 |
Product Approval
Information - Licensing Action
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
July 12, 2002
Our STN: BL 103946/0
Sanofi-Synthelabo, Inc.
Attention: Mr. Mark Moyer
Director, Drug Regulatory Affairs
9 Great Valley Parkway
P.O. Box 3026
Malvern, PA 19355
Dear Dr. Moyer:
This letter hereby issues Department of Health and Human Services
U.S. License No. 1294 to Sanofi-Synthelabo, Inc., Malvern,
Pennsylvania in accordance with the provisions of Section 351(a) of
the Public Health Service Act controlling the manufacture and sale
of biological products. This license authorizes you to introduce or
deliver for introduction into interstate commerce, those products
for which your company has demonstrated compliance with
establishment and product standards.
Under this license you are authorized to manufacture the product
Rasburicase. Rasburicase is indicated for the initial management of
plasma uric acid levels in pediatric patients with leukemia,
lymphoma, and solid tumor malignancies who are receiving anti-cancer
therapy expected to result in tumor lysis and subsequent elevation
of plasma uric acid.
Under this authorization, you are approved to manufacture
Rasburicase at your facility, Sanofi Recherche, in
-------------------------. Final formulated drug product will be
manufactured, filled, labeled and packaged at Sanofi-Synthelabo, in
----------------------------------. In accordance with approved
labeling, your product will bear the proprietary name Elitek and
will be marketed in 1.5 mg single-use vials.
The dating period for Rasburicase shall be 36 months from the
date of manufacture when stored at 2-8°C. The date of manufacture
shall be defined as the date of final sterile filtration of the
formulated drug product. The dating period for drug substance shall
be ---------- when stored at ---°C. Results of ongoing stability
studies should be submitted throughout the dating period, as they
become available, including the results of stability studies from
the first three production lots. The stability protocols in your
license application are considered approved for the purpose of
extending the expiration dating period of your drug substance and
drug product as specified in 21 CFR 601.12.
You are not currently required to submit samples of future lots
of Rasburicase to the Center for Biologics Evaluation and Research (CBER)
for release by the Director, CBER, under 21 CFR 610.2. FDA will
continue to monitor compliance with 21 CFR 610.1 requiring assay and
release of only those lots that meet release specification. Any
changes in the manufacturing, testing, packaging or labeling of
Rasburicase or in the manufacturing facilities will require the
submission of information to your biologics license application for
our review and written approval consistent with 21 CFR 601.12.
All applications for new active ingredients, new dosage forms,
new indications, new routes of administration, and new dosing
regimens are required to contain an assessment of the safety and
effectiveness of the product in pediatric patients unless this
requirement is waived or deferred (21 CFR 601.27). We note that you
have fulfilled the pediatric study requirement at this time.
We acknowledge your written commitments as described in your
letter of July 12, 2002, and as outlined below:
Chemistry Manufacturing and Controls:
- To submit a complete validation report for the ---------------
method of determining urate oxidase enzyme activity, including a
review of provisional acceptance criteria on the basis of
additional data, by August 31, 2002. The provisional limits
submitted to the BLA have been implemented for all production
batches.
- To submit a complete validation report for the revised
------------------------------- analysis used in drug substance
release testing and for in-process testing, including a review
of provisional acceptance criteria on the basis of additional
data, by August 31, 2002. The provisional limits submitted to
the BLA have been implemented for all production batches.
- To submit a complete validation report for the revised
------------------------------- analysis used in drug substance
release testing, including a review of provisional acceptance
criteria on the basis of additional data, by August 31, 2002.
The provisional limits submitted to the BLA have been
implemented for all production batches.
Clinical:
- To develop a quantitative ELISA for antibodies in patient sera
for use in clinical safety studies and to submit information
demonstrating assay sensitivity (with limit of quantification
defined in mass units), specificity, reproducibility,
robustness, and ruggedness. Until the final assay is validated,
serum samples will be collected and banked for future analysis.
The protocol for assay methods and the validation plan for the
new ELISA will be submitted to CBER by August 31, 2002. The
complete validation data will be available by March 31, 2003,
and a final report submitted to CBER by September 30, 2003.
- To submit information on the enzyme inhibition (antibody
neutralization) assay to be used in clinical safety studies,
demonstrating assay sensitivity, specificity, reproducibility,
robustness, and ruggedness. This information will include
assessments of optimal concentrations of reagents to detect
antibodies, and assurance that pharmacological levels of product
in serum samples do not influence detection of antibodies. The
protocol for assay methods and the validation plan for the new
antibody neutralization assay will be submitted to CBER by
December 30, 2002. The validation data will be available by June
30, 2003, and a final report submitted to CBER by September 30,
2003.
