[Federal Register Volume 69, Number 159 (Wednesday, August 18, 2004)]
[Rules and Regulations]
[Pages 51162-51171]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-18846]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 514
[Docket No. 2000N-1399]
Presubmission Conferences
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing this final
rule to amend its new animal drug regulations to implement a new
provision of the Federal Food, Drug, and Cosmetic Act (the act). Under
this new provision of the act, as amended by the Animal Drug
Availability Act of 1996 (ADAA), any person intending to file a new
animal drug application (NADA) or supplemental NADA or to investigate a
new animal drug is entitled to one or more conferences with FDA to
reach an agreement establishing a submission or investigational
requirement. This final rule describes the procedures for requesting,
conducting, and documenting such presubmission conferences.
DATES: This rule is effective November 1, 2004.
FOR FURTHER INFORMATION CONTACT: Gail Schmerfeld, Center for Veterinary
Medicine (HFV-100), Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 301-827-1796, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
Congress enacted the ADAA on October 9, 1996. Section 512(b)(3) of
the act (21 U.S.C. 360b(b)(3)), as amended by the ADAA, provides that
any person intending to file an NADA or supplemental NADA or to request
an investigational exemption is entitled to one or more conferences
with FDA prior to such submission to reach an agreement establishing a
submission or investigational requirement. In the Federal Register of
August 25, 2000 (65 FR 51782), we proposed amending the new animal drug
applications regulations in part 514 (21 CFR part 514) to describe the
procedures to be followed for requesting, conducting, and documenting
presubmission conferences. Under the proposed rule and final rule,
persons intending to file an abbreviated new animal drug application
(ANADA) as well as persons intending to file an NADA or supplemental
NADA are entitled to request presubmission conferences. FDA provided 75
days for public comment on the proposed rule.
II. Comments on the Proposed Rule
We received four letters from government, industry, and trade
associations commenting on the proposed presubmission conference rule.
Our response to the comments, grouped by codified section, follows.
A. General Comments
(Comment 1) Two comments assert that presubmission conferences
under section 512(b)(3) of the act represent a fundamental change in
the manner the agency is to operate and a new way for the agency to do
business.
(Response) FDA disagrees with these comments. Presubmission
conferences under 512(b)(3) of the act do not represent a fundamental
change in the manner we operate. Although there was no statutory or
regulatory entitlement to a presubmission conference prior to enactment
of the ADAA, FDA's Center for Veterinary Medicine (CVM) had already
been encouraging sponsors of NADAs to participate in conferences with
us to discuss in detail what studies would be necessary to demonstrate
the safety and effectiveness of particular new animal drugs being
investigated. We found, as a result of this direct communication during
the development and review of new animal drugs, that fewer unusable
studies were conducted and there were fewer delays in the review
process. Although such agreements were not legally binding, we
attempted to be sensitive to industry's concern that we not change such
requirements without justification. Our goal was to not change
requirements unless we became aware of new information that suggested
such requirements may no longer support approval.
B. Definitions (Sec. 514.3)
In the proposed rule, the preamble discusses definitions in
proposed Sec. 514.3. However, the Definitions section in the codified
text in the proposed rule was mistakenly numbered Sec. 514.2. The
definitions added by this final rule will be added to existing Sec.
514.3 Definitions in alphabetical order.
In the proposed rule, potential applicant was defined to mean any
person intending to: (1) Investigate a new animal drug under section
512(j) of the Federal Food, Drug, and Cosmetic Act (the act), (2) file
a new animal drug application (NADA) or supplemental NADA under
512(b)(1) of the act, or (3) file an abbreviated new animal drug
[[Page 51163]]
application (ANADA) under section 512(b)(2) of the act. Under Sec.
514.5(c), a potential applicant may request one or more presubmission
conferences prior to the filing of a NADA, supplemental NADA, or an
ANADA. Thus, a person investigating a new animal drug under section
512(j) of the act is also a potential applicant. We are revising the
definition of ``potential applicant'' to include ``any person
investigating a new animal drug under section 512(j).''
In the proposed rule, the last sentence in the definition of
presubmission conference agreement stated that ``The presubmission
conference will be binding on the potential applicant and FDA unless it
is modified as described in Sec. 514.4(g).'' We are deleting this
sentence because it is unnecessary. As defined in the proposed and
final rule, a presubmission conference is binding.
(Comment 2) One comment expresses concern that the discussion in
the preamble to the proposed rule appeared to limit presubmission
conferences to just safety or effectiveness data generation.
(Response) The specific statement that raised the concern appeared
in the second section entitled ``Description of the Proposed Rule,''
``* * *. Meetings in which the focus is other than to establish the
safety and effectiveness data requirement for new animal drugs (e.g.,*
* *) are not specifically covered by this proposed rule'' (65 FR 51782
at 51783).
We did not intend that statement to be read to limit which meetings
will be considered presubmission conferences. Most, if not all,
investigational and submission requirements relate to establishing
safety or effectiveness data requirements.
The key factor in determining whether a meeting is a presubmission
conference is, as implied in section 512(b) of the act and the
definition of presubmission conference in Sec. 514.3(b), whether such
meeting is ``* * * to reach a binding agreement establishing a
submission or investigational requirement.'' Generally, the goal of a
presubmission conference is to reach agreement on some or all of the
investigational or submission requirements for a particular new animal
drug. But, so long as the intent of a meeting is to discuss
investigational or submission requirements, it is a presubmission
conference even if the parties are unable to reach agreement.
However, there may be some meetings that are not related to the
establishment of investigational or submission requirements that will
not be covered by this regulation because they are not presubmission
conferences. For example, a meeting requested by a company to present
information about all of its ongoing research and development projects
would not be a presubmission conference. Furthermore, a meeting to
discuss a pending submission would not be a presubmission conference.
As the term ``presubmission'' implies, submission requirements should
be discussed before we receive a submission. Meetings to discuss
pending submissions could give potential applicants an unfair advantage
because they could have the effect of requiring the review of the
submission prior to the meeting, thus pushing the review up in the
queue. Therefore, we neither anticipate meeting with potential
applicants to discuss pending submissions, nor would any such meeting
fall within 512(b)(3) of the act or this rule.
