[Federal Register Volume 61, Number 83 (Monday, April 29, 1996)]
[Notices]
[Pages 18747-18749]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-10485]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 93D-0025]
Target Animal Safety and Drug Effectiveness Studies for Anti-
Microbial Bovine Mastitis Products; Guidance Document; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of the revised guidance document entitled ``Target Animal
Safety and Drug Effectiveness Studies for Anti-Microbial Bovine
Mastitis Products (Lactating and Non-lactating Cow Products)'' prepared
by the Center for Veterinary Medicine (CVM). This guidance document
serves to interpret statutory and regulatory requirements and outlines
general procedures for conducting evaluations for anti-microbials being
considered for approval.
DATES: Written comments on the guidance document may be submitted at
any time.
ADDRESSES: Submit written requests for single copies of the revised
guidance document entitled, ``Target Animal Safety and Drug
Effectiveness Studies for Anti-Microbial Bovine Mastitis Products'' to
the Communications and Education Branch (HFV-12), Center for Veterinary
Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville,
MD 20855, 301-594-1755. Send two self-addressed adhesive labels to
assist that office in processing your requests. Submit written comments
to the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
Requests and comments should be identified with the docket number found
in brackets in the heading of this document. A copy of the guidance
document and received comments may be seen at the Dockets Management
Branch between 9 a.m. and 4 p.m., Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Naba K. Das, Center for Veterinary
Medicine (HFV-133), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-594-1659.
SUPPLEMENTARY INFORMATION: FDA is announcing the availability of the
revised guidance document entitled ``Target Animal Safety and Drug
Effectiveness Studies for Anti-Microbial Bovine Mastitis Products
(Lactating and Non-lactating Cow Products)'' prepared by CVM. The
guidance document is intended to be used by the pharmaceutical industry
for information regarding the types of data that will demonstrate that
an anti-microbial mastitis product is safe and effective for both
lactating and non-lactating cows. In the Federal Register of February
10, 1993 (58 FR 7893), FDA issued a notice of availability of the CVM
draft guideline entitled ``Guideline for Target Animal and Human Food
Safety, Drug Efficacy, Environmental and Manufacturing Studies for
Anti-Infective Bovine Mastitis Products.'' Comments by interested
persons were requested.
In response to the February 19, 1993, notice, the Animal Health
Institute (AHI) notified CVM, by letter dated June 28, 1993, of its
intent to form a working group, the Dairy Industry Consortium (DIC), to
address the draft CVM guideline ``Guideline for Target Animal and Human
Food Safety, Drug Efficacy, Environmental and Manufacturing
[[Page 18748]]
Studies for Anti-Infective Bovine Mastitis Products.'' Comments and
alternative proposals from the AHI/DIC were forwarded to FDA/CVM in a
letter dated May 24, 1994.
Because AHI/DIC put forth extensive complex scientific comments,
CVM agreed to participate in a workshop to further discuss and clarify
the AHI/DIC comments. FDA/CVM representatives participated in the
workshop, which was held on June 2, 1994, in Alexandria, VA. The
objective of this workshop was to hold a public meeting to allow for
the discussion of AHI/DIC comments. The draft guideline was discussed
at the workshop. In a letter dated July 14, 1994, AHI circulated
minutes of the workshop to all attendees. In a letter dated August 11,
1994, CVM provided comments on the July 14, 1994, AHI minutes of the
workshop. As a result of CVM's comments, a subsequent meeting was held
on September 23, 1994, between representatives of FDA/CVM and AHI/DIC
to clarify scientific points made in the minutes of the workshop.
No other comments on that draft guideline were received by the
agency. The comments on the draft guideline from AHI/DIC are discussed
below:
1. General Issues
It was recommended that the final guidance document encompass only
the efficacy and target animal safety of anti-infective bovine mastitis
products. The draft guideline provided a discussion on other components
of the new animal drug application (NADA).
CVM concurs with this comment. The guidance document will mainly
address efficacy and target animal safety. Other components of the NADA
will be addressed under separate guidance documents (e.g.,
environmental assessment and manufacturing).
