[Federal Register Volume 75, Number 233 (Monday, December 6, 2010)]
[Notices]
[Pages 75682-75689]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-30441]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2000-N-0163; Formerly Docket No. 2000N-1219]


Reclassification of Category IIIA Biological Products, Bacterial 
Vaccines and Related Biological Products; Implementation of Efficacy 
Review; Final Order; and Delmont Laboratories, Inc.: Denial of Request 
for a Hearing, and Revocation of License

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; final order.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final 
order pursuant to the reclassification procedures under the biologics 
regulations; denying the request by Delmont Laboratories, Inc. 
(Delmont), for a hearing on FDA's proposal to revoke Delmont's license 
based on the proposed reclassification of its product, Polyvalent 
Bacterial Antigens with ``No U.S. Standard of Potency,'' Staphage 
Lysate[supreg] (SPL) (hereinafter referred to as SPL) into Category II 
(unsafe, ineffective, or misbranded); and revoking Delmont's U.S. 
License No. 299. The final order finalizes the proposed order published 
in the Federal Register of May 15, 2000 (65 FR 31003) (May 2000 
proposal), to reclassify Category IIIA bacterial vaccines and bacterial 
antigens into Category I or Category II.

DATES: The final order reclassifying Delmont's SPL into Category II, 
and Sanofi Pasteur Inc.'s (Sanofi's) Tetanus Toxoid Adsorbed and 
Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (DECAVAC\TM\) 
into Category I for both primary immunization and booster use is 
effective December 6, 2010. The revocation of Delmont's license (U.S. 
License No. 299) is effective December 6, 2010.

FOR FURTHER INFORMATION CONTACT: Stephen Ripley, Center for Biologics 
Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, Suite 200N, Rockville, MD 20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background on the Efficacy Review Process

    In the Federal Register of February 13, 1973 (38 FR 4319), FDA 
issued procedures for the review by independent advisory panels of the 
safety, effectiveness, and labeling of biological products licensed 
before July 1, 1972. These procedures were later codified in Sec.  
601.25 (21 CFR 601.25) (38 FR 32048 at 32052, November 20, 1973). Under 
Sec.  601.25, FDA assigned responsibility for the initial review of 
each of the biological product categories to a separate independent 
advisory panel consisting of qualified experts. Each panel was charged 
with preparing for the Commissioner of Food and Drugs an advisory 
report which was to: (1) Evaluate the safety and effectiveness of the 
biological products for which a license had been issued; (2) review 
their labeling; and (3) identify the biological products that are safe, 
effective, and not misbranded. Each advisory panel report was also to 
include recommendations classifying the products reviewed into one of 
three categories.
     Category I, designating those biological products 
determined by the panel to be safe, effective, and not misbranded.
     Category II, designating those biological products 
determined by the panel to be unsafe, ineffective, or misbranded.
     Category III, designating those biological products 
determined by the panel not to fall within either Category I or 
Category II on the basis of the panel's conclusion that the available 
data were insufficient to classify such biological products, and for 
which further testing was therefore required. Category III products 
were assigned to one of two subcategories. Category IIIA products were 
those that would be permitted to remain on the market pending the 
completion of further studies. Category IIIB products were those for 
which the panel recommended license revocation on the basis of the 
panel's assessment of potential risks and benefits.
    In accordance with Sec.  601.25, after reviewing the conclusions 
and recommendations of the review panels, FDA would publish in the 
Federal Register a proposed order containing: (1) A statement 
designating the biological products reviewed into Categories I, II, 
IIIA or IIIB; (2) a description of the testing necessary for Category 
IIIA biological products; and (3) the complete panel report. Under the 
proposed order, FDA would propose to revoke the licenses of those 
products designated into Category II and Category IIIB. After reviewing 
public comments, FDA would publish a final order on the matters covered 
in the proposed order.
    Two original advisory panels reviewed the four Category IIIA 
products that are the subject of this final order. The advisory panel 
for Bacterial Vaccines and Bacterial Antigens with

[[Page 75683]]

``no U.S. Standard of Potency'' (the Original Antigen Panel) reviewed 
Delmont's SPL product. The advisory panel for Bacterial Vaccines and 
Toxoids with Standards of Potency (the Original Toxoid Panel) reviewed 
Sanofi's Tetanus Toxoid Adsorbed and Tetanus and Diphtheria Toxoids 
Adsorbed For Adult Use products. The above definition of Category IIIA 
was applied at the time of each advisory panel's review and served as 
the basis for their recommendations.
    In the Federal Register of October 5, 1982 (47 FR 44062), FDA 
revised Sec.  601.25 and codified Sec.  601.26 (21 CFR 601.26) to 
establish procedures to reclassify those products in Category IIIA into 
either Category I or Category II based on available evidence of safety 
and effectiveness. Under Sec.  601.26, Category IIIA products that 
would be reclassified included products that an advisory panel had 
recommended be assigned to Category IIIA, that FDA had proposed to 
place into Category IIIA, or for which FDA had issued a final order 
reclassifying the products into Category IIIA.
    Under the procedures specified in Sec.  601.26, FDA appointed an 
advisory panel and used existing advisory panels to review Category 
IIIA products and to make recommendations to reclassify each Category 
IIIA product into Category I or Category II. FDA assigned the 
reclassification review of bacterial vaccines and bacterial antigens 
with ``no U.S. standard of potency'' to the Vaccines and Related 
Biological Products Advisory Committee (VRBPAC). FDA also assigned the 
reclassification review of bacterial vaccines and toxoids with 
standards of potency to the VRBPAC.
    During the reclassification review process, interested persons were 
permitted to attend meetings, appear before the advisory panels, and 
submit data to the panels for review. The advisory panels then 
submitted reports to FDA that recommended the reclassification of each 
Category IIIA product into either Category I or II. According to Sec.  
601.26, after reviewing the conclusions and recommendations of the 
advisory panels, FDA must publish in the Federal Register a proposed 
order containing: (1) A statement designating the products as Category 
I or Category II, (2) a notice of availability of the full panel 
report, (3) a proposal to accept or reject the findings of the advisory 
panels, and (4) a statement identifying those products that FDA 
proposes to permit to remain on the market because of a compelling 
medical need and because no suitable alternative exists as described in 
Sec.  601.26(d)(4).