The proposed definition of presubmission conference limits
presubmission conferences to conferences ``requested by the potential
applicant.'' The act provides that any potential applicant is entitled
to a presubmission conference. However, the act does not specify that
requests for presubmission conferences may be initiated only by
potential applicants. Thus, we are revising the definition of
presubmission conference to remove this restriction. While, typically,
potential applicants will initiate requests for meetings to discuss
investigational or submission requirements, FDA may encourage potential
applicants to request a presubmission conference if we believe such a
meeting may facilitate the development of data to support approval.
(Comment 3) One comment expresses concern that the binding nature
of presubmission conferences results in a process that appears to be
somewhat inflexible. The comment notes that a new animal drug (i.e.,
the formulation) or its proposed uses (i.e., the intended uses or
conditions of use) may change as the product is developed and was
concerned that data requirements may change in the time it takes FDA to
draft and clear the presubmission conference agreement.
(Response) The act requires that agreements reached in
presubmission conferences be binding. However, the act also provides
flexibility by allowing for changes to such agreements if FDA and the
applicant or requester mutually agree to modify the requirement, or if
FDA determines that a substantiated scientific requirement essential to
the determination of safety or effectiveness of the animal drug
involved appears after the conference. Thus, although the parties may
agree to modify a presubmission conference agreement, FDA cannot
unilaterally change the agreement unless there are valid scientific
reasons for doing so.
To ensure that investigational and submission requirements do not
become outdated before a presubmission conference agreement is sent to
a potential applicant, we are revising Sec. 514.5(f)(1) in the final
regulation (as described in the following paragraphs) to add a
timeframe in which we will send a copy of the memorandum of conference,
which includes any presubmission conference agreement, to the potential
applicant to review.
(Comment 4) One comment requests that the regulations make it
absolutely clear that the sponsor should be able to determine, with
certainty, through a presubmission conference all the studies necessary
to establish the human safety, animal safety, and efficacy of a new
animal drug. Another comment expresses concern that the regulation
describes a process that appears to be somewhat inflexible because,
among other things, it requires us to establish investigational or
submission requirements for new animal drugs that may change (e.g., in
formulation, intended uses, and conditions of use) based on information
gathered throughout their development.
(Response) The act and this final regulation provide both certainty
and flexibility in determining investigational or submission
requirements. First, the act and the regulation specifically state that
any person intending to file a NADA or a request for investigational
exemption is entitled to one or more conferences in order to reach
agreement on certain submission requirements (section 512(b)(3) of the
act and Sec. 514.5(b)). Second, the act and the regulation specify
that an agreement may be changed if the following conditions are met:
(1) FDA and the applicant or requester mutually agree to modify the
requirement or (2) FDA by written order determines that a substantiated
scientific requirement essential to the determination of safety or
effectiveness of the animal drug involved has appeared after the
conference (section 512(b)(3) of the act and Sec. 514.5(g)). Thus, the
presubmission conference process provides certainty absent unforeseen
circumstances, but provides means to address contingencies that may
arise during new animal drug development.
The provision entitling a potential applicant to one or more
presubmission conferences is intended to recognize that it may not be
possible to establish
[[Page 51164]]
all of the investigational or submission requirements in one
presubmission conference because the new animal drug or its proposed
uses may change as it is being developed. The statute and regulation do
not preclude the parties from reaching agreement regarding all the
studies necessary to establish the human safety, animal safety, and
effectiveness of a new animal drug in a single presubmission
conference. However, we believe it is more likely that for most new
animal drugs the parties will participate in a series of presubmission
conferences.
Potential applicants may choose to and are encouraged to request
more than one presubmission conference. For example, if the outcome of
one study required to satisfy one of the approval requirements is
likely to affect the number or types of additional studies that would
be needed to satisfy the same or a different approval requirement, or
if it may affect the formulation or proposed uses of the new animal
drug. By sequencing presubmission conferences, a potential applicant
may be able to avoid conducting studies that will not support or be
necessary for approval.
Potential applicants should consider requesting presubmission
conferences on specific, manageable issues and should include in the
advance material to us all relevant information and data available to
date. Potential applicants should also consider the sequencing of such
conferences so that information and data on which future requirements
may depend are available. For example, a potential applicant may
request one presubmission conference to discuss the number and types of
studies necessary to demonstrate safety and request another
presubmission conference to discuss studies necessary to demonstrate
effectiveness after they have conducted studies to demonstrate that a
particular dose or dosage range is safe.
C. General (Sec. 514.5(a))
We are renaming this section ``General Principle Underlying the
Conduct of a Presubmission Conference.'' We are deleting the first two
sentences of proposed Sec. 514.5(a). Although these sentences
accurately reflect our view that a presubmission conference is the
forum for a potential applicant and FDA to reach agreement regarding
investigational or submission requirements and that the goal of such a
conference is to enhance the animal drug development and evaluation
process, these sentences do not set forth requirements or expectations
and should not be included in the codified language.
We are keeping the last sentence, but changing it to read as
follows: ``The general principle underlying the conduct of any
presubmission conference is that there should be candid, full, and open
communication.'' We believe it is important that all participants to a
presubmission conference, potential applicants and FDA representatives
alike, understand that candid, full, and open communication is
essential to ensuring that such conferences will enhance the animal
drug development and evaluation process.
D. Requesting a Presubmission Conference (Sec. 514.5(b))
We are revising the second sentence of proposed Sec. 514.5(b) to
read more clearly: ``A potential applicant's request for a
presubmission conference must be submitted to FDA in a signed letter.''
If an investigational new animal drug file has not been established
prior to receiving a request for a presubmission conference, our
general practice is to establish an investigational new animal drug
file for administrative reasons such as recordkeeping and protecting
the confidentiality of information submitted by potential applicants.
E. Advance Information (Sec. 514.5(d))
We are revising proposed Sec. 514.5(d), among other things, to
clarify what information is required to be submitted to FDA in advance
of a presubmission conference. Proposed Sec. 514.5(d) specified that:
The potential applicant must provide to FDA, at least 30 days
before a scheduled presubmission conference, a copy of any materials
to be presented at the conference, a list of proposed indications or
a copy of the proposed labeling for the product under consideration,
and any background material that provides an adequate scientific
rationale to support the potential applicant's position on issues
listed on the proposed agenda for the conference.
