Food and Drug
Administration
Center for Drug Evaluation and Research
Holiday Inn,
Kennedy Ballroom
Pediatric Oncology
Subcommittee of the Oncologic Drugs Advisory Committee
Donna
Przepirorka, M.D. Stephen
George, Ph.D. (On Phone)
Victor Santana, M.D. C. Patrick Reynolds, M.D. James Boyett, Ph.D.
Jerry Finklestein, M.D. Ruth Hoffman (patient rep.) Alice Ettinger, R.N.
Walter Shaw, Ph.D. Douglas Flanagan, Ph.D. Malcolm Smith, M.D.
Anne Zajicek, M.D. Don Mattison, M.D. Louis Cooper, M.D.
FDA
Participants
Richard Pazdur, M.D. Steven
Hirschfeld, M.D.
Rosemary Roberts, M.D. Patricia Dinndorf, M.D. Rik Lostrito, Ph.D.
These summary minutes for the
I
certify that I attended the
_________//S//______________________ ___________//S//____________________
Thomas H. Perez, M.P.H.,
R.Ph. Victor
Santana, M.D.,
Executive
Secretary Chair
The Pediatric Oncology
Subcommittee of the Oncologic Drugs Advisory Committee,
of the Food and Drug Administration, Center for Drug Evaluation and Research
met
During the morning session
the Subcommittee considered off-patent oncology drugs for which pediatric
studies are needed and discussed the
availability of information concerning the safe and effective use of the drugs
in the pediatric population; whether additional information is needed; and
whether new pediatric studies concerning the drugs may produce health benefits
in the pediatric population, as mandated by the Best Pharmaceuticals for
Children Act (BPCA). During the afternoon session the Subcommittee discussed
age-appropriate formulation changes to facilitate dosing of products used in
the pediatric oncology setting.
The Committee had received a briefing document from
the FDA.
There were approximately 18 persons in the
audience. The meeting was called to
order at
The
scheduled presentations began at
Labeling &
Formulation: Steven Hirschfeld,
M.D, Ph.D., Medical Officer
Challenges in Pediatric Therapeutics Division of Oncology Drug Products
BPCA: For Oncology
Drugs Louis I. Cooper, M.D., Medical Officer
Division of Pediatric Drug Development
BPCA: Role of the
NIH Anne Zajicek,
M.D., Pharm.D.
National
Off-patent Drugs
for Young Children Malcolm Smith, M.D., Ph.D.
With Cancer – Gaps in Knowledge
Cancer Therapy Evaluation Program, NCI
And Public Health Needs
Population
Pharmacokinetics in Peter C. Adamson,
M.D.,
Childhood Cancer Drug Development
The Children’s
The
subcommittee continued with a period of questions on the presentations, and
paused for a brief Break at
The
morning session was adjourned for lunch at
At
Lym-X-Sorb™ Walter A. Shaw, Ph.D., Avanti
Polar Lipids, Inc.
A Revolution in Oral Drug Delivery
Best
Pharmaceuticals for Children Douglas
R. Flanagan, Ph.D.,
Best Formulation
for Children
Drug Formulation in
Pediatrics: Jeffrey Blumer, Ph.D., M.D.,
If it tastes bad it must be good for you
The
subcommittee continued with a period of questions on the presentations, and at
The meeting was adjourned at
The subcommittee discussed the following questions for which no votes were requested or taken.
Questions to Subcommittee
Off-patent
oncology drugs for which pediatric studies are needed:
availability of information concerning the safe and effective use of the drugs
in the pediatric population; whether additional information is needed; and
whether new pediatric studies concerning the drugs may produce health benefits
in the pediatric population, as mandated by the Best Pharmaceuticals for
Children Act (BPCA)
The BPCA of 2002 provides a
mechanism to study off-patent medications in pediatric populations.
1.
What factors
should be considered in selecting off-patent drugs for study in children with
cancer (these may include use in only a pediatric population, use in particular
diseases, use in particular age groups, or toxicity questions of particular
concern)?
The
Subcommittee consensus was that there is no one unique factor, but a matrix of
factors that included the following: issues that address toxicity (acute and
long term for patients being cured and end organ toxicity),frequency of use
particularly use in younger age groups where the incidence of cancer is the
highest, efficacy and safety profile-particularly if there is loss of efficacy
or increased toxicity in a particular population, likelihood of drug-drug
interactions, dosing issues in obese patients, and feasibility - availability
of validated assays and relevant patient populations.
2.
Are there any
comments, on the proposed selections as discussed by the National Cancer
Institute, on the drugs actinomycin-D and vincristine as priority choices, and
others to follow?
The
Subcommittee endorsed the choices with an optional suggestion that both can be
studied together in a reasonable study design and allow for an efficient use of
limited resources. Other drugs were also
mentioned as meriting priority (see answer to next question), but not
necessarily at the expense of dactinomycin and vincristine.
3.
Are there any
other off-patent oncology drugs that should be studied in children with cancer
that you would suggest? Please indicate
the rationale.
Cisplatin
because of its short and long term toxicity, use in many tumor types and lack
of detailed knowledge on individualizing the dose for maximum benefit and
minimal toxicity.
6-thioguanine because of its unexpected
hepatotoxicity.
Anthrocyclines
because of the increased incidence of cardiotoxicity in the youngest patients children.
Alkylating
agents cyclophosphamide and ifosfamide due to
toxicity.
13-cisretinoic acid and other retinoids to better
understand dosing and to avoid underdosing.
Corticosteroids due to the unpredictably of a wide
range of toxicities.
Products
used in supportive care such as anti-emetics and analgesics are also good
candidates for study in cancer patients. The committee suggested that if
products that are used in cancer patients were being considered in other
settings, that including the oncology use would be desirable and beneficial.
Age-appropriate formulation changes
to facilitate dosing of products used in the pediatric
oncology setting
1.
What factors
would be considered essential in the development of a formulation for children
with cancer? Please comment on any age-,
disease-, or pharmaceutical-specific considerations.
Factors
that were discussed included the anticipated length of therapy, the usage, age
and developmental stage of the patient, ability to use with food, palatability,
volume or size of dose, development of a range of dose sizes for solid oral
medications, ease of standardization, development of several alternatives to
provide flexibility, stability and uniformity.
Discussion
on the applicability of pediatric formulations to other populations such as
geriatric patients, handicapped patients, patients with chronic illness,
post-surgical patients, patients requiring greater precision in dosing, and
patients who wished to have alternatives recommended calling attention to
manufacturers of the potential for greater use for a pediatric formulation.
2.
What type of testing
or clinical trial design would you recommend for establishing the efficacy and
safety of a new formulation for an existing oncology drug that already has
efficacy and safety demonstrated in the same population?
Limited
studies were recommended that would address bioequivalence and if needed, some
proof of principle for efficacy. Similar response based on surrogate endpoints
rather than complete demonstration of clinical benefit would likely be
sufficient.
3.
What type of
testing or clinical trial design would you recommend for establishing the
efficacy and safety of a new formulation for an existing oncology drug that
already has efficacy and safety demonstrated in a different population?
A
separate efficacy study in the new population was recommended.