II. Category IIIA Products Subject to This Final Reclassification Order

    FDA published the May 2000 proposal to reclassify Category IIIA 
bacterial vaccines and bacterial antigens into Category I or Category 
II. FDA based the proposed order on its review of all the evidence, and 
considered the findings and recommendations of the VRBPAC. The proposed 
order also announced FDA's intent to revoke the biologics licenses for 
those bacterial vaccines and bacterial antigens that FDA proposed 
reclassifying into Category II.
    FDA agreed with VRBPAC's recommendations and 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 immunogen. FDA proposed that some bacterial 
vaccines with standards of potency be classified into Category II for 
use as a primary immunogen, but into Category I for use as a booster 
immunogen.
    FDA further proposed that bacterial vaccines and bacterial antigens 
with ``no U.S. standard of potency'' be classified into Category II for 
all labeled indications, agreeing with the VRBPAC's recommendations.

A. Category IIIA Products That FDA Had Proposed To Reclassify Into 
Category II

    Five manufacturers of Category IIIA products that VRBPAC 
recommended for reclassification into Category II were subject to the 
May 2000 proposal (Table 1 of this document). After publication of the 
May 2000 proposal, four of the five manufacturers voluntarily submitted 
to FDA requests for revocation of their licenses for the applicable 
products. Subsequently, FDA revoked these licenses. Therefore, no 
further action is required on these manufacturers' products. The 
reclassification of the Category IIIA product of the remaining 
manufacturer, Delmont, is discussed in a later section of this 
document.

              Table 1--Category IIIA Products That FDA Had Proposed To Reclassify Into Category II1
----------------------------------------------------------------------------------------------------------------
        Manufacturer/License No.                     Product(s)                Proposed Category II indication
----------------------------------------------------------------------------------------------------------------
Bioport Corporation, No. 1260...........  Diphtheria and Tetanus Toxoids    Primary immunogen.
                                           Adsorbed \2\.
                                          Tetanus Toxoid Adsorbed \2\.....
Delmont Laboratories, Inc., No. 299.....  Polyvalent Bacterial Antigens     All labeled indications.
                                           with ``No U.S. Standard of
                                           Potency'' Staphage
                                           Lysate[supreg] (SPL).
Hollister-Stier Laboratories LLC, No.     Polyvalent Bacterial Vaccines     All labeled indications.
 1272.                                     with ``No U.S. Standard of
                                           Potency'' (Bacterial Vaccines
                                           Mixed Respiratory (MRV or
                                           MRVI), Bacterial Vaccines for
                                           Treatment, Special Mixtures)
                                           \3\.
Sanofi Pasteur Inc., No. 1725...........  Tetanus Toxoid \4\..............  Primary immunogen.
Wyeth Laboratories, Inc., No. 3.........  Tetanus and Diphtheria Toxoids    Primary immunogen.
                                           Adsorbed (Adult Use) \5\.
----------------------------------------------------------------------------------------------------------------
\1\ FDA is not relisting in this document the licenses FDA listed in and revoked before the May 2000 proposal.
\2\ The licenses for these products were transferred from Michigan Department of Public Health, No. 99, to
  BioPort Corporation, License No. 1260 on November 12, 1998. The licenses were subsequently revoked by FDA on
  November 20, 2000, at the request of the manufacturer (66 FR 29148 at 29149, May 29, 2001).
\3\ The licenses for these products were transferred from Bayer, Inc., No. 8 to Hollister-Stier, LLC, No. 1272
  on June 2, 1999. The licenses were subsequently revoked by FDA on August 3, 2000, at the request of the
  manufacturer (66 FR 29148 at 29149, May 29, 2001).
\4\ The license for this product was transferred from Merrell-National Laboratories Division of Richardson-
  Merrell, Inc. (License No. 101) to Connaught Laboratories, Inc. (License No. 711) on January 3, 1978; from
  Connaught Laboratories, Inc. (License No. 711) to Aventis Pasteur, Inc. (License No. 1277) on December 9,
  1999; and from Aventis Pasteur, Inc. (License No. 1277) to Sanofi Pasteur Inc. (License No. 1725) on December
  19, 2005. The license for this product was subsequently revoked by FDA on July 16, 2009, at the request of the
  manufacturer.
\5\ The license for this product was revoked by FDA on May 30, 2002, at the request of the manufacturer.


[[Page 75684]]

Delmont Laboratories, Inc., SPL
    On August 9, 2000, Delmont submitted to FDA a response to FDA's May 
2000 proposal to reclassify SPL into Category II. Information regarding 
Delmont's response and FDA's actions are discussed in section III of 
this document.

B. Category IIIA Products That FDA Had Proposed To Reclassify Into 
Category I

    Four manufacturers of Category IIIA products, recommended by VRBPAC 
for reclassification into Category I for both primary and booster 
immunization, were subject to the May 2000 proposal (Table 2 of this 
document). After publication of the May 2000 proposal, three of the 
four manufacturers voluntarily submitted to FDA requests for revocation 
of their licenses. FDA subsequently revoked these licenses. Therefore, 
no further action is required on these manufacturers' products. The 
reclassification of the Category IIIA products of the remaining 
manufacturer, Sanofi, is discussed in this section of this document.