Under Sec. 514.5(b), a potential applicant is required to provide
a proposed agenda with their request for a presubmission conference. We
are revising Sec. 514.5(d) to clarify that a potential applicant is
required to submit a detailed agenda as part of the advance materials
submitted to FDA at least 30 calendar days before the scheduled
meeting. We expect that many potential applicants will schedule
presubmission conferences more than 30 days before the date they want
to meet with FDA so that they can increase the likelihood that the
appropriate staff representing the potential applicant and FDA will be
available to meet on a particular date or within a particular
timeframe. If the agenda is drafted at the time the meeting is
requested, the potential applicants may not be able to provide the
detail and focus for each of the agenda items at the level that is
needed for reviewers to prepare for the presubmission conference. The
proposed agenda submitted at the time of the request should identify
the general areas of discussion and provide enough information to allow
us to evaluate who from FDA should attend the meeting. But, we also
need a detailed agenda at least 30 days before the presubmission
conference is scheduled so that attendees can prepare for a productive
discussion of the issues.
What constitutes a ``detailed agenda'' will depend on the purpose
of the presubmission conference. The question the potential applicant
should ask in preparing a detailed agenda is ``what information is
necessary for a full and productive discussion on the issues identified
in the agenda?'' Consistent with this revision, we are removing the
word ``proposed'' that appears before agenda at the end of the first
sentence in proposed Sec. 514.5(d).
Proposed Sec. 514.5(d) also required the potential applicant to
provide to FDA ``* * * a list of proposed indications or a copy of the
proposed labeling for the product under consideration* * *.'' We are
revising Sec. 514.5(d) to require submission of a list of proposed
indications and also to require a copy of proposed labeling, if
available.
We encourage potential applicants to develop proposed labeling
early in the drug development process. By proposed labeling we mean
that textual portion of the label that describes, among other things,
the new animal drug, dosage form, route of administration, and the
intended uses and conditions of use for the new animal drug at a level
of specificity appropriate to the stage of development. Because this
wording often drives the submission or investigational requirements,
proposed label would assist us in establishing appropriate
requirements.
Finally, we are adding the words ``a copy of'' and deleting the
word ``adequate'' to clarify that a potential applicant is required to
provide ``a copy of any background material that provides scientific
rationale to support the applicant's position on issues listed in the
agenda for the conference.'' We do not need originals of the background
material. Readable copies may be provided in lieu of originals. The
background material should provide a scientific rationale for the
applicant's position on issues listed in the detailed agenda. We will
determine after review
[[Page 51165]]
and discussion at the presubmission conference whether the materials
provide ``adequate'' scientific rationale to support such positions.
(Comment 5) One comment states that, based on their experience with
FDA, if the amount of advance information requested in the proposed
rule is provided, there may be little opportunity for dialog or need
for the meeting because the agency will have made its decisions prior
to the actual meeting. Two comments suggest rather than requiring all
information to be submitted prior to the meeting, providing background
materials to acquaint participants with information that will be
discussed should be sufficient.
(Response) The goal of a presubmission conference is to reach
agreement regarding some or all of the investigational or submission
requirements. If we are to be prepared for a meeting, and prepared to
make binding decisions at such a meeting, sufficient scientific
background materials must be provided in advance for our review and
consideration. That does not mean that we will not be open to
discussion. In fact, having the material in advance will allow our
participants to prepare for a productive discussion because they will
be able to formulate appropriate questions, conduct further research on
issues, and apply their review experience, as appropriate.
It should be easier for potential applicants to provide copies of
all material they evaluated or referenced relating to an issue listed
in the agenda, rather than selecting or summarizing relevant material.
FDA participants should have the opportunity to review all
documentation in order to exercise their scientific judgment and, in
many cases, years of experience reviewing new animal drugs to determine
what information is relevant. If potential applicants select what
information is submitted or not submitted, FDA participants may not
have all the materials needed to make the decision or to provide the
best advice to the potential applicants regarding the least burdensome
investigational or submission requirements that are likely to result in
approval.
(Comment 6) One comment believes there should be a mechanism for
FDA to ask the applicant questions or request additional information
via telephone call or e-mail, rather than delay the meeting. The
comment hopes delays in holding a presubmission conference will be the
exception, not the norm.
(Response) Nothing in this rule prevents FDA staff from contacting
a potential applicant to ask clarifying questions or to request minor
(i.e., nonvoluminous, noncomplex) additional information. If questions
can be answered and minor additional materials can be provided to us in
a timely manner prior to the presubmission conference, there would be
no need to postpone a meeting.
The advance materials must permit a productive discussion of the
issues, and if we are to reach a binding agreement with a potential
applicant, sufficient information on which to make an informed
decision. Whether and how often presubmission conferences are delayed
will depend in part upon the quality and completeness of the advance
materials submitted by the potential applicant.
We are revising the last sentence in proposed Sec. 514.5(d) to
clarify that: ``* * * FDA may elect to postpone part or all of the
meeting until sufficient materials are provided to FDA.'' If sufficient
materials are available to proceed with a productive discussion on some
issues but not others, we intend to meet with the potential applicant
to discuss those issues for which sufficient advance materials have
been provided, if the issues are severable. Our goal is to assist
potential applicants in moving forward with the development and
approval of new animal drugs.
F. Conduct of a Presubmission Conference (Sec. 514.5(e))
We are revising the last sentence of proposed Sec. 514.5(e) to
clarify that: ``The submission or investigational requirement may
include, among other things, the number, types, and general design of
studies that are necessary to demonstrate the safety and effectiveness
of a new animal drug.'' We are changing ``will'' to ``may'' because any
particular submission or investigational requirement may include the
number, types, general design, or some combination of these elements,
of studies that are required to demonstrate safety and effectiveness,
but not all of them. We are adding the phrase ``among other things''
because requirements may address issues other than number, type, or
general design of studies, e.g., labeling requirements or methods
validation. The first sentence of proposed Sec. 514.5(a) stated that
presubmission conferences provide a forum to discuss the objectives and
general design of particular studies. Because we are deleting that
sentence in the final rule, we are clarifying in final Sec. 514.5(e)
that submission or investigational requirements may include the general
design of the studies.