- To design an appropriate antigen-specific assay for IgE
assessment, such as RAST or radioallergosorbent testing, and to
use the specific assay for IgE, in addition to the ELISA and
enzyme inhibition assays, at appropriate times during the
clinical trials. Until the specific test for IgE is
appropriately designed and validated, serum samples will be
collected and banked for future analysis. The protocol for assay
methods and the validation plan for the antigen-specific IgE
assay will be submitted to CBER by December 30, 2002. The
complete validation data will be available December 30, 2003,
and a final report submitted to CBER by March 31, 2004.
You have committed to collect and analyze data, as part of
ongoing and future protocols, to further characterize the incidence
of immune responses utilizing the assays specified in commitments
4-6 and to evaluate the pharmacodynamic and clinical consequences of
such immune responses. In addition, analyses of the relationship of
development of IgE or IgG antibodies to development of allergic
reactions will be conducted within and across studies. All serum
samples collected for immunogenicity testing will be sent to
Sanofi-Synthelabo, Inc., who will be responsible for appropriately
tracking, storing, and aliquoting a sufficient number and volume of
sera for all three assays. When qualified assays have been developed
and determined to be acceptable to CBER, the assays will be used to
test the stored serum samples and all samples subsequently collected
for immunogenicity testing. The specific studies are follows:
- To include in all corporately-sponsored, ongoing or future
studies, a systematic approach for collection of serum samples
at baseline in all patients and, in those patients who
experience an allergic reaction, additional serum samples will
be collected within 48 hours of the reaction, at three months,
at six months, and every six months thereafter, until the
immunogenicity assays described above are validated. Once
validated assays are available, only patients with persistent
immune responses at six months will have serum collected every
six months for each assay, until the results of all assays are
negative. A proposal for the following will be developed:
systematic collection and analysis of plasma uric acid levels in
patients with antibody responses including allergic reactions;
collection and reporting of adverse events; analysis of the
pharmacodynamic effects of antibody responses; and, analysis of
the correlation between allergic reactions and antibody assay
results. Copies of revised protocols containing these
modifications will be submitted by August 31, 2002 for all
on-going studies.
You have also committed to incorporate a plan in two studies
(described in items 8 and 9) to collect and analyze data that will
further characterize the incidence, type and duration of immune
responses in all patients enrolled in those studies, [i.e., in those
with and without allergic reactions (All-Patient Schedule)]. Both
studies will also include a plan for collection and analysis of data
to characterize the pharmacodynamic effects and clinical
consequences of the various types of immune responses. In both
studies, serum will be collected at baseline, between 7 to 14 days,
at five weeks, three months and six months after Rasburicase dosing,
then every six months thereafter until the immunogenicity assays
described above are validated. These two studies will utilize the
assays specified in commitments 4-6. Once validated assays are
available, only patients with persistent immune responses at six
months will have serum collected every six months for each assay,
until the results of all assays are negative. All patients with an
allergic reaction will have additional serum collected within 48
hours after the allergic reactions as described in commitment 7
above. The specific studies are as follows:
- To conduct a study to assess the safety and efficacy of
repetitive treatment with Rasburicase. This study will enroll at
least 100 uricolytic therapy-naive patients and 50 patients with
prior exposure to uricolytic therapy. Antibody therapies
directed against B-cells, including but not limited to rituximab,
may not be administered to patients on study or within the
12-month period prior to study entry because they will confound
the ability to assess immune responses. Data will be collected
on concurrent antineoplastic therapy, on the most recent prior
chemotherapy regimen, and on uric acid levels immediately prior
to and during Rasburicase therapy. Immunogenicity studies will
use the All-Patient Schedule described above. Plasma uric acid
levels will be assessed at pre-specified time points in all
patients and should be sufficient to assess maintenance of uric
acid over various time points throughout Rasburicase treatment.
Maintenance of uric acid levels will be as defined in the
package insert. The protocol will include a detailed description
of the analyses to characterize the following:
- the incidence, duration, and type of immune responses
(i.e., IgG, IgE, neutralizing);
- clinical toxicity associated with an immune response;
- maintenance of uric acid levels at 4, 24, 48, 72 and 96
hours after first dose of Rasburicase;
- impact of immune response on maintenance of uric acid
levels, i.e., pharmacodynamic impact; and,
- effect of prior uricolytic treatment on ability to
maintain uric acid levels below the upper limit of normal
and on immune response.
The draft protocol will be submitted by August 31, 2002,
and a final protocol will be submitted by November 30, 2002.
The study will be completed by December 31, 2005. The final
study report, will include an assessment of the binding (IgG),
neutralizing antibody, and IgE profile in naive and
retreated subjects, the impact of immunogenicity on safety
and efficacy, and the safety and efficacy of retreatment
with Rasburicase. This report will be completed and
submitted by September 30, 2006.