Table 2--Category IIIA Products That FDA Had Proposed to Reclassify Into
        Category I for Both Primary and Booster Immunization \1\
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        Manufacturer/License No.                    Product(s)
------------------------------------------------------------------------
Lederle Laboratories, Division,          Tetanus Toxoid.\2\
 American Cyanamid Company, No. 17.
                                         Diphtheria and Tetanus Toxoids
                                          and Pertussis Vaccine
                                          Adsorbed.\2\
                                         Diphtheria and Tetanus Toxoids
                                          Adsorbed.\2\
                                         Tetanus and Diphtheria Toxoids
                                          Adsorbed (Adult Use).\2\
                                         Tetanus Toxoid Adsorbed.\2\
Sanofi Pasteur Inc., License No. 1725..  Tetanus Toxoid Adsorbed.\3\
                                         Tetanus and Diphtheria Toxoids
                                          Adsorbed (Adult Use).\3\
Swiss Serum and Vaccine Institute        Tetanus Toxoid Adsorbed.\4\
 Berne, No. 21.
Wyeth Laboratories, Inc., No. 3........  Diphtheria and Tetanus Toxoids
                                          Adsorbed.\5\
                                         Tetanus Toxoid.\5\
                                         Tetanus Toxoid Adsorbed.\5\
                                         Diphtheria and Tetanus Toxoids
                                          and Pertussis Vaccine
                                          Adsorbed.\5\
------------------------------------------------------------------------
\1\ FDA is not relisting in this document the licenses FDA listed in and
  revoked before the May 2000 proposal.
\2\ The licenses for these products were revoked by FDA on March 4,
  1994, July 24, 2002, May 10, 2002, May 10, 2002, and May 22, 2002,
  respectively, at the request of the manufacturer.
\3\ The licenses for these products were transferred from Merrell-
  National Laboratories Division of Richardson-Merrell, Inc. (License
  No. 101) to Connaught Laboratories, Inc. (License No. 711) on January
  3, 1978; from Connaught Laboratories, Inc. (License No. 711) to
  Aventis Pasteur, Inc. (License No. 1277) on December 9, 1999; and from
  Aventis Pasteur, Inc. (License No. 1277) to Sanofi Pasteur Inc.
  (License No. 1725) on December 19, 2005.
\4\ The license for this product was revoked by FDA on August 29, 2000,
  at the request of the manufacturer.
\5\ The licenses for these products were revoked by FDA on May 30, 2002,
  May 30, 2002, May 30, 2002, and October 15, 2002, respectively, at the
  request of the manufacturer.

1. Sanofi Pasteur Inc., Tetanus Toxoid Adsorbed
    The Original Toxoid Panel recommended that all licensed and 
marketed tetanus toxoid products be classified into Category I for 
booster immunization (50 FR 51002, December 13, 1985). The Original 
Toxoid Panel reviewed Sanofi's Tetanus Toxoid Adsorbed product and 
recommended that the product be placed into Category I for booster use 
and Category IIIA for primary immunization (50 FR 51002 at 51029). FDA 
agreed with the Original Toxoid Panel's recommendations to classify 
this product into Category I for booster use and Category IIIA for 
primary immunization (50 FR 51002 at 51105 and 51106). The VRBPAC 
reviewed the Category IIIA primary immunization indication for Sanofi's 
Tetanus Toxoid Adsorbed. Based on additional data from a clinical study 
performed by the firm, the VRBPAC recommended that the product be 
placed into Category I for primary immunization. (See Ref. 1, at pages 
19 and 20). FDA agrees with the Original Toxoid Panel's and VRBPAC's 
recommendations and is reclassifying Sanofi's Tetanus Toxoid Adsorbed 
product into Category I for both primary immunization and booster use.
2. Sanofi Pasteur Inc., Tetanus and Diphtheria Toxoids Adsorbed (Adult 
Use)
    The Original Toxoid Panel reviewed Sanofi's Tetanus and Diphtheria 
Toxoids Adsorbed (Adult Use) and recommended that the product be placed 
into Category I for booster immunization and Category IIIA for primary 
immunization (50 FR 51002 at 51040). FDA agreed with the Original 
Toxoid Panel's recommendations to classify this product into Category I 
for booster use and Category IIIA for primary immunization (50 FR 51002 
at 51105 and 51106). The VRBPAC reviewed the Category IIIA primary 
immunization indication for Sanofi's Tetanus and Diphtheria Toxoids 
Adsorbed (Adult Use). Based on additional data from a human clinical 
study performed by the firm, the VRBPAC recommended that the product be 
placed into Category I for primary immunization. (See Ref. 1, at pages 
21 and 22). FDA agrees with the Original Toxoid Panel's and VRBPAC's 
recommendations and is therefore reclassifying Sanofi's Tetanus and 
Diphtheria Toxoids Adsorbed For Adult Use product into Category I for 
both primary immunization and booster use.

III. Denial of a Hearing on Proposed License Revocation--Delmont 
Laboratories, Inc.

A. Notice of Opportunity for a Hearing

    On August 9, 2000, Delmont submitted to FDA a written comment 
opposing FDA's May 2000 proposal to reclassify its product, SPL, into 
Category II. Delmont proposed, instead, reclassifying SPL into Category 
I and submitted information supporting its proposal. FDA carefully 
considered the information that Delmont provided and found that the 
information did not support a reclassification of SPL into Category I.
    Accordingly, a Notice of Opportunity for Hearing (NOOH) on a 
proposal to revoke the license for Delmont's SPL was published in the 
Federal Register of February 26, 2003 (68 FR 8908). In the NOOH, FDA 
provided a detailed analysis and discussion of the information that 
Delmont submitted in its response to FDA's May 2000 proposal. Further, 
in the NOOH, FDA

[[Page 75685]]

advised Delmont that a request for a hearing should identify the 
specific fact or facts that are genuine, substantial, and in dispute 
(Sec.  12.24(b)(1) (21 CFR 12.24(b)(1)). FDA put Delmont on notice that 
mere allegations or denials are not enough to obtain a hearing (Sec.  
12.24(b)(2)). FDA also put Delmont on notice that the Commissioner 
would deny a hearing request if the Commissioner concluded that the 
data and information submitted are insufficient to justify the factual 
determination urged, even if accurate (Sec.  12.24(b)(3)).

B. Delmont's Hearing Request

    On April 28, 2003, Delmont submitted to FDA a letter objecting to 
FDA's proposal to revoke its license and requested a hearing. In the 
letter, Delmont did not submit any evidence that raised a genuine and 
substantial issue of fact justifying a hearing. Instead, Delmont 
resubmitted data on SPL that it previously submitted to FDA and made 
procedural arguments for why it is entitled to a hearing. Specifically, 
Delmont argued that FDA applied the wrong effectiveness standard when 
evaluating the studies that Delmont previously submitted, and that FDA 
used incorrect procedures when proposing to reclassify SPL and to 
revoke Delmont's license.