G. Documentation of a Presubmission Conference (Sec. 514.5(f))
We are revising the first sentence in proposed Sec. 514.5(f)(1) to
clarify the contents of the memorandum of conference. ``FDA will
prepare a memorandum for each presubmission conference that will
include, among other things: any background information pertinent to
the request for the meeting; a summary of the key points of discussion;
agreements; and action items and assignments of responsibility.'' Other
changes to Sec. 514.5(f)(1) are described in the responses to comments
that follow. Further, we are dividing final Sec. 514.5(f)(1) into
paragraphs to improve clarity and readability.
(Comment 7) One comment seems concerned that the presubmission
conference agreement is part of the memorandum of conference. Further,
the comment suggests that it may be more expeditious and timely for the
registrant to prepare the memorandum of understanding with subsequent
approval by the agency.
(Response) We note that the comment uses the term ``memorandum of
understanding.'' Neither FDA nor potential applicants draft memorandum
of understanding to document presubmission conferences. As defined in
FDA's Staff Manual Guide 2830.1, the term ``Memoranda of
Understanding'' is primarily used by FDA to refer to formal agreements
between FDA and other Government (Federal, State, or local) agencies.
We assume that the comment meant ``memorandum of conference.''
As discussed in the proposed rule, that portion of the memorandum
of conference that documents any agreements reached regarding all or
part of a submission or investigational requirement will be included
under the heading ``Presubmission Conference Agreement'' (65 FR 51782
at 51783). We believe it is more efficient for us to prepare the
memorandum of conference and that it is important to provide the
agreement in the context of the information and discussions that took
place during the presubmission conference.
We are revising the sentence in proposed Sec. 514.5(f)(1) that
read: ``If a memorandum is silent on an issue, * * * such silence
cannot be construed as agreement between FDA and the potential
applicant on the issue'' to clarify that it is specifically the
presubmission conference agreement section of the memorandum in which
silence does not constitute agreement.
[[Page 51166]]
This sentence logically follows the sentence explaining that the
presubmission conference agreement is a section of the memorandum and
will read as follows: ``If the presubmission conference agreement
section of the memorandum is silent on an issue, including one that was
discussed in the conference or addressed by materials provided for the
conference, such silence does not constitute agreement between FDA and
the potential applicant on the issue.''
(Comment 8) The preamble to the proposed rule states that
presubmission conference agreements would generally include timeframes
for completion. One comment acknowledges that scientific knowledge on
which agreements are based may change over long periods of time, but
expresses concern that no guidance on the duration of those timeframes
was given.
(Response) Presubmission conference agreements will be based on
scientific knowledge available at the time of the agreement. The
inclusion of timeframes in a presubmission conference agreement is
intended, as the comment notes, to recognize that the state of
scientific knowledge may change over time. The inclusion of a timeframe
signals to a potential applicant or us the need to revisit whether the
submission or investigational requirements are still relevant after
that time.
What constitutes a reasonable timeframe will vary significantly
depending on, among other things, the nature of the product, the
species for which the drug is intended, and the proposed uses. For
example, time may affect the inferential value of data. Time-dependent
factors include, e.g., genetics of the target animal and the target
organism, husbandry practices, and diets (62 FR 59830 at 59833,
November 5, 1997).
Timeframes and any other caveats should be discussed as part of the
process of reaching agreement. Examples of other caveats that might be
included in a presubmission conference agreement include specification
of the formulation (e.g., final formulation) on which the studies
should be conducted and timeframes for updating literature searches.
(Comment 9) All of the comments express concern that the proposed
regulation does not include a timeframe in which FDA would issue the
memorandum of conference, and thus, the presubmission conference
agreement, if one is reached. Most comments suggest that FDA should be
required to provide the memorandum of conference to the potential
applicant within 25 days of the conference. They state that this
timeframe is consistent with the timeframe in which FDA must provide
written justification if it is requiring more than one field study to
provide substantial evidence of effectiveness. One comment is
specifically concerned that in the time it takes for the agreement to
clear the agency, the submission or investigational requirements might
change.
(Response) We agree that FDA should provide the memorandum of
conference to the potential applicant in a timely manner and will
provide the memorandum no later than 45 days after the date of the
presubmission conference. Accordingly, we are revising the sentence in
proposed Sec. 514.5(f)(1) that read: ``FDA will provide a copy of the
memorandum to the potential applicant for review'' to read: ``FDA will
send a copy of the memorandum to the potential applicant for review no
later than 45 calendar days after the date of the conference.''
We cannot provide the memorandum in 25 days because it is not a
practical timeframe for issuing most memoranda of conference
considering all of our other review responsibilities. Further, we
expect that many agreements will relate to investigational or
submission requirements other than those that relate to effectiveness
and will not include a requirement for more than one field study. If we
require more than one field study to provide substantial evidence of
effectiveness, we will provide our justification for that requirement
no later than 25 calendar days after the date of the conference as
required by section 512(b)(3) of the act and as described in Sec.
514.5(f)(2).
We are also revising the fourth sentence of proposed Sec.
514.5(f)(1) to clarify that as follows: ``The potential applicant will
have 30 calendar days from the date a copy of the memorandum of
conference is sent to the applicant to request changes to, or
clarification of, the substance of the memorandum.'' For purposes of
calculating the timeframe for the potential applicant to respond, the
only date of record from which we can calculate the time is the date
the memorandum is sent. This sentence will follow the sentence that
discusses that silence of a presubmission conference agreement on an
issue does not constitute agreement.
We are removing the sentence in proposed Sec. 514.5(f)(1)
regarding calculation of the timeframe because this is an
administrative matter and need not be addressed by regulation.
(Comment 10) Two comments note that the potential applicant is
given 30 days to request changes to or seek clarification of FDA's
memorandum of conference, but no timeframe is given in which FDA must
respond to the potential applicant's request. One comment proposed that
FDA respond within 25 days, another proposed 15 days.
(Response) We will send a response to the potential applicant's
request for changes to or clarification of a memorandum of conference
no later than 45 calendar days after the date such request is received.