2. Enrollment in Study for Clinical Infectious Mastitis
It was recommended that the enrollment of a clinical mastitis case
in an efficacy study include the presence of abnormal milk and/or udder
clinical signs at enrollment as the primary element. The presence of
microorganisms should be strictly secondary. The experimental unit
should be the lactating dairy cow with clinical mastitis (abnormal milk
and/or udder clinical signs). For future clinical studies, only cows
with a single quarter with clinical mastitis should be enrolled. CVM
should use this single quarter data base to infer efficacy to all cows
with mastitis in one or more quarters. The diagnosis of clinical
mastitis should be the only signalment needed for enrollment in the
study. Prior to treatment, single samples for microbiologic and somatic
cell count (SCC) assessment should be obtained. Only the single
affected quarter will be treated. Any cow developing mastitis in
additional quarters during her enrollment should be dropped from the
study and not considered failure. Cows requiring and/or receiving
treatment in an additional mastitic quarter should be excluded from
consideration in the study. Only clinical cases of mastitis in which a
mastitis pathogen is isolated in the pretreatment sample should be used
to calculate cure rate. It should be necessary to submit to CVM the pre
and posttreatment bacteriological culture data from those cows that
were initially enrolled in the study but subsequently cultured negative
on the pretreatment sample.
CVM agrees with these comments. The guidance document has been
revised to reflect these comments.
3. Definition of Cure-
It was recommended that the definition of cure should include two
parts, a clinical portion and a bacteriological portion. The current
definition of cure lacks the clinical assessment. The cure should be
assessed between 14 and 28 days posttreatment based on the negative
control study design. Clinically, a cured quarter should have normal
milk and no clinical signs of mastitis in that quarter.
Microbiologically, the mastitis pathogen isolated in the pretreatment
sample should be absent from two posttreatment test samples. A minimum
of two single microbiology test samples should be obtained at least 5
days apart during the assessment period (14 to 28 days posttreatment).
Two single SCC samples should be obtained at the same time. SCC should
not be used in the determination of cure for the individual cow. SCC
results should only be used as a check of the numerical trend between
the means of SCC for ``cured'' and ``not-cured'' cows within each
treatment group to determine if other studies are needed for
inflammation and safety.
CVM agrees with the proposed definition of cure. The guidance
document has been revised to reflect these comments.
4. Enrollment in Study for Subclinical Mastitis
It was recommended that all new anti-infective products for
mastitis in the lactating dairy cow must show efficacy for clinical
mastitis. No new product should be licensed with subclinical data as in
the old guidelines. CVM should consider alternative approaches with
adequate justification. To obtain a subclinical indication, additional
subclinical data should be required. With acceptable clinical mastitis
efficacy results, the subsequent subclinical mastitis study should
require that the new therapy demonstrate efficacy but at a lower
probability level (p<0.10). This should require fewer cows to be
necessary for the subclinical study because elimination of the
pretreatment pathogen is required in the clinical study. Subclinical
trial(s) should select cows with a positive quarter, thus fewer cows
may be needed. The subclinical study should be a randomized study.
Prior to treatment, two single microbiology and SCC samples should be
obtained at a 24-hour interval. At 14 to 28 days posttreatment, two
single microbiologic and SCC samples should be obtained at least 5 days
apart. In the subclinical study, only one quarter from any cow would be
treated. For cows infected in multiple quarters, the quarter to be
treated would be randomly selected. The other quarters would not be
treated. If additional quarters of clinical mastitis requires
additional treatment, the cow would be ineligible for inclusion in the
study. Definition of cure for the subclinical study constitutes the
elimination of the bacteria isolated in both pretreatment samples. SCC
results should be used similarly in subclinical studies as for clinical
studies to detect changes and perhaps indicate possible safety
problems. Products with acceptable efficacy data from both clinical and
subclinical studies should receive the following indication:
``Effective for the treatment of clinical and subclinical mastitis
caused by* * *''.
CVM agrees with these comments. The guidance document has been
revised to incorporate these comments.