C. Commissioner's Determination That Delmont Has Not Justified a 
Hearing

    As explained in subsection 1 in this section of this document, FDA 
applied the correct effectiveness standard to SPL. In subsection 2 in 
this section of this document, we explain that SPL does not satisfy 
that standard. Specifically, this document explains why most of the 
data on which Delmont relies came from studies that do not meet that 
standard either because they were not human studies or were not 
adequately controlled studies. For the few studies that were controlled 
or even partially controlled, this document explains why they did not 
show that SPL is effective. Therefore, Delmont fails to raise a genuine 
and substantial issue of fact regarding the effectiveness of SPL for 
resolution at a hearing. Moreover, the procedural objections that 
Delmont raises do not create a basis for a hearing (Sec.  12.24(b)(1)). 
These arguments are discussed in subsection 3 of this section of this 
document.
1. Biologics Effectiveness Standard
    Under FDA regulations, codified from the final rule published on 
February 13, 1973 (38 FR 4319 at 4322), biologics manufacturers, like 
Delmont, whose products were licensed before 1972, must prove that 
their products are effective by submitting data from ``controlled 
clinical investigations'' as defined in Sec.  314.126 (21 CFR 314.126) 
(``Adequate and well-controlled studies''), unless FDA waives that 
requirement (Sec.  601.25(d)(2)). To obtain a waiver, the sponsor must 
show that controlled clinical investigations are ``not reasonably 
applicable to the biological product or essential to the validity of 
the investigation, and that an alternative method of investigation is 
adequate to substantiate effectiveness'' (Sec.  601.25(d)(2)) (emphasis 
added).
    Delmont attempted to argue that FDA should not have applied that 
standard to SPL. Instead of arguing that controlled clinical 
investigations are not reasonably applicable to SPL or essential to the 
validity of SPL investigations, and instead of advancing an alternative 
method of investigation and explaining why it would be adequate to 
substantiate SPL's effectiveness, Delmont simply argued that FDA should 
never require data from controlled clinical investigations for 
biologics. The basis for its argument is the following statement in the 
preamble to FDA's proposed reclassification rule for Category IIIA 
products (46 FR 4634 at 4635, January 16, 1981): ``While it is clear * 
* * that the applicable statutory requirement for potency in the Public 
Health Service Act has been interpreted as requiring that a product be 
effective, the specific statutory criteria governing new drugs, 
`adequate and well-controlled clinical studies,' have not been applied 
to biological drugs.''
    FDA's final reclassification rule for Category IIIA products (47 FR 
44062 at 44067, October 5, 1982), however, confirmed that FDA ``does 
indeed consider controlled clinical studies to be the preferred form of 
evidence for documenting a product's effectiveness.'' Furthermore, FDA 
clarified that ``unless unusual circumstances justify a special 
exemption for a particular product,'' controlled clinical 
investigations are required to establish effectiveness (47 FR 44062 at 
44067).
    In this case, Delmont did not attempt to show that SPL meets the 
criteria for a special exemption, namely, that an alternative method of 
investigation is adequate to substantiate SPL's effectiveness, and that 
controlled clinical investigations are either inapplicable to SPL or 
not essential to the validity of the investigation. In fact, Delmont 
sponsored a controlled clinical trial of SPL (in patients suffering 
from the disease hidradenitis suppurativa), but as FDA explained at 
length in the February 26, 2003, NOOH, the data showed no statistically 
significant difference between SPL and a placebo. Therefore, the data 
were inadequate to demonstrate that the product was effective. See 68 
FR 8908 at 8909.
    Clearly, FDA applied the correct standard when evaluating SPL.
2. Application of the Standard to SPL
    Since FDA's biologics review began, Delmont has submitted to FDA 
data on SPL at four different times: (a) Before 1978, as part of FDA's 
initial biologics review process; (b) between January and May 1978, to 
convince FDA to classify SPL into Category IIIA rather than IIIB so 
that Delmont could continue marketing SPL while obtaining data from 
effectiveness studies; (c) in 1983, as part of FDA's reclassification 
procedures; and (d) in 1994, to supplement its reclassification data 
with the results of studies that were incomplete in 1983. As discussed 
in turn below, none of the data are sufficient to demonstrate that SPL 
is effective.
a. Pre-1978 Data
    As part of FDA's initial biologics review process, Delmont 
submitted data to the Original Antigen Panel. The Original Antigen 
Panel issued a report, which is published in the Federal Register of 
November 8, 1977 (42 FR 58266 at 58270), that analyzed in detail all 
the studies that Delmont had submitted, and described deficiencies in 
each one. Based on that analysis, the Original Antigen Panel concluded 
that Delmont had provided ``no substantial evidence of safety or 
effectiveness,'' and ``no evidence presumptive of safety'' (42 FR 58266 
at 58285). Consequently, the Original Antigen Panel recommended that 
FDA classify SPL into Category IIIB and revoke Delmont's license (42 FR 
58266 at 58285). In the Federal Register of November 8, 1977, FDA 
issued a proposed order notifying Delmont that it agreed with the 
Original Antigen Panel's findings and that it intended to revoke 
Delmont's license (42 FR 58266 at 58318). As discussed in subsection 
b.iii of this section of this document, FDA ultimately classified SPL 
into category IIIA based on additional safety data that Delmont 
submitted (44 FR 1544 at 1548, January 5, 1979), but FDA agreed with 
the Original Antigen Panel's criticisms of SPL's effectiveness data (44 
FR 1544 at 1546, comment 5) and ordered Delmont to complete and submit 
the effectiveness testing that the Original Antigen Panel had 
recommended (44 FR 1544 at 1548).

[[Page 75686]]

