broad hives or urticaria.
11 DR. D'AGOSTINO: i'll get off but I just want
12 to understand. We're saying we don't think that there's
13 a database for hives.
14 DR. HOLMAN: No, there's none that I'm aware
15 of. I think again, as mentioned earlier, it's just an
16 ability to conduct the study to determine that.
17 DR. D'AGOSTINO: Thank you.
18 DR. CHOWDHURY: In response to your
19 question, I would probably also ask Schering to see if
20 they have any data in hives of other types because they
21 have two of the four antihistamines that has a CIU
22 indication in the U.S.
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1 DR. CLAYTON: We do not have any clinical
2 data on acute hives. I think, back to Doctor Wilkin's
3 presentation, the mechanism of action is the same and
4 it is still the first line therapy for acute hives, as
5 was in his presentation. But no clinical data that I'm
6 aware of.
7 DR. CANTILENA: Other questions, Doctor
8 Szefler.
9 DR. SZEFLER: This is perhaps for Doctor
10 Chowdhury. As I looked at the literature, and it's not
11 an area that I look at intensively, but as I tried to
12 look at it, I tried to understands what are the
13 pharmacodynamics of the effects of the antihistamines
14 and does it reduce the course of episodes? Does it just
15 merely reduce the itching? If it just merely reduces
16 the itching, then how does that differ from acute hives
17 where that would be the main purpose would be to reduce
18 the itching? So I'm trying to kind of sort out the
19 dynamics in terms of time-related effects, magnitude of
20 effects. Statistically it's there in a lot of these
21 parameters, but I'd kind of like to get a feeling of what
22 you would select as a primary outcome variable if you
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1 had to look at this area.
2 DR. WILKIN: I can speak to that.
3 Basically, it's a symptomatic kind of therapy. If you
4 want to think of it as the where is the disease, if it's
5 the IGE mediated, it's the B-cells, the -- arm of the
6 immune system recognizing something that really doesn't
7 pose that much of a threat to the body being recognized
8 as foreign and then being over-reacted to by the
9 production of IGE that will bind to the mast cell. That's
10 probably the disease part. Where the histamine is
11 downstream from the mast cell, how the antihistamines
12 work is they just work for that particular episode but
13 they don't have any effect on long-term prognosis over
14 the course of the disease. Sometimes patients will have
15 IGE and later they'll develop IGG blocking antibodies
16 are sort of things that they'll have a natural tolerance
17 develop, but that's not because they were on the
18 antihistamine therapy. Antihistamine therapy is
19 symptomatic. It blocks the histamine receptors that
20 mediate the itch and also the vasodilation and the
21 vascular permeability.
22 DR. SZEFLER: Let me just tease it out a
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1 little bit more. Is this something that -- again, when
2 I was looking at the pharmacodynamics, there weren't
3 diagrams jumping out. There were tables in terms of
4 durations. is this something that you expect to see at
5 12 hours a statistical difference, 24 hours? There's
6 not a lot of literature and the literature is not kind
7 of crystal clear in terms of these effects. I'm trying
8 to look at how do you look at it in terms of if you were
9 to look at acute urticaria, what could you see and what
10 would be the primary outcomes that you could measure and
11 look at?
12 DR. WILKIN: Well, acute urticaria, although
13 it gives the picture of a single episode where one breaks
14 out and the hives are there for maybe 24 - 36 hours,
15 something like that. In point of fact, the hives migrate
16 around so it's mast cells releasing the mediators in
17 different portions of the skin at different times. If
18 at the beginning of one of those episodes one takes the
19 antihistamines, you can actually then shorten the
20 particular course. Does that speak to the question?
21 DR. SZEFLER: Yes. i'm trying to decide in
22 my own mind whether this is an area that's been poorly
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1 studied because there's been just not enough direction
2 and there's been so much assumption there, we don't have
3 to study this in depth and it's really not been looked
4 at as a discipline the same as, say, things like asthma
5 have been looked at and defining primary outcomes and
6 getting a real good -- area because what I get the
7 impression of is that well, it's a tough area to study
8 and it's kind of hopeless and maybe we shouldn't go for
9 acute urticaria but then, on the other hand, maybe the
10 incentive has not been there to come up with clever methods
11 to really look at this in depth.
12 DR. WILKIN: I think you've actually touched
13 on the real piece and that's the methodology. How does
14 one actually look at acute urticaria? You would almost
15 need to be clairvoyant to know who's going to get acute
16 urticaria to capture them in time to give them a medication
17 so that you could follow them for what very often is just
18 a couple of days of an acute urticaria episode. I mean
19 we talk about the six week point being the time where
20 we then will define it as chronic urticaria but most of
21 the patients who have acute urticaria don't have six weeks
22 worth of acute urticaria. That time point is just simply
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1 to separate those who have the bad prognosis. It's very
2 likely theirs is not going to go away. Most urticaria
3 goes away in the first couple of days or the first week.
4 So it would be very difficult to recruit patients, study
5 them, give them drug or give them placebo and make the
6 comparisons because there's going to be a high spontaneous
7 disappearance of the urticaria during that time period.
8 I think acute urticaria is just incredibly difficult
9 to study.
10 Now, what you can say about acute urticaria
11 and chronic urticaria, many of the etiologies if you will,
12 the things that ultimately are outside of the mast cell
13 that then impact on the mast cell, many of those are in
14 common. The mast cell only has one trick. It's got the
15 same little vesical filled with all of these things that
16 it releases. It is an identical vesical, regardless of
17 what the difference etiologies, be they immunologic or
18 direct mast cell media release, it still releases that
19 same vesical which still has the same effects on the
20 vasculature and the afferent nerve endings.
21 So I do think that it's not data. It's going
22 from first principles but I think it's acceptable to
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1 approach urticaria as being very homogeneous in its final
2 terminal pathways unless you've got one of the mechanisms
3 that we know about, one of the compliment deficiencies
4 or other sorts of things that it's a special variety and
5 there are some findings that could, I think, be crafted
6 into labeling that would alert patients about the
7 additional associated features or the notion that the
8 urticaria doesn't itch.
9 DR. SZEFLER: I guess, again, I kind of
10 wonder just how much time has been spent in terms of trying
11 to come up with studies because I recall one of the slides
12 that said food is a precipitant in about 10 percent of
13 the patients and you could challenge patients as long
14 as you didn't think that this would cause anaphylaxis
15 if that wasn't a component so you could time the challenge.
16 As long as you looked at what was your primary outcome
17 variable, I think you could measure in a suitable enough
18 population whether there was an effect on this kind of
19 parameter. So again, I'm just kind of wondering how much.
20 Maybe it's been assumed that because the sedating
21 antihistamines work in these areas that it's not an area
22 of concentrated studies. But I think I could sit back
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1 and design studies on this. As long as you had some feel
2 from the literature what were primary outcome variables,
3 what would you measure.
4 DR. CANTILENA: Actually, I think some of
5 these issues will come up this afternoon, if we can hold
6 that, because then we have Doctor Wood, Doctor Davidoff
7 and Doctor Sachs next.
8 DR. WOOD: I have two questions. I'd like
9 to ask them separately because they're sort of unrelated.
10 I guess I'd like to address them to Lloyd and Doctor
11 Rosenberg. As I hear this, it seems to me that as we
12 try to put it together, we're hearing evidence that the
13 drugs are effective in the treatment of CIU and the worry
14 seems to be that patients with other types or urticaria
15 and potentially other skin diseases will use this therapy.
16
17 So my question to the dermatologists is
18 should I care about that? I mean does that really matter
19 if other patients use it because if it doesn't, then these
20 other issues that are kind of just bubbling up here and,
21 although they're interesting, they're not really relevant
22 to the decision on the table.
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1 So the question I'm really putting to you
2 is there bad things that are going to happen to patients
3 who have other skin diseases and, apart from delay, who
4 might take this acute urticaria or for other diseases
5 or whatever?
6 DR. ROSENBERG: I would say no based on long
7 experience and being in dermatology for a long time.
8 Also, I'll ask the chairman about this afternoon's
9 meeting. Have the Academy of Dermatology, the Allergy
10 Society, sent people here and request a place on this
11 meeting?
12 DR. CANTILENA: No, it actually doesn't look
13 like that. We only have three individuals who have
14 registered for this afternoon.
15 DR. ROSENBERG: I think that answers your
16 question, Doctor Wood, like the dog that didn't bark.
17 I've been involved in these proceedings when we talked
18 about Acutane and the pediatricians were here in force
19 and when some of us were trying to have over-the-counter
20 hydrocortisone made a legal prescription in this country,
21 the Academy of Dermatology expressed at that time grave
22 reservations about the safety of things being missed and
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1 it just went on and on over many, many meetings. I think
2 that those bodies all pay close attention to what goes
3 on at FDA and would have sent somebody here had they raised
4 any issues at all.
5 DR. KING: I have to agree, having been on
6 the Acutane study in which everybody got on a campaign
7 about all the regulations that should be in place. It
8 is a dog that didn't bark. Many of the folks we see come
9 in and we have them fill out lots of sheets about what
10 they've done. They know more about Benedryl sometimes
11 than our residents do. So I think they're going to be
12 taking it because mama, the neighbors, particularly
13 people who are English as a second language are going
14 to take it anyway. I can't remember a case in which taking
15 a first or second generation antihistamine blocked or
16 in any way endangered a patient from taking it prior to
17 coming to see a dermatologist or other physician.
18 DR. WOOD: So the answer to that is thaI
19 shouldn't care.
20 DR. KING: Shouldn't care.
21 DR. WOOD: The second question I have is a
22 sort of question from a simple guy in Tennessee. I'm
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1 interested in the labeling idea, that you should only
2 take the drug if you've been told by a physician that
3 you have chronic idiopathic urticaria, but just in the
4 patients I see in Tennessee, I don't think many of them
5 leave our hospital saying to themselves as they walk out
6 the door, I've got chronic idiopathic urticaria. That
7 doesn't sound like a phrase that drops off the lips of
8 the average patient somehow.
9 So I wonder if that's the right label and
10 if there's something that's more commonly used by lay
11 people and this gets back to the question of the hives.
12 That seems to me something that people would use more
13 commonly. I just worry about demanding a label be given
14 to something that patients don't customarily use,
15 certainly not my patients. Maybe other people, the
16 sophisticated people in the northeast. Lloyd, what's
17 you feeling about that?
18 DR. KING: Well, actually I'm biased because
19 I'm from Tennessee, too. Is there anyone here who's not
20 from Tennessee? Well, there are several. We have had
21 notoriety because of Vice President Gore. I think the
22 issue as I thought about it is if we're going to have
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1 across the world, you almost have an issue of labeling
2 which is what do you do about groups of people in which
3 English is a second language or conversely in which French
4 or Russian is a second language, so to speak. You really
5 have to talk about the issues of access to drugs which
6 potentially can hurt you and what percentage of those
7 people will be hurt. Having worked for cause of orphan
8 drugs, one percent of a huge number is still a huge number.
9 And so I think the issue would be how many people would
10 actually be hurt if we just put chronic hives on the label.
11 I suspect it wouldn't be that many in any case and so
12 if you had to put on there that for aspirin it can trigger
13 fatal reactions, it almost did my mother times two, you
14 could get into a labeling nightmare. So I would have
15 no trouble putting on there indicated for chronic hives,
16 see your doctor, and I'd like to see something like a
17 big eye ball and MD or its equivalent and then whatever
18 language saying see your doctor if there's --
19 DR. WOOD: In my mind, it would seem like
20 insisting that patients with a diagnosis of acute
21 myocardial infarction rather than a heart attack which
22 for most patients is what they're really going to carry
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1 in their conversation. So both of these seem to circle
2 back to the conclusion that if we are not worried about
3 patients taking the drug for other types of hives because
4 of risk to them and, in addition, the vernacular that
5 patients use is hives rather than chronic idiopathic
6 urticaria, then that seems to me to answer some of the
7 other issues that are on the table which are more
8 scientifically interesting perhaps but are not
9 practically enforceable. Is that fair?
10 DR. KING: I agree. I think if you have,
11 as I often times approach a Palm Pilot or some of these
12 PDA kind of things, if you don't know how to use it or
13 you don't understand that, I'd rather have something
14 straightforward, chronic hives as opposed to see your
15 doctor if you have chronic hives of undetermined etiology.
16 I like your thought.
17 DR. CANTILENA: Doctor Davidoff and Sachs,
18 then Gilliam.
19 DR. DAVIDOFF: Yes. I have a question
20 primarily for Doctor Chowdhury. Others may want to
21 comment. It has to do with the efficacy data because,
22 even though I realize, as I understand, the OTC decisions
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1 rest primarily on issues of safety, it's really more,
2 I think, a balance of safety and efficacy because even
3 if a drug is not very toxic, if it's ineffective, that's
4 not a very good equation. Which raises the question about
5 how to interpret the data on efficacy in CIU. The data
6 that were presented there, comparing the non-sedating
7 antihistamines to placebo are really, as was commented
8 on in the materials provided, fairly under-whelming.
9 The difference is, I guess, about a mean of half a point
10 on a four point scale. But beyond that, there were no
11 confidence intervals, so I don't know how to interpret
12 that since I don't know what the possible range of quote
13 "true" effects was or wasn't.
14 But underlying all of that is the question
15 of well, even accepting .5 on a scale of total of four,
16 that may be statistically significant, which I guess it
17 was, but is that clinically significant or maybe others
18 could comment on what is felt to be clinically
19 significant? To help with that, it would help to know
20 the distribution of responses because it could be that
21 a substantial portion of the patients so treated really
22 got very strikingly positive responses but it might be
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1 sort of a bell shaped curve. Maybe you could elaborate
2 a bit on the meaning of significance here.
3 DR. CHOWDHURY: Well, this is a very
4 difficult question to answer what is a clinically
5 meaningful difference versus a statistically significant
6 difference and for evidence of efficacy we compare to
7 placebo and if the drug is statistically significantly
8 superior in situations like this where we did not really
9 have a prior understanding what difference is clinically
10 meaningful. The differences, as you saw, in the
11 urticaria trials were not that remarkable. Really, for
12 antihistamines, were there indications also like allergic
13 rhinitis. The differences from placebo are usually not
14 that remarkable. And also there is a significant -- not
15 statistically so but just numerically a placebo response
16 there for the two arms as the time goes on comes closer
17 and closer.
18 So it's very difficult really to put a number
19 on that that kind of difference would be clinically
20 meaningful. We don't have that, and the data, as you
21 correctly pointed out, are from CIU patients and how that
22 translates to acute urticaria is not known. As Doctor
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1 Szefler mentioned, those studies are not done, not
2 necessarily that it can not be done. It has just not
3 been approached, not been done. Perhaps one could design
4 clever studies to answer these questions.
5 DR. DAVIDOFF: I understand about the later
6 data on acute hives, but do you have any information on
7 what the distribution of responses is within the study
8 population?
9 DR. CHOWDHURY: I don't have it right on top
10 of my head here and I would ask Schering to see if they
11 can share some of the data that they have from their
12 studies. I do not.
13 DR. CANTILENA: Doctor Temple might have
14 that somewhere.
15 DR. TEMPLE: I only want to point out that
16 the same questions arise in studies of angiolytics,
17 antidepressants and things like that. If you look at
18 the mean difference from placebo, it's relatively small
19 compared to the spontaneous improvement in the untreated
20 placebo group and we don't really know whether that's
21 a condition of the study. For example, with respect to
22 allergic rhinitis, if you do so-called field studies,
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1 the differences are small, hard to detect. Most trials
2 fail. If you do chamber studies where you control the
3 antigen and introduce it, it's very easy to show effects
4 and dose response and all that kind of thing.
5 Nobody quite knows whether this is a
6 phenomenon of the study or is really true because people
7 certainly have the impression that they have visible
8 effects from antihistamines and yet if you look at the
9 study results, the results are puny. So as was said,
10 we consider it quite remarkable if you can actually beat
11 placebo in these settings. We have in a number of cases
12 tried to look at the distribution of responses. It turns
13 out if the median effect is tiny, the distribution of
14 responses isn't very different either as a rule. There
15 could be exceptions to that, I suppose, and we always
16 look for tails on the thing. But that on the whole has
17 been remarkably unproductive. So that's unsatisfactory
18 in some ways but that does seem to be how a lot of these
19 turn out.
20 DR. CANTILENA: Okay. Thank you, Doctor
21 Temple.
22 Doctor Sachs and then Doctor Gilliam.
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1 DR. SACHS: In the past we have been
2 presented with actual use studies of the drug kind of
3 as it would be given OTC and I was just wondering if that
4 was not going to be done this time, #1. #2, sine we met
5 in May, has the FDA received any more of the indicators,
6 for example, from Poison Control or overdose or things
7 like that which we usually look at in having the drugs
8 go OTC.
9 DR. CANTILENA: Doctor Ganley.
10 DR. GANLEY: As far as an actual use study,
11 that was the determination of the sponsor that they didn't
12 need a study. We didn't have many discussions with them
13 before they submitted their application to even discuss
14 that. So that would need to be addressed by the sponsor.
15 Quite frankly, I think an actual use study in a general
16 population to look at hives is probably a tough study
17 to do because you can imagine if you have a population
18 that you're actually trying to look at acute hives, how
19 frequently does that occur and how many people would you
20 have to actually enroll in a study like that over how
21 many month period of time to follow up to just get 200
22 events of hives and did they use it correctly. You may
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1 be talking thousands or tens of thousands of people to
2 be followed for several months. So that's one of the
3 issues that you would have to discuss today is whether
4 an actual use study is the best mechanism if you needed
5 additional information or other alternative mechanisms
6 to address that.
7 I don't believe we have more data. Doctor
8 Chowdhury may be able to address that as far as the Poison
9 Control information. The company had submitted some data
10 regarding the safety of the drug and I don't believe there
11 were many cases, particularly in reports reported to them
12 and the agency with regard to people using it for a hives
13 indication or chronic idiopathic urticaria indication
14 where they ran into a lot of problems. There were a few
15 serious cases, and I think we have someone here who could
16 address those if you have questions regarding that.
17 MR. LEE: I'm Charles Lee, medical reviewer
18 in Division of Pulmonary Allergy Drug Products.
19 As far as the overdose information, there
20 didn't appear to be any signal in the data that the sponsor
21 submitted. There did seem to be a difference, however,
22 in the proportion of serious adverse events that were
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1 due to anaphylaxis in patients who had so to speak CIU
2 as compared with patients who had allergic rhinitis.
3 In the initial submission, 11 percent of serious adverse
4 events were for -- how do I want to say this? Of patients
5 with CIU who had anaphylaxis, there were 11 percent of
6 the entire population of patients who had serious adverse
7 events as compared with two percent of patients with
8 allergic rhinitis.
9 Probably saying to say it more clearly, the
10 proportion of patients with serous adverse events due
11 to anaphylaxis was higher in patients who had so to speak
12 CIU compared with patients who had allergic rhinitis.
13 If one looks at those reports, most of those patients,
14 in fact, did not have CIU. Only one of those patients
15 had CIU. The others were actually patients who had
16 urticaria for other reasons. So I think what that kind
17 of may suggest is that perhaps there is a little bit of
18 a difference in the risk profile in patients who will
19 be taking the product urticaria as compared to the
20 population that would take it for allergic rhinitis.
21 DR. WOOD: Is that what you're saying or that
22 more patients had anaphylaxis and were confused in the
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1 situation? I mean I'm not understanding, I guess, what
2 you're saying. I would not interpret that to imply that
3 more patients developed anaphylaxis due to the drug in
4 that group than patients who were treating for allergic
5 rhinitis rather than there was more of a background of
6 an anaphylaxis that was mistakenly being treated. Have
7 I got that wrong?
8 DR. GANLEY: Yes. I think that's what he
9 meant is that if there's an increased frequency of
10 anaphylaxis in the urticaria population to begin with,
11 then you would expect potentially to see a difference
12 in the percentage comparing allergic rhinitis versus the
13 urticaria population. I think that gets back to one of
14 the issues that I raised in my summary is what is the
15 frequency of these events. Are they of a high enough
16 frequency that we should have cause for concern or is
17 it something that should be addressed in labeling or how
18 do you handle that situation?
19 There was clearly, I think, one case and
20 Charlie can clarify it was the case, of a person who had
21 an allergy to shrimp, I believe.
22 MR. LEE: Right. The one fatality due to
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1 anaphylaxis was in a seafood allergic patient or seafood
2 sensitive patient who apparently chose to ingest a pizza
3 with the seafood removed from the pizza apparently
4 developed urticaria, early symptoms of anaphylaxis, took
5 the product in what appears to be an attempt to treat
6 the symptoms and who eventually died from the anaphylaxis.
7 It's one single case. However, I think that in
8 conjunction with what Doctor Holman had on his slide with
9 16 percent of the general population believing that the
10 product is intended for food allergy, I think it does
11 raise some concerns about potential misuse of the product
12 in patients who had inappropriately selected,
13 particularly if one takes into account that that
14 population making that inappropriate choice, when you
15 throw in, say for instance, a direct to consumer
16 advertising, how patients perceive advertising, if that
17 in fact might increase the risk of that happening or
18 increase the likelihood of increasing the percentage of
19 patients that might make a poor choice like that.
20 DR. CANTILENA: Okay. Well, thank you. Some
21 of those issues I'm sure will come up this afternoon and
22 then our final question for this morning would be with
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1 Doctor Gilliam.
2 DR. GILLIAM: I was wondering if the FDA or
3 maybe Doctor Monroe knows. What's the incidence of CIU
4 in general or of hives in general and what made me think
5 of this was the package insert that was going around.
6 I'm a little concerned that they're going to come out
7 with separate packaging just for CIU. It would make me
8 much comfortable if it was on the box with allergy
9 indication. Also, I just see this as being maybe them
10 using this to make a whole other market for something
11 that's not really a big issue and if somebody could shed
12 some light on that.
13 DR. CANTILENA: Charlie, do you want to try
14 that one?
15 DR. GANLEY: Well, I think in our executive
16 summary we sort of threw that in as an issue for how do
17 you market and what is the -- you know, you look at these
18 numbers and it's hard to get a sense of how many patients
19 per year have hives I think is really what you're asking
20 because a lot of the percentages that are provided is
21 the cumulative prevalence over time. The issue really
22 comes down to well, are there 10 million cases of hives
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1 in the United States each year and 20 percent of those
2 are chronic and 80 percent are acute or something related
3 to that. That's I think what you're asking and I think
4 that's an important question to understand. I don't know
5 what the answer is because most of the figures I've seen
6 are cumulative prevalence over a lifetime.
7 DR. CANTILENA: Is there anyone from the
8 sponsor who would like to add to that?
9 DR. MONROE: I would agree. As we said,
10 about 15 to 20 percent of the population experiences
11 urticaria and only about up to three percent of those
12 in their lifetime have chronic idiopathic urticaria but
13 at one point in time what the incidence is, I'm not aware.
14 DR. GILLIAM: My question is is there really
15 an indication for CIU if the prevalence of this is so
16 small, is it really needed?
