[Federal Register: February 26, 2003 (Volume 68, Number 38)]
[Notices]
[Page 8908-8910]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26fe03-67]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 00N-1219]
Delmont Laboratories, Inc.; Opportunity for Hearing on a Proposal
to Revoke U.S. License No. 299
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for hearing on a proposal to revoke the biologics license
(U.S. License No. 299) issued to Delmont Laboratories, Inc. (Delmont),
for Polyvalent Bacterial Antigens with ``no U.S. Standard of Potency''
(Staphage Lysate). The proposed revocation is based on FDA's proposed
reclassification of this product in Category II (unsafe, ineffective,
or misbranded), based on the recommendations of the Vaccines and
Related Biological Products Advisory Committee (VRBPAC).
DATES: Delmont Laboratories, Inc., may submit written or electronic
requests for a hearing by March 28, 2003, and any data and information
justifying a hearing by April 28, 2003. Other interested persons may
submit written or electronic comments on the proposed revocation by
April 28, 2003.
ADDRESSES: Submit written requests for a hearing, any data and
information justifying a hearing, and any written comments on the
proposed revocation to the Dockets Management Branch (HFA-305), Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. Submit electronic requests or comments to http://www.fda.gov/
dockets/ecomments.
FOR FURTHER INFORMATION CONTACT: Astrid L. Szeto, Center for Biologics
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION: In the Federal Register of May 15, 2000 (65
FR 31003), FDA issued a proposed order to reclassify certain Category
IIIA (remaining on the market pending further studies in support of
effectiveness) bacterial vaccines and related biological products into
Category I (safe, effective, and not misbranded) or Category II
(unsafe, ineffective, or misbranded). This action was taken under the
reclassification review procedures in Sec. 601.26 (21 CFR 601.26), and
was based on the findings and recommendations of the VRBPAC and the
Panel on Review of Allergenic Extracts (the Allergenics Panel). The
proposed order also announced our intent to revoke the biologics
licenses for those bacterial vaccines and related products proposed for
reclassification in Category II.
Based on VRBPAC's recommendations, FDA proposed that bacterial
vaccines and toxoids with standards of potency be classified into two
separate categories based upon their use as either a primary immunogen
or as a booster. FDA further proposed that bacterial vaccines and
related biological products with ``no U.S. standards of potency'' be
classified into Category II for their labeled indications based on
either the VRBPAC's or the Allergenics Panel's recommendations. Five
manufacturers of Category IIIA products were subject to the proposed
order, as listed in the following table:
Table 1--Category IIIA Products Proposed by FDA for Reclassification Into Category II as a Primary Immunogen or
for All Labeled Indications
----------------------------------------------------------------------------------------------------------------
Proposed Category II
Manufacturer/License Number Product(s) Indication
----------------------------------------------------------------------------------------------------------------
Aventis Pasteur, Inc., No. 1277 Tetanus Toxoid (fluid) Primary Immunogen
BioPort Corporation, No. 1260 Diphtheria and Tetanus Toxoids Adsorbed Primary Immunogen
Wyeth Laboratories, Inc., No. 3 Tetanus and Diphtheria Toxoids Adsorbed (Adult Primary Immunogen
Use)
Delmont Laboratories, Inc., No. 299 Polyvalent Bacterial Antigens with ``No U.S. All Labeled Indications
Standard of Potency'' (Staphage Lysate)
Hollister-Stier Laboratories LLC, Polyvalent Bacterial Vaccines with ``No U.S. All Labeled Indications
No. 1272 (1) Standard of Potency'' (Bacterial Vaccines
Mixed Respiratory (MRV or MRVI, Bacterial
Vaccines for Treatment, Special Mixtures)
----------------------------------------------------------------------------------------------------------------
\1\As described in the proposed order, this product was reviewed by the Allergenics Panel. The remaining
products in this table were reviewed by the VRBPAC.
FDA also proposed that the bacterial vaccines with U.S. standards
of potency recommended for classification into Category II as a primary
immunogen be placed into Category I for use as a booster immunogen.
Manufacturers who intended to market their products for use as a
booster immunogen needed to submit supplements for changes to the
container and package labels and the package insert, to include the
statement, ``For Booster Use Only''.