b. January to May 1978 Data
i. Delmont's Hearing Request
    In response to FDA's revocation proposal (42 FR 58266), Delmont 
requested a hearing on whether FDA should classify SPL into Category 
IIIA or IIIB, and submitted to FDA additional data on January 8, 1978, 
February 7, 1978, March 31, 1978, and May 26, 1978. Those submissions 
are all currently in the public docket relating to this matter, Docket 
No. 2000N-1219, as attachments to Delmont's April 28, 2003, hearing 
request. None of the data satisfied the controlled clinical 
investigations standard for proving effectiveness, as discussed in 
subsection b.iii of this section of this document, even though FDA 
eventually determined that the safety data were sufficient to classify 
SPL into Category IIIA to allow Delmont to continue marketing SPL while 
obtaining effectiveness data.
ii. Deficiencies in Delmont's Data
(1). January 8, 1978, Submission
    In a letter dated January 8, 1978 (Docket No. 2000N-1219, Item 
SUP1, Tab C to Delmont's April 28, 2003, hearing request), Delmont 
submitted to FDA additional study reports. Delmont stated that the 
reports ``show that no risk to human safety can result from continued 
marketing of SPL for a limited period while further studies are 
conducted.'' As to effectiveness, however, Delmont said only that the 
study reports ``demonstrate that further studies of SPL in accordance 
with FDA requirements for clinical investigations will very likely 
provide substantial evidence that the product is effective for its 
labeled indications * * *.'' Therefore, Delmont admitted that the data 
it was submitting were collected from studies that were not conducted 
in accordance with FDA requirements for clinical investigations.
    Most of those studies failed to satisfy FDA's controlled clinical 
investigations standard because they were preclinical studies not 
performed on humans, and therefore, were not clinical investigations. 
Specifically, those reports were as follows: ``Chronic Toxicity Test of 
SPL in Rats'' (Fujino, et al.) (Ref. 2); ``Acute and Subacute Toxicity 
Tests of SPL'' (Fujino, et al.) (mice and rats) (Ref. 3); 
``Teratologenicity Study of SPL in Rats and Rabbits'' (Hachihiko 
Hirayama) (Ref. 4); ``Effect of SPL on the Development of Skin Lesion 
in Mice after Inoculation with Herpes Simplex Virus'' (Department of 
Microbiology, School of Medicine, Kyushu University) (Ref. 5); 
``Chemotactic Accumulation of Macrophages in the Peritoneal Cavity 
after Inoculation of SPL and their Antitumor Activity'' (Department of 
Microbiology, School of Medicine, Kyushu University) (mice) (Ref. 6); 
and ``S-27: Summary of Results of Tests Conducted at Fuji-Zoki 
Pharmaceutical Research Division'' (safety tests in mice and guinea 
pigs) (Ref. 7).
    Two other studies that Delmont included in its January 8, 1978, 
submission, ``Susceptibility of Staphylococcus aureus Clinical Isolates 
to Gratia Bacteriophage'' (Shigeno, et al.) (Ref. 8) and ``Influence of 
Staphage Lysates (SPL) on Immune Responses In Vitro'' (Mitsuma, et al.) 
(Ref. 9), do not qualify as controlled clinical investigations because 
they were in vitro studies. Moreover, the limited data contained in the 
abstracts that Delmont submitted to FDA on these two studies limit 
their usefulness for any purpose. Therefore, they are not adequate to 
support reclassifying SPL into Category I.
    Delmont also submitted two reports on studies of SPL in humans, 
``Immunopotiator Activity of Staphage Lysate (Mudd)'' (Azuma, et al.) 
(Ref. 10) and ``Immunochemotherapy for Infections--With Particular 
Reference to Staphage Lysate'' (Tsuda, et al.) (Ref. 11). Neither of 
those qualifies as a controlled clinical investigation, for a number of 
reasons. First, neither study was controlled as required in FDA's 1979 
final order, which included Delmont's product in Category IIIA (44 FR 
1544 at 1548). A fundamental characteristic of controlled clinical 
investigations is that they ``use a design that permits a valid 
comparison with a control to provide a quantitative assessment of drug 
effect'' (Sec.  314.126(b)(2)). A control is necessary to ``distinguish 
the effect of a drug from other influences, such as spontaneous change 
in the course of the disease, placebo effect, or biased observation'' 
(Sec.  314.126(a)). While different types of controls are permitted 
under different conditions, neither study reports that the 
investigators used controls.
    Second, both a protocol and a study result report should contain a 
clear statement of the objectives of the investigation and a summary of 
the methods of analysis (Sec.  314.126(b)(1)). Delmont did not submit 
the protocol for either study, and the resulting reports for the two 
studies did not explain how the investigators measured or analyzed the 
results of treating their study subjects with SPL. Although the Tsuda 
study report (see Ref. 11) contains a summary of clinical results in 
Table 8, which lists the investigators' assessments of subjects' 
responses to SPL--either ``Excellent,'' ``Greatly improved,'' or 
``Unimproved''--the study does not state what criteria were used to 
reach those assessments. Moreover, as the report itself admits, ``no 
conclusive statement can be made here because of the relatively small 
series studied.'' Clearly, the reports do not provide ``sufficient 
details of the study design, conduct, and analysis to allow critical 
evaluation and a determination of whether the characteristics of an 
adequate and well-controlled study are present'' (Sec.  314.126(a)).
    The studies also failed to meet other characteristics of a 
controlled investigation. The study reports fail to show that the 
``method of selection of subjects provides adequate assurance that they 
have the disease or condition being studied or evidence of 
susceptibility and exposure to the condition against which prophylaxis 
is directed'' (Sec.  314.126(b)(3)). In the Tsuda study (see Ref. 11) 
the diseases being studied were chronic intractable staphylococcal 
infections or other viral infections. In the Azuma study (see Ref. 10), 
the condition being studied was defensive capacity against infection 
generally. However, neither study report showed how the subjects were 
selected to meet these criteria. Similarly, the studies fail to show 
that the ``method of assigning patients to treatment and control groups 
minimizes bias and is intended to assure comparability of the groups 
with respect to pertinent variables'' (Sec.  314.126(b)(4)); fail to 
show that ``[a]dequate measures [were] taken to minimize bias on the 
part of the subjects, observers, and analysts of the data'' (Sec.  
314.126(b)(5)); fail to demonstrate that the ``methods of assessment of 
subjects' response [were] well-defined and reliable'' (Sec.  
314.126(b)(6)); and fail to provide ``an analysis of the results of the 
study adequate to assess the effects of the drug'' (Sec.  
314.126(b)(7)). Clearly, then, these two studies do not meet the 
criteria for controlled clinical investigations.
    Finally, Delmont submitted what it described as a protocol for ``a 
study based on short- and long-term surveillance of patients receiving 
SPL therapy under the care of Arthur G. Baker, M.D.'' The study had not 
begun, and Delmont had no results to report at that time. Therefore, it 
did not contribute to the effectiveness assessment.
    In summary, none of the submissions that Delmont included with its 
January 8, 1978, letter constituted controlled clinical investigations. 
Thus, they were insufficient to establish SPL's effectiveness at that 
time.