17 DR. CANTILENA: Well, I think probably the
18 answer is obvious if you ask the sponsor because that's
19 why they're here. So maybe on that note we will break
20 for lunch and actually if you wouldn't mind, can we come
21 back at 1:15. We'll go an extra 15 minutes. We'll have
22 the public comment session start at 1:15. Thank you.
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1 (Whereupon, off the record at 12:07 p.m. to
2 reconvene at 1:15 p.m.)
3
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1 A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
2 (1:19 p.m.)
3 DR. CANTILENA: I have just one carryover
4 from this morning's question and answer session of Dr.
5 Clayton, I believe, would like to share with us some
6 information that was in response to a question from Dr.
7 Uden. They have some information that they would like
8 to show us.
9 Do you have that, Dr. Clayton or Mr. Neuman?
10 DR. CLAYTON: Mr. Neuman.
11 MR. NEUMAN: This was in regard to the
12 question on the race regarding the label comprehension
13 study. I had the wrong chart when we spoke. The African
14 American population in that study was significantly
15 larger than what I had portrayed it to be. It was 20
16 percent in total.
17 In the CIU population it was 10, in the
18 general population it was 22 percent, 52 percent of the
19 low literacy group, and 20 percent of the special
20 population, and 11 percent of the acute hives cohort.
21 DR. UDEN: And do you have Hispanic
22 information from Dr. Gilliam?
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1 MR. NEUMAN: Yes. The Hispanic population
2 was 5 percent over all. It was largest in the low literacy
3 cohort where it was 10 percent.
4 DR. UDEN: Okay. So 65 percent of the low
5 literacy group were African American and Hispanic?
6 MR. NEUMAN: That is correct. 62 percent
7 actually.
8 DR. UDEN: Thank you.
9 DR. CANTILENA: Okay. Thank you for that
10 information.
11 We'll now move to the public comment section
12 of the agenda. We have three speakers. Each speaker
13 is reminded that they have five minutes for their entire
14 talk. Our first speaker will be Dr. Gary Kay.
15 DR. KAY: Good afternoon, Dr. Cantilena, and
16 members of the committee, I'm Gary Kay. I'm the Associate
17 Clinical Professor of Neurology. I'm a
18 Neuropsychologist from Georgetown and also Director of
19 the Washington Neuropsychological Institute. By means
20 of disclosure, nobody has sponsored my trip. I live here
21 in Bethesda so it wouldn't be much sponsorship anyway.
22
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1 Other than that, with respect to financial
2 support I have received grant and research contracts
3 support from Schering-Plough and from Aventis
4 Pharmaceutical in the area of antihistamines. I've been
5 a consultant to Schering and to UCB in the area of
6 antihistamines in the past.
7 My comments are on chronic idiopathic
8 urticaria and considerations related to quality of life
9 and to CNS issues. First of all, I think it hasn't been
10 really brought out today in our discussions of CIU the
11 impact this has on patients besides the symptoms of their
12 rash, the amount of itch and scratch and all this.
13 These patients really suffer a great deal
14 of distress and discomfort. One of the most prominent
15 quality of life impacts are on their sleep. These
16 patients report very disturbed sleep. Also there is the
17 social embarrassment. The disruption of sleep is
18 probably due to a combination of the disease and the
19 treatment that is often used, the sedating antihistamine
20 treatment for the chronic idiopathic urticaria.
21 Running a simple Medline search typing in
22 the words chronic idiopathic urticaria in combination
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1 with any of the OTC antihistamines like diphenhydramine,
2 chlorpheniramine, triproladine (phonetic). If you run
3 that, you are going to find about 24 current articles
4 in there about efficacy and use of the over-the-counter
5 sedating antihistamines for chronic idiopathic
6 urticaria.
7 Run the same search with the words again
8 chronic idiopathic urticaria, loratadine, desloratadine,
9 fexofenadine, cetirizine, and you get a list of 67 current
10 studies on efficacy.
11 Obviously these medications are widely used.
12 There's a lot of description in these articles,
13 especially review articles, that this is a mainstay of
14 treatment for chronic idiopathic urticaria.
15 Well, I think we all have to recognize we're
16 talking about risks of medications. All of the current
17 over-the-counter antihistamines used for treatment of
18 CIU carry a precautionary statement, "May cause
19 drowsiness. Use caution when driving or operating
20 dangerous machinery."
21 Obviously you have concerns about people
22 reading labels and following labels and how seriously
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1 do they consider those labels. I would just suggest that
2 you take a look at the findings from the hearing that
3 was held for the FDA NTSB hearing in November, the hearings
4 on sedation and impairment, to take a look at particular
5 issue. We are not going to recover that again today.
6 The fact is that if you look at the studies
7 I mentioned, those 24 studies where they review the
8 adverse events in those chronic idiopathic urticaria
9 trials, the most common AEs that are found in those studies
10 is sedation in combination with those medications.
11 Another issue in CIU is that there's an
12 attitude among many of the physicians that one of the
13 things they are going to do to treat this patient is to
14 help them sleep at night and so administer to them a
15 sedating antihistamine at bedtime. That may help them
16 with the scratch and the itch and may help them because
17 they've been complaining of not sleeping well at night
18 but, in fact, that may not be so recommended.
19 Still, you are going to find if you look in
20 the current literature even references to AM and PM
21 dosing. Treat the patient with a sedating antihistamine
22 at bedtime and give them a non-sedating antihistamine
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1 in the morning so they won't have a sedating effect.
2 The reality is that you can treat CIU with
3 non-sedating antihistamines and actually improve
4 people's reported sleep and daytime wakefulness and
5 daytime functioning treating them with a non-sedating
6 antihistamine.
7 The study that we did at Georgetown was to
8 give people an 8 or 12 milligram dose of chlorpheniramine
9 at bedtime at 10:00 at night and in the morning we gave
10 them a dose of terfenadine. We followed the Harvard
11 Pilgrim Healthcare AM/PM dosing regime.
12 And we studied their sleep latency the
13 following day all day long from 9:00 a.m. to 5:00 at night.
14 Every two hours they took a nap. With the EG we could
15 see when sleep latency began. We got the average for
16 sleep latency for the whole next day after a night time
17 dose of 8 or 12 milligrams chlorpheniramine. What we
18 found was that patients getting placebo had a greater
19 than 10 minute MSLT, which is normal.
20 Those receiving the chlorpheniramine at
21 bedtime and terfenadine in the morning had a sleep latency
22 diminished down to six minutes which is about where a
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1 sleep apnea patient would be. It's not inconsequential.
2 What is also disturbing from that particular
3 study was the patients receiving the 8 milligram dose
4 of chlorpheniramine did not report feeling any more sleepy
5 than the patients on placebo. Yet they were clearly
6 physiologically impaired in their ability to stay awake.
7 You can also look at a study we recently
8 submitted to the FDA, a contract research study that we
9 did at Georgetown, showing impairment seven hours after
10 dosing even with doses as low as two or four milligrams
11 chlorpheniramine. Seven hours post-dosing is impairment
12 on tracking testing.
13 Summarizing, successful treatment of CIU
14 does not depend upon sedating the patient. Sedation in
15 CIU is an adverse event and one that can be avoided.
16 Non-sedating antihistamines are as effective as sedating
17 antihistamines in treatment of CIU.
18 Patients who have been previously diagnosed
19 with CIU, as I think we saw this morning, maybe they're
20 not good at self-diagnosis but the issue of recognition.
21 Can they recognize the disease? I think that was
22 demonstrated. Obviously I think these patients would
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1 benefit from access to a non-sedating over-the-counter
2 antihistamines.
3 Finally, the impact and risks of sedation
4 can be reduced by making a non-sedating antihistamine
5 available over the counter. Thank you very much.
6 DR. CANTILENA: Thank you, Dr. Kay. Our
7 next speaker is Dr. Engle, Dr. Janet Engle.
8 DR. ENGLE: Good afternoon. Thank you for
9 the opportunity to present the views of the American
10 Pharmaceutical Association, a national professional
11 society of pharmacists.
12 I am Jan Engle. I'm Associate Dean for
13 Academic Affairs and Clinical Professor of Pharmacy
14 Practice at the University of Illinois in Chicago. I'm
15 also President of APHA.
16 My comments focus on the role of the
17 pharmacist in helping consumers navigate the use of
18 loratadine in the OTC environment. Particularly if they
19 may need to seek care for chronic conditions such as
20 chronic idiopathic urticaria.
21 APHA's 50,000 members include pharmacist
22 practitioners, pharmaceutical scientists, and student
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1 pharmacists. APHA members provide care in all practice
2 settings such as community pharmacies, hospitals,
3 long-term care facilities, managed care organizations,
4 hospice settings, and the military.
5 In each of these settings pharmacists help
6 consumers manage and improve their medication use
7 including the appropriate selection and monitoring of
8 prescription and over-the-counter products. Ensuring
9 the public's health and safety, especially with respect
10 to medication use, is the pharmacist's and APHA's highest
11 priority.
12 In the interest of full disclosure, APHA
13 frequently partners with federal agencies, consumer
14 groups, and the pharmaceutical industry and others to
15 help develop educational programs. The association did
16 not receive funding to participate in today's meeting
17 and the views that I'm presenting are solely those of
18 the association and its membership.
19 The pharmacist's role in OTC drug use is
20 different from the role that is provided by other
21 healthcare providers. Most OTC products are purchased
22 at a pharmacy positioning pharmacists to work with
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1 consumers at the point of decision making and purchase.
2
3 Pharmacists serve as the bridge between
4 consumer self-care activities and interaction with the
5 formal healthcare system. Today I will address the
6 pharmacist's role in bridging these two systems in the
7 context of loratadine and its use for CIU.
8 APHA agrees that the proposed switch of
9 loratadine from prescription to nonprescription status
10 may potentially improve patient safety and clinical
11 outcomes by expanding consumer access to therapy with
12 fewer sedating side effects than with the available OTC
13 products.
14 Important to the safety equation, however,
15 is the appropriate use of the TOC product and this is
16 where pharmacists can help. Pharmacists can and do play
17 and valuable role in helping consumers use OTC products
18 for short-term treatment or symptom control in acute and
19 chronic situations and recommend physician or other
20 prescriber involvement when acute or chronic conditions
21 requiring additional attention are identified.
22 Pharmacists work with consumers and
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1 prescribers every day to selected appropriate
2 medications. The proposed switch of loratadine to OTC
3 status for the treatment of allergic rhinitis and
4 diagnosed chronic idiopathic urticaria can be successful.
5 Proper symptom identification by consumers
6 and pharmacists will be essential to appropriate use.
7 Each day pharmacists assist in the proper identification
8 of nonprescription medicines to treat a number of clearly
9 identified and easily treatable conditions.
10 OTC products have been used to treat allergic
11 rhinitis for many years. Expanding access to
12 non-sedating antihistamines will improve OTC management
13 of this condition. Currently we have no OTC options to
14 treat CIU. Approving loratadine for the OTC treatment
15 of previously diagnosed CIU after analysis of appropriate
16 studies of safety and efficacy and labeling comprehension
17 will improve management of this condition.
18 Pharmacists can help assure that consumers
19 using the product to treat CIU have had this condition
20 diagnosed by a physician, are not experiencing an acute
21 anaphylactic reaction, and are using this product
22 appropriately. I think those are some of the issues that
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1 came up this morning.
2 The success of the pharmacists efforts in
3 this role, however, will be directly related to the amount
4 of information available to them. Product labeling
5 should clearly articulate the situations where self care
6 or OTC use is appropriate and direct consumers to their
7 pharmacist or their physician when the use of the product
8 falls outside of label parameters.
9 Additionally, an extensive educational
10 campaign geared toward pharmacists to equip them with
11 the proper tools to identify triage and select OTC
12 treatment for CIU will be needed. Pharmacists are in
13 an excellent position to work both with physicians and
14 consumers as well as the industry and government agencies
15 to improve patient outcomes associated with
16 nonprescription medicines.
17 Whether it be by patient compliance
18 strategies, medication assessment, counseling on proper
19 usage and side effects, and identification of patients
20 who need therapy, pharmacists are committed to engaging
21 in activities to promote better healthcare for all
22 consumers.
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1 My comments today are supported by the action
2 taken by our APHA's House of Delegates which is our policy
3 making body for our association. In March of 2001 the
4 delegates debated and adopted policy on this issue. Our
5 adopted policy reads, "The American Pharmaceutical
6 Association as an issue of public safety encourages
7 manufacturers and the food and drug administration to
8 transition non-sedating antihistamines from prescription
9 to nonprescription status."
10 The nation's pharmacists encourage the FDA
11 and manufacturers of second generation antihistamines
12 to embark on a reasoned path to increase access to these
13 products. Thank you for your consideration of the views
14 of the nation's pharmacists.
15 DR. CANTILENA: Thank you, Dr. Engle. Our
16 third and final speaker in the public comment section
17 will be Dr. Joseph Ferguson.
18 DR. FERGUSON: Distinguished members of the
19 FDA, distinguished representatives of Schering, ladies
20 and gentlemen, including the man in the back who has been
21 snoring all day, I am very appreciative of this
22 opportunity to speak before you. It is truly an honor
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1 for me.
2 In the interest of disclosure, I have worked
3 as a consultant for Schering as well as Pfizer, the makers
4 of Zyrtec, and I am currently doing clinical research
5 for Adventis, the makers of Allegra.
6 I'm here today after a Schering
7 representative suggested that I speak at this meeting.
8 Neither Schering nor any other corporation nor
9 individual has offered compensation for my appearance
10 today. No one has stated or implied that I will be
11 rewarded in any way. My expenses for attendance at this
12 meeting will not be reimbursed.
13 I'll be speaking today for only a few minutes
14 and I'll limit my comments to the question of whether
15 loratadine should be allowed to have over-the-counter
16 chronic idiopathic urticaria indication. I will leave
17 to others the question of whether to broaden the
18 indication.
19 The title of the talk is, "To deny loratadine,
20 the over-the-counter indication for chronic idiopathic
21 urticaria, is to misinform the American people." It's
22 my opinion that a prescription antihistamine that has
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1 been proven to be effective in treating chronic idiopathic
2 urticaria should not have that indication striped simply
3 because the drug has been found to be appropriate for
4 over-the-counter use.
5 Instead, the antihistamines should have a
6 label that might read as follows, "This medication can
7 be useful in the treatment of chronic idiopathic urticaria
8 (unexplained hives that keep coming back). Anyone
9 considering the use of this product for urticaria (hives)
10 should first seek prompt medical attention."
11 I'll repeat that. "This medication can be
12 useful in the treatment of chronic idiopathic urticaria
13 (unexplained hives that keep coming back). Anyone
14 considering the use of this product for urticaria (hives)
15 should first seek prompt medical attention."
16 Such a label would be an education for the
17 American public. A man who has been using antihistamines
18 for what he thinks are recurrent hives would realize that
19 maybe it's time for him to check in with his primary care
20 doctor before he continues to self-treat.
21 So what if the man does not want to see his
22 physician? If a person who should be getting medical
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1 attention makes an informed decision not to do so, it
2 is not the place of our government to step in and force
3 medical attention on that person obviously.
4 Nor is it the place of our government to
5 withhold information from the public such as the fact
6 that a certain antihistamine was found to be safe and
7 effective in the treatment of chronic idiopathic
8 urticaria.
9 It is not the place of our government to
10 withhold information from the public just because there
11 are people who would make informed but unwise decisions
12 with that information.
13 Nor is it the place of our government to seek
14 out those who are eating too many cheeseburgers and send
15 in nannies to make them eat broccoli. It just doesn't
16 make sense.
17 I would appreciate it now if you would allow
18 me to finish this talk by indulging in a bit of
19 speculation, speculation about an America in which
20 loratadine has been approved for over-the-counter use,
21 but the makers of loratadine have been forced to keep
22 quiet about the fact that the drug has been found to be
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1 safe and effective in the treatment of chronic idiopathic
2 urticaria.
3 A woman, a long-distance truck driver, has
4 chronic idiopathic urticaria. She has seen her physician
5 who has ruled out the dangerous causes and a prescription
6 antihistamines has been quite effective in controlling
7 her symptoms over the years.
8 But here she is now. She's 2,000 miles away
9 from home and she is struck with the most ferocious case
10 of hives she's ever experienced and she realizes that
11 she forgot to bring her prescription antihistamines.
12 She is itching like crazy. It's even dangerous for her
13 to be driving but she manages to make it to a truck stop.
14
15 She runs inside and she finds the isle with
16 the allergy pills. She picks up a body of loratadine
17 which is the only one that doesn't put her to sleep, and
18 she is crestfallen when she realizes that that bottle
19 says that this medication is only for runny nose type
20 symptoms, not hives.
21 Clawing at her skin she slumps back to the
22 truck and figures she'll drive and get in touch with her
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1 doctor in the morning. She shutters. It's going to be
2 a long night.
3 Distinguished members of the FDA,
4 representatives of Schering, ladies and gentlemen, thank
5 you so much for your time and attention.
6 DR. CANTILENA: Thank you, Dr. Ferguson.
7 Before we get to the open committee
8 discussion, what I would like to do is offer the members
9 of the committee an opportunity to get an unanswered
10 questions, anything that they would like to ask of the
11 sponsor or of the FDA presenters, anything that was not
12 completely covered in their minds this morning that they
13 would like to first obtain information before we get into
14 the open discussion. Does anyone have any questions?
15 DR. DYKEWICZ: I would like to follow up a
16 bit on some of the data that was discussed earlier about
17 the actual usage of medications when there has been a
18 stipulation or a statement within the product labeling
19 for the patient not to use it. I believe the example
20 that was given was for the antifungal products to be used
21 for vaginal infections.
22 It really gets at the whole question about
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1 actual usage versus what is being placed upon the product
2 labeling. We know apparently in that particular
3 over-the-counter usage that many patients are using the
4 medication, if you will, inappropriately despite the
5 statements.
6 Now, in terms of label comprehension, is the
7 FDA aware of any studies that show that people or women
8 were appropriately understanding what the label said but
9 despite that went forward and used it inappropriately
10 anyway?
11 DR. KATZ: Back when these products first
12 went over the counter, there actually were no label
13 comprehension or actual use studies for the vaginal
14 antifungal products. There have subsequently been some
15 literature that has been published suggesting that, in
16 fact, there are a group of women who may be using the
17 product inappropriately. Not all women who are using
18 the product have previously seen a physician and have
19 had a previously diagnosis.
20 We don't really have the data that would
21 correlate how well they understood what was in the label
22 and if the reason why they are using the product is that
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1 they didn't understand the labeled instructions, or that
2 they had just chose to use the product because they thought
3 that they really had a vaginal yeast infection even though
4 they have never actually been diagnosed as having one.
5 DR. CANTILENA: Okay. Dr. Alfano next and
6 then I saw another hand.
7 DR. ALFANO: Yes. The sponsor presented
8 some data and Dr. Ganley referred to it that 62 percent
9 of people with CIU self-medicated prior to a physician
10 diagnosis.
11 My question either to the sponsor or to the
12 agency is do we know what percent of people with acute
13 hives premedicate seeking medical attention?
14 DR. CANTILENA: Dr. Clayton, would you like
15 to try that one?
16 DR. CLAYTON: We do not have that specific
17 information, but since these individuals use an OTC
18 antihistamine prior to diagnosis, we will assume that
19 episode was an acute episode but it was prior to a
20 physician diagnosis of CIU.
21 DR. CANTILENA: Dr. Ganley, is there any
22 other information that you have other applications or
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1 products? Okay.
2 Dr. Joad.
3 DR. JOAD: I was curious for the FDA about
4 how they felt in general about the general concept of
5 having a drug OTC that prior to that they had to see a
6 physician one time for a diagnosis and then thereafter
7 everything should be OTC.
8 That strikes me as something I wouldn't like
9 very much because I would like to see a patient back so
10 I could have another shot at that diagnosis if I was wrong.
11 Is that something you plan to do in general or are you
12 comfortable with it and is it a direction for the FDA?
13 DR. GANLEY: Actually, that's what we were
14 hoping you would answer for us today. I think, though,
15 if you really -- you know, that's why it's pivotal to
16 try to think of this spectrum of patients that are going
17 to take it and try to figure out what's the down side
18 of that.
19 I think it would be every difficult based
20 on just the facts that we know in this case to ever create
21 any label that unequivocally is going to ensure that
22 people only with CIU are going to use this product. I
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1 think it's virtually impossible to do that.
2 That's why it becomes important to understand
3 what is the frequency and significance of these other
4 conditions such as angioedema that may be associated with
5 urticaria or acute urticaria. Is that acute urticaria
6 somehow different than this population of chronic in terms
7 of the frequency and severity of conditions.
8 I think it would be difficult based on the
9 facts we have that people already use it and there's a
10 perception out there that you can use it for these
11 conditions to just believe that we are going to limit
12 it by putting something on a label.
13 In the converse then if you go down a path
14 that says this could be just for the treatment of hive
15 and then you actually put in labeling or something that
16 defines the parameters of when someone needs to see a
17 physician, repeated episodes and daily for seven days.
18 I think we are having the cart lead the horse here where
19 you're saying that it's only this population that has
20 a diagnosis of chronic urticaria.
21 Actually if you put on a label that it's for
22 recurring episodes of hives and people just ignore that
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1 they should see a doctor for that actually to get a
2 diagnosis of exclusion, then you may have people that
3 actually use it thinking this is for recurring hives.
4 DR. CANTILENA: Dr. Temple.
5 DR. TEMPLE: In some sense this is an issue
6 that arises every time you make an OTC switch whether
7 it's heartburn that may or may not have been bad esophageal
8 disease or the use of low-dose hydrocortisone
9 preparation. Prior to their availability over the
10 counter, there was always a doctor intervening and
11 deciding whether this was serious enough to require
12 recurrent visits.
13 Every time we do that, that is why we have
14 public discussion of whether it seems like the same thing.
15 The vaginal anti-candidiasis drugs was a very difficult
16 one for us. As you may remember, we turned it down several
17 times before we finally concluded it was okay. This is
18 not unfamiliar territory. That's why we need advice.
19 DR. JOAD: Just as a follow-up, it seems to
20 me different between saying somebody can diagnose
21 themselves and, therefore, they go get the OTC versus
22 it's complicated enough that a physician has to diagnose
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1 it but then now it's OTC. Those seem like very different
2 things to me.
3 DR. TEMPLE: You mean the explicit
4 requirement that it be diagnosed first?
5 DR. JOAD: Right.
6 DR. TEMPLE: That's why the vaginal
7 candidiasis was just a problem because that's what the
8 labeling said and obviously people knew that not everybody
9 would go to the doctor first for that.
10 There had been a view that dermatosis that
11 might be steroid sensitive ought to be considered the
12 same way, that you ought to go to the doctor and find
13 out what to do first. We have survived switching them,
14 at least for low-dose drugs, to let patients give
15 themselves a crack at it. But that's why it's hard.