Three of the five manufacturers submitted requests to voluntarily
revoke their licenses. Accordingly, FDA revoked the licenses for: (1)
Polyvalent Bacterial Vaccines with ``no U.S. Standard of Potency''
(Bacterial Vaccines Mixed Respiratory), Hollister-Stier Laboratories,
U.S. license No. 1272, effective August 3, 2000 (66 FR
[[Page 8909]]
29148, May 29, 2001); (2) Diphtheria and Tetanus Toxoids Adsorbed and
Tetanus Toxoids Adsorbed, BioPort Corporation, U.S. license No. 1260,
effective November 20, 2000 (66 FR 29148, May 29, 2001); and (3)
Tetanus and Diphtheria Toxoids Adsorbed (for Adult Use), Wyeth
Laboratories, Inc., U.S. license No. 3, effective May 30, 2002.
On January 18, 2002, we approved a license supplement for Aventis
Pasteur, Inc.'s, Tetanus Toxoid fluid. In this supplement, Aventis
Pasteur, Inc., requested that their license for Tetanus Toxoid fluid be
amended to revoke the primary immunization indication and maintain the
booster use only indication. In addition, the supplement included
updated labeling for the Tetanus Toxoid fluid product stating that the
product was for ``Booster Use Only'', as specified in the proposed
order.
Comments on Proposed Reclassification
Polyvalent Bacterial Antigens with ``No U.S. Standard of Potency''
[Staphage Lysate (SPL)], Delmont Laboratories, Inc., U.S. License No.
299
On August 9, 2000, Delmont submitted a written comment on the
proposed order opposing the proposed Category II reclassification of
its product. Delmont proposed, instead, reclassification into Category
I and submitted information in support of its proposal, including an
SPL clinical trial summary dated February 28, 1994, an English
translation of a clinical study report for a study performed in the
Czech Republic, and an abstract of a 1994 in vitro study performed by
Delmont. We have carefully considered the information provided by
Delmont, and find that it does not support a reclassification of SPL
into Category I. A discussion of the studies included in Delmont's
submission follows.
The February 28, 1994, clinical trial summary contained data from
two human clinical studies. The first study in the submission was a
prospective, double blind, placebo controlled study of the efficacy of
SPL for the treatment of Hidradenitis Suppurativa (HS). The clinical
trial summary stated that, ``under the conditions of the study, SPL was
not demonstrated to be effective in the treatment of HS,'' and that no
significant differences between treatment groups (SPL, placebo) or
between clinical centers ``were found in any of the efficacy analyses
for any of the parameters analyzed.'' Delmont stated in its written
comment on the proposed order that a data reanalysis provided by an
independent third party engaged by Delmont demonstrated ``approximately
two times greater reductions from baseline in total score for SPL
treated patients than for placebo treated patients'' and that SPL
showed a ``trend among the more severely affected patients for the
change from baseline to last visit.'' However, the reanalysis of the
data was performed after the patient data were unblinded. In addition,
the method of efficacy assessment was changed from the initial blinded
and controlled study, and a subset analysis of a selected subgroup of
patients was performed in order to reach these conclusions. There was
no statistically significant difference between the SPL and placebo
treatment groups after the reanalysis was performed. The data are
inadequate to support a reclassification of SPL from Category II to
Category I.
The second study included in the 1994 clinical trial summary was an
open label (unblinded) comparative study between SPL and 2 similar
products, STAVA and POLYSTAFANA, not licensed in the United States. The
study was performed in the Czech Republic and included patients with
staphylococcal diseases of various types. An English translation of the
study report was included in Delmont's submission. The study report
contained several deficiencies, such as: No patient recruitment details
with respect to the diagnoses of various staphylococcal infections, no
detailed explanations of patient inclusion or exclusion criteria, no
adequate control group, no description of patient randomization
procedures (if performed), no explanation of how patients were
reassigned to treatment groups after clinics refused to continue
administering the POLYSTAFANA, no information on treatment compliance
or individual dose regimens, no clinical descriptions or associated
clinical measurements for the endpoints of ``cured,'' ``lasting
stabilization,'' ``improved,'' or ``no effect,'' no statistical
analysis performed (only observed cure rates were reported), and no
reporting of individual adverse events. These deficiencies are
inconsistent with generally accepted standards of clinical trial design
and performance. Therefore, this clinical study is also inadequate to
support reclassification of SPL from Category II to Category I.
