[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