[[Page 75687]]

(2). February 7, 1978, Letter
    On February 7, 1978, Delmont sent to FDA additional data to support 
its request for a hearing on whether to classify SPL into Category IIIA 
or IIIB (Docket No. 2000N-1219, Item SUP1, Tab D to Delmont's April 28, 
2003, hearing request). Delmont categorized much of the data and 
reports as safety data, but did include a set of attachments that it 
labeled ``Effectiveness Data.'' Delmont divided those attachments into 
``Controlled Studies,'' and ``Other Efficacy Data.'' The Controlled 
Studies section contains only a protocol for a study that was then in 
early stages, and does not contain a report on the results of that 
study. Thus, Delmont admitted that its February 7, 1978, submission did 
not contain effectiveness data that met the controlled clinical 
investigations standard.
    The ``Other Efficacy Data'' section was divided into two 
subsections: ``Studies in Humans'' and ``Studies in Animals.'' The 
first paper in the human studies subsection, Salmon G.G. and M. 
Symonds, ``Staphage Lysate Therapy in Chronic Staphylococcal 
Infections,'' (Ref. 12), is a duplicate of a published article that 
Delmont had submitted to the Original Antigen Panel in 1977. The 
Original Antigen Panel rejected that article, stating that in the 
article ``patients are said to have recovered because of antibody 
induction but no data demonstrating such responses are provided'' (42 
FR 58283). The next three reports were duplicates of reports that 
Delmont had submitted with its January 8, 1978, letter, which are 
deficient for the reasons discussed previously in this section of this 
document. Finally, Delmont submitted two summaries of case studies, 
``Immune Stimulation Therapy for Inflammatory Disease of the Gut,'' 
(Ref. 13) and ``Immune Stimulation for Aphthous (Herpetic) Stomatitis & 
Rhinitis,'' (Ref. 14) that Dr. Dale Rank had sent to Delmont. These 
reports contain little information, and therefore do not ``provide 
sufficient details of study design, conduct, and analysis to allow 
critical evaluation and a determination of whether the characteristics 
of an adequate and well-controlled study are present'' (Sec.  
314.126(a)). Moreover, the terse case reports of Dr. Rank's patients 
contain no indication that any type of control was used.
    Therefore, none of Delmont's February 7, 1978, submissions 
satisfied the controlled clinical investigations standard.
(3). March 31, 1978, Letter
    On March 31, 1978, Delmont sent to FDA another letter (Docket No. 
2000N-1219, Item SUP1, Tab E to Delmont's April 28, 2003, hearing 
request). That letter served primarily to answer questions that FDA had 
raised about the animal studies in Delmont's January 8, 1978, 
submission. The letter also included three new reports. One reported on 
tests in rabbits and another reported the results of in vitro assays, 
neither of which constituted controlled clinical investigations in 
humans. The letter also included a one-page ``report of a double blind, 
placebo controlled trial for evaluation of SPL as a treatment for 
warts, dated March 7, 1978.'' The one-page summary clearly did not 
``provide sufficient details of study design, conduct, and analysis to 
allow critical evaluation and a determination of whether the 
characteristics of an adequate and well-controlled study are present,'' 
as Sec.  314.126(a) requires, for many reasons. Among them are that it 
provided: No patient recruitment details on their diagnoses, as Sec.  
314.126(b)(3) requires; no explanation of patient inclusion and 
exclusion criteria (Sec.  314.126(b)(3)); no description of patient 
randomization procedures (if performed), as Sec.  314.126(b)(4) 
requires; and no clinical descriptions or associated clinical 
measurements for the endpoints of ``Excellent,'' ``Good,'' and ``No 
change,'' as Sec.  314.126(b)(6) and (b)(7) require. Thus, Delmont's 
March 31, 1978, submissions did not satisfy the controlled clinical 
investigations standard.
(4). May 26, 1978, Letter
    In a letter dated May 26, 1978 (Docket No. 2000N-1219, Item SUP1, 
Tab F to Delmont's April 28, 2003, hearing request), Delmont submitted 
one last supplement to its comments on FDA's proposal to classify SPL 
into Category IIIB. The letter stated that ``[t]his information further 
supports Delmont's position, set out in its January 8, 1978, comments, 
that SPL is safe and that an opportunity should be provided for the 
completion of clinical studies to provide additional information 
demonstrating the product's effectiveness.'' Thus, Delmont acknowledged 
that its May submissions did not demonstrate SPL's effectiveness.
    The first set of documents contains case reports on 50 patients 
that Dr. Arthur Baker had treated with SPL. Delmont submitted those 
individual case reports to ``show that no allergic reactions or adverse 
effects were observed in any of the patients who received SPL over 
extended periods of time.'' Delmont did not include a study result 
report analyzing the data for effectiveness.
    The second set of documents consists of protocols for two clinical 
studies of SPL that Dr. John Silva was conducting. One was then 
underway at the Department of Veterans Affairs hospital in Biloxi, MS 
and the second had not begun. Delmont did not submit any effectiveness 
data from the ongoing study. Instead, it submitted a letter from Dr. 
Silva stating that no allergic reactions or other adverse effects had 
been observed. Therefore, the information related to safety rather than 
efficacy.
iii. FDA's 1979 Final Order on SPL
    On January 5, 1979 (44 FR 1544), FDA published a final order 
formally classifying into Category IIIA those products, including 
Delmont's SPL, for which the data were insufficient to determine their 
safety and effectiveness, but which FDA would allow to remain on the 
market pending completion of testing. That final order confirmed that 
the Commissioner agreed with the Original Antigen Panel's conclusions 
and recommendations about all the deficiencies in the Category IIIA 
data (44 FR 1544 at 1546, comment 5). It further confirmed that the 
manufacturers of those products had to submit data from controlled 
clinical investigations, and that their products could not remain in 
category IIIA indefinitely (44 FR 1544 at 1545 to 1548).
    That final order also expressly confirmed that SPL was subject to 
the same requirement. The order stated as follows: ``Because data 
submitted by Delmont Laboratories, Inc., have been found to be adequate 
to reclassify its staphage lysate types I and [III] combined, License 
No. 299, from Category IIIB to IIIA, the requirements concerning 
completion of testing and labeling apply to these products'' (44 FR 
1544 at 1548) (emphasis added). The order also made clear that those 
testing requirements were the ones that the Original Antigen Panel had 
recommended; after listing all of the Category IIIA products, including 
SPL, the order stated that ``[l]icenses remain in effect for these 
products pending conformance with the Panel's recommendations and 
completion of testing'' (44 FR 1544 at 1548) (emphasis added). As 
discussed above, the Original Antigen Panel was clear that all Category 
IIIA products reviewed by that Panel needed further clinical 
investigations to establish their effectiveness.