16 DR. CANTILENA: Yes, Dr. Clapp.
17 DR. CLAPP: I have two questions. First,
18 could someone from the FDA addressed the data from the
19 UK and Canada. As I recall, since 1990 Canada has had
20 hives as an OTC indication for use. They mentioned that
21 there were no adverse effects noted in Canadian
22 literature. Could you address that more precisely in
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1 the UK? That's the first question.
2 DR. GANLEY: The data I think you may be
3 referring to, and you can correct me if I'm wrong, is
4 the data that Dr. Lee had talked about, and that was
5 information that had actually been reported. We focused
6 mainly on serious adverse events.
7 As he had said, there were some cases of
8 anaphylaxis and things like that. I think one of the
9 difficulties, and it's a problem in this country as well
10 as in Canada and the UK, is the reporting of these events.
11 You have to have -- there has to be some type of faith
12 in that things are going to get reported that may be a
13 problem.
14 I think there are some cases that Dr. Lee
15 had talked about which is of some concern, if people would
16 actually have food allergies and think that mistakenly
17 that you could prevent the allergy by just taking the
18 medicine and you may end up with numerous cases like the
19 woman who ate the seafood pizza. She took it after the
20 fact.
21 Here, though, if you have a drug on the market
22 where they are advocating use for allergy or urticaria,
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1 is this going to create a problem and how do you -- it's
2 really coming down to if it is a problem, how can you
3 prevent that problem whether it's through labeling or
4 education or whatever.
5 DR. CLAPP: What I was interested in the
6 Canadian experience.
7 DR. GANLEY: As I said, there are cases of
8 anaphylaxis that have been associated with the use of
9 the drug for the treatment of urticaria. Unless you have
10 more specific, clearly that is one of the issues here
11 is what are the significant adverse events. We would
12 be less concerned with very minor adverse events if
13 someone reports a headache or anything like that.
14 DR. CLAPP: I certainly understand that.
15 What I was wondering is in the body of research that you
16 have gleaned from, UK and Canada, whether or not there
17 have been a significant number of adverse events, serious
18 adverse events reported because of the longevity of their
19 experience having used it as an over-the-counter drug
20 for hives. I don't think they mentioned recurring hives
21 but included hives as well as seasonal allergic rhinitis
22 as an indication.
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1 DR. KATZ: I think the question that you're
2 asking, we can only give you some sketchy information
3 because we don't keep track of other countries' adverse
4 event data. We do have one table that was provided to
5 us but the total end that they provide for the adverse
6 events is an end of 26 so we're talking a low number.
7 Now, I can't tell you over what period of
8 time it is because it doesn't state in the information
9 that's here. But if you look at it, actually it looks
10 like there may be a response from Schering. The adverse
11 events that are being reported here would be things along
12 the line of pain, dyspepsia, headache, urticaria
13 aggravated abdominal pain, back pain.
14 All of these are numbers that are less than
15 three or three and below. Again, it doesn't really help
16 you because I can't put it into a perspective of what
17 time frame we're talking about. If this is coming from
18 their adverse event reporting like our Medwatch system,
19 you don't have a denominator.
20 The numbers are low and the reporting system
21 is whatever gets reported back. There doesn't look like
22 from this that we have that there is anything that would
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1 be unusual or unexpected as compared to our own database
2 where the product is Rx.
3 DR. CLAPP: Thanks. I would like Dr.
4 Chowdhury to address some data he mentioned. In the
5 literature we received it said 79 percent of those who
6 read the labels incorrectly mentioned or identified the
7 use of the drug for just hives, not the CIU indication
8 that is being promoted by the drug company.
9 In that the interest is inadequate directions
10 for use, how does the FDA feel comfortable representing
11 this drug without addressing the fact that most of those
12 who use it will likely use it incorrectly? Should we
13 address the fact in the direct way that the likelihood
14 is that most of those who use it will use it incorrectly
15 and then guide them in appropriate usage of the drug?
16 DR. CANTILENA: I think that was to Dr.
17 Chowdhury. Is that correct?
18 DR. CHOWDHURY: Is it directed to me? I was
19 not really present on the use study.
20 DR. CLAPP: You did mention that the
21 likelihood was that it was going to be used
22 inappropriately in your presentation.
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1 DR. CHOWDHURY: Correct. That was a
2 statement that I made, that if the drug is going to be
3 made over the counter for chronic idiopathic urticaria,
4 as we have been talking about this indication, the drug
5 possibly is going to be used for all kinds of urticaria.
6 DR. CLAPP: With that likelihood, as you
7 mentioned, you said the likelihood was that it would be
8 used for broader indications or other indications for
9 acute urticaria. I think the next gentleman mentioned
10 the label study quoting 79 percent of those who read the
11 label as identifying its use incorrectly as for acute
12 hives or any type of hives.
13 How do you reconcile giving the public
14 appropriate guidance in the usage if we are pretty clear
15 on the fact that it won't be used correctly by the majority
16 of those who purchase the drug?
17 DR. CANTILENA: Sure. Dr. Wood will comment
18 on that and then we'll go to the sponsor. I think they
19 have a comment.
20 DR. WOOD: I think we have to be careful about
21 saying it's being used incorrectly. I think we need to
22 define that. That was sort of the interaction that Lloyd
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1 and I had before lunch.
2 DR. CLAPP: Not for the indication as the
3 CIU indicates.
4 DR. WOOD: Well, hang on. The CIU, they are
5 going for a limited indication. That doesn't mean that
6 the other indications will be incorrect, No. 1. No. 2,
7 incorrect implies a sort of value judgement that if you
8 were to give it for these other indications, something
9 bad would happen to you.
10 That was what I tried to put light on this
11 morning. I guess the response I got was that nothing
12 bad does happen to you if you use it for these other
13 indications. The acute urticaria may not be an
14 appropriate indication.
15 It's just that it is impossible. As I
16 understood the responses, it's just that it's impossible
17 to study. At least to me, we're not exposing people to
18 increased risk because of that which seems to me the
19 absolute clear bottom line.
20 DR. CLAPP: I agree but my question is are
21 we guiding them on how to use if appropriately? Are we
22 giving them some indication and guidance for the use other
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1 than CIU and recognizing clearly that most of it will
2 be used for the non-CIU indication. Is that a
3 responsibility to then appropriately direct them for the
4 usage in other than the CIU indication? That's my
5 question.
6 DR. CANTILENA: Right. I think that's a key
7 point. Dr. Temple and then Dr. Clayton from the sponsor.
8 DR. TEMPLE: Dr. Ganley wasn't trying to push
9 anybody around but if you read his review, he's clearly
10 interested in a labeling that goes toward a more general
11 statement about urticaria than about the CIU. Part of
12 the reasoning, I think, is just that. A lot of the use
13 is going to be for people who don't meet that test.
14 If labeling is directed toward that, you are
15 better able to give the best advice you can. Charlie
16 may want to say more about that but that is really one
17 of the questions here. Do you pick out something that
18 happens already to be in the Rx labeling so it's nice
19 and solid and you don't have to worry about where the
20 evidence is even if you know people will use it outside
21 that which, as Alastair said, is not necessarily the wrong
22 thing to do.
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1 It's just not the labelled thing to do. Or
2 do you try to write a broader indication and do you have
3 the data that allows you to do it and then give advice
4 that corresponds to how it is actually going to be used.
5 I think if you read his review, he raises that very
6 question also.
7 DR. CANTILENA: Yes, Dr. Clayton.
8 DR. CLAYTON: There's a number of questions
9 on the table since I stood up. I really stood to try
10 to clarify the Canadian experience if that was still
11 needed. I think Dr. Katz helped to put that in
12 perspective. The database was with the 10 years of
13 marketing experience since the product was launched in
14 Canada so it is over quite an excessive time period.
15 The adverse event experience tracks very
16 clearly the experience with allergic rhinitis overall
17 with types of adverse events, both the prescription
18 experience and the OTC experience, CIU, and allergic
19 rhinitis. We can address specifically the numbers if
20 there is still confusion if that would help.
21 I think there is also a question about the
22 survey in terms of the respondents who answered
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1 incorrectly. The 79 percent number was of the 30 percent,
2 the 79 percent of the 30 percent who answered incorrectly.
3 If there is any confusion there, hopefully that can help
4 to explain it.
5 Is there any value in pursuing the Canadian?
6 We could get into the specifics if that is still an issue.
7 DR. CANTILENA: No. I think that is
8 probably okay of that's all right with you, Dr. Clapp.
9 Dr. King.
10 DR. KING: I'm just reminded that all these
11 kind of things they've gone through often times you say
12 you have to see your doctor first so it's like justice
13 delayed is justice denied. Denying people access to
14 these medications brings up the issue of education and
15 accessibility.
16 Dr. Engle's presentation that pharmacists
17 are in a primary position to be available 24/7 and then
18 to advise folks there, there is a counterweight to that.
19 People either go to the emergency room or they go to
20 the pharmacist in general. They may stop at truck stops.
21 I'm not in that crowd.
22 Anyway, it seems to me the issue is if we
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1 are going to talk about why would the FDA considering
2 broadening the indications, we have to talk about what
3 are the real indications and what is the real affect.
4 It seems to me if you have available a system
5 of pharmacists, the change of labeling and just basically
6 a good old fashioned spin of TV and web kinds of things
7 where you educate the public, I think everybody has a
8 right to do something dumb and stupid. Just because 40
9 million people do something dumb and stupid, it's still
10 dumb and stupid.
11 I'm not going to get into that issue. I think
12 the issue is education and accessibility. I think there
13 is everything on the table to think about maybe broadening
14 it through access and to general limitations on this
15 application are not going to work.
16 I think people are going to take what they
17 want to take and have a system of pharmacist and education
18 and labeling actually could improve the overall use of
19 this drug and prevent lots of people not doing something
20 dumb and stupid.
21 They will know in multiple directions from
22 the label, from the pharmacist, and their back door
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1 neighbors. They are likely to get much better care than
2 they are right now.
3 DR. CANTILENA: Yes. Dr. Ganley, do you
4 have any idea in terms of the amount or the percent of
5 over-the-counter drugs that are actually sold outside
6 of a pharmacy like in the truck stop or the gas station?
7
8 DR. GANLEY: No, we don't have any
9 information like that.
10 DR. UDEN: Dr. Engle's talk had a reference
11 in there that 61 percent of prescriptions are purchased
12 in a pharmacy.
13 DR. CANTILENA: Thank you, Dr. Uden.
14 DR. UDEN: Not of prescriptions. All of
15 prescriptions are purchased in a pharmacy. You mean OTC
16 meds.
17 DR. CANTILENA: Yes.
18 DR. SZEFLER: I'm going to ask a simple
19 question, and maybe I missed it in the reading, but if
20 loratadine was not going up for OTC and if they presented
21 these two studies for chronic idiopathic urticaria, would
22 that be sufficient to approve labeling for prescription
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1 use?
2 DR. CHOWDHURY: Yes.
3 DR. SZEFLER: For that indication.
4 DR. CHOWDHURY: For chronic idiopathic
5 urticaria. Those studies were the basis for approval
6 for chronic idiopathic urticaria.
7 DR. SZEFLER: Okay. So you don't have any
8 trouble in terms of its indication for that?
9 DR. CHOWDHURY: That's correct. For
10 indication only.
11 DR. WOOD: It's already approved for that.
12 That needs to be clarified.
13 DR. CHOWDHURY: I mean, that was a question.
14 DR. WOOD: Right.
15 DR. CHOWDHURY: Were the two studies
16 adequate for approval for chronic idiopathic urticaria
17 and the answer is yes, there are two.
18 DR. CANTILENA: And how about in terms of
19 the indication of just hives in general? Do you have
20 efficacy data that would support that indication?
21 DR. CHOWDHURY: Well, I mean, currently
22 Claritin is not approved for anything beyond symptom
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1 control of chronic idiopathic urticaria. That really
2 has not been an application. In other ways would those
3 studies be adequate just to give their approval in a
4 prescription setting for urticaria of other kinds? The
5 answer possibly is going to be no without really probably
6 going into the full rationale for that and --
7 (Whereupon, off the record.)
8 DR. CHOWDHURY: -- which perhaps can be done
9 for other types of urticaria.
10 DR. CANTILENA: So the purpose of -- I mean,
11 sort of question 1A then, you don't have efficacy data
12 that would support an indication of hives then?
13 DR. CHOWDHURY: That is a question, I think,
14 for the committee to discuss, but there is no data outside
15 the chronic idiopathic urticaria.
16 DR. CANTILENA: Thank you.
17 Dr. Wood.
18 DR. WOOD: I think we are sort of getting
19 hoisted by a patod that goes something like this, that
20 when drugs are approved for prescription indications,
21 they are approved on the basis of the studies that were
22 done with sometimes incredibly complex. If you think
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1 of some of the heart failure indications, some of the
2 indications there were incredibly complex based on the
3 studies that were performed.
4 Once you try to translate that into an
5 over-the-counter indication, it seems to be we need to
6 be less rigid. There is little point just because CIU
7 was the prescription indication insisting on that wording
8 in an over-the-counter label. It seems to me
9 counterproductive and doesn't serve patients well.
10 I think we need to step back from a rigid
11 position that says this is what the study said, this is
12 what the definition was in the paper that was published,
13 and move towards the sort of, if you like, the Tennessee
14 view that preferred earlier on.
15 We need to translate it into words that mean
16 something to patients. I don't think CIU, which is now
17 being tossed around here as though we use that term
18 everyday, is really going to be helpful to the majority
19 of patients who walk into Dr. Engle's Walgreens or
20 whatever.
21 DR. CANTILENA: Dr. Temple.
22 DR. TEMPLE: Based on conversations among
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1 the people at FDA at least who are supposed to know about
2 these things, it seems quite uncertain as to whether we
3 would think new data would be needed for a claim of simple
4 hives or not.
5 Mechanistically there's a belief that we're
6 talking about the same thing. I don't want to dismiss
7 the concern, although I think Alistair is right. Maybe
8 you owe some practical look. I don't think there has
9 been an internal decision that we don't have that data
10 or do and it's something we need to think about. I'm
11 sure advice would be welcome.
12 DR. WOOD: Bob, the issue I think is not the
13 one that you're dwelling on. For the average person they
14 would translate -- they would see urticaria and hives
15 as being words of equivalent meaning, hives being a word
16 that is much more in widespread use than urticaria in
17 the population that is going to buy drugs over the counter.
18
19 I don't think we should force ourselves into
20 a box that says the only vocabulary that can be used for
21 the label is the vocabulary that was used in New England
22 Journal that got the drug approved for Rx indication.
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1 That's different from the -- that's one
2 issue. Then the acute hives is an additional argument
3 that can be entered into. Just translating urticaria
4 into hives doesn't seem to me to need a study.
5 DR. TEMPLE: No. That's perfectly right.
6 If people eventually concluded that CIU was a really
7 distinct disease from one episode in response to
8 something, then you would have to ask do those data apply.
9 That seems like a legitimate question, but I don't
10 believe there's an agreed on answer internally yet. It
11 does appear that there haven't been any, or very few at
12 best, actual studies of acute episodes of hives.
13 DR. WOOD: But you would be comfortable with
14 chronic idiopathic hives?
15 DR. TEMPLE: Oh, I don't think anybody mines
16 that.
17 DR. WOOD: As idiopathic would mean very
18 little to most people, you would be prepared to drop
19 idiopathic?
20 DR. TEMPLE: No. Whether you translate the
21 language that you do think you have -- sorry, the disease
22 that you do think you have data for into a different
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1 language is the sort of thing you have to think about
2 all the time.
3 There's always worry about whether people
4 understand your indications. There is a separate
5 question of whether there is a different disease here.
6 I certainly have no opinion but there was a divided view
7 when we were talking about it, or an unsettled view anyway.
8 DR. CANTILENA: Okay. Dr. D'Agostino and
9 then Dr. Wilkin.
10 DR. D'AGOSTINO: Yeah. Well, some of my
11 comments have just been aired there. I don't see any
12 problem with having hives being used for this condition
13 when we're talking about long-term and so forth. My
14 difficulty comes with the acute. If hives is being used
15 in just a generic sense, it encompasses the acute also
16 and what do we have on that.
17 When I started with the FDA back in the '70s
18 they used to have this grasp, "Generally recognized as
19 safe and effective." I hear a lot of that going on here
20 that somehow or the other the field is comfortable with
21 the use of the drug. I don't know enough about the process
22 and what have you to object to that.
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1 I think that in many ways once we move to
2 hives, to me that's our real issue, do we have enough
3 sense that the acute is going to be included. If we don't,
4 then I think we are going to get ourselves in a real bind
5 with how to handle that with new studies and what have
6 you.
7 DR. CANTILENA: Dr. Wilkin.
8 DR. WILKIN: Yeah. I actually have a
9 concern that some patients who have CIU suffer from a
10 nomilism kind of issue that if they are told they have
11 chronic idiopathic urticaria, they think they have
12 something that is fairly specific. What they really
13 have, as you have translated it, the urticarial hives.
14 Idiopathic means they had a workup but nothing was found.
15 Chronic means it's been there longer than six weeks.
16 Maybe it's because I trained in Tennessee
17 but I've always had the notion that you call it chronic
18 idiopathic urticaria perhaps because you can charge more
19 than if you say you have hives, you've had it longer than
20 six weeks, and I don't know what it is.
21 There's a point to this. It could be many
22 different kinds of things still. Calling it CIU is not
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1 a thing. It is the residue after you've taken the things
2 that you know out.
3 DR. WOOD: Right.
4 DR. D'AGOSTINO: Are you answering my
5 question? Are you saying that acute hives is really just
6 the same and it's all vocabulary?
7 DR. WOOD: No. That's a different question.
8 There are two questions on the table. One is, is acute
9 hives the same as chronic hives in terms of response.
10 I think the answer to that is we don't know. At least
11 that is the answer I'm hearing.
12 The second question is does telling a patient
13 that they have chronic idiopathic urticaria, which
14 translated into the vernacular means chronic, it's been
15 there for a while, idiopathic meaning the physician
16 doesn't know what's causing it, and urticaria being hives,
17 if you translate that into you've got chronic hives and
18 forget that the physician doesn't know what caused it,
19 I don't see that adds much or loses much frankly.
20 DR. D'AGOSTINO: I think that's great. I
21 think it's the acute hives that --
22 DR. WOOD: We can show results on the issues
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1 if we take some of them and deal with them, I think.
2 DR. CANTILENA: Yes, Dr. Rosenberg.
3 DR. ROSENBERG: If I may, I'll try and answer
4 what I think is a good question. Is acute urticaria one
5 thing and chronic idiopathic urticaria another thing,
6 or is it just that chronic is the same thing but we still
7 haven't figured it out?
8 In preparation for this meeting, I tried to
9 do some reading and I must say I was very taken with this
10 supplement to the Journal of Investigative Dermatology
11 which is our premier research journal.
12 It's the official journal of both the
13 European Society for Investigative Dermatology and the
14 American one. This was released in November 2001. It's
15 the account of a proceeding held in Europe the preceding
16 year, I must say, under the auspices of the -- in Berlin
17 in the year 2000.
18 Somewhere it mentions that the UDC company
19 sponsored this meeting. It has really all the very good
20 people from Europe, or many of the very good people from
21 Europe there. I know these names and I know some of these
22 people.
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1 They say that acute urticaria you usually
2 know the cause. Maybe not the first time but the second
3 time. It hits very quickly and the sufferer can get an
4 idea what's happened, or somebody makes sense of it very
5 quickly.
6 Apparently the feeling here, and they are
7 quoting work from Switzerland and Berlin, it's a bonafide
8 allergy and there's an instant reaction. It's on and
9 off. The juxtaposition in time makes it.
10 The word that was unfamiliar to me turns up
11 in here called pseudo-allergy. Most of the other
12 material -- I can show some of this stuff in a little
13 bit. Most of the other that accounted for what we are
14 calling chronic idiopathic urticaria is not that kind
15 of an immediate reaction. It does not show up on the
16 allergy skin test.
17 In fact, what it is it's all the other
18 material that was on Jonathan's slide that he showed where
19 all the other parts of the immune system come into play
20 and act on the final cells including the mass cells rather
21 than just the particular allergen.
22 That's an explanation for why analgesics --
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1 it's not just aspirin. It's things that look and work
2 like aspirin all seem to do it. They divert the immune
3 response system somehow. There's work in here that if
4 it's really a food to which you are allergic, or a product
5 which you are allergic, you are better in a few days when
6 you stop it.
7 But if you're dealing with what they are
8 calling pseudo-allergy, you have to be off the food or
9 whatever and certain natural foods. Tomatoes are
10 mentioned and others that have these properties in some
11 people. You have to be off of it for some months.
12 There's one claim in here that patients who do this
13 conscientiously that 60 percent get better which is much
14 better than anything we are doing over here.
15 Again, I'll keep reverting to the enormous
16 use of prednisone in the practice of medicine in all the
17 different specialties for this condition. It's
18 inappropriate in my opinion. Thank you.
19 DR. CANTILENA: Is there a comment from Dr.
20 Monroe, the sponsor?
21 DR. MONROE: I would just like to say that
22 I'm not from Tennessee but I'm going to try and make this
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1 as simple as I can. I view urticaria as a spectrum of
2 a disease and it can be classified as acute or chronic
3 and that is a totally arbitrary time limit.
4 As Dr. Wilkins pointed out, the basic
5 pathophysiology of all urticaria is that slide he showed
6 with the mass cell at the center, the release of the
7 mediators, multiple mediators, but the best documented
8 mediator is histamine and that's the same in acute
9 urticaria, that's the same in chronic urticaria, that's
10 the same in chronic idiopathic urticaria.
11 I think if you're looking at what's going
12 on, there's a common theme. Are there differences? I
13 think you alluded to some excellent differences. If any
14 chronic idiopathic urticaria is a more complex
15 pathophysiology where you've got a cellular and
16 inflammatory response on top of the more simplistic acute
17 urticarial response. That's what makes that subset any
18 harder to treat.
19 I think the message that I would carry away
20 is histamine is the mediator involved in the whole
21 spectrum. We have different causes on the acute side.
22 They are usually identifiable causes but what we're
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1 treating is the symptom that is being generated by the
2 release of the histamine.
3 We're not curing the problem. The reason
4 acute urticaria is an easier problem is we can usually
5 identify the cause and move it out. The drug therapy
6 is totally symptomatic to affect what has already been
7 released whether it's acute or chronic.
8 To me the issue of are antihistamines, H1
9 antihistamines, going to be effective in acute. The
10 answer is they are the standard of care approved in all
11 algorithms published by the leading specialties in
12 allergy and dermatology where urticaria is in their domain
13 heavily. I think clearly that is the way to treat.
14 It is very difficult, however, to do a
15 scientifically controlled study in acute urticaria
16 because it's a very self-limited short disease. Again,
17 if you look at the basic underlying chemical that is
18 causing the problem, it's histamine.
19 If you look at the accepted standards of care
20 it's H1 antihistamines. If you look at the real world,
21 most of those patients are self-treating, never seen a
22 doctor, and using much less safe medicines with side
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1 effects right now. I think we have clear scientific
2 evidence that urticaria as a whole has the same basic
3 mediator and the same first line treatment.