If we agree that the memorandum of conference needs to be changed to
correct or clarify content, we will prepare an amended memorandum of
conference and include a copy of the amended memorandum as part of our
response to the potential applicant.
In the final rule, Sec. 514.5(f)(1)(iii) will include a timeframe
for FDA to send a response to a potential applicant's request for
changes or clarification, and clarify the administrative steps relating
to requesting and documenting changes to the presubmission conference
agreement. Accordingly, the last three sentences of final Sec.
514.5(f)(1) will read: ``If a potential applicant requests changes or
clarification, the request must be sent to FDA. If the potential
applicant requests changes or clarification, FDA will send the
potential applicant a response to their request no later than 45
calendar days after the date of receipt of the request.'' The last
sentence of Sec. 514.5(f)(1)(iv), under the paragraph ``Administrative
record,'' will read: ``A copy of FDA's original memorandum of
conference and, as appropriate, a copy of an amended memorandum to
correct or clarify the content of the original memorandum will be made
part of the administrative file.''
We hope to minimize the need for changes to or clarification of the
memorandum by summarizing at the close of each presubmission conference
the key points of discussion, agreements, and action items, and the
assignments of responsibilities for each of those items. That summary
of key points will provide the potential applicant with the first and
best opportunity to ensure that the discussions and any agreements
reached will be accurately documented in the memorandum of conference.
If the potential applicant disagrees with the summary presented at the
end of the presubmission conference, the potential applicant should
discuss the disagreement with us before the close of the presubmission
conference. In the event the potential applicant finds, after reviewing
FDA's memorandum of
[[Page 51167]]
conference, that correction to or clarification of the memorandum is
needed, the potential applicant should request changes to or
clarification of the memorandum by submitting a letter. Following the
presubmission conference, FDA will only review a request for changes to
or clarification of the memorandum that is submitted within 30 calendar
days from the date a copy of the memorandum is sent to the applicant.
The potential applicant should not request changes to or clarification
of the memorandum of conference by submitting the potential applicant's
version of the memorandum.
(Comment 11) The act, as amended by the ADAA, requires that FDA
justify a requirement for more than one field study to provide
substantial evidence of effectiveness. Two comments assert that FDA is
attempting to circumvent the intent of the ADAA by indicating that it
may require a single study in multiple locations.
The comments assert that the issue of whether a field study
conducted at multiple sites using a single protocol is a single study
or represents more than one study has long been an area of disagreement
between industry and FDA. But, one comment acknowledges it may be true
that, for some small animal clinical studies, multiple locations may be
necessary to obtain sufficient numbers of patients.
(Response) FDA is not attempting to circumvent the intent of the
ADAA. Whether a study conducted at multiple sites following the same
protocol is most appropriately considered a single study or multiple
studies depends upon the degree of coordination between the sites, the
intent of the analysis, whether the data would be pooled to assess
statistical significance, and the generalizability of the findings
(inferential space). Although ADAA does not require FDA to provide
justification for a multilocation field study, FDA has agreed that in
the spirit of ADAA it will provide justification of the need for a
multilocation field study (substantial evidence final rule at 64 FR
40746 at 40750, July 28, 1999). To that end, proposed Sec. 514.5(f)(2)
provided: ``If FDA requires one field study to be conducted at multiple
locations, FDA will, at the request of the potential applicant, provide
written or verbal justification for requiring multiple locations'' (64
FR 51786).
If we require more than one field study, we will provide written
justification within 25 days of a conference why more than one field
study is essential to demonstrate by substantial evidence that the new
animal drug is effective. After further consideration FDA has decided
that if we require one field study with multiple locations, we will
provide both verbal justification for why more than one location is
required during the presubmission conference and written justification
as part of the memorandum of conference, which must be provided in
accordance with this final rule no later than 45 days after the date of
the conference. We are revising the last sentence of proposed Sec.
514.5(f)(2) to clarify when and how we will provide justification for
requiring multiple locations: ``If FDA requires one field study to be
conducted at multiple locations, FDA will provide justification for
requiring multiple locations verbally during the presubmission
conference and in writing as part of the Memorandum of Conference.''
The principles governing the number and types of studies necessary
to demonstrate by substantial evidence that a new animal drug is
effective are addressed in Sec. 514.4(b)(3) and, extensively, in the
preambles to the proposed and final rules (62 FR 59830 and 64 FR
40746). The preambles to the proposed and final substantial evidence
rule (62 FR 59830 at 59833 and 64 FR 40746 at 40749) further describe
the considerations for designing a single adequate and well-controlled
study that may demonstrate substantial evidence of effectiveness. A
single multilocation study may be an accepted way of evaluating drugs
efficiently if it is designed to provide independent substantiation and
inferential value. In any instance, presubmission conferences give
potential applicants a venue to discuss, among other things, the least
burdensome requirements for demonstrating effectiveness.
H. Modification of Presubmission Conference Agreements (Sec. 514.5(g))
(Comment 12) One comment states that the Federal Register document
for the proposed rule left Sec. Sec. 514.4 or 514.5 open for future
language that would specify how the presubmission conference agreement
could be modified.
(Response) In both the proposed and final rule, the bases for
modifying a presubmission conference are found in Sec. 514.5(g). The
preamble to the proposed rule stated that proposed Sec. 514.4
describes procedures for requesting, conducting, and documenting a
presubmission conference. These procedures were proposed, however, to
be codified at Sec. 514.5, not in Sec. 514.4 of the proposed rule. In
the final rule, these procedures are codified at Sec. 514.5. Existing
Sec. 514.4 further defines substantial evidence.
I. When the Terms of a Presubmission Conference Agreement Are No Longer
Binding (Sec. 514.5(h))
(Comment 13) Two comments believe the provisions in proposed Sec.
514.5(h), when the terms of a presubmission conference are no longer
binding, are outside the statutory authority of the agency. The act, as
amended by the ADAA, provides that agreements regarding submission or
investigation requirements reached at a presubmission conference shall
bind the Secretary of Health and Human Services (the Secretary) and the
applicant or requester except in two specific situations. The first is
by agreement of both parties, and the second is where the Secretary, by
written order, determines that a substantiated scientific requirement,
essential to the determination of safety or effectiveness of the animal
drug involved, has appeared after the conference. The comments assert
that the agency does not have the authority to create other mechanisms
by which FDA can unilaterally declare presubmission conference
agreements not binding.