- To conduct a study designed to assess the comparative safety
and efficacy of the approved dose and schedule of Rasburicase
with a regimen of sequential Rasburicase and allopurinol. This
study will be conducted in adults and will enroll a sufficient
number of subjects to randomize at least 60 patients
(approximately 30 per treatment arm), following a short
induction course of Rasburicase (two days treatment). The
objectives of this trial will include a comparison of the
adequacy of control of plasma uric acid concentration and
comparison of the toxicity profile for the two regimens,
including the comparability of the immunogenicity profile of
Rasburicase in the two regimens. This study will use the
all-patient schedule to assess immunogenicity. Plasma uric acid
levels will be assessed at pre-specified time points in all
patients and should be sufficient to assess maintenance of uric
acid over various time points throughout Rasburicase treatment.
Maintenance of uric acid levels will be as defined in the
package insert. The protocol will include a detailed description
of the analyses to characterize the following in each arm and a
comparison between arms;
- the incidence, duration, and type of immune responses
(i.e., IgG, IgE, neutralizing);
- clinical toxicity associated with an immune response;
- maintenance of uric acid levels at 4, 24, 48, 72 and 96
hours after first dose of Rasburicase; and,
- impact of immune response on maintenance of uric acid
levels, i.e., pharmacodynamic impact. The protocol will
include a detailed description of all analyses intended to
assess these objectives.
A draft protocol will be submitted by August 31, 2002,
and the final protocol will be submitted by November 30,
2002. Accrual to the study will be completed by September
30, 2004. The final study report will include an assessment
of the binding (IgG), neutralizing antibody, and IgE
immunogenicity profile, the impact of immunogenicity on
safety and efficacy, and the analysis of the comparable
safety and efficacy of the sequential regimen to the
approved regimen. The final study report will be completed
and submitted by June 30, 2005.
- For both expanded access studies --------- and ---------,
Sanofi-Synthelabo agrees to submit a draft publication,
protocol, blank case report forms, case report forms for all
serious adverse events and deaths within 30 days of dosing, and
an electronic database that includes demography, dosing and
safety information to CBER by September 30, 2003.
Sanofi-Synthelabo agrees to attempt to collect additional
information on volume and rate of administration of Rasburicase
in patients three months of age or younger.
The protocols described in items 7, 8, and 9 above may be
submitted for review under the Special Protocol Assessment
procedure. Please refer to the December 1999 DRAFT “Guidance
for Industry - Special Protocol Assessment” available at http://www.fda.gov/cber/gdlns/protocol.htm
and submit final protocol(s) to the IND for FDA review as a REQUEST
FOR SPECIAL PROTOCOL ASSESSMENT (SPA) in bolded block
letters at the top of your cover letter.
It is required that adverse experience reports be submitted in
accordance with the adverse experience reporting requirements for
licensed biological products (21 CFR 600.80) and that distribution
reports be submitted in accordance with 21 CFR 600.81. Postmarketing
adverse experience reports and distribution reports should be
submitted to the Center for Biologics Evaluation and Research,
HFM-210, Food and Drug Administration, 1401 Rockville Pike,
Rockville, MD 20852-1448. All adverse experience reports should be
prominently identified according to 21 CFR 600.80.
You are required to submit reports of biological product
deviations in accordance with 21 CFR 600.14. All manufacturing
deviations, including those associated with processing, testing,
packing, labeling, storage, holding and distribution, should be
promptly identified and investigated. If the deviation involves a
distributed product, may affect the safety, purity, or potency of
the product, and meets the other criteria in the regulation, a
report must be submitted on Form FDA-3486 to the Director, Office of
Compliance and Biologics Quality, Center for Biologics Evaluation
and Research, HFM-600, 1401 Rockville Pike, Rockville, MD
20852-1448.
Please submit all final printed labeling at the time of use and
include implementation information on FDA Form 356h. Please provide
a PDF-format electronic copy as well as original paper copies (ten
for circulars and five for other labels). In addition, you may wish
to submit three draft copies of the proposed introductory
advertising and promotional labeling with an FDA Form 356h or Form
2253 to the Center for Biologics Evaluation and Research,
Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville
Pike, Rockville, MD 20852-1448. Final printed advertising and
promotional labeling should be submitted at the time of initial
dissemination, accompanied by a FDA Form 356h or Form 2253. All
promotional claims must be consistent with and not contrary to
approved labeling. No comparative promotional claim or claim of
superiority over other products should be made unless data to
support such claims are submitted to and approved by the Center for
Biologics Evaluation and Research.
Sincerely yours,
--- signature ---
Steven A. Masiello
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
--- signature ---
Jay P. Siegel, M.D., FACP
Director
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
Last Updated: 7/16/2002
Date created: September 26, 2003
 Back
to Top 
Back to Index
Date created: September 25, 2003 |
|