4 DR. CANTILENA: Okay. Thank you. Dr.
5 Davidoff.
6 DR. DAVIDOFF: This has been a very
7 interesting somewhat academically oriented discussion
8 and through a rather sort of tunnel vision, it seems to
9 me, in terms of the broader problem. I think that the
10 average person coming into the drug store with a skin
11 problem that's bothering them because it's itchy and maybe
12 somewhat red isn't going to be trying to make this fine
13 distinction between is it acute hives or is it chronic
14 hives.
15 I suspect that -- well, I guess my question
16 really is are there data on how the general public decides
17 to call something hives? My suspicion is that they
18 frequently refer to something as hives that a
19 dermatologist or an internist or family practitioner
20 would not call hives. Even if you use hives as the word
21 on the package, my question is how frequently will that
22 be helpful in guiding people?
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1 The flip side of that question is since a
2 great fraction of all skin conditions itch, are there
3 data on how frequently that itch is relieved in things
4 other than hives by antihistamines? If they are
5 frequently relieved, then that's going to be positive
6 reinforcement they will continue taking it and then not
7 be seeing the dermatologist or whoever to try to get a
8 proper diagnosis made.
9 I wonder if there are data in those two areas?
10 How do people define something as hives and how often
11 is that correct? Secondly, how often do non-hives and
12 itchy skin conditions respond to antihistamines?
13 DR. ROSENBERG: If I could answer that. The
14 antihistamines are really not very good for itch per se.
15 They are not very effective atopic dermatitis. They
16 work more as sedatives, the more sedating the better.
17 They are really not -- atopic dermatitis doesn't go this
18 way or it's got a little piece to it. Eczema Dr. King
19 says for those.
20 This really is a histamine induced disease,
21 as Dr. Monroe has said. The antihistamines really shine
22 here. This is where they have a place in treatment of
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1 itch.
2 DR. CANTILENA: Yes, Dr. Lam.
3 DR. LAM: I still have a concern that
4 consumer is placed a tremendous burden in terms of knowing
5 not to use the product without seeing a physician. Usage
6 data from fungal vaginitis would suggest that's not the
7 case.
8 My question to sponsor is given this fact
9 of all the educational program that they have proposed
10 in slide No. 78 in the presentation, in their experience
11 which one actually is most successful in terms of reducing
12 this type of misuse behavior? If none of them is
13 reasonable or successful, do they have any innovative
14 program on the drawing board?
15 DR. CANTILENA: Dr. Clayton, would you like
16 to address that for Dr. Lam?
17 DR. LAM: Do you want me to repeat the
18 question?
19 DR. CLAYTON: Yes, please.
20 DR. LAM: Of all the educational program that
21 they have proposed in slide No. 78 in the presentation,
22 in their experience which one actually is most successful
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1 in terms of reducing this type of misuse behavior meaning
2 that they should actually not use it without seeing a
3 physician and if none of them is appropriate or
4 successful, do they have any innovative program on the
5 drawing board?
6 DR. CLAYTON: We have used this approach with
7 prescription drugs. We have not used it to this point
8 with OTC drugs. We'll be building off of that experience.
9 I don't think that there have -- I'm not aware of any
10 test data that point out which path is the most successful
11 but rather a combination of approaches to achieve the
12 end result. Education is clearly key.
13 There has been a lot of discussion about
14 experience with vaginal yeast products and has been a
15 success, I believe, on migraine which uses the very same
16 approach. I think it is important to point out that the
17 experience now 11 years OTC with vaginal yeast products
18 has been a very positive one in terms of the safety
19 experience.
20 There are certainly cases we acknowledge of
21 failure to achieve a physician diagnosis in advance.
22 There are studies out there also that support that the
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1 incidence of inappropriate use is low.
2 There are also studies that show people
3 self-treat with home remedies at a fairly high percentage
4 that tend to do harm. I think it's a combination of
5 various approaches to education to really work toward
6 solving the problem.
7 DR. CANTILENA: Yes, Dr. Sachs.
8 DR. SACHS: Anyway, it seems like we are kind
9 of circulating around the main issue which would be that
10 if we agree that an OTC indication for CIU would be given
11 that were basically kind of approving it for a more broader
12 indication of hives, versus the other which would be to
13 just continue it for the allergic rhinitis indication
14 and educate the affected patients who are seeing their
15 doctors anyway, that would be permissible to take
16 something that's already OTC for their condition which
17 is kind of a backhand look at it, okay?
18 DR. UDEN: Dr. Sachs, do you believe that
19 if Claritin went OTC for allergic rhinitis that if they
20 went to see their physician, they wouldn't walk out with
21 a prescription for Clarinex instead?
22 DR. SACHS: Actually, I don't like writing
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1 prescriptions so it would be recommended at least in my
2 practice.
3 DR. CANTILENA: Yes, Dr. King.
4 DR. KING: I guess if I understand that
5 you're saying that if we left it like that, you're going
6 to encourage the physician to promote the off-label use
7 of a drug? I don't think the FDA would want to be in
8 that position if you understand what I'm saying. Either
9 it's a yes or no.
10 DR. SACHS: If it was approved over the
11 counter for the indication of allergic rhinitis and it's
12 also approved for chronic idiopathic urticaria, then
13 would it have two classes, I guess. At a practical level
14 I didn't think it would.
15 DR. KING: I just have that problem. I think
16 there is one way to get some data here. One of the things
17 I thought about is that the most common cause of workman's
18 compensation claims are for skin problems. The most
19 common workman's compensation disability is for joint
20 and muscle pains.
21 There's a whole batch of data from the NIOSH
22 and so forth and companies who are in a financial position
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1 to keep up with nurses and the workforce and so forth.
2 I think you could get at that database for how many
3 patients had itchy rashes, whether it's urticaria or it's
4 contact allergy or irritants from manufacturing or
5 whatever.
6 I think the FDA is not in a position
7 necessarily to talk across the government lines, but I
8 think there is a database there we are just ignoring
9 because there's going to be a whole lot of antihistamines
10 and a whole lot of other things given for workman
11 compensation kind of things so I think we could look at
12 that. I just don't want to get in a position recommending
13 that physicians do with federal sanction off-label use
14 of drugs. That puts everybody at risk.
15 DR. CANTILENA: Yes, Dr. Johnson and then
16 Dr. D'Agostino.
17 DR. JOHNSON: I have a couple questions that
18 I would like the dermatologist to answer and then the
19 latter question I would like the sponsor to also address.
20 The first centers around what the actual need is for
21 the physician diagnosis in most of these situations.
22 Is it, in fact, necessary to be diagnosed or will most
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1 people if they self-treat for a period of time and don't
2 have resolutions seek medical care anyhow? That's my
3 first question.
4 DR. KING: I'll start. One of the things
5 that keep allergists and dermatologists in business is
6 itching. People are just not going to ignore itching
7 for a long time. It's just one of Mother Nature's kind
8 of thing from the cave.
9 If you've got bugs on your skin, you start
10 itching and you're really going to go after it so I think
11 the dermatologists take the viewpoint it's often times
12 that you're just not ready access and that people are
13 going to self-treat first and then they are going to go
14 to primary care doctors or pharmacists or whatever.
15 I think the fundamental issue is that I don't
16 think it's a problem from the dermatologist point of view
17 saying you can't charge or you can't whatever. It's a
18 matter of access.
19 If people have it persistently, then you are
20 going to have to do the workup because there is this five
21 percent that have related to cancers, related to
22 connective tissue disease and so forth. We're at the
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1 end of a long tunnel and for my purposes, the land of
2 the rare, the rare is common.
3 I have a misperception of I don't see nearly
4 as many people with urticaria as the pharmacists do.
5 I have no problem with their education system, their
6 labeling system. When they get to me it's already tests
7 for thyroid, tests for other things so it's a very limited
8 population.
9 DR. ROSENBERG: If I could take a crack, the
10 question is is it all right if people should treat
11 themselves without prior diagnosis by a physician. I
12 have something I want to say about that.
13 First of all, there's the acute severe
14 urticaria that no one is talking about here. When it's
15 very severe, people know that it's severe and they medical
16 attention the only way they can get it which is in an
17 urgent clinic or emergency room or they dial 911.
18 We know that people in general make the right
19 choices. There are lots and lots of studies that show
20 that self-medicators have more education and do better
21 and have better health outcomes than people who seek
22 medical care on all occasions. The really bad cases that
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1 need epinephrine are not part of this system.
2 Now, there are two more cases. There's acute
3 urticaria that's not life threatening. All of a sudden
4 you've got itchy hives. You've never had it before.
5 Then there's the other case where you've had episodes
6 before and before and before and now you have it again.
7 Let's talk about the two of them. First,
8 acute urticaria. It's the first time you've ever had
9 it. It's hard to see a dermatologist without waiting
10 a couple of weeks for an appointment. I don't think I
11 see much acute urticaria except in family members and
12 in house officers and nurses.
13 To go back to this symposium that I'm so taken
14 with, it's a discussion of urticaria in general. One
15 of the items in here is a consensus statement, "The
16 Management of Urticaria - A Consensus Report" by these
17 professors from prominent people in Europe, Vienna,
18 London, Berlin, and so forth.
19 First, type of urticaria A, acute urticaria.
20 The standard treatment, non-sedating H1 antihistamine.
21 This standard treatment for acute urticaria is
22 non-sedating H1 antihistamine. That has a little
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1 superscript A which says, "Efficacy proven by double blind
2 placebo controlled studies," but I can't find the
3 references here in this paper. I'm sure it will show
4 up otherwise.
5 An alternative treatment, second choice for
6 acute urticaria is initially prednisolone 50 milligrams
7 a day for three days. You don't see many three-day
8 prescriptions around our way. That's their second choice
9 if this didn't help.
10 Next we go to chronic urticaria. The
11 standard therapy, the first therapy for chronic urticaria
12 according to these European professors, non-sedating H1
13 antihistamines, again with a superscript A, proven in
14 double blind.
15 The second standard treatment if that doesn't
16 work, increase the dose if necessary. Now there is a
17 list of alternative treatments. They are listed as
18 alternative treatments. I'll read down the list of them
19 because there are 12 or so. I'll go quickly.
20 Combination dapsone and pentoxiline,
21 combination H1 and H2 blockers, combination H1 blocker
22 and beta sapathomymedic (phonetic), i.e., terabutaline,
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1 combination H1 blocker and cykatrophic (phonetic) drug,
2 trisiclic (phonetic) antidepressant doxipen (phonetic),
3 danisol, stanisol (phonetic), lucotriantagonsis
4 (phonetic), selfosalozine (phonetic). Corticosteroids
5 come in after all this other. Cyclosporin A, wow.
6 Interferon, poova (phonetic), plasmaforesis (phonetic),
7 and immunoglobulants. The corticosteroids coming in
8 about 12.
9 Again, that data we saw from the company
10 showed that 40 percent of primary care doctors, that's
11 their first treatment, not non-sedating antihistamines,
12 not non-sedating antihistamines at a higher dose but
13 first. And 28 percent of the pediatricians and so forth.
14
15 I mean, if you talk in terms of what's the
16 worse thing that could happen if somebody got hold of
17 some of this, aside from the 911 cases, what's the worse
18 thing that could happen? They are right in line with
19 the European standard for both diseases and better than
20 they are going to get in most medical offices in the United
21 States of America.
22 DR. WOOD: But the worse thing that could
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1 happen is they go to the doctor. Isn't that right?
2 DR. ROSENBERG: If we force them to go to
3 the doctor because they can't get an over-the-counter
4 thing without waiting until a week from next Friday, yeah.
5 DR. CANTILENA: Did you have a second
6 question, Dr. Johnson?
7 DR. JOHNSON: My second question probably
8 is more directed at the sponsor. If I recall in the
9 background materials that we were provided, there was
10 an expert panel that was convened and it said that their
11 recommendation was to pursue or that the indication should
12 be limited to CIU.
13 I guess from what I've been hearing today,
14 is that because that expert panel really perceived that
15 there were risks associated with sort of the broader
16 indication or it just seemed to be the safer easier route
17 to pursue?
18 DR. CANTILENA: Yes, Dr. Monroe.
19 DR. MONROE: I was a member of that expert
20 panel. The expert panel simply addressed the issue of
21 taking the prescription indication over the counter and
22 felt very comfortable with that. That would be the CIU
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1 indication.
2 The expert panel did not address the broader
3 indication. Personally as one member, and in my
4 presentation, I don't see any harm in the broader
5 indication but that panel simply addressed the narrower.
6 They did not have reservations and didn't address that
7 issue.
8 DR. CANTILENA: Yes, Dr. Sachs and then Dr.
9 Dykewicz.
10 DR. SACHS: It has been stated to my kind
11 of surprise by both the FDA and by the sponsor that it
12 would be very difficult to do a study in acute urticaria.
13
14 As a clinician participating sometimes in
15 research trials in my office, I'm kind of struck by I
16 don't think it would be that hard given that we do studies,
17 for example, on croup which is an acute self-limited
18 disease that last maybe two to three days, that can be
19 either spasmatic and may occur one time in the middle
20 of the night type thing.
21 It would not be a tough thing to do to do
22 such a study in the ER other than the fact that it might
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1 be a little more difficult to do placebo because of the
2 wider acceptance of antihistamines already.
3 Having said that, I'm not sure I have such
4 a big difficulty in the use of these antihistamines and
5 hives. I am just wondering more about the broader sense
6 that it's okay for us to say, sure, without efficacy data
7 it's okay to broaden an indication for a drug that would
8 be used so widely over the counter.
9 DR. CANTILENA: Yes.
10 DR. WOOD: I don't think I was arguing for
11 broadly an indication. The issue we're discussing is
12 the risk of it being misused in an indication for which
13 it's not approved. That seems to me a fundamentally
14 different argument.
15 DR. CANTILENA: I think actually question
16 1A is asking us should it be broader.
17 DR. SACHS: I think the reason that we're
18 asking that question should it be broader is because it
19 is totally unrealistic to expect that it wouldn't be used
20 for acute hives or other urticarial as demonstrated by
21 the sponsor data, by our experience with use.
22 DR. CANTILENA: Yes, Dr. Dykewicz and then
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1 Dr. D'Agostino.
2 DR. DYKEWICZ: I would like to direct the
3 question head on as to what the potential adverse outcomes
4 would be of inappropriate use by the consumer of this
5 medication for urticaria of all sorts of ilk, acute versus
6 chronic idiopathic.
7 I can see several potential areas where there
8 would be potential adverse outcome. Take, for instance,
9 the example of use for acute urticaria for food. There,
10 on one hand, would be the concern maybe based upon
11 particularly, I think, the specter of what Dr. Lee had
12 presented this morning about some of the patients who
13 are developing anaphylaxis on the antihistamine agent.
14
15 I think there would be the consideration that
16 you would have some people who would feel, shall we say,
17 comfortable dealing with food induced urticaria by the
18 availability and the indication over the counter for
19 treatment of urticaria by this product.
20 They might be kind of lulled into a false
21 sense of security that they can treat this themselves,
22 that they can suppress maybe even a food allergic reaction
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1 from occurring, and they may miscalculate with the result
2 being anaphylaxis and death. I actually think if you're
3 looking at worse case scenario, that is something that
4 is going to happen.
5 I think one of the things then that would
6 have to be considered is the frequency of that happening
7 and that for the greater benefit of society is that a
8 risk that is balanced by the greater benefit to society.
9 Unfortunately, I think in terms of trying to assess what
10 the frequency of that would be, we are really not going
11 to know.
12 Another food related issue that comes up,
13 and I do see this when patients come into the office,
14 is the patients have been under the belief that their
15 urticaria is food related so they have been self-treating
16 themselves with currently available over-the-counter
17 antihistamines.
18 The reality is that they have inappropriately
19 assessed that they are allergic to foods and they are,
20 in fact, getting nutritionally deficient diets as a
21 result. They've eliminated wheat products, dairy
22 products, meat products. You really are seeing a patient
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1 who, I think, is having some adverse outcome on that basis.
2
3 Then, of course, the other issue is, and this
4 is why the original indication was trying to be restricted
5 to chronic idiopathic urticaria where there has already
6 been a prior physician evaluation, and that would be these
7 less common but real issues of a patient who has maybe
8 some connective tissue disorder or urticaria vasculitis
9 where they may be getting some benefit with their skin
10 condition by the use of the over-the-counter product,
11 but then we less likely to seek the attention of a
12 physician of medical intervention and, thereby, allow
13 the progression of the underlying disease process leading
14 to, among other things, some renal disease.
15 I think there are certainly a number of
16 situations or scenarios that could occur where the
17 inappropriate use in the broad stroke terms of this agent
18 over the counter for urticaria might lead to some adverse
19 outcomes.
20 I think the dilemma that we are facing here
21 is that even if you tried with all the product labeling
22 as has been appropriately proposed, even if you tried
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1 to warn the consumer about all of these different
2 concerns, would the consumer heed these in practice or
3 would actual use be such that there would be just kind
4 of across-the-board use of the products with some of the
5 adverse outcomes that I've discussed.
6 DR. UDEN: But those would not be because
7 they are taking antihistamines. All those examples you
8 cited were because they would have delayed seeking medical
9 care. They would have been driven to take antihistamines
10 for some reason.
11 It's just like when you go to see a physician,
12 "Oh, no. I've got to do it Friday night at midnight,"
13 something happened that they are seeking treatment. It's
14 not really antihistamines that are causing those issues.
15 It's really them delaying going to therapy.
16 DR. DYKEWICZ: Right. It's not an adverse
17 effect of the medication. It's that, say we say, the
18 certain amount of comfort level that they may have that
19 they are doing the appropriate thing with the
20 over-the-counter product might thereby decrease their
21 threshold or change the threshold for seeking appropriate
22 medical intervention.
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1 DR. UDEN: I hear that but I don't hear in
2 your examples like when we discussed phenylpropanolamine
3 here and people were dying of -- had a risk of hemorrhagic
4 strokes or dying, I'm not hearing that level of concern
5 of medical catastrophes by delaying a diagnosis.
6 DR. CANTILENA: Okay. Dr. D'Agostino, Dr.
7 Temple, then Dr. Alfano.
8 DR. D'AGOSTINO: This is for Dr. Wilkin
9 actually. I'm trying to figure out one can take the data
10 that we have and say that we can bring it down to acute
11 high situation and feel comfortable with it. Now, if
12 you go into other fields like analgesics, periodontal
13 fields, and weight reduction, you go after individuals
14 in the study who have serious conditions, headaches five
15 times a week or something like that.
16 If you establish with the clinical trials
17 that the drug is effective for these individuals, then
18 by extrapolation, or whatever you want to call it, you
19 say that individuals with less severe conditions can,
20 in fact, also take the drug without having to produce
21 new data.
22 Are we talking about the mechanism of action
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1 that you've described and so forth? Are we talking about
2 possibly that type of situation that the chronic data
3 and the mechanism which you say is involved here that
4 would allow us to have comfort that, in fact, it can be
5 brought down to acute conditions?
6 I realize there's some that are triggered
7 by foods and what have you that might be different in
8 terms of the general type of statement for labeling and
9 for these questions we have to face.
10 DR. WILKIN: The answer is yes. I mean,
11 you're saying essentially that if it's acute urticaria
12 and you know it's acute urticaria that it should respond
13 in the same way as patients who have the diagnosis of
14 chronic urticaria or chronic idiopathic urticaria.
15 I think where the catch comes is is there
16 a greater chance for a patient to make a misdiagnosis
17 of self with short-term kind of urticaria as opposed to
18 something that has been seen by a physician and labeled
19 chronic idiopathic urticaria. That's where the struggle
20 is on this.
21 I don't think -- one of your colleagues
22 mentioned that it doesn't seem that the scenarios that
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1 are playing out for the differential of acute urticaria
2 have things that really would be made worse by
3 non-sedating H1 antihistamines. The whole notion is one
4 of delay.
5 Many of the things that we're talking about
6 that would be really worrisome and you wouldn't want delay
7 to occur, some of those are going to be things that occur
8 perhaps more often in a medical setting. The really world
9 class anaphylaxis is very often associated with
10 parenteral antibiotics, penicillin, cephalosporin.
11 The radio contrast materials can lead to
12 something that looks very similar and doesn't often have
13 the immune system involved so it's called an anaphylactic
14 kind of reaction. Really the reactions that occur within
15 seconds are going to be of a medical variety.
16 There are some that can occur outside the
17 medical setting. There can be insect things,
18 hymenoptera, stings that can lead to very rapidly
19 developing anaphylaxis. Many of the patients who have
20 anaphylaxis will actually develop their anaphylaxis over
21 a somewhat more prolonged time period. I can't imagine
22 that this would adversely affect a patient to have the
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1 H1 non-sedating antihistamine.
2 In fact, if they get to the point where they
3 start having some swelling inside the mouth and the throat
4 and they feel they are getting short of breath and they
5 hop into the car and are driving down the road to the
6 emergency room, it might be more beneficial to be on a
7 non-sedating than a sedating antihistamine. In general,
8 I think it really the things that are chronic idiopathic
9 urticaria they have the same pathophysiologic mechanism.
10 DR. D'AGOSTINO: I'm concerned, as everyone
11 else is, with the two wishes of the efficacy and the
12 safety. The question I was addressing was in some sense
13 the efficacy part that do we have enough data to feel
14 that we don't necessarily need to do more.
15 I think the delay issue was certainly before
16 as the safety issue but, in some sense, it would be nice
17 if we would not separate them but there is an efficacy
18 issue. Do we really have to run acute studies? You can
19 run acute studies.
20 I would be happy to design a study for you.
21 I'm sure I could do it but do we really need to given
22 the database we have. Then the second question is about
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1 the delay for the safety implications which you are
2 addressing now.
3 DR. WILKIN: I think it comes back to what
4 do we gain from the acute studies versus the resource
5 intensity and what one might actually -- how one can
6 extrapolate. First of all, of the acute urticaria
7 patients that I most recently saw, and this was at Ohio
8 State University, so we had three sources of urticaria
9 patients.
10 One would be those who had really severe
11 urticaria that bothered them enough to go to the emergency
12 and they would often be treated at the emergency room
13 before they would send them over to our gun clinic. They
14 would get the systemic corticosteroid, parenteral,
15 diphenhydramine, perhaps some other sorts of things.
16 That was one group.
17 Then we had the clinic at the campus was on
18 the bus line so we had a lot of indigent patients that
19 would just come to a walk-in setting. Typically they
20 had urticaria the day before, but you wouldn't see it
21 that morning.
22 Then the other place we saw patients was out
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1 in one of the tinier suburbs of Columbus, Ohio, Dublin,
2 Ohio. There we treated diseases of the insured. They
3 would often go through a family practice doc or an
4 internist before they would come to us. It was actually
5 rare in my experience, and I've seen a lot of patients
6 who had urticaria, but to actually see urticaria at the
7 time they are coming to the clinic visit so it's a little
8 different.