(Response) We are revising the heading in proposed Sec. 514.5(h),
``When the terms of a presubmission conference agreement are no longer
binding'' to ``When the terms of a presubmission conference agreement
are not valid.'' The heading in the proposed regulation did not
accurately reflect the content or intent of the provision.
The intent of proposed Sec. 514.5(h) was not to describe
additional conditions under which a presubmission conference agreement
is no longer binding. The intent of the provision was to emphasize that
if presubmission conference agreements are to be meaningful and valid,
they must be based on the truthful submission of information and must
bind both parties. There cannot be agreement between parties if
statements or representations made by one party are materially false,
fictitious, or fraudulent. Thus, FDA considers agreements based on
untrue statements or mispresentations of material facts to never have
been valid. Further, if a party fails to follow any material term of
the agreement, such agreements may become invalid.
We disagree with the comments that assert that the provisions in
proposed Sec. 514.5(h) are outside the statutory authority of the
agency. As stated by one comment, no one should be untruthful or
mislead the agency. In fact it is a crime to knowingly and willfully
make an untruthful statement to FDA on matter within its jurisdiction;
specifically, 18 U.S.C. 1001(a) provides:
[[Page 51168]]
Except as otherwise provided in this section, whoever, in any
matter within the jurisdiction of the executive, legislative, or
judicial branch of the Government of the United Stated, knowingly
and willfully--
(1) falsifies, conceals, or covers up by any trick, scheme, or
device a material fact;
(2) makes any materially false, fictitious, or fraudulent
statement or representation; or
(3) makes or uses any false writing or document knowing the same
to contain any materially false, fictitious, or fraudulent statement
or entry;
shall be fined under this title or imprisoned not more than 5
years, or both.
The ADAA does not limit or in any way affect the applicability of
the criminal code to potential applicants who provide materially false,
fictitious, or fraudulent information to FDA in the course of providing
information to facilitate the conduct of a presubmission conference or
to support new animal drug approval.
Further, section 701(a) of the act (21 U.S.C. 371(a)) vests in the
Secretary the authority to issue regulations for the efficient
enforcement of the act. No provision of the ADAA limits or supersedes
the authority granted to the Secretary, and FDA by delegation, under
section 701(a) of the act. FDA has the authority to make clear the
conditions under which agreements were never valid or are no longer
valid.
(Comment 14) Two comments are concerned by the provision in the
proposed rule that stated: ``[a] presubmission conference agreement
will no longer be binding * * * if the potential applicant fails to
follow any term of the agreement.'' Both comments believe that it would
be inequitable for an entire agreement to be voided if the applicant
failed to comply with some nonmaterial portion of the agreement. One
comment suggests that each component of the presubmission conference
agreement should be judged upon its own merits and that failure to meet
one provision of the agreement should not automatically invalidate the
whole agreement. The other comment is particularly concerned that
failure to meet timeframes provided for in presubmission conference
agreements may frequently cause agreements to be invalidated.
(Response) We do not intend to invalidate an entire presubmission
conference agreement if the potential applicant fails to follow
immaterial term(s) of the agreement and the term(s) of the
presubmission conference agreement are severable. Thus, we are adding
``material'' before the word term in Sec. 514.5(h)(1)(ii). We intend
to examine the severability of the terms of a presubmission conference
agreement on a case-by-case basis.
For example, a determination of whether a timeframe is a material
term of the agreement will be made by FDA on a case-by-case basis. We
understand the comment's concern that timeframes included as terms of
the presubmission conference agreement may result in invalidation of
the presubmission conference agreement. However, we believe that steps
have been built into the presubmission conference process to decrease
the likelihood that timeframes will present a major obstacle to
complying with the terms of the agreement. First, the potential
applicant and FDA should discuss and agree to reasonable timeframes
during the presubmission conference. Second, we have added timeframes
for FDA to provide the memorandum, including the presubmission
conference agreement, and our response to any requests for correction
or clarification to ensure our timely response to potential applicants.
Finally, we anticipate that the recent enactment of the Animal Drug
User Fee Act of 2003 will minimize any significant delays that occur
within FDA in reviewing submissions that may affect the potential
applicant's ability to meet reasonable timeframes in the agreement.
III. Environmental Impact
This final rule clarifies the procedures for requesting,
conducting, and documenting presubmission conferences. We have
carefully considered the potential environmental impacts of this rule
and determined that this action is of a type, as described in 21 CFR
25.30(h), that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
IV. Analysis of Impacts
We have examined the impacts of this final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages, distributive impacts and equity). We believe that this
final rule is consistent with the regulatory philosophy and principles
identified in Executive Order 12866. We have also determined that the
rule is not a significant regulatory action as defined by the Executive
order and, therefore, is not subject to review under the Executive
order. Under the Regulatory Flexibility Act, if a regulation has a
significant economic impact on a substantial number of small entities,
the agency must analyze regulatory options that would minimize the
impact on small entities. FDA certifies in accordance with the
Regulatory Flexibility Act (5 U.S.C. 601-612) that this rule will not
have a significant economic impact on a substantial number of small
entities, and therefore, a regulatory flexibility analysis is not
required.
Under section 512(b)(3) of the act, as amended by the ADAA, any
person intending to file an NADA or supplemental NADA or to investigate
a new animal drug is entitled to one or more conferences prior to such
submission to reach an agreement establishing a submission or
investigational requirement. The purpose of presubmission conferences
is to allow a potential applicant and FDA to reach agreement regarding
a submission or investigational requirement, including the number and
types of studies that are necessary to demonstrate that the new animal
drug is safe and effective for its intended uses.
Prior to the enactment of the ADAA, CVM had already been
encouraging sponsors of NADAs to participate in conferences with FDA to
discuss in detail what studies are necessary to demonstrate the safety
and effectiveness of the particular new animal drug being investigated.
We found that, as a result of this direct communication during the
development and review of new animal drugs, both the drug development
and review processes became more efficient. This final rule implements
the statutory entitlement to a presubmission conference, and thus, it
will ensure that this benefit will continue where potential applicants
request a presubmission requirement.
