80 FR 14146 - Identification of Alternative In Vitro Bioequivalence Pathways Which Can Reliably Ensure In Vivo Bioequivalence of Product Performance and Quality of Non-Systemically Absorbed Drug Products for Animals; Public Meeting

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 80, Issue 52 (March 18, 2015)

[Federal Register Volume 80, Number 52 (Wednesday, March 18, 2015)]
[Notices]
[Pages 14146-14147]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-06119]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-N-0684]


Identification of Alternative In Vitro Bioequivalence Pathways 
Which Can Reliably Ensure In Vivo Bioequivalence of Product Performance 
and Quality of Non-Systemically Absorbed Drug Products for Animals; 
Public Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notification of public meeting; request for comments.

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    The Food and Drug Administration (FDA) is announcing a public 
meeting entitled ``Identification of Alternative In Vitro 
Bioequivalence Pathways Which Can Reliably Ensure In Vivo 
Bioequivalence of Product Performance and Quality of Non-Systemically 
Absorbed Drug Products for Animals''. The purpose of the public meeting 
is to discuss the use of in vitro methods as a mechanism for assessing 
the in vivo product bioequivalence (BE) of non-systemically absorbed 
drug products intended for use in veterinary species. FDA is seeking 
additional public comment to the docket, and is requesting that any 
written comments be submitted by May 18, 2015.
    Date and Time: The public meeting will be held on April 16, 2015, 
from 9 a.m. to 4 p.m.
    Location: The public meeting will be held at the Center for 
Veterinary Medicine (CVM), Food and Drug Administration, 7519 Standish 
Pl., 3rd Floor, Conference Room A, Rockville, MD 20855. Parking is 
free.
    Contact Person: Aleta Sindelar, CVM, Food and Drug Administration, 
7519 Standish Pl., Rm. 144, Rockville, MD 20855, 240-276-9230, FAX: 
240-276-9241, email: 
[email protected].
    Registration: Registration is free and available on a first-come, 
first-served basis. Persons interested in requesting an opportunity to 
speak during the open public comment period must register by April 8, 
2015, and must include a brief summary of comments with their 
registration. Those individuals will be contacted prior to the meeting 
regarding their participation. Persons interested in attending this 
meeting who are not requesting an opportunity to speak at the meeting 
must register by April 14, 2015. For general questions about the 
meeting, for assistance registering for the meeting, to request an 
opportunity to make an oral presentation, or to request special 
accommodations due to a disability, contact Aleta Sindelar (see Contact 
Person). Please include your name, organization, and contact 
information. Early registration for the meeting is encouraged due to 
limited time and space.

SUPPLEMENTARY INFORMATION: 

I. Background

    Given the imprecision and logistic challenges associated with 
clinical endpoint BE studies, FDA is exploring alternative pathways 
that can be applied to help ensure the equivalence of product 
performance and quality for those products that are non-systemically 
absorbed (locally acting).
    The assessment of in vivo BE of non-systemically absorbed drug 
products has been a longstanding challenge facing drug manufacturers 
and regulators of human and animal health products. Although blood 
level BE trials remain the standard for comparing drug products that 
are systemically absorbed and that act at a target site reached via the 
blood (systemic circulation), such studies cannot confirm product in 
vivo BE when a drug is either not systemically absorbed or when it is 
associated with therapeutic effects occurring proximal to the site of 
absorption. To date, unless the active pharmaceutical ingredient met 
the criteria for highly soluble, as defined in CVM Guidance #171 
entitled ``Waivers of In Vivo Demonstration of Bioequivalence of Animal 
Drugs in Soluble Powder Oral Dosage Form Products and Type A Medicated 
Articles,'' clinical endpoint BE trials have provided the only option 
for generating inter-product comparisons. FDA is exploring whether an 
alternative in vitro BE approach may be considered when blood level BE 
studies are either not feasible or not appropriate, and when products 
do not meet the criteria for applying a Guidance #171-based biowaiver.
    The assumption underlying the application of the in vitro BE 
approach is that equivalence in product physicochemical attributes and 
in vitro product performance translates to equivalence in product in 
vivo behavior. For sponsors with a right of reference to underlying 
safety and effectiveness data, the criteria for similarity of 
physicochemical attributes would be defined on the basis of the 
underlying dataset to confirm the comparability of the original 
formulation and pre- and post-approval changes in formulation or method 
of product manufacture. In the case of generic products, a more rigid 
approach to sameness would be used in terms of product composition and 
physicochemical characteristics. In both situations, physicochemical 
comparisons would be based upon a battery of in vitro test procedures, 
including a comparison of in vitro dissolution behavior under a range 
of physiologically-relevant conditions.
    Examples of the kinds of products where in vitro bioequivalence 
concepts can potentially be applied include some orally administered 
products (e.g., Type A medicated articles), solutions, emulsions, 
ointments, creams, suspensions, transdermal products, and intra-mammary 
formulations. Due to unique issues raised by products