9 I mean, those folks come in and they have
10 croup when you're seeing them. I still think this is
11 a very tough group to study. Hopefully you find some
12 who have a history of food intolerance and you could
13 recreate an acute episode of urticaria in the laboratory
14 but undiagnosed they would be chronic. I mean, it gets
15 back to what you mean.
16 I think the real fundamental piece is that
17 all of the different ideologies that ultimately lead to
18 the weal and to the itch do so by acting on the mass cell.
19 It's the same vesical that's released in every single
20 instance and it leads to the same itching, c-fibers,
21 superficial dermis, and the same kind of weal because
22 that superficial vascularplexis becomes leaky. I think
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1 it's one common mechanism.
2 DR. CANTILENA: Okay. Thank you.
3 Dr. Temple, Alfano, Dykewicz.
4 DR. TEMPLE: I don't know if this will
5 reassure Ralph or not. We can't agree to labelling unless
6 we believe there is substantial evidence that the drug
7 is effective for what it's labelled for. One way or
8 another perhaps by reference to other closely related
9 diseases or whatever, we are going to have to reach that
10 conclusion.
11 We've asked you what you all think about it
12 and that will help but we have to under law reach that
13 conclusion. We have no choice. We'll have to do it.
14 If we can't reach that conclusion without another trial
15 being designed, then somebody is going to have to be smart
16 enough to design another trial. The question is, and
17 you just heard Jonathan address this, you may not need
18 to do that. You may know enough already.
19 DR. D'AGOSTINO: That is obviously what I
20 was trying to flush out.
21 DR. TEMPLE: No. It's a perfectly good
22 question and we may have mislead you slightly by the
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1 question. We have to be convinced one way or another
2 that there is something called substantial evidence which
3 means it has to come from well controlled studies and
4 then we'll argue about the applicability of whether it's
5 really the same disease and so on. Those are things you
6 have to argue about.
7 I wanted to follow up on one safety matter
8 that Jonathan mentioned also. I mean, the nightmare here
9 is that somebody is gulled by the availability of this
10 drug when he wasn't gulled by the availability of the
11 sedating antihistamines all these years into delaying
12 treatment for his anaphylactic shock.
13 I would be curious whether other people
14 agreed with what Jonathan said which I'm going to say
15 was my impression, that other things being equal, even
16 if you're going to the emergency room, you are probably
17 better laying down a little antihistamine base before
18 you do it. It can't hurt and you won't attach more while
19 you're waiting. Probably the odds are you will be better
20 off if more people use this if they are about to develop
21 something really nasty.
22 DR. D'AGOSTINO: Before that gets responded
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1 to, the question I was -- part of the question I was raising
2 is we do have studies. There were studies that were done
3 for the Rx. Is it possible in the appeal to the database
4 that we appeal to those in terms of then an extrapolation?
5 DR. TEMPLE: Yeah. That's what I was trying
6 to say.
7 DR. D'AGOSTINO: I just wanted to make sure
8 I understood.
9 DR. TEMPLE: There's plainly some judgement
10 involved in whether the situations are close enough for
11 that to be relevant. We have written documents about
12 how to go with one study or no studies or multiple studies.
13 Those would all have to be part of the consideration
14 and the advice of experts figures into those
15 considerations.
16 DR. CANTILENA: Okay. There's just a quick
17 comment here from Dr. Sachs and then we'll go back to
18 Alfano, Dykewicz, and then --
19 DR. SACHS: Just an important clinical point
20 about anaphylaxis. The treatment for anaphylaxis is
21 adrenaline or epinephrine. Giving an antihistamine
22 doesn't actually treat anaphylaxis. I don't know that
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1 -- I mean, as long as giving the antihistamine didn't
2 delay the seeking of treatment, it wouldn't affect the
3 course but it certainly doesn't really help it.
4 DR. WOOD: But it doesn't make it worse.
5 DR. SACHS: If it delays the treatment, it
6 makes it worse. If you look at anaphylaxis studies,
7 particularly in kids where the kids died where the kids
8 that got antihistamine and didn't get epi.
9 DR. WOOD: But that was in a hospital
10 setting.
11 DR. SACHS: That's part of what led to have
12 epi pens in schools and things like that was to make it
13 more available. That's just my point. You need the epi.
14 That's all.
15 DR. WOOD: No one is arguing with that. The
16 issue though is do we -- the real question is do we
17 visualize that people with anaphylaxis because of this
18 drug, because a non-sedating antihistamine is on the
19 market, that people are going to rush down to Walgreens
20 to get themselves a non-sedating antihistamine and,
21 therefore, delay their access to epinephrine which they
22 would not have done with a sedating antihistamines. That
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1 seems to me fundamentally improbable.
2 So, I mean, the issue is not does epinephrine
3 -- is epinephrine the treatment for anaphylaxis. Clearly
4 it is. The issue though for today's discussion surely
5 is will marketing a non-sedating antihistamine over the
6 counter prevent patients getting epinephrine. I think
7 the answer to that is no.
8 DR. CANTILENA: Okay. Dr. Alfano and then
9 Dykewicz.
10 DR. ALFANO: Yes. I didn't realize that
11 when I raised my hand the seqway would be so appropriate.
12 I wanted to sort of offer two comments on anaphylaxis.
13 One, at least some bee sting kits include diphenhydramine
14 tablets as a sort of prelude to the more definitive
15 epinephrine treatment as an event unfolds. At least one
16 manufacturer sort of deemed it appropriate to put together
17 a kit in that fashion.
18 The second comment relates to the fact that
19 a comment earlier from this morning was suggesting that
20 perhaps there should only be -- if this does go OTC there
21 should only be one put-up. This becomes, I think, a great
22 debate topic and you could pick either side.
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1 I kind of come down on the side that a second
2 put-up is advantageous because it makes the product
3 visible and available to individuals who are suffering
4 from CIU in a way that they have access to a non-sedating
5 antihistamine. It would be the first time, I think, in
6 which a proper label is available for these indications
7 -- for that indication over the counter.
8 They are going to the counter now and they
9 are acquiring sedating antihistamines and they are not
10 labeled in the fashion that would warn a consumer about
11 the risk of anaphylaxis. This product conceivably would
12 be the first to be properly labeled.
13 The third issue is it would be shelved in
14 this skin irritation section where someone who has these
15 chronic conditions would likely see it and pick it up
16 and read it. The other way it's just going to be in a
17 wrong section of the pharmacy.
18 DR. CANTILENA: Okay. Thank you.
19 Dr. Dykewicz and then Dr. Szefler.
20 DR. DYKEWICZ: Well, several comments on
21 this specific issue about anaphylaxis, delay in
22 treatment, risk for fatality, rapidity of onset.
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1 First of all, maybe just to return to some
2 comment that were made earlier, it is certainly true that
3 anaphylaxis can occur in medical settings due to use of
4 parenteral medications, antibiotics, radio contrast
5 media, but what we're looking at really in a nonmedical
6 setting would be the risk of anaphylaxis from foods and
7 potentially certain oral medications, maybe even
8 including aspirin and nonsteroidal anti-inflammatory
9 drugs with the pseudo-allergic reaction that was
10 addressed earlier.
11 It has been found in some studies that food
12 induced anaphylaxis can be more problematic to treat.
13 The reason is that because there is some time delay in
14 the onset of the symptoms and the progression of the
15 symptoms by virtue of the requirement for a need for oral
16 absorption that, in fact, fatal food anaphylaxis can have
17 a slower onset, a slower progression, but still lead to
18 fatality.
19 If we're getting at the questions that have
20 been raised earlier about whether somebody would run down
21 to the local drug store and because at that point the
22 person is only having hives and they pop a tablet of a
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1 medication which now has over-the-counter indication for
2 hives, there would be the possibility that would, as Dr.
3 Sachs brings up, prolong or delay the patient seeking
4 medical attention and thereby delay the administration
5 of epinephrine and thereby cause a greater risk of
6 fatality. If you're going to go the whole nine yards,
7 that is a scenario.
8 The other thing, though, about the kits that
9 are commercially available that do have antihistamines
10 in them, actually it's chlorpheniramine with epinephrine
11 in a kit, it is certainly appropriate to use
12 antihistamines in the treatment of anaphylaxis, but that
13 is always viewed as only an adjunct to the primary
14 treatment with epinephrine.
15 Any type of scenario in which someone would
16 delay receiving epinephrine, whether it's use of an
17 antihistamines with over-the-counter indication or not,
18 that would result in fatality or greater risk thereof.
19 DR. CANTILENA: Okay. Dr. Szefler, then Dr.
20 Joad, then Dr. Davidoff.
21 DR. SZEFLER: I guess I just want to clarify
22 a few points. Because the package inserts change so much
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1 I haven't read every one or do I read every one. Let
2 me just get it clear in terms of loratadine. It is
3 approved in the package insert for chronic urticaria.
4 Is that right? The studies that were done were deemed
5 sufficient.
6 DR. CHOWDHURY: Chronic idiopathic
7 urticaria.
8 DR. SZEFLER: Okay. So the discussion that
9 we're having is not about the indication for the disease.
10 It's about sharing the information and putting it in
11 the product. I mean, why would you not want to put
12 information in terms of its approval? I guess may Dr.
13 Ferguson's talk crystallized that for me.
14 What reason would you not want to put the
15 information in there other than maybe the misinformation
16 about other urticaria? I mean, it's like sharing
17 information that is reassuring the patient that they have
18 been receiving adequate treatment.
19 Maybe I just missed that point in the whole
20 review. I didn't have a package insert on hand but if
21 it's there already, it just seems like it's a logical
22 transfer of information. It's not new information.
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1 It's a logical transfer of information.
2 DR. CHOWDHURY: To answer the question and
3 to address the point here, the studies for loratadine
4 and most other new antihistamines were done on CIU
5 patients. The application that we reviewed we hadn't
6 had where to get the indication of CIU. There were no
7 acute urticaria or other studies for these
8 antihistamines.
9 DR. SZEFLER: But it is approved for chronic
10 idiopathic so it's already there. It's not like we're
11 discussing the approval.
12 DR. CHOWDHURY: Already approved and
13 marketed with the indication of chronic idiopathic
14 urticaria.
15 DR. SZEFLER: Okay. So my second question
16 is --
17 DR. GANLEY: Can I just add something to
18 that? If you put it into the package insert, you are
19 in essence giving it as an OTC indication. The company
20 can have an add-on tomorrow for direct consumer labeling
21 for their prescription product to go see your doctor for
22 your urticaria. It's not that we're withholding
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1 information from the public. All this is public
2 information. Anyone can go get the package insert. They
3 are readily available.
4 DR. SZEFLER: But the patient still kind of
5 deems the responsibility of treating themself even though
6 it's a medical disease.
7 DR. GANLEY: If you start putting uses into
8 a package insert that's labeling. If it's an OTC product,
9 you are essentially giving it an OTC claim. I think
10 that's what the issue is here. It's not that we're trying
11 to withhold that.
12 I'm not sure if people -- there is some
13 confusion abut that but if this was not an OTC claim it
14 would still remain a prescription claim. It's not that
15 the FDA is taking something away from them.
16 The issue is if allergic rhinitis becomes
17 an OTC claim, should this also become a OTC claim? If
18 it doesn't, it remains a prescription claim. They can
19 still market the product as a prescription product and
20 do their direct-to-consumer advertising.
21 DR. SZEFLER: Maybe this gets to the root
22 of a problem and maybe I'm just not clear on payments.
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1 I'm trying to figure out who this benefits and how it
2 might be used to benefit.
3 Suppose I'm a patient and I go in and I see
4 a physician and I have chronic idiopathic urticaria.
5 I have medical benefits. The physician feels that the
6 most appropriate drug for me is loratadine and then tells
7 me, "For the next year go out there and purchase it on
8 your own." I bear the cost.
9 On the other hand, if it's not on the label,
10 can the physician then say, "Your best drug is loratadine.
11 Because it's not in the label it's a prescription and,
12 therefore, your insurance company should pay for this."
13 Is that what it boils down to?
14 DR. GANLEY: I'm not sure we factor that into
15 our decision as to whether this is an appropriate
16 indication for an OTC setting.
17 DR. SZEFLER: It is for the patient.
18 DR. GANLEY: I understand but this came up
19 at least year's meeting, I think, and we don't factor
20 that into the decision process. I suspect we could get
21 by with --
22 DR. SZEFLER: I guess I would like to factor
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1 it in.
2 DR. GANLEY: You're welcome to do that but
3 we don't factor that into our decision. I think some
4 of the issues, I don't know what individual's co-payment
5 is for prescription products. Mine is, I think, $15 a
6 month unless I get a three-month prescription. There's
7 still some co-payment on the side of a consumer in most
8 cases, even if they have a prescription plan.
9 DR. SZEFLER: I guess I have to sort out the
10 issues.
11 DR. GANLEY: It's what can we factor into
12 that decision and that's generally not been a factor.
13 DR. CANTILENA: Dr. Temple, do you have a
14 comment before we go to the next one?
15 DR. TEMPLE: Yeah. I mean, as I'm sure
16 people are aware, there are a number of drugs that are
17 available where the same new molecular entity or the same
18 actimority (phonetic) is available both as an
19 over-the-counter drug and as a prescription drug.
20 Ibruprofen, for example, remains as
21 prescription Motrin in doses -- in tablet sizes above
22 200 milligrams. Nothing stops a physician from
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1 prescribing it that way in which many people will cover
2 it or telling someone to go get it as an over-the-counter
3 drug in which cases I understand most of the time will
4 not be covered. We don't deal with that.
5 But in case you have any doubt about whether
6 most Ibruprofen is used as an over-the-counter drug, try
7 to find the labeling for Motrin in the current PDR. You
8 won't find any Rx Ibruprofen labelling. People can do
9 what they want with that. The question here is only
10 suitability of a particular claim for over-the-counter
11 use.
12 There are specifications for what makes a
13 drug suitable or a claim suitable for over-the-counter
14 use. You have to be able to diagnose it, manage it, and
15 so on. That's why we worry about each of the claims
16 individually. Before you put it in OTC labeling, you
17 have to believe -- usually we have a way out of that,
18 too -- you have to believe it can be used by the individual
19 that way.
20 There is such a thing as professional claims
21 for over-the-counter drugs. Aspirin has professional
22 labeling where you are absolutely positively supposed
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1 to go see the doctor to get your cardiovascular disease
2 prevented. Does that always happen? We don't know.
3 DR. CANTILENA: Okay. Dr. Joad and then Dr.
4 Davidoff.
5 DR. JOAD: I wanted to speak to the general
6 indication of hives and whether the evidence we have so
7 far about the use of antihistamines in this specific CIU
8 is sufficient for us to approve it or have packaged
9 labeling for acute hives.
10 I would argue for evidence based medicine
11 on that. That is a big number of patients in comparison
12 with the CIU patients, No. 1. Secondly, I think you could
13 make an argument that is a theoretical one that
14 antihistamines and CIU are there present all the time
15 occupying those H1 receptors so that they are not
16 available for the release of antihistamines.
17 Whereas, in acute hives if it's really a
18 single hit one especially, the event will have already
19 happened. The histamine receptors will be occupied.
20 The secondary effects are already well underway. You
21 may not be able to go back with an antihistamine and
22 reverse that.
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1 There's no reason to say I'm right
2 particularly but if you don't do an evidenced based study
3 of what really happens for acute hives, I don't think
4 you know the answer to that. I think Dr. Sachs is telling
5 us that primary care physicians are seeing people with
6 acute hives and they could be studied in a primary care
7 setting.
8 DR. CANTILENA: Dr. Davidoff.
9 DR. DAVIDOFF: Just to stress that last
10 point, I agree. I think it would be perfectly doable
11 to design an appropriate study for studying acute hives.
12 I actually had a question, though, that had to do with
13 the presentation Dr. Engle made about pharmacist
14 involvement in guiding patients about taking
15 over-the-counter drugs.
16 I think that is a very important point since
17 it does say in the footnote that 61 percent of the
18 respondents in one survey said that they did use
19 over-the-counter drugs at one or another type of pharmacy.
20 That raised a question in my mind as to how
21 often that really -- the pharmacists really get involved
22 in interaction with patients at the time they purchase
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1 over-the-counter drugs. In the pharmacies I've gone
2 into, most of the antihistamine type preparations are
3 in an open display. They are not behind the counter.
4 If the person purchasing it wanted
5 information from the pharmacist, they would have to go
6 over to the pharmacist and ask them. The pharmacist is
7 usually busy filling prescriptions so it is hard to get
8 their attention.
9 I actually wondered if there are any data
10 on how often pharmacists are actually asked about
11 over-the-counter preparations because my suspicion is
12 that it's actually not very often unless the drug is behind
13 the counter.
14 That led to my second question which is --
15 it expresses my naivety in this, and that is is there
16 any kind of behind-the-counter system in the U.S, formal
17 or otherwise? I didn't think so. It certainly doesn't
18 look like there is but I thought maybe there was. I do
19 think there are such systems in some other countries.
20 Am I correct? But not in the U.S.
21 My first question really is are there any
22 data on how often pharmacists are actually involved in
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1 over-the-counter type purchases?
2 DR. CANTILENA: Okay. The answer to the
3 second question is that there is not that category
4 available in the United States and that I will ask our
5 Drs. of Pharmacy of they would like to respond to your
6 first question.
7 DR. JOHNSON: I am not aware of any specific
8 data that describe how often individual seek pharmacy
9 input. It's been a long time since I worked in a retail
10 setting but I have worked in a retail setting and you
11 do have a fair number of people who come and ask.
12 Typically it will be in the first time they
13 would use such a product. Obviously once they've used
14 it and are familiar with it, they are much less likely
15 to come back and ask for that input. It's clearly a
16 process that is driven by the patient seeking information.
17
18 There's nothing that forces the patient to
19 see the pharmacist. I mean, I think there is a fair amount
20 of it and if the labeling on the box -- not on the inside
21 of the carton but on the box suggest that they may want
22 to consult a pharmacist, I think that might increase it.
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1 I mean, there are a couple -- we do have a
2 few drugs that are, in a sense, behind the counter.
3 Insulin, for example. In some states there are Schedule
4 V compounds cough products that have codine, for example.
5 In general we don't have that category that some other
6 countries do.
7 DR. DAVIDOFF: Well, could I ask in
8 connection with that on the last point you made, are there
9 examples of over-the-counter medications that say on the
10 box that you should consult your pharmacist as well as
11 you should see a physician in certain circumstances?
12 Are there any examples of that? It seems to me that could
13 be very constructive.
14 DR. WOOD: Well, there are data from the UK
15 behind the counter prescriptions. The data say that
16 almost uniformly no advice is offered. The drug is
17 actually behind the counter and the person goes up to
18 the counter, asks for the drug, and it's passed over with
19 no advice being offered.
20 There are also data from this country
21 offering advice on prescription medicines and the
22 frequency which that happens and there's very little
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1 advice offered on that. In fact, the majority of patients
2 in surveys don't recognize that when they sign that form,
3 they are signing that they are actually turning down the
4 advice for prescription drugs. There's actually a lot
5 of data on the advice for prescription drug issues.
6 DR. UDEN: But pharmacists are the -- they
7 are there and are available to be consulted with if, in
8 fact, there is -- and labeling might take care of it.
9 I know in TV ads you consult your doctor or your pharmacist
10 but I don't think that there's any OTC labeling which
11 does that. I won't make my next comment.
12 DR. CANTILENA: Are there examples, Dr.
13 Ganley or Dr. Katz?
14 DR. KATZ: The new drug facts on labeling
15 actually does have specific headers that will advise a
16 consumer to go seek their physician or healthcare provider
17 or to go ask the pharmacist. It's very specific and has
18 listed bullet points underneath.
19 Some may be related to asking for information
20 regarding other concomitant medications or concomitant
21 medical problems that someone may have so they shouldn't
22 take the problem together. We'll say ask a doctor or
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1 pharmacist in certain headers. In others it will say
2 just ask your doctor or healthcare practitioner.
3 DR. CANTILENA: Okay. I think actually what
4 I would like to do now is just take a 15-minute hiatus
5 here from this interesting discussion and have everyone
6 come back in 15 minutes. We'll clear up any other
7 questions and then we'll go to our questions. Thank you.
8 (Whereupon, at 3:12 p.m. off the record until
9 3:25 p.m.)
10 DR. CANTILENA: Before we go ahead with
11 questions, Dr. Monroe has asked to clarify a point on
12 the question on anaphylaxis for the sponsor.
13 Dr. Monroe.
14 DR. MONROE: Thank you. I'd just like to
15 make a couple of very brief comments on the issue of
16 safety. The first has to do with anaphylaxis. I think
17 there is consensus that it's a rare situation.
18 Antihistamines are not the treatment of choice.
19 Epinephrine, adrenaline is.
20 An issue was brought up would the approval
21 of an agent like loratadine OTC create a sense of
22 complacency that might cause added delay in the consumer
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1 seeking appropriate care. I think the best answer I can
2 give is that we've got 10 years of experience in Canada
3 and the UK where this is an OTC medication and there's
4 no indication of increased incidence of complications
5 or deaths related to this condition. We appreciate it's
6 rare. It's a serious thing but we don't think that making
7 loratadine OTC would in any way change in a negative
8 fashion the status quo.
9 I would also just like to say on safety I
10 think that the lack of approval of such an effective and
11 safe agent as loratadine OTC would create the maintenance
12 or the perpetuation of the status quo where most patients
13 who have urticaria, the spectrum of urticaria, that's
14 the vast majority of people with acute and some with
15 chronic who now access the only OTC medicines that they
16 have.
17 They are accessing sedating antihistamines
18 that are far from safe. I don't think you should
19 underestimate the potential harm in the perpetuation of
20 those people who right now, and it's the majority of people
21 with hives, access care through a sedating much less safe
22 medication than loratadine.
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1 I would also say there are subsets of the
2 current population, particularly the elderly, who are
3 taking these medicines and they are more than
4 antihistamines. They are anti-colonurgics (phonetic).
5 They affect urinary retention. They affect glaucoma.
6 I think if you're looking at patient and
7 consumer safety, the movement of this drug, Claritin,
8 to the OTC scenario, I think, creates a much greater
9 improvement in the safety equation than not doing it.
10 DR. CANTILENA: Yes, Dr. Davidoff.
11 DR. DAVIDOFF: Just a quick point in
12 connection with your first issue. Absence of evidence
13 is not the same as evidence of absence. It seems to me
14 that unless someone has specifically gone and looked at
15 the fatal cases of anaphylaxis in over-the-counter
16 countries to see whether or how often the availability
17 of the over-the-counter antihistamine might have, in
18 fact, delayed treatment, I don't think you can say there
19 is any information one way or the other on whether this
20 availability in those countries has delayed treatment
21 and contributed to fatalities?
22 DR. CANTILENA: Dr. Uden.
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1 DR. UDEN: I just have to take this
2 opportunity to remind us that 11 months ago these drugs
3 weren't safe enough to be OTC and now they are. It's
4 quite a reversal.
