Food and Drug Administration
Center for Drug Evaluation
and Research
October 29 & 30, 2003
Mary Glode, M.D. Steven
Ebert, Pharm. D.
Patricia Chesney, M.D. Victor Santana, M.D. Norman Fost, M.D.
David
Danford, M.D. Robert Fink, M.D. Richard
Gorman, M.D., FAAP
Roselyn Epps, M.D. Thomas Ten Have, Ph.D. Sharon
Raimer, M.D.
Elizabeth Andrews, Ph.D.
HHS Guests
Don Mattison, M.D. Benjamin
Wilfond M.D. Constantine
Stratakis, M.D.
Charles
Rabkin, M.D. Phyllis
Wingo, M.D. Lois Travis,
M.D.
FDA
Participants
Dianne
Murphy, M.D. Jonathan
Wilkin, M.D. Anne Trontell, M.D.
Shirley
Murphy, M.D. Susan
Cummins, M.D. Lois
LaGrenade, M.D.
Solomon
Iyasu, M.D. Denise Cook, M.D.
These summary minutes for the October 29 & 30,
2003 meeting of the Pediatric Subcommittee of the Anti-Infective Drugs Advisory
Committee were approved on
I
certify that I attended the October 29 & 30, 2003 meeting of the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee, and that these minutes accurately reflect what
transpired.
_________//S//______________________ ___________//S//____________________
Thomas H. Perez, M.P.H., R.Ph. Patricia
Chesney, M.D.
The Subcommittee and invited guests received a
briefing document from the FDA in preparation for this meeting.
There were approximately 80 persons present at the
meeting on October 29. The meeting was called to order at
Presentations began at
Atopic Dermatitis: Its Clinical Course Bindi
Nikhar, M.D.
and Therapeutic Options Division of Dermatologic
and Dental Drug Products
Overview of HPA Axis Suppression Jean Temeck, M.D., Division of
Pediatric Drug Development
FDA Experience:
Topical Corticosteriods Denise Cook, M.D.
and HPA Axis
Suppression Division of Dermatologic and
Dental Drug Products
Post
Marketing Adverse Event Reports Claudia Karwoski, Pharm.D.
Division
of Drug Risk Evaluation
At
Framework for Risk Assessment &
Management Anne Trontell, M.D., Deputy Director, Office
of Drug Safety
At
At
The
subcommittee reconvened at
There were no participants for the Open Public
Hearing. The chair, Dr. Joan Chesney
provided the final comments, and the meeting was adjourned at
The Subcommittee and invited guests received a
briefing document from the FDA in preparation for this meeting.
There were approximately 75 persons present at the
meeting on October 30. The meeting was called to order at
Presentations began at
Review
of Topical Calcineurin Inhibitors Bindi
Nikhar, M.D.
Division
of Dermatologic and Dental Drug Products
Topical
Immunosuppressants Barbara
Hill, Ph.D.
(Calcineurin
Inhibitors) – Animal Toxicology Division
of Dermatologic & Dental Drug Products
Post
Marketing Adverse Event Reports Marilyn
Pitts, Pharm. D.
Division
of Drug Risk Evaluation
At
Studying the Risk
of Cancer with Topical Lois LeGrenade, M.D., Office of
Drug Safety
Calcineurin Inhibitor Use in Children: Design Issues
Practical and
Methodological Issues in Elizabeth Andrews, Ph.D., RTI
Health Solutions
Long Term
Follow-up Studies
The Role of Cancer
Registries in Long Term Phyllis
Wingo, Ph.D., Centers for Disease Control
Follow-up
Studies Cancer
Registry Program
At
At
On October 29, the Subcommittee discussed the
following questions to which no votes were requested or taken. The discussion will be made available through
the meeting transcripts and placed on the web in approximately three
weeks. Transcripts may be accessed
at: www.fda.gov/ohrms/dockets/ac/acmenu.htm.