[[Page 14147]]

employing modified release technologies, only immediate release 
formulations would be candidates for the in vitro BE assessment. For 
orally administered products, in vitro BE would be limited to 
disintegrated dosage forms. In cases when the administered drug acts 
both locally and systemically, blood level data may be used to confirm 
drug product BE of the systemic effects (and to confirm comparability 
of in vivo product disintegration in cases where multiple drugs are 
combined in a single solid oral dosage forms), while the additional in 
vitro dissolution data could be used to support the comparability of 
the local actions.
    The in vitro BE approach should not be construed as a biowaiver, 
but rather as an alternative set of tests that would be handled in a 
manner consistent with that of an in vivo BE study. Specifically, (1) 
because an in vitro BE approach is not a biowaiver, sponsors would 
still need to meet the same environmental safety and human food safety 
requirements associated with products undergoing in vivo BE studies; 
(2) one in vitro study may not suffice when there are multiple product 
strengths (e.g., varying concentrations of an intra-mammary infusion); 
and (3) the in vitro method could be applied both to fully soluble and 
poorly soluble compounds. In vitro BE determinations would be based 
upon a battery of in vitro dissolution studies and physicochemical 
tests. Links to additional background material are provided on the 
Agency's Web site at: http://www.fda.gov/AnimalVeterinary/NewsEvents/WorkshopsConferencesMeetings/ucm435459.htm.
    To assist FDA in developing guidance for demonstrating in vitro BE, 
with this notice the Agency is convening an open forum, providing a 
summary of what the Agency envisions as considerations pivotal to the 
BE assessment and inviting public comment on the various components of 
an in vitro BE determination.

II. Participation in a Public Meeting

    While oral presentations from specific individuals and 
organizations may be limited due to time constraints during the public 
meeting, stakeholders may submit electronic or written comments 
discussing any issues of concern to the administrative record (the 
docket) for the rulemaking. All relevant data and documentation should 
be submitted with the comments. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at http://www.regulations.gov.

III. Comments, Transcripts, and Recorded Video

    Information and data submitted voluntarily to FDA during the public 
meeting will become part of the administrative record for the 
rulemaking and will be accessible to the public at http://www.regulations.gov. The transcript of the proceedings from the public 
meeting will become part of the administrative record for the 
rulemaking. Please be advised that as soon as a transcript is 
available, it will be accessible at http://www.regulations.gov under 
the docket number found in brackets in the heading of this document, 
and at FDA's Web site at http://www.fda.gov/AnimalVeterinary/NewsEvents/WorkshopsConferencesMeetings/ucm435459.htm. It may also be 
viewed at the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. A 
transcript will also be available in either hardcopy or on CD-ROM, 
after submission of a Freedom of Information request. Written requests 
are to be sent to the Division of Freedom of Information (ELEM-1029), 
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg., 
Rockville, MD 20857.
    Additionally, the public can access the meeting remotely by using 
the following Adobe Connect link: https://collaboration. fda. gov/
cvm_bioequivalence_meeting/. The link will become active shortly before 
the meeting begins at 9 a.m. on April 16, 2015. Anyone interested in 
viewing the meeting remotely using this link will need to register as a 
guest using the registration information in this document. The Agency 
will be recording the meeting for subsequent viewing by the public. 
Once the recording has been made 508 compliant, it will be accessible 
at FDA's CVM Web site at http://www.fda.gov/AnimalVeterinary/NewsEvents/WorkshopsConferencesMeetings/ucm435459.htm.

    Dated: March 12, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-06119 Filed 3-17-15; 8:45 am]
 BILLING CODE 4164-01-P