[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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="">