5 DR. CANTILENA: Thank you for that
6 historical point.
7 Dr. Clayton, are there any other issues that
8 you wish to clarify from the discussion that was not
9 absolutely clear? Okay. I just actually have a question
10 for Dr. Ganley. As we go through the packet we're looking
11 at in essence a switch application because it's already
12 an approved Rx indication.
13 I guess are there examples in your files that
14 I'm not familiar with where we have actually accomplished
15 a switch recommendation without an actual use study with
16 the use of the Internet, I guess, as a survey of consumers.
17 Is there anything that you can point to in the files
18 that we have experienced in this area?
19 DR. GANLEY: I think there have been. The
20 vaginal antifungals actually did not have an actual use
21 study but I think there are probably other applications
22 that have never made it to the committee that we haven't
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1 required actual use studies on.
2 Clearly when the discussion occurred last
3 year -- the committee meeting occurred last year regarding
4 allergic rhinitis, we had actually come out on the
5 positions that we didn't think it would need an actual
6 use study because it's a category of drug that is already
7 available OTC for this indication. I think there are
8 examples where we don't require that.
9 I think the issue with the consumer surveys
10 is what kind of -- with that type of study what is the
11 value of that study. Is that a study that helps you design
12 a better label comprehension study because you understand
13 a population's perceptions of how they should use certain
14 products, or should it be used to improve the design of
15 an actual use study or things like that.
16 Again, I go back to what the questions in
17 this population they were actually asking. I didn't
18 really need that study to be convinced that someone who
19 had gone to a physician and had been told they had chronic
20 urticaria and was instructed to use a specific product.
21
22 They wouldn't do it necessarily correctly
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1 had all these steps in the physician/patient interaction
2 occurred. You could take many diseases that have
3 intermittent symptoms where this would occur. Migraine
4 headaches where there is something prescribed to a person
5 and they are told to take it when they have a severe
6 headache because they already know what their migraine
7 is like.
8 A patient with anginepectoris (phonetic) who
9 is given sublingual nitroglycerin, most of them know when
10 to use that correctly so you don't need to do a study
11 to tell me that someone that has a diagnosis of CIU would
12 be able to use this product. But that's really not the
13 major issue here. I think it's how is the general
14 population going to use this product.
15 The question with the surveys, I think, is
16 this type of study that the committee would like to see
17 come in supporting applications that would limit use to
18 a specific population, or should it be some type of study
19 that is used to -- I think Dr. Davidoff had mentioned
20 earlier we don't know what the general
21 -- how the general population is going to use this.
22 I may have been better to survey them and
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1 see how they use these products and then try to create
2 a label because clearly I think there are issues in the
3 label comprehension that even the way it was written that
4 the cohorts in the general population and the acute hives
5 population they weren't going to use it as it was labeled.
6 Could that consumer survey have been better used to
7 create a better label?
8 DR. CANTILENA: Okay. Thank you. Are
9 there any other specific issues that the committee would
10 like to discuss before we go to the questions? Any other
11 pieces of information?
12 Dr. Sachs.
13 DR. SACHS: The one question I have is what
14 age is this supposed to be approved down to?
15 DR. CANTILENA: Dr. Ganley. Is it 12 and
16 above or six and above?
17 DR. GANLEY: I think it was about six years
18 of age.
19 DR. CANTILENA: Okay. Any other questions?
20 Yes, Dr. Rosenberg.
21 DR. ROSENBERG: Just without harping on this
22 just to say one more time that the patient will do one
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1 of three things. They will either seek medical care and
2 get it at a physicians office, they will buy what is
3 presently available over the counter which is sedating,
4 or they will go to a health food store and go to that
5 sort of thing. These are the only options.
6 I turn again to that chart on Tab 7 that shows
7 the preferred treatment, No. 1 choice of so many
8 physicians is corticosteroid. In the material that we
9 were sent there are these review articles and I've
10 reviewed textbook articles. Malcolm Grave says use a
11 non-sedating antihistamine once in a while.
12 Anytime you're on a consensus committee you
13 always have to say something. Everybody is afraid they
14 are going to be sued unless you make it okay to put
15 everything else in. What they really say is try the
16 antihistamine.
17 Then there's a statement from another
18 consensus from Europe. Then there's another authority
19 and a book on urticaria that I've always found the most
20 sensible one. It's an older book by Dr. Champion from
21 Britain who is one of the original editors of the Rook
22 series of that major textbook.
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1 He wrote a whole book about urticaria and
2 he concluded that after this and that and trying your
3 best, he said the best thing to do for these people is
4 interdict aspirin and try to find an antihistamine that
5 will give them some relief without putting them to sleep.
6 We have that here now.
7 I think truly there are hard cases but if
8 the people do this first and then go to the doctor if
9 they didn't get better, then prednisone and so forth is
10 okay, I mean, if they're that sick and maybe they are
11 going to get a workup but they're sure getting an awful
12 -- too much of it now in my opinion.
13 I see cases. I mean, I've testified for a
14 plaintiff and a fellow you had urticaria didn't want to
15 miss work so he stopped at the emergency room on the way
16 to work in Honolulu every two weeks for a refill of his
17 dose back. He had urticaria and he had aseptic narcosis
18 of the hip.
19 Another patient who has just been referred
20 in because of generalized coccidioidomycosis to our
21 infectious disease fellow. It was a dermatologist who
22 made the diagnosis and he called me and said, "You don't
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1 want me. You want our infectious disease guy."
2 I saw him and I said, "Did that fellow come
3 in from Jonesboro?" He said, "Yeah." I said, "Does he
4 have AIDS?" He said, "No, he doesn't have AIDS.
5 Somebody has been giving him 40 milligrams a day of
6 prednisone." Thank you.
7 DR. CANTILENA: Okay. Dr. Ganley.
8 DR. GANLEY: I think the one thing about if
9 you're talking about the physician survey and the first
10 line therapy, I think you have to -- there's details
11 missing there where you can't really figure out what's
12 going on there unless you ask more questions.
13 It may be that many of these individuals who
14 come in have already tried multiple antihistamines and
15 they have failed them. We don't know that. If you ask
16 follow-up questions to those questions and get the
17 details, that may be the bias of that physician because
18 95 percent of the people who come in with chronic urticaria
19 have already tried diphenhydramine and chlorpheniramine
20 and they just didn't work.
21 I don't know how much to place on that. I
22 think the issue that you make that's valid is that we
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1 should be advocating these as first line therapy. The
2 question is how best to do that. Is it narrowing this
3 claim down or is it having a more broader claim, for
4 example, if it's to go OTC.
5 DR. CANTILENA: Okay. Thank you. Any
6 other comments before we move to the questions? Very
7 good. What I would like to do then is actually go around.
8 We'll start with question No. 1. What we'll have you
9 do is indicate your vote, yes or no, and then comment
10 if you would like to comment. For the first question,
11 "Is urticaria a disease process appropriate for an OTC
12 indication?"
13 Actually, we can start on that side of the
14 table. Dr. Alfano, you can comment but, unfortunately,
15 you can't vote. If you would like to start with your
16 comment if you have one. If not, then we'll just head
17 around the table with our vote and comment.
18 DR. ALFANO: Yes. I believe it is an
19 appropriate indication.
20 DR. D'AGOSTINO: Dr. Dykewicz.
21 DR. DYKEWICZ: I'm going to vote no because,
22 at this point in time, I don't believe we have sufficient
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1 use studies to be assured of how this is actually going
2 to be used in practice.
3 I say this though with kind of a divergent
4 view in my sole, and that is I think we do recognize that
5 there's a problem with the urticaria as it currently
6 exist. I agree that the de facto use of the currently
7 available over-the-counter antihistamines with their
8 sedating properties is undesirable if it were in an
9 alternative way available for the patient to get a
10 non-sedating antihistamine that would be effective.
11 I guess my dilemma as I've tried to express
12 during the course of these meetings is what can be done
13 to educate the patients so that they would use these
14 medications most appropriately and minimize risk to them.
15 It occurs to me that the efforts to provide
16 appropriate labeling on the package might actually be
17 a very good educational thing for the public and if the
18 public were to adhere and to follow the recommendations
19 that are listed on the label, that would be a good thing.
20
21 I think if anything there is probably both
22 among physicians and among patients an under-recognition
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1 of the potential seriousness of urticaria sometimes being
2 an indication of a serious underlying disease. There
3 may be too much of a kind of cavalier approach to it where
4 you just give some antihistamines and don't worry about
5 the full workup of it.
6 Although I do vote no, I think with some
7 additional use studies, one might be convinced that this,
8 in fact, would be a good thing to have available and,
9 if you will, even give the opportunity to gain greater
10 education for the public.
11 DR. CANTILENA: And just as a point of
12 clarification, when you say use studies, you mean actual
13 use studies where they can buy it like in the pharmacy?
14 DR. DYKEWICZ: Well, I'm not really clear
15 on whether there would be some type of -- the thing about
16 surveys versus where they would actually be using it,
17 I think once you actually would approve it for
18 over-the-counter use once the horse is out of the barn,
19 you probably can't come back very readily with that I
20 would think.
21 I guess some sort of limited use studies maybe
22 where people would be given the opportunity to obtain
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1 the drug in limited circumstances as part of a study group.
2 DR. CANTILENA: Yes. Actually, those are
3 called actual use studies. Go ahead.
4 DR. GANLEY: Yeah. I think his answer is
5 then yes, that it could be an OTC indication but you need
6 these types of studies. I tried to point out earlier
7 if you're answering no, you're coming to the conclusion
8 that this never -- there's nothing that the sponsor could
9 do that could actually convince you that this could be
10 an OTC drug.
11 If you think this is a possible OTC
12 indication, it would be a yes and then what kind of data
13 would you be interested in seeing. If you say no, then
14 that's shutting the door on anyone coming in for this
15 indication.
16 DR. CANTILENA: So would you like to amend
17 the wording of the question to be, "Could urticaria be
18 a disease that was appropriate for OTC?"
19 DR. GANLEY: I'll leave it to your
20 discretion.
21 DR. CANTILENA: I think that's what you're
22 asking so why don't we actually amend the question, "Could
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1 urticaria be a disease process appropriate for an OTC
2 indication?" Your vote, Dr. Dykewicz?
3 DR. DYKEWICZ: With all the caveats that I've
4 stated, then I could state yes.
5 DR. CANTILENA: Thank you.
6 Dr. Joad.
7 DR. JOAD: I vote also yes, that it could
8 potentially be OTC. I would recommend that it be
9 broadened to all reasons for urticaria due to the things
10 we mentioned about, that it would be impossible in
11 practical terms limited to chronic idiopathic urticaria.
12
13 Then the studies I would like to see would
14 be a study that shows people recognize hives versus other
15 important things that could be mistaken for hives in a
16 study of efficacy, an outcome study of efficacy and acute
17 hives and studies in children.
18 DR. CANTILENA: Okay. So we've actually --
19 we've had you cover actually question 1 and 1A.
20 DR. JOAD: And 2.
21 DR. CANTILENA: I've chosen to ignore that
22 response because it's out of sequence now. Just kidding.
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1 If we can actually go back to Dr. Dykewicz for 1A and
2 actually what we'll do is if you answer yes for 1, then
3 you can also answer 1A.
4 DR. DYKEWICZ: Well, should the indication
5 be for chronic idiopathic urticaria? Potentially yes
6 with the caveats. Should it be broader such that it
7 includes acute urticaria hives? Potentially yes but my
8 caveat to the FDA would be I think it would be much more
9 difficult to gain confidence about the appropriate use
10 of this medication by patients then it would be under
11 the very restrictive provisal of chronic idiopathic
12 urticaria. I'm saying yes, but hear all my caveats.
13 DR. CANTILENA: Okay. Thank you.
14 Dr. Szefler.
15 DR. SZEFLER: I would vote yes. I don't know
16 how you do it but I would like to see studies done with
17 acute urticaria. Again, as I said this morning, I think
18 if people really sat down and thought about it in terms
19 of primary variables and conditions to study it, and I
20 think it's feasible, then I would like to see those put
21 into the package so that it rules out any of these
22 considerations about inappropriate use.
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1 DR. CANTILENA: So yes for 1 and yes for 1A?
2 DR. SZEFLER: Well, in 1A it's really a
3 desire to see the studies. I think the implications of
4 the study -- the implications of the question if I said
5 yes to A would mean that I approve it right now for both.
6 DR. CANTILENA: Actually, the question is
7 now could it be a process and, if it could, would the
8 indication then -- should the indication be broader to
9 include hives. Then we'll actually talk about the
10 studies that you would like to see and others would like
11 to see under question No. 2.
12 Dr. D'Agostino.
13 DR. D'AGOSTINO: Yes to both.
14 DR. CANTILENA: Dr. Krenzelok.
15 DR. KRENZELOK: Yes to No. 1. We certainly
16 have an established indication. I don't think we have
17 information to allow us to put the general urticaria
18 statement on it but I think that post-marketing
19 surveillance of off-label use could provide us with a
20 wonderful opportunity to extend that indication sometime
21 down the line.
22 DR. CANTILENA: So yes to 1 and qualified
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1 yes to 1A.
2 DR. KRENZELOK: Yes.
3 DR. CANTILENA: Dr. D'Agostino.
4 DR. D'AGOSTINO: I guess I'm really
5 confused. This doesn't sound like a question that's
6 directed to the product so why are we talking about the
7 product? I mean, it's a question about the indication,
8 isn't it?
9 DR. GANLEY: Yeah, it's about the indication
10 because this company isn't the only company that is
11 interested in this claim so if we have to give advice
12 to other companies, it's important for us to understand
13 what we should be telling them, that you need to go for
14 a broader claim or you limit it to chronic urticaria.
15 Once we get over that hurdle, then looking
16 at the data that Schering-Plough has submitted, does that
17 lead to an indication in the OTC setting or do they need
18 to do other studies? Should they go after a more broader
19 claim?
20 So this is the more general question that
21 you have to overcome and it's mainly because we already
22 have gotten inquiries from other companies that have
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1 antihistamines that have an interest in getting this
2 claim.
3 Dr. Krenzelok's comments, I think, appear
4 to be directed at the company's product and that's really
5 question No. 2 where, you know, what do you think if you
6 vote yes that this could be an OTC claim is it chronic
7 urticaria, is it acute hives. That's where we need some
8 input.
9 DR. CANTILENA: So if I understand you then,
10 really question 1 is in general and question A is product
11 specific.
12 DR. WOOD: Question A needs to be qualified
13 because I don't people have a clear understanding of what
14 we're voting for there. The question A as written must
15 relate to the evidence that's been offered for a specific
16 drug.
17 Clearly if you vote yes to the stem, then
18 presumably other hives in any subdivision could be
19 potentially approvable to provide data, but having the
20 data has to relate to a product. The way it's been
21 modified doesn't make much sense unless we modify it
22 again.
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1 DR. GANLEY: Well, I guess it depends on what
2 your priors are here, whether you think that this is
3 already being used out there by the population in some
4 respects.
5 DR. WOOD: Well, let's read it. What we've
6 modified it to, as I understood it, was, "Is urticaria
7 a disease process which could be appropriate for an OTC
8 indication." That was the modified stem. Right? Then
9 if yes, should the indication be for chronic idiopathic
10 urticaria or should it be broader to include acute
11 urticaria.
12 Well, these two subdivisions depend on --
13 are data driven and they are data driven depending on
14 the drug that you've got in front of you so it's not
15 appropriate as written like that. That's why the
16 discussion each time raises issues related to the drug.
17 DR. CANTILENA: But I heard a lot of
18 discussion actually that said that to have the indication
19 just be CIU is actually confusing to the consumer and
20 it should actually just be hives. I thought we were
21 actually addressing that by broadening it. I actually
22 sort of see that as a general issue and not product
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1 specific.
2 Before we give you confusing advice, maybe
3 we should get on the same page. Dr. Temple.
4 DR. TEMPLE: Each of these has multiple
5 variations. One question you could ask is if you had
6 the data for acute hives, would it be better to label
7 it more broadly. That's one kind of question. I don't
8 hear anybody thinking that wouldn't be good
9 Then there's the question of do you have the
10 data to do that. There's been a lot of discussion one
11 way or the other. Some people probably think they have
12 the expert views to contribute to that but maybe not
13 everybody does. As I said before, in the end we have
14 to conclude that the data exist for that or we can't say
15 yes. We can't legally say yes. I don't know if that
16 helps.
17 DR. CANTILENA: Yes, a comment, Dr.
18 Rosenberg.
19 DR. ROSENBERG: Can I speak to that? I think
20 that you were wise to broaden it because that was one
21 of the things that, in fact, did come up and everything
22 comes out more neatly.
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1 On the other hand, the Schering company is
2 asking for the chronic idiopathic urticaria and brought
3 an exhaustive and complete search of this but not the
4 other. The reference that I showed sites this as evidence
5 based and had one reference.
6 I'm not going to be here tomorrow but other
7 on this panel will be here tomorrow. We've got members
8 of the panel from the Pacific time zone. I'm sure that
9 one could come up with literature, a search done by an
10 expert informationist that would help everybody by
11 getting up in time tomorrow morning.
12 DR. CANTILENA: Yeah, I actually think we
13 are sort of confined to this day on this agenda. I guess
14 what I would like to suggest, and please, Dr. Ganley and
15 Dr. Temple, if you're comfortable with us going in the
16 generic sense as the overall indication could be.
17 Are we confusing you, Dr. Titus, in terms
18 of the answer to 1A? Should we just go one at a time?
19 Overall I think their answer is clear with the following
20 qualifiers. I think if you're okay, if the FDA contingent
21 nods their head, I guess we will go forward as we are.
22 I didn't say nod off. I said nod your head. Are we
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1 okay?
2 DR. GANLEY: I think the issue is that we
3 have a claim that's -- you know, I think every prescription
4 product has a claim for chronic idiopathic urticaria.
5 I think Dr. Wood got into the discussion earlier about
6 whether that should just be made a broader claim.
7 Do we have a comfort level of efficacy or
8 should be segment it to that population and allow
9 companies to either do chronic idiopathic urticaria or
10 they could go after acute hives or they could subsegment
11 it into any other population that they see fit.
12 I think that's where it was sort of directed
13 at in general terms is that this is the claim on all of
14 the prescription products right now. To carry it
15 straight over is a choice, too, or should we ask -- should
16 we try not to confuse consumers and have some products
17 labeled for chronic idiopathic urticaria and some labeled
18 for acute hives or hives in general.
19 We would like to come up with some consensus
20 as what to tell people as to what the label should look
21 like. It should be similar, I think, potentially across
22 the board unless someone has a differing opinion on that.
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1 DR. WOOD: Could I offer a solution?
2 Supposing we said that the indication would be hives after
3 you had seen a physician? Would that deal with the --
4 DR. TEMPLE: Can I make a counter? Maybe
5 this is what Charlie was suggesting. First cover the
6 question of whether urticarial disease of some sort is
7 suitable for over the counter. Get that out of the way.
8 Then you can elaborate on what exact claim you like best.
9 Knowing that urticarial disease is suitable for over
10 the counter, the first thing is absolutely critical to
11 us.
12 DR. CANTILENA: Okay.
13 DR. TEMPLE: The other is a refinement.
14 Alistair's suggestion is certainly one to think about
15 as would a variety. Again, remember that we're going
16 to have to be satisfied the data support whatever we say
17 or whatever you suggest.
18 DR. CANTILENA: Okay. Just so we're clear
19 on what everyone's intentions were, Dr. Dykewicz, Joad,
20 Szefler, D'Agostino, and Krenzelok voted yes to question
21 1 as modified and yes to question 1A in the general sense,
22 not product specific.
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1 DR. D'AGOSTINO: I want to make it clear that
2 I understood 1A to be as it's written and I voted yes
3 on that. I think that we're talking about if you're
4 trying to make it too segmented, it's not a very useful
5 claim for OTC so I was answering the question as it was
6 originally written. I believe I understood it correctly.
7 DR. CANTILENA: Okay. The other four
8 individuals voted yes. Let's continue.
9 DR. GANLEY: Lou, can we just get the answer
10 to No. 1 and then go back and just --
11 DR. CANTILENA: Let's do 1 first.
12 DR. GANLEY: Don't take a vote on 1A of yes
13 or no. Just let me put their comments on the record
14 because that's actually more important and we can sort
15 of swift through that.
16 DR. CANTILENA: So you want their comments
17 while they're voting?
18 DR. GANLEY: It's easier to go through one
19 and just give a yes or no and then go back and get the
20 comments on 1A.
21 DR. CANTILENA: So the attempt to expedite
22 things, I guess, didn't work out exactly as planned.
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1 Okay. The first five have voted yes to one. Dr. Uden,
2 question 1 as modified.
3 DR. UDEN: Yes to 1 and I'll comment on 1A
4 when appropriate.
5 DR. CANTILENA: Thank you very much.
6 Dr. Johnson.
7 DR. JOHNSON: Yes.
8 DR. CANTILENA: Dr. Lam.
9 DR. LAM: Yes.
10 DR. CANTILENA: Dr. Davidoff.
11 DR. DAVIDOFF: Yes.
12 DR. CANTILENA: Dr. Gilliam.
13 PARTICIPANT: He's out.
14 DR. CANTILENA: Dr. Gilliam will be back.
15 Dr. Sachs.
16 DR. SACHS: Yes.
17 DR. CANTILENA: Dr. Wood.
18 DR. WOOD: Yes.
19 DR. CANTILENA: Dr. Williams.
20 DR. WILLIAMS: Yes.
21 DR. CANTILENA: Dr. Clapp.
22 DR. CLAPP: Yes.
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1 DR. CANTILENA: Dr. King.
2 DR. KING: Yes.
3 DR. CANTILENA: Dr. Rosenberg.
4 DR. ROSENBERG: Yes.
5 DR. CANTILENA: Thank you. Let's go back
6 around for question 1A as written if yes for the general
7 condition not product specific, should the indication
8 be for CIU/Hives or should it be broader such that it
9 includes acute urticaria/hives. We're broadening it
10 beyond CIU. If I may, Dr. Dykewicz, Joad, Szefler,
11 D'Agostino, and Krenzelok have voted in the affirmative
12 yes.
13 Dr. Uden, 1A.
14 DR. UDEN: Broader, yes.
15 DR. CANTILENA: Should it be broader or
16 should it be restricted?
17 DR. UDEN: I think it should be broader and
18 I find it real interesting that we are using the product
19 that might be going nonprescription as the battle ground
20 or the proving ground for acute urticaria. It has not
21 been done with prescription drugs before.
22 DR. CANTILENA: Dr. Johnson, should it be
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1 CIU only or should it be broader?
2 DR. JOHNSON: My feeling is that it should
3 be broader and there's a couple reasons for that. One
4 is really sort of reality based, and that is that's how
5 patients are going to use it. Everybody with urticaria
6 is going to use it.
7 The second as it relates to data, I mean,
8 I think, you know, in this perfect academic world it might
9 be nice to see data. But I guess I am comfortable where
10 we are because at present to say these agents are not
11 acceptable for acute urticaria means that we don't believe
12 that all the consensus bodies and experts in dermatology
13 know what they're talking about.