Questions to the Subcommittee
Questions to the Committee for
1) Clinical
trials have demonstrated Hypothalamic–Pituitary–Adrenal axis (HPA axis)
suppression using the cosyntropin stimulation test with the use of topical
corticosteroids. Is the cosyntropin
testing performed during drug development sufficient to determine the
risk? Are there additional specific
tests that the Subcommittee would recommend to measure this risk?
The Subcommitee’s consensus was that the cosyntropin test is a
reasonable screening test to determine if there is an effect on the
adrenals. It also elaborated that the
tests should be prioritized. The peak
value 18 mcg/dl, considered the most valuable followed by increment, and
baseline tests. In addition the
following tests were discussed; tests of absorption during early and late drug
development, individual and population PK/PD.
2) Younger
pediatric patients have a larger surface area to mass ratio when compared to
adults and may be at greater risk of higher systemic exposure to topically
applied drugs. Because of this, the FDA
has usually requested that the Sponsor conduct suppression studies in older age
groups first, and if there is no evidence of suppression, to proceed in
sequentially younger patients until all age groups have been studied, or until
there is evidence of significant suppression.
Given the data from clinical trials that was presented today, does the
Subcommittee recommend continuing this sequential testing, or should the
testing be performed concurrently?
If
the Subcommittee recommends sequential testing, what percent of children who
suppress should be utilized to determine if further studies may proceed? (e.g. should the
studies be stopped if any single patient in the clinical trial group
demonstrates suppression by cosyntropin testing, or 10 percent demonstrate
suppression, or 50 percent demonstrate suppression, etc.)?
The
Subcommittee provided a variety of responses with reasons for doing sequential
and concurrent testing with an associated consistent criteria
for testing. Responses included some
members recommending sequential testing while testing for suppression more
frequently, and others doing concurrent testing based on the evidence that
suppression is occurring at a rate of 30 – 50%.
Some of the recommendations hinged on the significance of suppression
and evidence of resulting life threatening problems.
Background to Question 3
Fact 1: There are only a few post-marketing
cases of adrenal suppression in patients using topical corticosteroids.
Fact 2:
Data from clinical studies has consistently demonstrated that a
percentage of pediatric patients using topical corticosteroids under the
maximal labeled use conditions will experience adrenal suppression. This suppression is most likely transient in
nature and related to extent of exposure to the steroid.
Fact 3:
Patients with a post-ACTH stimulation cortisol level of ≤ 18
mcg/dL by cosyntropin stimulation
testing require corticosteroid replacement at stress doses if they experienced
trauma, sepsis, or are challenged with any other cause of physiologic stress.
Premise:
It may not be recognized that the clinical course of patients who have
undergone trauma, sepsis, or major surgery is complicated by adrenal
suppression from underlying topical corticosteroid use, and hence, this adverse
event may go unrecognized and under-reported.
3) Given
the above information, does the Subcommittee think this represents a clinically
significant (or relevant) concern for pediatric patients exposed to topical
corticosteroids?
If
yes, should any additional risk management action be taken? Please discuss which risk management
approaches listed below you think would be appropriate, and why.
·
Additional
studies
·
A
box warning
·
Limiting
the indication to certain age groups,
·
Recommending
against use in certain age groups
·
Contraindicating
use of the product in populations that demonstrate HPA axis suppression
·
Include
a Patient Package Insert to inform the patient or parent/guardian of the risk
·
Require
that a Medication Guide be dispensed with every prescription
·
Unit
of use packaging
·
Issuing a “Dear
Health Care Provider” letter to groups of health care providers most likely to
prescribe topical corticosteroids to pediatric patients
·
Education
programs for providers (including emergency room physicians, anesthesiologists,
dentists, practitioners who perform procedures in their office under anesthesia
or heavy sedation) and patients/caregivers
The
Subcommittee felt that use of topical corticosteroids was a relevant concern
for pediatric patients. The following
risk management approaches were discussed:
Additional
studies in children: epidemiological studies relating to steroid exposure and
effect on risk, study to look at cortisol levels in patients under conditions
of high stress.