FDA is not able to make a precise estimate of the savings that
industry has realized through presubmission conferences, or of any
increase in the number of presubmission conferences that may be
requested as a result of the statutory entitlement. This final rule
describes the procedures for requesting, conducting, and documenting
presubmission conferences and secures an avenue of communication
between us and the potential applicants through which both can agree on
the studies needed for a certain drug, thereby reducing unnecessary
studies and review periods.
[[Page 51169]]
In the proposed rule, we forecasted a range of savings that may be
expected from any decrease in approval time resulting from a potential
applicant requesting a presubmission conference. We estimated a
straight-line increase of a prospective drug's sales revenues from the
application's approval up to $5 million in the 10th year and then
deceasing again to zero in the 20th year. Because many new animal drugs
attain sales much greater than $5 million, we estimated results in a
rather conservative benefit. Assuming pretax profit of 20 percent of
sales revenue, we estimated the present value of the profits from a 1-
to 6-month decrease in approval time at $20,000 to $120,000 using a 7
percent discount rate. Research costs saved by the firm from not
conducting unnecessary studies would be added to this amount.
Regardless of the exact reduction in the drug review period, potential
applicants would only be expected to request a presubmission conference
if they expected the net benefit of the conference to be positive. We
also concluded that the proposed rule would not impose any mandatory
compliance costs.
We did not receive any comments that challenged our conclusions
concerning the benefits or costs of the proposed rule. Further, the
modifications made to this final rule would not lead us to change our
conclusions concerning the aforementioned costs and benefits of the
rule.
Section 202(a) of the Unfunded Mandates Reform Act requires that
agencies prepare a written statement of anticipated costs and benefits
before proposing any regulation that may result in an expenditure by
State, local and tribal governments in the aggregate, or by the private
sector, of $100 million or more (adjusted annually for inflation) in
any one year. The Unfunded Mandates Reform Act does not require FDA to
prepare a statement of costs and benefits for this final rule because
the rule is not expected to result in any 1-year expenditure that would
exceed $100 million adjusted for inflation. The current inflation-
adjusted statutory threshold is approximately $110 million.
V. Federalism
We have analyzed this final rule in accordance with the principles
in Executive Order 13132. We have determined that the final rule does
not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, we have concluded that the
final rule does not contain policies that have federalism implications
as defined in the order and, consequently, a federalism summary impact
statement has not been prepared.
VI. Paperwork Reduction Act of 1995
This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description, and respondent description of the information collection
provisions are shown in the following paragraphs with an estimate of
the annual reporting burden. Included in the estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
Title: Presubmission Conferences
Description: This final rule is intended to implement section
512(b)(3) of the act which entitles any person intending to file an
NADA or supplemental NADA or to investigate a new animal drug to
request one or more conferences with FDA to reach an agreement
establishing a submission or investigational requirement. Prior to the
enactment of the section 512(b)(3) of the act, we encouraged sponsors
to meet with FDA to discuss the number and types of studies necessary
to demonstrate that a new animal drug is safe and effective. We found
that these meetings increased the efficiency of the drug development
and drug review processes. We are publishing this final rule to
describe how to request, conduct, and document a presubmission
conference.
Final Sec. 514.5(b) describes the information that must be
included in a letter submitted by a potential applicant requesting a
presubmission conference, including a proposed agenda and a list of
expected participants. Final Sec. 514.5(d) lists the information that
must be provided by the potential applicant to FDA at least 30 days
prior to a presubmission conference. This information includes a
detailed agenda, a copy of any materials to be presented at the
conference, a list of proposed indications and, if available, a copy of
the proposed labeling for the product under consideration, and a copy
of any background material that provides scientific rationale to
support the potential applicant's position on issues listed in the
agenda for the conference. Final Sec. 514.5(f) discusses the content
of the memorandum of conference that will be prepared by FDA and gives
the potential applicant an opportunity to seek correction to or
clarification of the memorandum.
Description of Respondents: Potential applicants
Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
No. of Annual frequency Total annual Hours per
21 CFR respondents per response responses response Total hours
----------------------------------------------------------------------------------------------------------------
514.4(b) 190 1 190 7 1,330
----------------------------------------------------------------------------------------------------------------
514.4(d) 190 1 190 123 23,370
----------------------------------------------------------------------------------------------------------------
514.4(f) 190 1 190 16 3,040
----------------------------------------------------------------------------------------------------------------
Total Hours 27,740
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection of information.
Table 1 of this document provides, by relevant section, the
estimated burden of requesting, preparing for, and participating in
presubmission conferences. The numbers in the chart are based on
consultation with several of the major research and development firms
that are responsible for the development of new animal drugs. While we
estimate that the final regulation will increase the annual paperwork
burden associated with the
[[Page 51170]]
submission of NADAs, supplemental NADAs, and abbreviated NADAs, and
requests for guidance on investigational requirements, we believe this
increase will be offset by the resulting efficiencies (e.g.,
eliminating the conduct of studies that are not needed to support
approval, decreasing requests from reviewers for additional or
clarifying information during the review process).
The information collection provisions of this final rule have been
submitted to OMB for review.
Prior to the effective date of this final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
List of Subjects in 21 CFR Part 514
Administrative practice and procedure, Animal drugs, Confidential
business information, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs and
redelegated to the Center for Veterinary Medicine, 21 CFR part 514 is
amended as follows:
PART 514--NEW ANIMAL DRUG APPLICATIONS
0
1. The authority citation for 21 CFR part 514 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 360b, 371, 379e,
381.
0
2. Section 514.3 is amended by adding the following definitions in
alphabetical order:
Sec. 514.3 Definitions.
* * * * *
Potential applicant means any person:
(1) Intending to investigate a new animal drug under section 512(j)
of the Federal Food, Drug, and Cosmetic Act (the act),
(2) Investigating a new animal drug under section 512(j) of the
act,
(3) Intending to file a new animal drug application (NADA) or
supplemental NADA under section 512(b)(1) of the act, or
(4) Intending to file an abbreviated new animal drug application
(ANADA) under section 512(b)(2) of the act.