[[Page 75688]]

c. 1983 Data
    In December 1982, FDA assigned the VRBPAC to follow the 
reclassification procedures in Sec.  601.26 (65 FR 31003 at 31004) to 
reclassify the bacterial vaccines and antigens with ``no U.S. standards 
of potency'' that had been previously classified into Category IIIA, 
including SPL into either Category I or Category II. Under these 
procedures, Delmont submitted to the VRBPAC additional data on SPL. The 
VRBPAC held reclassification meetings in January, June, and September 
1983 (65 FR 31003 at 31006).
    After reviewing all of the data, VRBPAC voted to recommend placing 
SPL into Category II and to revoke Delmont's license. VRBPAC's Final 
Report provides VRBPAC's detailed critique of all the data that Delmont 
submitted (see Ref. 1, at pages 47 to 54). The Final Report confirmed 
that the VRBPAC members voted unanimously to recommend placing SPL into 
Category II because the evidence was insufficient to prove 
effectiveness. (See Ref. 1, at page 55). We continue to agree with the 
VRBPAC's analysis as described in that portion of the Final Report at 
page 55.
d. 1994 Data
    On February 28, 1994, Delmont submitted to FDA results from a study 
on hidradenitis suppurativa (HS) that had just begun in 1983, along 
with the results from some other studies. (A copy of Delmont's February 
28, 1994, submission is attached as Tab C to comments that Delmont 
submitted to the Docket No. 2000N-1219, Item C1 on August 9, 2000). In 
FDA's February 26, 2003, NOOH, FDA published a detailed critique of 
Delmont's 1994 data (68 FR 8908 at 8909). Of all the study results that 
Delmont submitted, only the HS study, a prospective, double-blind, 
placebo controlled trial, constituted a controlled clinical 
investigation (68 FR 8908 at 8909). The investigators in that study, 
however, found ``[n]o significant differences between treatment groups 
or between the two centers'' after performing efficacy analyses, and 
concluded that ``[u]nder the conditions of the study, SPL was not 
demonstrated to be effective in the treatment of HS'' (Delmont's 
February 28, 1994, submission, at page 9). A third party that Delmont 
contracted with to perform a reanalysis of the data reached a more 
optimistic conclusion (Delmont's February 28, 1994, submission, pages 9 
to 11, and 68 FR 8908 at 8909). But it reached that conclusion only 
after first unblinding the patient data and performing a subset 
analysis on a selected subgroup of patients based on a different method 
of assessing effectiveness (68 FR 8908 at 8909). Even then, the third 
party found no statistically significant difference between the 
patients treated with placebo and with SPL (68 FR 8908 at 8909).
    The rest of Delmont's 1994 data fails to satisfy the controlled 
clinical investigations standard, as FDA explained in its February 26, 
2003, NOOH (68 FR 8908 at 8909). We continue to support the analysis 
described in the Federal Register document of February 26, 2003 (68 FR 
8908).
    Significantly, Delmont's April 28, 2003, hearing request does not 
attempt to argue that any of the data it submitted to FDA during the 
reclassification process in 1983 and 1994 satisfies the controlled 
clinical investigations standard or otherwise is adequate to 
demonstrate effectiveness. Instead, Delmont's hearing request argues 
that the data that it submitted to FDA in 1978 sufficiently 
demonstrates that SPL is effective. Delmont does not, however, discuss 
the specific data that it submitted in 1978 or explain why it is 
sufficient to prove that SPL is effective. Rather, Delmont argues that 
in 1978, FDA stated that Delmont's data were sufficient to justify a 
hearing. What FDA actually stated, however, is that the data justified 
a hearing only on whether FDA should classify SPL into Category IIIA or 
IIIB--not Category I. In other words, FDA did not find that the data 
justified a hearing on whether SPL was effective--only on whether SPL 
was safe enough to allow Delmont to keep marketing it while Delmont 
conducted further effectiveness studies. Indeed, even Delmont admitted 
that further effectiveness studies were necessary.
    Therefore, Delmont has not raised a genuine and substantial issue 
of fact justifying a hearing as to whether SPL is effective.
3. Delmont's Procedural Objection
    Delmont also argues that FDA did not follow correct procedures 
during the effectiveness reclassification process and that, therefore, 
Delmont deserves a hearing on SPL's effectiveness. Delmont's specific 
objection is that because FDA issued a NOOH before finally 
reclassifying SPL into Category II, FDA has violated its own procedures 
and has deprived Delmont of fair notice and opportunity for judicial 
review.
    Delmont is incorrect that FDA violated its own procedures. The 
reclassification procedures, set forth in Sec.  601.26, are silent as 
to when FDA should issue an NOOH. However, the preamble to Sec.  601.26 
provides that the procedures for review and reclassification of the 
Category IIIA products were designed to be ``analogous to the 
procedures in Sec.  601.25 for the 1972 biologics review,'' as Delmont 
itself admits (Delmont's April 28, 2003, hearing request, at page 4) 
(46 FR 4634, January 16, 1981). Section 601.25 required FDA to issue an 
NOOH before issuing its final classification order. Specifically, Sec.  
601.25(g) required FDA's final classification order to address all 
matters in the proposed order, and Sec.  601.25(f)(2) required that for 
products that FDA proposed to classify into Category II, FDA also 
include a license revocation proposal in the proposed order. However, 
before revoking a license, FDA first had to issue an NOOH (Sec.  
601.5(b(1) (21 CFR 601.5(b)(1)). Therefore, under Sec.  601.25, FDA had 
to issue an NOOH before issuing a final classification order because 
that final classification order had to include the license revocation.
    Although Sec.  601.26 is silent on this issue, as stated in the 
preamble, the agency did follow the process analogous to Sec.  601.25 
for this license revocation. In the proposed order issued at 65 FR 
31003, May 15, 2000, FDA stated that the proposed order contained the 
agency's intent to revoke the licenses of certain products that the 
agency proposed to reclassify into Category II. The agency further 
stated that, after the end of the comment period on the proposed order, 
if it decided to proceed with the license revocation proceeding, it 
would publish a NOOH on the revocation of the license of each Category 
II product. The agency also stated it would issue a final order on all 
matters covered by the proposed order (65 FR at 31005). In fact, Sec.  
601.26(e) provides for the final order to cover all matters in the 
proposed order. As with the procedures under Sec.  601.25, FDA included 
notice of its intent to revoke certain licenses in the proposed order. 
In order to finalize all matters in the proposed order in the final 
order, it was necessary for FDA to issue the NOOH prior to the final 
order. Therefore, contrary to Delmont's arguments, FDA has not violated 
its procedures.
    In addition, Delmont is mistaken that FDA has deprived Delmont of 
fair notice and an opportunity for judicial review. This final order, 
which contains all of FDA's reasons for denying Delmont a hearing and 
for revoking Delmont's license, is final agency action that is 
reviewable in the courts (Sec.  12.28(d) (21 CFR 12.28(d))). Moreover, 
Delmont has had years of notice that FDA intends to reclassify SPL into 
Category II and to revoke its license based on that

[[Page 75689]]

reclassification, and has availed itself of two opportunities to 
comment on and object to FDA's proposal: (1) On August 9, 2000, in 
response to FDA's May 2000 proposal, and (2) on April 28, 2003, in 
response to FDA's NOOH (68 FR 8908). FDA has not deprived Delmont of 
fair notice, nor has FDA precluded Delmont from seeking judicial 
review.