14 Apparently all of them recommend this as the
15 appropriate therapy and the pathophysiology of the
16 process suggest that is appropriate therapy. I guess
17 I feel comfortable that the information we have is
18 appropriate for broadening without actual use kind of
19 studies.
20 DR. CANTILENA: Dr. Lam.
21 DR. LAM: Yes in a general sense.
22 DR. CANTILENA: So yes, it should be broader?
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1 DR. LAM: Um-hum.
2 DR. CANTILENA: Dr. Davidoff.
3 DR. DAVIDOFF: Possibly. I don't want to
4 say an absolute no picking up on Dr. Ganley's concern
5 about what absolute no means. I don't understand what
6 he means by that because I can't see how a no is ever
7 absolute. It seems to me there would always be the
8 opportunity to bring back new information that would open
9 the door again but that's another discussion.
10 The reason I'm hesitating is I'm somewhat
11 impressed with Dr. Dykewicz' comments about concerns
12 about anaphylaxis. I think it would be feasible to gather
13 information from the other countries that have had OTC
14 non-sedating antihistamines to see -- to look at their
15 cases of fatal anaphylaxis and try to get a direct body
16 of information on whether or not there's been a
17 contribution to delay and perhaps to fatality.
18 It seems to me that the likelihood is that
19 there will either be no evidence that that happens or
20 it will be very, very minimal amount, but at least the
21 decision would have been made with their eyes open instead
22 of doing it in the dark. As it is now, this would be
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1 a decision, yes, to broaden it but made on the basis of
2 really no input. I think it's not good for the public
3 health and it makes everyone in this room rather
4 vulnerable.
5 I also think I would wait until there had
6 been some search for the data. Possibly there are data
7 on management in acute anaphylaxis. An exhaustive search
8 would be very helpful. That could be done fairly quickly.
9
10 I would also like this information on how
11 often acute hives is, in fact, misdiagnosed by
12 self-diagnosis. It seems to me that's information that
13 may not be critical but it would certainly be very, very
14 reassuring to have that information before there was a
15 decision made to broaden the indications.
16 DR. CANTILENA: Thank you.
17 Dr. Sachs, broader or CIU only?
18 DR. SACHS: Actually, I also agree with
19 broadening the indication with the caveats that have
20 already been raised.
21 DR. CANTILENA: Thank you.
22 Dr. Wood.
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1 DR. WOOD: I would like to see us remove
2 idiopathic which I think is meaningless to most
3 individuals. Remembering this is an indication for an
4 over-the-counter drug it needs to be understandable to
5 patients. I would argue for making it hives, removing
6 urticaria.
7 If we say the indication is hives after you've
8 seen your doctor and he or she has made that diagnosis,
9 then essentially we avoid the problem of misdiagnosis,
10 at least for the first episode, which is, after all --
11 and it also fits with the indication that the sponsor
12 is seeking. Secondly, given the time it takes to see
13 a dermatologist, some might have many acute urticaria
14 patients in there anyway.
15 DR. CANTILENA: Thank you.
16 Dr. Williams.
17 DR. TEMPLE: Lou, that was actually a do not
18 broaden it. You want to change the name but you don't
19 want to broaden it.
20 DR. WOOD: No. The indication would be
21 hives.
22 DR. TEMPLE: Oh. Hives after you've seen
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1 your doctor.
2 DR. WOOD: Right.
3 DR. TEMPLE: I see. So that's something
4 different. Okay.
5 Dr. Williams.
6 DR. WILLIAMS: Yes and broader.
7 DR. CANTILENA: So the indication should be
8 broader to 1A?
9 DR. WILLIAMS: Yes.
10 DR. CANTILENA: Thank you.
11 Dr. King. Excuse me. Dr. Clapp.
12 DR. CLAPP: Yes to broaden it and my
13 reasoning is for many of the caveats shared previously,
14 but also because of the basic responsibility I think we
15 have to consumers and patients to adequately inform them
16 of appropriate usage of a medication rather than to narrow
17 down the spectrum of using to add further confusion to
18 a medicine that they will likely use anyway.
19 DR. CANTILENA: Thank you.
20 Dr. King.
21 DR. KING: Yes, should broaden it. I would
22 like to see two things happen. One is I would like to
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1 postmark the surveillance simply to come after the data
2 because I think we need to know how many may have had
3 delay in diagnosis or complications.
4 There's data out there from the European
5 group and also probably from the occupational health
6 groups. I think we're just looking in a darkened alley
7 here and we need to find out more in that area so broadening
8 it would get us there with public education.
9 DR. CANTILENA: Thank you.
10 Dr. Rosenberg.
11 DR. ROSENBERG: Yes, broader.
12 DR. CANTILENA: Broader. Okay. My vote
13 was on 1, could it be, yes, and on 1A, broader. We're
14 still missing Dr. Gilliam.
15 Okay. We'll move on to the second question.
16 Here we are product specific. We are specifically
17 concerned are there sufficient data to support an OTC
18 switch of loratadine for CIU or a more general urticaria
19 claim. We're talking specifically about the data we
20 heard about this morning.
21 What I would like to do here is limit this
22 really just to answer the first part yes or no. Comment
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1 if you feel strongly but really the second part of the
2 question is where we'll have an opportunity to talk about
3 specific trials if you think they are indicated.
4 Let's start on this side of the table, please,
5 Dr. Rosenberg answering just the first part of question
6 2.
7 DR. ROSENBERG: Yes.
8 DR. CANTILENA: Dr. King.
9 DR. KING: Yes.
10 DR. CANTILENA: Dr. Clapp.
11 DR. CLAPP: Yes.
12 DR. CANTILENA: Excuse me?
13 DR. D'AGOSTINO: The question is an or
14 question, CIU or more general. What are we responding
15 to?
16 DR. CANTILENA: Yes, it's actually an or so
17 it's either/or.
18 Dr. Ganley, do you want the specific as the
19 indication or just either/or?
20 DR. GANLEY: Well, I think it would be
21 helpful rather than just giving yes or no. There's an
22 over-emphasis on a vote of yes or no and the thoughts
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1 are more important.
2 I think the dermatologists voted they would
3 like a broader claim and by voting yes here they would
4 be stating that they think the company has provided
5 sufficient information for a broader claim. If that's
6 your opinion, that's fine and they don't need to do any
7 other study presumably.
8 DR. KING: I was voting for a follow-up study
9 so that's different.
10 DR. ROSENBERG: I misunderstood. I'm
11 sorry.
12 DR. CANTILENA: I apologize for that. I was
13 actually using that as written as sort of an either/or.
14 As I understand it now, Dr. Ganley, you would like yes
15 or no and an explanation in terms of the specific
16 indication as proposed versus a more general indication.
17 Is that correct? Yes or no for the specific switch for
18 CIU. Yes or no for the general urticaria.
19 DR. GANLEY: I think --
20 DR. CANTILENA: Is it yes or no for CIU only,
21 yes or no for general urticaria? We're sort of splitting
22 it into two questions.
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1 DR. TEMPLE: You really already answered the
2 first part of that question. That is, everybody agrees
3 there's enough data for a switch for CIU because --
4 DR. CANTILENA: No. Actually that was just
5 --
6 DR. TEMPLE: No.
7 DR. CANTILENA: -- as modified could it be
8 an OTC indication. Now we are product specific in terms
9 of the data presented.
10 DR. TEMPLE: Okay.
11 DR. CANTILENA: The question would be
12 basically split into two questions.
13 DR. TEMPLE: That's fair. Fine.
14 DR. CANTILENA: Okay. Let's go ahead and
15 split the question, Dr. Rosenberg. Are there sufficient
16 data to support an OTC switch of loratadine for CIU?
17 DR. ROSENBERG: Yes.
18 DR. CANTILENA: Are there sufficient data
19 to support a switch of OTC for a more general urticaria
20 claim?
21 DR. ROSENBERG: There may be but we haven't
22 seen it here.
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1 DR. CANTILENA: So that would be a no?
2 DR. ROSENBERG: That would be a no as we
3 didn't ask for it and they didn't bring it. Yes, it would
4 be a no as of this minute.
5 DR. GANLEY: The answer to question 1 seems
6 like there was a consensus that it should be a broader
7 claim. I'm not sure that it's relevant then. The CIU
8 sounds like that's not what people what to have. The
9 question really should read if your answer to question
10 is yes, is there sufficient data to support an OT switch
11 of loratadine for a more general urticaria claim.
12 Everyone has said that they would like a broader claim.
13 DR. ROSENBERG: Well, if I'm still voting
14 I would say whether that information -- let's read it
15 exactly. Are there sufficient data? Whether there are
16 or are not I don't think as I sit here to vote I don't
17 know if there are or not.
18 DR. CANTILENA: But as it is we have amended
19 question 1 to the more generic sense, could CIU be an
20 OTC indication. Answering in the affirmative there and
21 saying that it should be broader. Now question 2 --
22 DR. GANLEY: Could urticaria be and then you
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1 followed it up by saying should it be --
2 DR. CANTILENA: What I specifically said
3 before the vote question 2 is product specific. It's
4 actually their data and that's why --
5 DR. GANLEY: Question 1 was not whether could
6 CIU be a OTC. It was could urticaria be an OTC claim.
7 Then it was followed up with whether it should be CIU
8 or should it be a broader claim.
9 DR. CANTILENA: Right. But that was not
10 product specific or had anything to do with the data.
11 DR. GANLEY: No, but if everyone here is
12 saying that they think it should be a broader claim, then
13 if you answer yes, that they have enough information to
14 switch loratadine for a CIU claim, there's something
15 missing there for me.
16 DR. TEMPLE: Charlie, that's true but I think
17 what Lou is saying is now they are asking -- I mean,
18 whatever your preference might be, maybe you really think
19 a broader claim would be a really great thing, but you
20 still have to ask whether there's a basis for it. The
21 first step in question 2 is to say do they have the data
22 for CIU claim.
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1 Presumably that's what their studies are in
2 but I guess there's other questions. Then the next part
3 of that is do they have data for a broader claim. The
4 committee may say, "I don't know," or "Yes," or send it
5 back to you to think about or a lot of other things.
6 How does that sound?
7 DR. CANTILENA: That sounds reasonable.
8 Thank you.
9 DR. CANTILENA: Jonca.
10 DR. BULL: One other point of clarification
11 here. Based on the approach you've taken to question
12 1, which is looking broadly at whether or not it's
13 appropriate to have the OTC indication and you're saying
14 yes to the OTC indication, and yes that it should be the
15 broad one. Is that right? Is that what we want just
16 in terms of conceptually?
17 DR. CANTILENA: Right.
18 DR. BULL: Okay.
19 DR. CANTILENA: In sort of a generic sense.
20 DR. BULL: On No. 2 where you are more product
21 specific it appears that if you -- the question now is
22 on the data to support the general claim because you've
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1 already agreed that you want to see a general claim.
2 Is it mute for the CIU or general claim or are we going
3 back to that?
4 DR. ROSENBERG: I think it's what the meaning
5 of "are" are.
6 DR. CANTILENA: Let's not get into that.
7 Seriously, I think --
8 DR. BULL: I just want to clarify what
9 groundwork you've laid with question 1 for question 2.
10 DR. CANTILENA: Question 1 was really in sort
11 of a generic sense. Now question 2 is product specific.
12 In essence we're saying are there data to support CIU
13 as presented as proposed and are there data to also support
14 the more general claim of urticaria. We're trying in
15 essence to go -- if you're comfortable extending the data
16 that they presented for CIU as adequate for the more
17 general claim, then the answer to the second question
18 is yes.
19 DR. GANLEY: But I think one of the things
20 here is whether we have to make decisions not on a general
21 -- if the committee feels that they -- if they want to
22 see an urticaria claim, they would want to see a broader
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1 claim, then that's the way we should go. If everyone
2 thinks it could be broader but I would accept CIU, that's
3 a different issue because if you answer that you want
4 a broader claim, then that's what we're going to tell
5 not just this company but other companies.
6 DR. WOOD: Charlie, you're getting yourself
7 into a box because if you follow that down the logical
8 path and the committee votes for a CIU as having data
9 and not having data for the other but they want a broad
10 claim, then that's your interpretation but it would be
11 hard to approve.
12 DR. GANLEY: Well, no. I think someone --
13 if you construct, as John has tried to construct, that
14 this and an antihistamine, he's very comfortable and I
15 may be very comfortable with that. There's no additional
16 efficacy studies to look at acute hives to see whether
17 that's a -- you know, you need to do additional efficacy
18 studies because if we've already established it worked
19 in hives, I don't need efficacy studies.
20 That being said, then, well, if this is a
21 general claim for hives, what additional information
22 would I want to have? Is it a labeling comprehension
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1 study or an actual use study? But to go back and revisit
2 when everyone has come to some understanding that the
3 preference here is whether it should be a broader claim
4 or CIU claim. The issue then comes for the company.
5 Do they have information to support a broader claim here.
6 DR. TEMPLE: But, Charlie, that's the
7 question.
8 DR. D'AGOSTINO: But what if you don't accept
9 our response to 1? Then you don't want to know about
10 if we were hemmed into CIU in 2 to give a response?
11 When you have deliberations, you say in the
12 broader claim we don't like at all what the committee
13 said so we're chucking out their response to 1. We go
14 to 2 and we're only responding to a broader claim so we
15 haven't given you much information. I think it would
16 be nice for us to do the two pieces.
17 DR. TEMPLE: Yeah, but 1 was the statement
18 about what you hoped there were data support. It wasn't
19 a statement that there were data support. That comes
20 later. We understand, I think, because it's going to
21 be used anyway and various other reasons, you would like
22 to see it labeled for urticaria as a more general matter.
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1
2 But this question was, as you're
3 understanding it, are there data that support a claim
4 in CIU only if that were the best we could do, or is there
5 good reason to extrapolate the information from that use
6 to a more general statement about urticaria on which
7 you're going to give a separate opinion. Part of it may
8 be that we have to go think about that some more. We
9 don't know yet.
10 DR. CANTILENA: Okay. So let me just
11 rephrase this. This was supposed to be the easy part.
12 All right. We basically agreed to split this question
13 to answer it basically separately for the indications.
14 Are there sufficient data to support an OTC switch of
15 loratadine for CIU? The first part.
16 Second part: Are there sufficient data to
17 support an OTC switch of loratadine for a more general
18 urticaria claim? Product specific, the information that
19 we heard this morning and it's in our packets.
20 So far we've had Dr. Rosenberg, I believe,
21 vote yes for CIU and no for the more general claim. Is
22 that correct?
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1 DR. ROSENBERG: Yes.
2 DR. CANTILENA: Okay.
3 Dr. King.
4 DR. KING: Same response. I think in terms
5 of the specific agent they did provide the data. I don't
6 think the data is here about the general thing. I would
7 like to see that as a goal. I think they would come
8 forward with that and it would be coupled with a use study
9 to find out when this is released, if that's true, after
10 the fact.
11 I think they didn't present the data because
12 they probably weren't thinking they were going to have
13 to do that. I think this group just haven't seen that
14 data.
15 DR. CANTILENA: Okay. Dr. Clapp.
16 DR. CLAPP: Yes for the switch for CIU but
17 no for the general claim. My concern is based on the
18 efficacy in children. Although we presume based on what
19 the dermatologists have said that the mechanism for
20 urticaria is the same regardless to the acute versus
21 chronic idiopathic as being the same, I still don't have
22 the sense of certainty that in children the efficacy is
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1 the same in the acute circumstance. I would like to see
2 some data to confirm that reality.
3 DR. CANTILENA: Thank you.
4 Dr. Williams.
5 DR. WILLIAMS: Yes to the first part and no
6 to the second part. I believe the sponsor should have
7 that type of information in the years of usage that they've
8 had already so I don't think it should be too difficult
9 for them to produce it.
10 DR. CANTILENA: Thank you.
11 Dr. Wood.
12 DR. WOOD: Yes to the first part and to the
13 second part I would defer to the FDA looking at the data
14 that I suspect is in the literature to make that decision
15 on the acute. From what we have from Dr. Rosenberg it
16 sounds like that data is already out there.
17 DR. CANTILENA: So based on the information
18 that was presented it would be a no. But if there was
19 sufficient information available in the file or in the
20 literature, then it would be a yes.
21 DR. WOOD: I'm precise. Are there
22 sufficient data to support an OTC switch for a more general
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1 claim. The answer to that is I don't know that we can
2 answer that question because we haven't had that data
3 presented. However, the answer might be yes or no and
4 that's why I'm saying defer it for further review to the
5 FDA. To say that there are not data I don't think anyone
6 can answer that.
7 DR. CANTILENA: Okay.
8 Dr. Sachs.
9 DR. SACHS: I would say yes to the CIU with
10 the one caveat I think the data presented only went down
11 to age 12, and no to the general indication because I
12 think we need the actual use studies as I've said before.
13 DR. CANTILENA: Dr. Davidoff.
14 DR. DAVIDOFF: I would say yes to the CIU
15 question and to the more general claim, I would say no,
16 that the data at least have not be presented to us here.
17 I think it's not just efficacy data which I think are
18 probably going to be pretty easy to come by.
19 I would be rather more concerned about safety
20 data. I think anaphylaxis is essentially not an issue
21 for CIU but it is potentially for acute urticaria. I
22 think they are rather different situations and we would
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1 need more information on that.
2 DR. CANTILENA: Thank you.
3 Dr. Lam.
4 DR. LAM: Yes to the first one and to the
5 second one, I don't know where there is data out there
6 and, therefore, I can't really make a decision whether
7 it's sufficient or not.
8 DR. CANTILENA: So you're voting like Dr.
9 Wood on the second part.
10 Dr. Johnson.
11 DR. JOHNSON: Yes to the CIU and, like many
12 around the table, for the more general clearly the data
13 weren't presented. They may be out there somewhere.
14 I'm not convinced that further trials are necessary but
15 I think we need more information.
16 DR. CANTILENA: Dr. Uden. Hold on one
17 second.
18 Dr. Johnson, so you're voting as Dr. Lam and
19 Dr. Wood. You're not sure about the second part. It's
20 not a yes or no.
21 Dr. Uden.
22 DR. UDEN: Yes for the first part and the
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1 second part I'm a Wood, Lam, Johnson believer.
2 DR. CANTILENA: Dr. Krenzelok.
3 DR. KRENZELOK: I vote yes for the first part
4 and my dimpled chad on part 2 will be that I'll vote no
5 until there are more data to change that vote.
6 DR. CANTILENA: Thank you.
7 Dr. D'Agostino.
8 DR. D'AGOSTINO: I vote yes on the first
9 part, but I want to emphasize that I was quite serious
10 about the response to question 1. I don't think that
11 -- I think this is much too narrow. I think they have
12 the data but it's much too narrow an indication for an
13 OTC.
14 On the second part I'm going to say no because
15 I haven't seen the data. The data may be there but I'll
16 say no for the data that I've seen and later we'll talk
17 about is there control clinical trial data on the
18 literature. There's a lot of data in where it has already
19 been approved for OTC use.
20 They should be able to collect data there
21 on at least the safety issues and other data sources which
22 would help in terms of whether or not there is enough
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1 data out there for approval. Right now I haven't seen
2 it so I vote no.
3 DR. CANTILENA: Dr. Szefler.
4 DR. SZEFLER: I haven't seen the specific
5 data for either indication other than the publications
6 that were included in the material we got so I'm going
7 to say yes to the first part presuming there was adequate
8 data there to get it approved as an Rx indication and
9 defer to the FDA for that decision and it's already been
10 made.
11 The second category really depends on whether
12 you accept chronic urticaria as a model for urticaria
13 in general. The FDA had said no to that. Either there
14 has to be data in the specific disease in terms of acute
15 urticaria or there has to be a reexamination of the
16 similarities between chronic urticaria and general
17 urticaria.
18 I think if they could settle on accepting
19 that as common mechanisms and as this being a palliative
20 drug, then I would go along with extending on current
21 data. Otherwise there's a need for additional data.
22 It would be essentially exactly what Dr. Wood said.
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1 DR. CANTILENA: Dr. Joad.
2 DR. JOAD: Yes to the first one and no to
3 the second one. I do think there needs to be a good solid
4 clinical trial in acute urticaria. I would also like
5 to add that special emphasis should be done on the product
6 label informing people about what to look for for
7 anaphylaxis and getting emergency help right away.
8 I think there were some concerns with the
9 sponsors. Results were there were a lot of the people
10 would talk to their doctor and it was not very clear that
11 they would recognize it as an emergency. A lot of work
12 on the product label about recognizing anaphylaxis as
13 an emergency.
14 DR. CANTILENA: Thank you.
15 Dr. Dykewicz.
16 DR. DYKEWICZ: Yes for CIU. No for general
17 at this time.
18 DR. CANTILENA: Okay. Comments from Dr.
19 Alfano?
20 DR. ALFANO: A couple comments. One, I
21 guess we see why the sponsor submitted for CIU as the
22 day plays itself out. Two, I wonder if we would have
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1 voted differently if instead of we asked the question
2 is there sufficient data we ask is there sufficient basis
3 to support a more general claim because we heard some
4 erudite physicians talk about the physiology of this as
5 being the same, and yet there was no data so there could
6 be a semantic witch haunting us as we made these decisions.
7
8 I guess the final comments would be you know
9 if we don't move this, then we will deal with the status
10 quo which is less safe products on the market used in
11 the fashion that they are for these conditions anyway
12 without the warning label for anaphylaxis. I guess the
13 question is will be have left the world a better place.
14 DR. CANTILENA: Okay. Thank you. My vote
15 is for the first part, yes, and the second part for the
16 general claim, no.
17 Before we get to the other types of data that
18 are needed for this second part, just an announcement.
19 Dr. Hoff has an emergency phone call at the registration
20 desk outside. It's just outside the door and to your
21 left is the registration desk if you would take care of
22 that.
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1 Okay. Question No. 2. Here I would
2 actually like not to talk about the label that they
3 proposed specifically, but I would like to advise the
4 sponsor and FDA here what other types of data are needed
5 such as clinical trials for efficacy, safety, label
6 comprehension or actual use.
7 Since I believe everyone answered in the
8 affirmative for CIU, then we are really just left with
9 those who answered negatively for the more general
10 urticaria claim.
11 What I would like to do is actually, if you
12 want to, just volunteer what specific kind of studies
13 you would like to see to support the more general claim,
14 I think we would do that as opposed to going around the
15 room we'll just open it up for a minute. Also, if you
16 voted you don't know or you're not sure because you haven't
17 seen it, you can also comment as well.
18 Dr. Rosenberg.
19 DR. ROSENBERG: I think a conscientious
20 literature search such as used for medianalysis.
21 DR. CANTILENA: Thank you.
22 Dr. Sachs.
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1 DR. SACHS: I am sure, as alluded to, that
2 data exist on drug/drug interactions or the absence of
3 them in these products if that would be helpful
4 information, the poison control data, and the actual use
5 studies in kids as well as adults if you're going to go
6 down to six.