Educational
items that provide practical information (eg.,
indications that reflect when specifically to treat, use of OTC topicals
recommended by family members and friends), such as the Patient Package Insert,
and education materials that provide information on issues on the topic that
are actively being discovered.
On October 30, the Subcommittee
discussed the following questions to which no votes were requested or
taken. The discussion will be made
available through the meeting transcripts and placed on the web in
approximately three weeks. Transcripts
may be accessed at: www.fda.gov/ohrms/dockets/ac/acmenu.htm.
Questions to the Subcommittee
Questions to the Committee for
1) What is a clinically meaningful increase in cancer risk from a treatment for a chronic non-life threatening disease? Does the present patient package insert appropriately reflect the information concerning cancer risk? Please discuss any recommendations.
The
Subcommittee felt that any increase in cancer risk was unacceptable. Educational information needs to explain why
these are second line drugs to physicians and patients. Underscoring the importance of what is
appropriate use of the drug (including information that communicates the amount
of application, duration of application, inappropriate use, in particular in
children <2 years of age, not to share medication with others, and the basis
for the short term use). For children
under 2, because of immune system development issues and lack of understanding
regarding the development of other systems in the very young a Box Warning was recommended. Additionally, the subcommittee recommended
the following; a study to determine quantitatively the effect on the rate of
infections and serious disease, the use of the Patient Package Insert, Dear
Doctor Letters, Educational Programs, use of the Contraindications Section of Labeling. Concern was also raised about using these
drugs in extemporaneous compounding and the dangers of using vehicles that may
promote their absorption, the gaps in knowledge, and the level of patient
understanding of information being provided to them. Also expressed was the need for cognitive
testing to determine the level of patient understanding of educational
materials developed.
Background to Question
2
Fact 1: Lymphoma has been associated with systemic use
of this class of immunosuppressants in both pre-clinical studies and in human
use. Cutaneous malignancies are the most
common malignancy associated with systemic use of this class of drugs.
Fact 2: Topical use of these immunsuppressants
results in some, albeit modest, systemic exposure. This may be increased in pediatric patients
due in part to increased body surface to mass ratio.
Premise: Malignancy may only be discernable via
longer-term exposure, especially with modest systemic exposure.
2) What is the best way to ascertain this clinical risk of malignancy (e.g. lymphomas or skin cancer) in clinical studies? Please discuss the merits and draw-backs of each of the following as well as study design considerations:
· Duration
of follow-up for each enrolled patient, keeping in mind that the latency period
of most cancers is at least 10 years
· Study
design requirements
· sample size needed to detect rare signals and feasibility
issues
· the approach to ascertainment of skin cancers (e.g. by
physical examination by physician, by physical examination by dermatologist, by
interview/questionnaire)
· the role of the comparison group
· design strategies to optimize retention
· Endpoint
issues
· Specific
cutaneous and systemic malignancies
· Other
biological endpoints
· Viral
infections of the skin/other (e.g. warts, EBV infection)
· Pre-malignancy
or early cancer endpoints (e.g. actinic keratoses)
The
Subcommittee provided a variety of responses including; using state registries
and the Children’s Oncology Group, annual examinations for cancer among
comparison groups, looking at information available on the systemic drug
formulations.
The
Subcommittee felt that long term studies would be needed in situations where
there is evidence of systemic absorption and systemic effects with potential
for serious and long term complications. Also when developmental time frames and life
stages determine what changes are expressed as a result of therapy.
Existing
registries and programs could play a role by identifying exposures and then
ascertaining outcomes.
5)
What other
studies would you recommend (eg. Animal)?
What
other risk management for this class would you recommend?
Systemic measure of immune response to vaccination.
Conditions
placed on sponsor marketing to limit the marketing and encourage the promotion
of knowledge and caution.