D. Denial of Hearing Request

    For the reasons stated previously in this document, the 
Commissioner of Food and Drugs (Commissioner) determines that Delmont 
has failed to raise a genuine and substantial issue of fact to justify 
a hearing on the proposed revocation of U.S. License No. 299 issued to 
Delmont Laboratories, Inc. for Polyvalent Bacterial Antigens with ``no 
U.S. Standard of Potency'' (Staphage Lysate), and, therefore, denies 
Delmont's request for a hearing. The Commissioner also determines that 
Delmont's procedural arguments do not provide a basis for a hearing.

IV. Categorization of Products--Final Order

    The Commissioner has considered all relevant information regarding 
the four Category IIIA bacterial vaccines and bacterial antigens 
subject to reclassification and concludes that FDA's proposal for the 
reclassification of Category IIIA products into Category I or Category 
II is adopted as set forth in this section of this document and hereby 
formally classifies:

    Category I--Biological products determined to be safe, effective, 
and not misbranded, and which may continue to be introduced into 
interstate commerce.

Sanofi Pasteur Inc., U.S. License No. 1725:
    Tetanus Toxoid Adsorbed (primary and booster use), and
    Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (DECAVAC\TM\) 
(primary and booster use).

    Category II--Biological products determined to be unsafe, 
ineffective, or misbranded, and which may not continue to be introduced 
into interstate commerce.

Delmont Laboratories Inc., U.S. License No. 299:
    Polyvalent Bacterial Antigens with ``No U.S. Standard of Potency'' 
Staphage Lysate[supreg] (SPL)

V. License Revocation--Final Order

    For the reasons set forth in this document, under section 351 of 
the Public Health Service Act (42 U.S.C. 262) and 21 CFR 
601.5(b)(1)(vi), the Commissioner revokes the license (U.S. License No. 
299) issued to Delmont Laboratories, Inc., for Polyvalent Bacterial 
Antigens with ``No U.S. Standard of Potency'' Staphage Lysate[supreg] 
(SPL).

VI. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.

 1. Final Report: Addendum to Previous Panel Reports for the 
Reclassification of Category IIIA Biologics, VRBPAC, 1984.
 2. Fujino, Ryuichi; Yuji Sugisaki; Junko Nakagawa; Masana Komatsu; 
and Hachihiko Hirayama, ``Chronic Toxicity Test of SPL in Rats,'' 
Fujizoki Pharmaceutical Co., Ltd., Shinjuku-ku, Tokyo.
 3. Fujino, Ryuichi; Yuji Sugisaki; Junko Nakagawa; Masana Komatsu; 
``Acute and Subacute Toxicity Tests of SPL,'' Fujizoki 
Pharmaceutical Co., Ltd., Shinjuku-ku, Tokyo.
 4. Hirayama, Hachihiko, ``Teratologenicity Study of SPL in Rats and 
Rabbits,'' Fujizoki Pharmaceutical Co., Ltd., Nerima-ku, Tokyo.
 5. ``Effect of SPL on the Development of Skin Lesion in Mice after 
Inoculation with Herpes Simplex Virus,'' Department of Microbiology, 
School of Medicine, Kyushu University, Fukuoka, Japan.
 6. ``Chemotactic Accumulation of Macrophages in the Peritoneal 
Cavity after Inoculation of SPL and their Antitumor Activity,'' 
Department of Microbiology, School of Medicine, Kyushu University, 
Fukuoka, Japan.
 7. ``S-27: Summary of Results of Tests Conducted at Fuji-Zoki 
Pharmaceutical Research Division,'' Fujizoki Pharmaceutical Co., 
Ltd., Tokyo.
 8. Shigeno, N.; T. Mitsuma; and K. Kojima, ``Susceptibility of 
Staphylococcus aureus Clinical Isolates to Gratia Bacteriophage,'' 
Junior College of Medical Technology and Nursing affiliated with 
Niigata University.
 9. Mitsuma, T.; N. Shigeno; K. Kojima; and M. Tanaka, ``Influence 
of Staphage Lysates (SPL) on Immune Responses In Vitro,'' Junior 
College of Medical Technology and Nursing affiliated with Niigata 
University and Santo Hospital.
 10. Azuma, C.; Y. Tokuda; and T. Shibata, ``Immunopotiator Activity 
of Staphage Lysate (Mudd),'' Department of Dermatology, Tokyo 
College of Medicine, Tokyo.
 11. Tsuda, Shingo and Kikuo Minami, ``Immunochemotherapy for 
Infections--With Particular Reference to Staphage Lysate,'' 
Department of Dermatology, Kurume University, School of Medicine, 
Kurume, Fukuoka Prefecture.
 12. Salmon, G.G. and M. Symonds, ``Staphage Lysate Therapy in 
Chronic Staphylococcal Infections,'' Journal of the Medical Society 
of New Jersey, 60:180-193 (1963).
 13. Rank, Dale, ``Immune Stimulation Therapy for Inflammatory 
Disease of the Gut,'' and ``Immune Stimulation for Aphthous 
(Herpetic) Stomatitis & Rhinitis,'' (Study Nov. 1975 to Dec. 1977).
 14. Rank, Dale, ``Immune Stimulation for Aphthous (Herpetic) 
Stomatitis & Rhinitis,'' (Jan. 1976 to Jan. 1978).

    Dated: November 24, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-30441 Filed 12-3-10; 8:45 am]
BILLING CODE 4160-01-P