7 DR. CANTILENA: Other types of study
8 recommendations, Dr. Krenzelok?
9 DR. KRENZELOK: I'm sorry. I was going to
10 make a comment about a label. Is that okay or do you
11 want to wait on that?
12 DR. CANTILENA: If we can cover that on No.
13 3 unless it's a comment about a label comprehension study.
14 Dr. Wood.
15 DR. WOOD: I think without sounding factious
16 we should have studies that actually determine whether
17 people understand chronic idiopathic urticaria better
18 than hives and really focus on what vocabulary people
19 really use.
20 The other types of data that are needed such
21 as clinical trials for efficacy, etc., I think most of
22 that data is already out there, at least from what Dr.
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1 Rosenberg days. I think it's just a question of
2 reanalyzing it and resurfacing it. I'm not sure that
3 we need to leave the impression that major new clinical
4 trials are needed.
5 DR. CANTILENA: Dr. D'Agostino.
6 DR. D'AGOSTINO: Do we think there are
7 clinical trials on Claritin in acute hives? I mean, when
8 we say there's data out there, clinical trial data, we're
9 talking about just the whole class of antihistamines that
10 we can extrapolate to this?
11 DR. WOOD: I think the answer is we don't
12 know. We've not had that presented and, therefore, it
13 would be foolish to comment on whether that exist or not,
14 except to say that the dermatologists, Dr. Rosenberg
15 specifically, said there were class A evidence to support
16 use of antihistamines.
17 DR. D'AGOSTINO: The old line
18 antihistamines? These antihistamines? Just so I'm --
19 DR. WOOD: Non-sedating.
20 DR. ROSENBERG: Non-sedating antihistamine
21 was given that citation. I mean, I didn't read the --
22 I didn't do a search for that.
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1 DR. D'AGOSTINO: Right. None of us have.
2 DR. CANTILENA: So your question is are there
3 studies that use this drug for acute hives? Is that your
4 question?
5 DR. D'AGOSTINO: Well, we've -- exactly.
6 We've said CIU was -- we believe the acute part is left
7 hanging.
8 DR. CANTILENA: Dr. Clayton, are there
9 studies using loratadine for acute hives?
10 DR. CLAYTON: Not that I'm aware of.
11 DR. CANTILENA: Okay. So they are not
12 available.
13 Any other comments about studies? Dr.
14 Davidoff.
15 DR. DAVIDOFF: Well, just to get back to the
16 point about studying safety versus studying efficacy.
17 Obviously studying safety is much more difficult,
18 essentially impossible to do in the broad sense in a
19 controlled trial of any manageable size.
20 I think safety is a big part of the issue
21 here so I would think the kind of data that would be needed
22 for convincing information about safety would include
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1 a variety of possible approaches.
2 Other people know them better than I, but
3 post-marketing surveillance clearly would be one of them,
4 retrospective looks, better or deeper looks into existing
5 data and so on. I think that distinction has to be made
6 because I think the efficacy data will not be so difficult
7 to get.
8 DR. CANTILENA: Yes, Dr. D'Agostino.
9 DR. D'AGOSTINO: Where -- in the countries
10 where this has been approved OTC, do they collect safety
11 data? Do you feel comfortable there will be safety data
12 from those countries?
13 DR. CANTILENA: Dr. Ganley or Katz, Temple?
14 DR. KATZ: They do collect safety data but
15 you run into the same problem.
16 DR. D'AGOSTINO: Spontaneous.
17 DR. KATZ: That's right. Spontaneous
18 reports so that you have no denominator. As a result,
19 certain countries are better than others at getting data
20 but you're not quite sure when you try to put into
21 perspective what it really means because, again, there's
22 no denominator.
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1 DR. CANTILENA: Dr. Temple.
2 DR. TEMPLE: We're talking about events that
3 must be unbelievably rare so your denominator is not
4 usually a problem on something like this. I think you
5 want to know whether there are really any people who didn't
6 go get their anaphylaxis treated because they were using
7 an over-the-counter non-sedating antihistamine. Like
8 most spontaneous reporting, the denominator is your whole
9 country. You can't do better. You can't do a study of
10 --
11 DR. D'AGOSTINO: So if the spontaneous
12 reporting good, then it counts.
13 DR. TEMPLE: In the UK it's thought to be
14 pretty good. In Canada it's thought to be pretty good
15 so those aren't so bad. You're not going to do a study
16 of 2,000 people and find --
17 DR. D'AGOSTINO: No, no. The question is
18 we're talking about safety data and one possibility is,
19 what do they say, 10 years of history?
20 DR. TEMPLE: Sure. That can be looked at.
21 DR. WOOD: But, Bob, you're absolutely
22 right. These are data that are going to be readily
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1 available. Anaphylaxis is not something that doesn't
2 get spotted.
3 DR. TEMPLE: Yeah. One of my questions is
4 what kind of anaphylaxis gets reported. For example,
5 if it doesn't seem to be related to a drug, it probably
6 wouldn't be reported to Medwatch.
7 DR. WOOD: No, but it's going to be a death
8 certificate data.
9 DR. TEMPLE: I don't think we know yet how
10 good it's going to be but that's what there's going to
11 be. There's isn't really going to be anything else.
12 You can't do a study of this. There can't be a lot of
13 them.
14 DR. JOAD: That was going to be my point.
15 I'm not sure it would be reported as an adverse drug event
16 because no one would think that the anaphylaxis was due
17 to the antihistamine but it certainly could be related
18 to delay in treatment.
19 I don't know how you would find that from
20 spontaneous reporting. I mean, if there's a way to do
21 it, if we approve this, we should try to figure out a
22 way to do it in the future for post-marketing research.
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1 DR. D'AGOSTINO: We are saying there's data
2 out there and it doesn't sound like we are offering much
3 by way of what data is and where they can get it. Am
4 I right?
5 DR. DYKEWICZ: If I can ask maybe Dr. Lee
6 with the SAE data that you had discussed earlier with
7 the 12 percent incidence of anaphylaxis of people who
8 had been on loratadine when there is a prior history of
9 urticaria, would that have enough detail in that database
10 to see whether, for instance, there had been, I don't
11 know, some effort to use loratadine during an anaphylic
12 event?
13 DR. LEE: Yes. Some of that data was pretty
14 detailed. I mean, there are individual case reports.
15 The case report that I mentioned of the Canadian woman
16 who took -- was the only anaphylaxis death in the database.
17
18 Some of these reports are detailed enough
19 to be able to get a feel as to whether or not the event
20 in some circumstances what the order of -- what happened
21 was, when the drug was taken. Was it taken after the
22 patient had symptoms. In some cases not.
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1 DR. CANTILENA: Okay. I think there was a
2 comment over here. Dr. Uden and then Dr. Davidoff. Do
3 you still have a comment?
4 MS. ROHANE: Excuse me. Do you need any more
5 information about the cases on anaphylaxis in the
6 post-marketing safety database? What I can tell you is
7 that within the entire marketing of loratadine there have
8 been 20 reported with the plain tablet.
9 Of those 20 four were in patients who took
10 the drug with a CIU diagnosis. Of the four there was
11 one in Canada who took the drug for acute urticaria.
12 The other 16 were in other diagnoses including allergic
13 rhinitis, sinusitis unspecified. There's a variety of
14 other things.
15 DR. SACHS: But do you have information on
16 whether taking loratadine, for example, delayed their
17 treatment? That's kind of the question we're asking.
18 MS. ROHANE: Well, the issue there is that
19 this all comes from post-marketing safety surveillance.
20 Some cases have very little information and others have
21 much more detail. It depends on the case.
22 DR. CANTILENA: Okay. Dr. Davidoff.
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1 DR. DAVIDOFF: Well, I agree here's detail
2 and you need to look at the detail of the case. There's
3 no other way to get the kind of information you'll need
4 because it's not going to be reported as an adverse affect
5 in the usual sense.
6 DR. CANTILENA: Dr. Uden.
7 DR. UDEN: I haven't heard it explicitly
8 stated in this round but assuming that there's going to
9 be a more general indication and assuming that might be
10 hives, that we do have them redo label comprehension study
11 that adequately represents the diversity of the United
12 States and the literacy of the United States again. Make
13 sure that they do something with a new label.
14 DR. CANTILENA: I would second that, Dr.
15 Ganley. I think it's a critical piece of the information
16 package is to make sure that we are effectively
17 communicating in the drug label and if you're going to
18 change the drug label now to a more general indication,
19 I think that has to be tested vigorously. I would agree
20 with Dr. Uden that subpopulations have to be adequately
21 represented.
22 Anymore comments regarding additional
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1 studies for the more general claim?
2 Dr. Wood.
3 DR. WOOD: I just want to make a general
4 point, and that is maybe we're all getting tired but we
5 seem to have developed a sort of negative tone about it
6 which I think would be unfortunate because it seems to
7 me that the sponsor came in with an application for CIU
8 and the committee, or the agency, has taken the position
9 that maybe it should be a broadened indication.
10 Now they are sort of getting attacked for
11 a broader indication they didn't actually ask for in the
12 first place. I think it's important for us to at least
13 convey to the agency that the sense I get from the
14 committee is there's a broad consensus for a positive
15 view on the CIU indication and this sort of other issue
16 which has been raised is kind of distracting us. I have
17 a sense of unfair play in some ways on that.
18 DR. CANTILENA: Well, I'm not sure if it's
19 unfair or if we are actually anticipating sort of the
20 next move and we're trying to help out on both sides.
21 It was actually our group that I think stimulated the
22 discussion for the more general claim. I understand your
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1 point and it's well taken.
2 DR. D'AGOSTINO: I thought I was following
3 your lead, Dr. Wood, in going to hives and so forth.
4 DR. WOOD: I still hives is the right way
5 to go.
6 DR. D'AGOSTINO: Can I --
7 DR. CANTILENA: Yes.
8 DR. D'AGOSTINO: If in the search for data,
9 safety, and efficacy it doesn't materialize, the safety
10 issues sound very profound and maybe there is enough from
11 the company's spontaneous reporting or whatever that they
12 do for adverse events.
13 What is our sense about the efficacy? I
14 mean, how much would be push on the efficacy part if it
15 turns out that the literature isn't convincing enough.
16 Do we feel that they must put together a clinical trial?
17 Is there no extrapolation?
18 DR. WOOD: Well, I think if there was no data
19 on the efficacy -- you mean in acute hives?
20 DR. D'AGOSTINO: In acute, yes.
21 DR. WOOD: Then I would return to the
22 original suggestion I made, that the indication should
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1 be hives that has been diagnosed by a physician which
2 would be compatible with the CIU indication but, it seems
3 to me at least, more understandable to the average patient
4 than over the counter.
5 DR. CANTILENA: Yeah. I think Dr. Temple
6 sort of explained the situation as far as how the agency
7 would have to sort of go by the law if there are no data
8 for that as a specific indication.
9 DR. D'AGOSTINO: Well, we said in No. 1 that
10 we think it should be broader and now I'm asking if the
11 broader data is not there, there's one way of getting
12 a good positive response by saying then put after you've
13 seen your physician and that doesn't compel the company
14 and the FDA and the advisory committees that you must
15 have efficacy data and, therefore, you must have a
16 clinical trial.
17 DR. CANTILENA: Okay. Any other comments
18 about additional studies before we answer the last
19 question?
20 Dr. Sachs.
21 DR. SACHS: It was raised. I just want to
22 make sure you do note about the patient's ability to
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1 recognize hives themselves. You may roll your eyes but
2 let me just point out that take a TB skin test. They
3 did a study on whether patients could self-read whether
4 a TB skin test was positive or negative and they could
5 not.
6 I think you do have to at least look at it,
7 you know, could you distinguish the dangerous things like
8 purpura from hives. It may not matter if you can't tell
9 a mosquito bite from a hive but purpura from a hive you
10 probably need to know.
11 DR. CANTILENA: Okay. Since we've split up
12 question 2, question 3 basically has to refer to the
13 indication of CIU which everyone answered yes to. Now
14 as we are referring specifically to CIU, what are your
15 recommendations for appropriate labeling of loratadine
16 with regard to indications, warnings, and directions for
17 CIU because that's what we answered in the affirmative.
18
19 Just so we are guaranteed to get everyone's
20 input and to keep everybody awake, why don't we start
21 with Dr. Alfano and just go around the table with specific
22 recommendations for CIU.
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1 DR. ALFANO: I just urge the sponsor to make
2 sure they have maximized the warning of the consumer for
3 anaphylaxis so they know to seek care.
4 DR. CANTILENA: Thank you.
5 Dr. Dykewicz.
6 DR. DYKEWICZ: Well, I'm a little bit torn
7 by the stricture not to go beyond the CIU indication.
8 I think even in a situation where CIU has been diagnosed
9 by a physician, one has to be mindful that there could
10 be evolution to a vasculated process, for instance.
11 I think that would be something about
12 purpuric however that would be found in a label
13 comprehension study or in a use study to indicate that
14 change in skin color at the site or a purple lesion, those
15 would be reasons to seek medical attention or something.
16 DR. CANTILENA: Thank you.
17 Dr. Joad.
18 DR. JOAD: For the CIU indication I don't
19 have any additional comments.
20 DR. CANTILENA: Dr. Szefler for CIU.
21 DR. SZEFLER: I think a clear definition.
22 I think as Dr. Wood mentioned a number of times now, I
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1 don't think the public is aware of what chronic idiopathic
2 urticaria means. We often just call it chronic hives
3 or recurrent hives.
4 I think a clear definition with some warnings
5 about when it extends beyond or went to see a physician
6 presumably again would be indicated. I don't know if
7 package inserts have actual pictures of what a hive looks
8 like but if that could be done, it would be help so they
9 could kind of understand what we're talking about.
10 DR. CANTILENA: Dr. D'Agostino.
11 DR. D'AGOSTINO: I don't have anything to
12 add.
13 DR. CANTILENA: Dr. Krenzelok.
14 DR. KRENZELOK: Thank you. Dr. Wood and Dr.
15 King expressed some very simplistic things about how
16 people in Tennessee perceive words and so on. I think
17 that is really good. I think we really need to downplay
18 this chronic urticaria business.
19 Dr. Ferguson in his presentation emphasized
20 unexplained hives that keep coming back. Well, there
21 might be a better way to say that but that is actually
22 fairly simplistic and I think we need to present it to
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1 the public that way.
2 Then Dr. Wilkin in slide 42 had some excellent
3 patient admonitions about when the patient needs to
4 contact a physician. I think those should really be
5 included on the outside of the package label or inside.
6 Somewhere to warn the patient accordingly. Thank you.
7 DR. CANTILENA: Dr. Joad, did you have
8 something else?
9 DR. JOAD: I just to make a comment about
10 the idiopathic or unexplained. My understanding from
11 the reading is that in 40 percent of the cases we do have
12 an explanation. It's the IGG against the IGE receptor
13 or the IGE. I realize historically we haven't known but
14 we do know. That's a complication, too. There sounds
15 like there is a disease out there that does have a
16 pathophysiology that explains everything.
17 DR. CANTILENA: Dr. Uden.
18 DR. UDEN: I have a question. Maybe the
19 sponsor can answer this. We handed around one of the
20 suggested labels prior to what our discussion was. Was
21 there anything -- this isn't related to urticaria.
22 Was there anything in there about sedation?
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1 They call it non-drowsy. Was there anything about
2 sedation as one of the side effects? I know your
3 advertisements say may cause drowsiness so this is a
4 clarification for me.
5 DR. CLAYTON: (Off microphone.)
6 DR. UDEN: Because -- well, this is a bigger
7 issue and it's not related to this so maybe I should just
8 shut up. I mean, the non-sedative antihistamines are
9 less sedative. I just wanted to know if "may cause
10 drowsiness" is actually in their label even though they
11 call it non-drowsy.
12 DR. CANTILENA: It's on the ads.
13 DR. UDEN: It's on the ads, you know, "This
14 may cause drowsiness." I just wanted to have truth in
15 label language and non-drowsy is not truth in labeling.
16 DR. CANTILENA: Dr. Johnson.
17 DR. CLAYTON: (Off microphone.)
18 DR. CANTILENA: Dr. Clayton, could you use
19 a microphone, please? We're having a hard time hearing.
20 DR. CLAYTON: I had given an incomplete
21 thought to Dr. Uden's comment. You mentioned the
22 advertising for non-sedating antihistamines. I'm
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1 talking specifically about loratadine, the advertising
2 just mentioned as the primary side effect but no greater
3 than placebo in the clinical trials.
4 DR. CANTILENA: Dr. Johnson.
5 DR. JOHNSON: My recommendations are related
6 to the packaging. I think I have concern about this with
7 a lot of OTC products. A lot of OTC products are packaged
8 in blister packs. I suspect what happens is people might
9 read the box when they purchase it. They go home and
10 open it up and they probably throw away the package insert.
11
12 They throw away the box, and what they have
13 left is a blister pack which on the back has the name
14 of the drug and the dose. One thing that I might suggest
15 is that there is consideration to give in to not marketing
16 these in blister packs but in bottles where you could
17 at least put critical warning information and it's always
18 there.
19 As long as the patient has tablets left they
20 always have the information. Whereas I think in blister
21 packs in most situations they are going to lose that
22 information as soon as they purchase the product.
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1 DR. CANTILENA: Thank you.
2 Dr. Lam.
3 DR. LAM: I like the information that Dr.
4 Wilkin has suggested, although I'm not really sure now
5 we can fit all that information into one tiny label.
6 DR. CANTILENA: Okay. Dr. Davidoff.
7 DR. DAVIDOFF: Yes. I would certainly
8 support the emphasis on hives rather than chronic
9 idiopathic urticaria, although I don't think it hurts
10 to put the longer term in because some doctors will have
11 used that with their patients.
12 On the safety issue, even though it's not
13 clear the extent to which anaphylaxis is more common,
14 or if it's more common in CIU, it seems to me that it
15 probably isn't less common in CIU than the rest of the
16 population so you may, in fact, still be at risk to develop
17 anaphylaxis and that does certainly provide a rationale
18 for including information, more specific information on
19 when to recognize something more serious is happening.
20 DR. CANTILENA: Dr. Gilliam.
21 DR. GILLIAM: Yeah. Just along this same
22 line. There was a list that somebody had of 10 points
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1 of when you should consult your physician or provider,
2 the peanut or latex allergy greater than six weeks, skin
3 bruising or skin tone changes, blistering, and so forth.
4 There were 10 of these points and I think they should
5 be in there.
6 DR. CANTILENA: On the box or in the package
7 or either?
8 DR. GILLIAM: I would say definitely on the
9 box. We all know that most people don't read the package
10 inserts so definitely on the box
11 DR. CANTILENA: Okay. Thank you.
12 Dr. Sachs.
13 DR. SACHS: I like the idea of having
14 pictures. Perhaps a do not use type thing. You guys
15 use a lot of color. I don't recall if the warnings said
16 anything about alcohol which probably should be and
17 something about the days of treatment. How are these
18 going to be packaged like a package of seven, package
19 of 21, package of whatever.
20 I think that would be useful information for
21 the future. Perhaps a warning to call 911 -- I apologize
22 if I lifted that from anyone over there -- in case of
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1 anaphylaxis or respiratory difficulty. Not just a
2 statement to consult your doctor but perhaps call 911.
3 DR. CANTILENA: Dr. Wood.
4 DR. WOOD: I don't know what I can add except
5 to say you've got to be careful not to overstuff the label
6 with so many warnings that it becomes incomprehensible
7 to the patient. I think it would be very important in
8 this setting to really try and prioritize what the major
9 issues are and not get it so filled with other things
10 that it becomes actually incomprehensible to a patient
11 which I think we do sometimes.
12 DR. CANTILENA: Dr. Williams.
13 MR. JACKSON: My concern is to make sure that
14 they read and follow the directions as indicated on the
15 package. Many of these medications are three times a
16 day or four times a day. We usually don't have that in
17 the information on the package that this is just a once
18 a day pill.
19 DR. CANTILENA: Dr. Clapp.
20 DR. CLAPP: Ditto to what has been said.
21 DR. D'AGOSTINO: Dr. King.
22 DR. KING: I'm concerned, again in the
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1 Tennessee phrase, about how much they are going to be
2 able to comprehend. I would like to see that there be
3 follow-up studies or preliminary studies on truth in
4 labeling so that we look at and see what you are talking
5 about and do what you're supposed to like once a day or
6 whatever and avoid whatever things you say, you need to
7 go to the physician or whatever.
8 I don't know about getting 10 indications
9 but I think it's up to the sponsors and the FDA to decide
10 what's going to be the best indication for labeling on
11 the outside of the box to find out if it's going to be
12 used effectively.
13 DR. CANTILENA: Dr. Rosenberg.
14 DR. ROSENBERG: I think if the indication
15 will be chronic idiopathic urticaria it has to be -- then
16 you have been seen previously by a doctor who told you
17 there was no known cause or he didn't know the cause at
18 that time and it should be treated symptomatically.
19 I think it relieves the symptoms rather than
20 cures. That would be one thing. If it did not have the
21 CIU claim, if, in fact, it were to achieve the broader
22 urticaria claim, then I think we could take out "see your
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1 doctor first."
2 I would think about it in the same way we
3 think about analgesics for headaches for people who could
4 have a brain tumor or laxatives for people who could have
5 cancer and so forth and have the kind of material that
6 John Clayton mentioned, things to look out for and the
7 kind of statement that if it doesn't get better, go see
8 somebody.
9 But, in addition, because of the anaphylaxis
10 piece, I think it could have a special box or so that
11 says sometimes like this is a symptom of a very serious
12 condition that can strike suddenly and if you think you're
13 having that, really dial 911. It is hard to write those
14 things and get them in little boxes but there are
15 specialist at that.
16 DR. CANTILENA: Okay. Thank you.
17 Dr. Ganley, would you like any additional
18 comments about the labeling for the more general claim
19 or have you had about all the advice you can take for
20 one day?
21 DR. GANLEY: I just want to make one final
22 note. This is the last formal meeting for Dr. Gilliam,
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1 Krenzelok, Sachs, and Dr. Neal who is not here today.
2 We appreciate their efforts over the last years and we
3 may look forward to having you back in the future sometime.
4 Thank you.
5 DR. CANTILENA: Yes. Thank you. Let's
6 give them a round of applause for their endurance.
7 Are there any other issues from FDA's side
8 or from the sponsor's side that you would like our
9 streamlined advice about?
10 DR. D'AGOSTINO: What time is it tomorrow
11 morning?
12 DR. CANTILENA: Tomorrow morning is --
13 DR. TITUS: Tomorrow morning starts at 9:00
14 and we are across the room right across the hallway in
15 a smaller room. If you come in here, you'll be in the
16 wrong meeting.
17 DR. CANTILENA: Okay. So the closed session
18 for the NDAC is tomorrow at 9:00. Thank you very much
19 everyone.
20 (Whereupon, at 5:03 p.m. the meeting was
21 adjourned.)
22
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