Delmont also included an abstract of an in vitro study performed in
two human cell lines. The study authors found that human cell cultures
secreted gamma interferon, interleukin 1, interleukin 2, and tumor
necrosis factor when exposed to SPL. Delmont interprets the study to
suggest that SPL ``may stimulate the production of immunocompetent
cells, triggering immune responses that might have clinical
significance in certain diseases.'' However, the data provided in the
abstract are limited, and deficiencies in the data exist (e.g., lack of
information on some positive and negative control results). While in
vitro studies are frequently used to study the biological mechanisms of
a product, they are not supportive of human efficacy in the absence of
adequate and well-controlled clinical trials. Therefore, the limited
data contained in Delmont's abstract are not adequate to support a
reclassification of SPL from Category II to Category I.
Delmont submitted no other data or information to support a
reclassification of SPL to Category I or to preclude FDA's
reclassification of this product to Category II.
Notice of Opportunity for Hearing
In accordance with 21 CFR 601.5(b) and 21 CFR 12.21(b), FDA is
offering an opportunity for hearing on its proposal to revoke the
biologics license, U.S. License No. 299, issued to Delmont
Laboratories, Inc., for Polyvalent Bacterial Antigens with ``no U.S.
Standard of Potency'' (Staphage Lysate). A copy of the August 9, 2000,
written comment is on file with the Dockets Management Branch (see
ADDRESSES) under the docket number found in brackets in the heading of
this notice. The document is available for public examination in the
Dockets Management Branch between 9 a.m. and 4 p.m., Monday through
Friday. Delmont may submit a written or electronic request for a
hearing to the Dockets Management Branch by March 28, 2003, and any
data and information justifying a hearing must be submitted by April
28, 2003 (21 CFR 12.22(b)(1)). Other interested persons may submit
comments on the proposed revocation by April 28, 2003.
FDA procedures and requirements governing a notice of opportunity
for a hearing, notice of appearance and request for hearing, grant or
denial of hearing, and submission of data and information to justify a
hearing on a proposed revocation of a license are contained in part 12
(21 CFR part 12) and 21 CFR part 601. In requesting a hearing, a person
must submit to FDA's Dockets Management Branch objections and a request
for a hearing on each objection, along with a detailed description and
analysis of the factual information to be presented in support of each
objection, as provided in Sec. 12.22. A deficient request or objection
[[Page 8910]]
will be returned; however, the deficient submission may be supplemented
and subsequently filed if submitted within the 30-day time period
(Sec. 12.22(c)). The objections should identify the specific fact or
facts that are genuine, substantial, and in dispute (Sec.
12.24(b)(1)). Mere allegations or denials are not enough to obtain a
hearing (Sec. 12.24(b)(2)). The Commissioner of Food and Drugs (the
Commissioner) will deny the hearing request if the Commissioner
concludes that the data and information submitted are insufficient to
justify the factual determination urged, even if accurate (Sec.
12.24(b)(3)).
Two copies of any submissions are to be provided to FDA except that
individuals may submit one copy. Submissions are to be identified with
the docket number found in brackets in the heading of this document.
Submissions, except for data and information prohibited from public
disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, may be examined in
the Dockets Management Branch (see ADDRESSES) between 9 a.m. and 4
p.m., Monday through Friday.
This notice is issued under section 351 of the Public Health
Service Act (42 U.S.C. 262) and sections 201, 501, 502, 505, 701 of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 355, and
371), and under authority delegated to the Commissioner (21 CFR 5.10)
and redelegated to the Director, Center for Biologics Evaluation and
Research (21 CFR 5.202).
Dated: February 4, 2003.
Mark Elengold,
Deputy Director for Operations, Center for Biologics Evaluation and
Research.
[FR Doc. 03-4491 Filed 2-25-03; 8:45 am]
BILLING CODE 4160-01-S