[Federal Register Volume 68, Number 38 (Wednesday, February 26, 2003)]
[Notices]
[Pages 8908-8910]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4491]


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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.

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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