Food and Drug
Administration
Center for Drug Evaluation and Research
Pediatric Oncology
Subcommittee of the Oncologic Drugs Advisory Committee
Jody
Pelusi, R.N., Ph.D. Gregory
Reaman, M.D.
Victor Santana, M.D. C.
Patrick Reynolds, M.D. Susan
Weiner, Ph.D.
Howard McLeod, Pharm.D. David Poplack, M.D. Naomi Winnick, M.D.
Susan Shurin, M.D.
Malcolm Smith, M.D. Barry Anderson, M.D. Leslie Ball, M.D.
Richard
Weinshilboum, M.D. Bruce
Morland, M.D. Joachim
Boos, M.D.
Gilles Vassal, M.D. Riccardo Riccardi, M.D. Ursula Kern, M.D.
Hugh Davies, M.D. Mark
Bernstein, M.D.
George
Ohye, J.D.
FDA
Participants
Murray Lumpkin, M.D. Grant
Williams, M.D.
Dave Maybee, M.D. Steven
Hirschfeld, M.D.
These summary minutes for the
I
certify that I attended the
_______________________________ _______________________________
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 discussed the pharmacogenetic testing for
thiopurine methyltransferase (TPMT) deficiency in patients for whom treatment
with Purinethol (6-mercaptopurine, 6MP) is being considered. During the
afternoon session the Subcommittee discussed overcoming challenges in pediatric
oncology product development: regulatory oversight of multi-national clinical
studies.
The Committee had received a briefing document from
the FDA.
There were approximately 40 persons in the
audience. The meeting was called to
order at
The
scheduled presentations began at
Introduction to Topics of Day Steven Hirschfeld, M.D, Ph.D., Medical Officer
Division of Oncology Drug Products
Description of CDER Office of Drug Safety Programs Victor Raczkowski, M.D.,
Director, Office of Drug Safety
Introduction to Thiopurine Methyltransferase Deficiency and Testing
Larry Lesko, Ph.D., Director, Office of Clinical Pharmacology and Biopharmaceutics, FDA
Howard McLeod,
Perspective of Children's Oncology Group on the use of 6-Mercaptopurine
Naomi Winick, M.D.,
The
subcommittee paused for a brief Break at
The
subcommittee began its discussion of the presentations at
At
Overview of Research Oversight
German Perspective Ursula Kern, Ph.D., Federal Institute for Drugs and Medical Devices
There
were no participants for the Open Public Hearing, and at
The meeting was adjourned at
The subcommittee discussed the following questions to which no votes were requested or taken.
Questions to Subcommittee
Pharmacogenetic testing for thiopurine
methyltransferase (TPMT) deficiency in patients
for whom treatment with Purinethol
(6-mercaptopurine, 6MP) is being considered
Food
and Drug Administration (FDA) pediatric initiatives are directed at identifying
opportunities for improving the clinical quality of therapeutics relating to
the use of already-marketed drugs in pediatric patients, and developing new
therapeutics for the treatment of childhood cancer. This includes updating product information in
the approved package insert or product label where such data is relevant to the
safe and effective use of the drug in the pediatric population. The Best Pharmaceuticals for Children Act of
2002 supports the pediatric use information of the approved package insert
(product label) as one of the primary mechanisms to publicly disseminate that
information.
Purinethol
(6-mercaptopurine, 6MP) is a marketed product that is indicated for remission
induction and maintenance therapy in acute lymphoblastic leukemia in pediatric
patients as well as in adults. The
Agency has reviewed recently published literature and corresponding data about
the variability in the metabolism of 6MP related to pharmacogenetics. There is evidence that the administration of
the usual doses of 6MP to patients with hereditary thiopurine methyltransferase
(TPMT) deficiency are at a substantially increased risk of toxicity. Previously the Pediatric Subcommittee, at a
meeting in November 2001, was presented clinical evidence that genotypes in the
pediatric patient population having little or no TPMT activity (0.3%), or
reduced TPMT activity (10%) are at risk for excessive myelosuppression.
The
Agency would like the Subcommittee to provide advice on what additional
information would be considered necessary or appropriate to be in the product
label for 6MP regarding pharmacogenetics.
Question
#1
The
current product package insert states in the Warning Section:
•
There are individuals with an
inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may
be unusually sensitive to the myelosuppressive effects of mercaptopurine and
prone to developing rapid bone marrow suppression following the initiation of
treatment. Substantial dosage
reductions may be required to avoid the development of life-threatening bone
marrow suppression in these patients. This toxicity may be more profound in
patients treated with concomitant allopurinol. This problem could be
exacerbated by coadministration with drugs that inhibit TPMT, such as
olsalazine, mesalazine, or sulphasalazine.
The
Dosage Section states:
•
PURINETHOL is administered orally.
The dosage which will be tolerated and be effective varies from patient to
patient, and therefore careful titration is necessary to obtain the optimum
therapeutic effect without incurring excessive, unintended toxicity.
•
Once a complete hematologic remission
is obtained, maintenance therapy is considered essential. Maintenance doses
will vary from patient to patient.
What
additional information should be included in the product label with regard to
TPMT metabolic activity and the potential for exposure to excessive bone marrow
toxicity in pediatric patients with acute lymphoblastic leukemia?
Additional
Information may include:
Yes, should be included
Current statement in labeling conveys the
information, but language should be adjusted to convey that only persons who
have the homozygous condition are at high and consistent risk of developing
toxicity. Preliminary data indicate that more than half of heterozygous persons
tolerate standard doses. In addition,
patients with normal TPMT status could have severe toxicity, so a normal
screening test does not preclude severe toxicity.
Statement that tests are available but no further
recommendations on use or interpretation other than response to question # 2.
No, dosage adjustment recommendations should be
included because insufficient data are available to make specific dose
recommendations. The committee sees
these as significant issues for research, and strongly recommends that such
studies be undertaken by investigators.
Since the drug is used in many different schedules and in combination
with other agents, the combined myelosuppressive effects should also be
considered.
Question
#2
If
pharmacogenetic information is added to the label, what other testing
information, if any, about genotyping or phenotyping for TPMT activity in
pediatric patients would you consider necessary or appropriate to include in
the product label?
Information may include:
No
No
Yes, with the statement conditional and not a
mandatory recommendation for testing.
No
further information than above.
Overcoming
challenges in pediatric oncology product development:
regulatory oversight of multi-national clinical
studies
What
core principles should be incorporated in the conduct and monitoring of
multinational pediatric oncology clinical studies?
Principles of Belmont Report, those of HHS 45 CFR 46
and those contained in the European Union Directive to become effective May
2004.
What
monitoring mechanism would be acceptable to assure adherence to these
principles?
A mutual recognition procedure that avoids
duplication and minimizes paperwork, yet that adheres to the same coherent set
of standards.