5. Design of Field Studies
It was recommended that clinical efficacy studies would be
multilocation/multiherd studies. CVM should eliminate the requirement
that a study herd must have a 20 percent incidence of clinical mastitis
to participate. Herds participating in a clinical study should have a
sufficient number of clinical mastitis cases to fill an adequate number
of blocks. Obtaining an adequate number of pathogens may involve
multiple locations to fulfill the number needed for each block within
the study. In the clinical study, the distribution of mastitis
pathogens from the study should be utilized to determine the label
efficacy statement. An example for an effective antibiotic for staph
and strep mastitis pathogens would be:
[[Page 18749]]
``Effective for the treatment of clinical and subclinical
mastitis caused by Staphylococcus species such as Staphylococcus
aureus, and Streptococcus species such as Streptococcus agalactiae,
Streptococcus uberis.''
This would eliminate the need in a clinical study to enroll 100
clinical cases per pathogen per treatment group. The study would need
to demonstrate adequate power to detect an overall treatment-cure rate
above that of the untreated control group. This would take into account
spontaneous cure rates.
CVM considered the above comments and has revised the guidance
document accordingly in light of CVM's position on this issue. CVM
believes that under current regulations, use of positive control
studies are permitted, however, CVM is trying to determine what
constitutes ``efficacy threshold.'' CVM would still require a negative
controlled study in order to separate the spontaneous cure rate from
the cure rate attributable to the drug. If a sponsor is considering a
positively controlled study, the sponsor should provide a basis for the
need to have such a study, and thus be exempted from this standard. It
should be discussed with and approved by CVM prior to the study. The
design of the positively controlled study needs to be such that
depending on the spontaneous cure rates, the study would detect an
overall cure rate for the treatment group of 65 to 70 percent per
pathogen.
6. Minimum Inhibitory Concentration/ Pharmacokinetic Data (MIC/PK Data)
The comment stated that utilization of MIC/PK data for
intramammary/mastitis products is still in the scientific discovery
stage. The basis for correlating milk residue/efficacy/MIC data to draw
a reasonable scientific conclusion is unavailable.
CVM agrees with the above comment, however, the use of MIC/PK data
for intramammary products should be addressed when CVM considers the
flexible labeling issues and should not be addressed in this current
anti-infective bovine mastitis drug guidance document.
7. Non-lactating Treatment and Prevention Products
The comment stated that separate studies would be necessary to
obtain a treatment and prevention label claim.
CVM agrees with the comment and has revised the draft guidance to
indicate that separate studies would be necessary to obtain a treatment
and prevention label claim for use in the dry cow. For the prevention
claim, the sponsor would need to establish, through a negative
controlled group, the new infection rate (estimates are approximately 2
to 3 percent) and demonstrate at least a 50 percent reduction in the
rate of new infections. The criteria for defining a cure is as for
clinical mastitis in the lactating cow, i.e., no clinical signs and
negative culture at time of freshening.
Guidelines are generally issued under Secs. 10.85(a) and 10.90(b)
(21 CFR 10.85(a) and 10.90(b)). The agency is now in the process of
revising Secs. 10.85(a) and 10.90(b). Therefore, this guidance document
is not being issued under Secs. 10.85(a) and 10.90(b), and it does not
bind the agency, and does not create or confer any rights, privileges,
or benefits for or on any person. However, it represents the agency's
current thinking on this issue. A person may follow the guidance
document or may choose to follow alternative procedures or practices.
If a person chooses to use alternate procedures or practices, that
person may wish to discuss the matter with FDA/CVM to prevent an
expenditure of money and effort on activities that may later be
determined to be unacceptable. When a guidance document states a
requirement imposed by statute or regulation, however, the requirement
is law and its force and effect are not changed in any way by virtue of
its inclusion in the guidance document.
Interested persons may, at any time, submit to the Dockets
Management Branch (address above) written comments on the document. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. The guidance
document and received comments are available for public examination in
the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through
Friday.
Dated: April 23, 1996.
William K. Hubbard,
Association Commissioner for Policy Coordination.
[FR Doc. 96-10485 Filed 4-26-96; 8:45 am]
BILLING CODE 4160-01-F