Presubmission conference means one or more conferences between a
potential applicant and FDA to reach a binding agreement establishing a
submission or investigational requirement.
Presubmission conference agreement means that section of the
memorandum of conference headed ``Presubmission Conference Agreement''
that records any agreement on the submission or investigational
requirement reached by a potential applicant and FDA during the
presubmission conference.
* * * * *
0
3. Section 514.5 is added to subpart A to read as follows:
Sec. 514.5 Presubmission conferences.
(a) General principle underlying the conduct of a presubmission
conference. The general principle underlying the conduct of any
presubmission conference is that there should be candid, full, and open
communication.
(b) Requesting a presubmission conference. A potential applicant is
entitled to one or more conferences prior to the submission of an NADA,
supplemental NADA, or an ANADA to reach an agreement establishing part
or all of a submission or investigational requirement. A potential
applicant's request for a presubmission conference must be submitted to
FDA in a signed letter. The letter must include a proposed agenda that
clearly outlines the scope, purpose, and objectives of the
presubmission conference and must list the names and positions of the
representatives who are expected to attend the presubmission conference
on behalf of the applicant.
(c) Timing. A potential applicant may request one or more
presubmission conferences at any time prior to the filing of a NADA,
supplemental NADA, or an ANADA. A request for a presubmission
conference must be received by FDA at least 30 calendar days in advance
of the requested conference date. FDA will schedule the presubmission
conference at a time agreeable to both FDA and the potential applicant.
(d) Advance information. The potential applicant must provide to
FDA, at least 30 calendar days before a scheduled presubmission
conference, a detailed agenda, a copy of any materials to be presented
at the conference, a list of proposed indications and, if available, a
copy of the proposed labeling for the product under consideration, and
copies of materials evaluated or referenced relative to issues listed
in the agenda for the conference. If the materials are not provided or
are not sufficient to provide the basis for meaningful discussion, FDA
may elect to postpone part or all of the meeting until sufficient
materials are provided to FDA.
(e) Conduct of a presubmission conference. The potential applicant
and FDA may each bring consultants to the presubmission conference. The
presubmission conference(s) will be directed primarily at establishing
agreement between FDA and the potential applicant regarding a
submission or investigational requirement. The submission or
investigational requirement may include, among other things, the
number, types, and general design of studies that are necessary to
demonstrate the safety and effectiveness of a new animal drug for the
intended uses and conditions of use prescribed, recommended, or
suggested in the proposed labeling for the new animal drug.
(f) Documentation of a presubmission conference--(1) Memorandum of
conference--(i) Preparation. FDA will prepare a memorandum for each
presubmission conference that will include, among other things, any
background pertinent to the request for meeting; a summary of the key
points of discussion; agreements; and action items and assignments of
responsibility. That portion of the memorandum of conference that
documents any agreements reached regarding all or part of a submission
or investigational requirement will be included under the heading
``Presubmission Conference Agreement.'' If the presubmission conference
agreement section of the memorandum is silent on an issue, including
one that was discussed in the conference or addressed by materials
provided for the conference, such silence does not constitute agreement
between FDA and the potential applicant on the issue.
(ii) Sending a copy to the potential applicant. FDA will send a
copy of the memorandum to the potential applicant for review no later
than 45 calendar days after the date of the conference
(iii) Requests for changes or clarification. If a potential
applicant requests changes to, or clarification of, the substance of
the memorandum, the request must be sent to FDA within 30 calendar days
from the date a copy of the memorandum is sent to the applicant. If the
potential applicant requests changes or clarification, FDA will send
the potential applicant a response to their request no later than 45
calendar days after the date of receipt of the request.
(iv) Administrative record. A copy of FDA's original memorandum of
conference and, as appropriate, a copy of an amended memorandum to
correct or clarify the content of the original
[[Page 51171]]
memorandum will be made part of the administrative file.
(2) Field studies. If FDA requires more than one field study to
establish by substantial evidence that the new animal drug is effective
for its intended uses under the conditions of use prescribed,
recommended, or suggested in the proposed labeling, FDA will provide
written scientific justification for requiring more than one field
study. Such justification must be provided no later than 25 calendar
days after the date of the conference at which the requirement for more
than one field study is established. If FDA does not believe more than
one field study is required but the potential applicant voluntarily
proposes to conduct more than one field study, FDA will not provide
such written justification. If FDA requires one field study to be
conducted at multiple locations, FDA will provide justification for
requiring multiple locations verbally during the presubmission
conference and in writing as part of the memorandum of conference.
(g) Modification of presubmission conference agreements. An
agreement made under a presubmission conference requested under section
512(b)(3) of the act and documented in a memorandum of conference is
binding on the potential applicant and FDA and may only be modified if:
(1) FDA and the potential applicant mutually agree to modify, in
part or in whole, the agreement and such modification is documented and
provided to the potential applicant as described in paragraph (f)(1) of
this section; or
(2) FDA by written order determines that a substantiated scientific
requirement essential to the determination of safety or effectiveness
of the new animal drug appeared after the conference.
(h) When the terms of a presubmission conference agreement are not
valid--(1) A presubmission conference agreement will no longer be valid
if:
(i) The potential applicant makes to FDA, before, during, or after
the presubmission conference, any untrue statement of material fact; or
(ii) The potential applicant fails to follow any material term of
the agreement; and
(2) A presubmission conference may no longer be valid if the
potential applicant submits false or misleading data relating to a new
animal drug to FDA.
(i) Dispute resolution. FDA is committed to resolving differences
between a potential applicant and FDA reviewing divisions with respect
to requirements for the investigation of new animal drugs and for
NADAs, supplemental NADAs, and ANADAs as quickly and amicably as
possible through a cooperative exchange of information and views. When
administrative or procedural disputes arise, a potential applicant
should first attempt to resolve the matter within the appropriate
review division beginning with the individual(s) most directly assigned
to the review of the application or investigational exemption. If the
dispute cannot be resolved after such attempts, the dispute shall be
evaluated and administered in accordance with applicable regulations
(21 CFR 10.75). Dispute resolution procedures may be further explained
by guidance available from the Center for Veterinary Medicine.
Dated: August 10, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-18846 Filed 8-17-04; 8:45 am]
BILLING CODE 4160-01-S