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)
Food and Drug Administration
Federal Register Volume 80, Issue 52 (March 18, 2015)
| Page Range | 14146-14147 | |
| FR Document | 2015-06119 |
[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] ----------------------------------------------------------------------- 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. ----------------------------------------------------------------------- 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: BioequivalencePublicMeetingRegistration@fda.hhs.gov. 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
![14146 Federal Register / Vol. 80, No. 52 / Wednesday, March 18, 2015 / Notices
calculation of AAC adjusted by a multiplier ACTION: Notification of public meeting; those products that are non-systemically
of 1.1 for multiple source drugs and 1.01 for request for comments. absorbed (locally acting).
single source drugs. In addition, this SPA The assessment of in vivo BE of non-
would apply a reimbursement methodology The Food and Drug Administration systemically absorbed drug products has
of wholesale acquisition cost (WAC) adjusted (FDA) is announcing a public meeting been a longstanding challenge facing
by a multiplier of 1.05 for state-defined entitled ‘‘Identification of Alternative In
specialty therapeutic classes of drugs.
drug manufacturers and regulators of
Vitro Bioequivalence Pathways Which human and animal health products.
The issues to be considered at the hearing Can Reliably Ensure In Vivo
are:
Although blood level BE trials remain
Bioequivalence of Product Performance the standard for comparing drug
• Whether the state’s proposed increased and Quality of Non-Systemically
payment methodology under Louisiana products that are systemically absorbed
Medicaid SPA 12–66–B complies with the
Absorbed Drug Products for Animals’’. and that act at a target site reached via
requirements of section 1902(a)(30)(A) of the The purpose of the public meeting is to the blood (systemic circulation), such
Act which requires, in part, that states have discuss the use of in vitro methods as studies cannot confirm product in vivo
methods and procedures to assure that a mechanism for assessing the in vivo BE when a drug is either not
payment rates are consistent with efficiency, product bioequivalence (BE) of non- systemically absorbed or when it is
economy, and quality of care. systemically absorbed drug products associated with therapeutic effects
• Whether the state demonstrated that the intended for use in veterinary species. occurring proximal to the site of
proposed payment increases are consistent FDA is seeking additional public
with the aggregate upper payment limits set
absorption. To date, unless the active
comment to the docket, and is pharmaceutical ingredient met the
in implementing regulations at 42 CFR
447.512 which provide that payments for
requesting that any written comments criteria for highly soluble, as defined in
drugs are to be based on the lower of: 1) the be submitted by May 18, 2015. CVM Guidance #171 entitled ‘‘Waivers
ingredient EAC of the drug and a reasonable Date and Time: The public meeting of In Vivo Demonstration of
dispensing fee; or 2) the provider’s usual and will be held on April 16, 2015, from 9 Bioequivalence of Animal Drugs in
customary charges to the general public. a.m. to 4 p.m. Soluble Powder Oral Dosage Form
• Whether the proposed calculation of Location: The public meeting will be Products and Type A Medicated
EAC used in calculating upper payment held at the Center for Veterinary Articles,’’ clinical endpoint BE trials
limits (based on a multiple of the AAC) is Medicine (CVM), Food and Drug have provided the only option for
consistent with the definition of EAC in 42 Administration, 7519 Standish Pl., 3rd
CFR 447.502, which defines EAC as ‘‘the
generating inter-product comparisons.
Floor, Conference Room A, Rockville, FDA is exploring whether an alternative
agency’s best estimate of the price generally
MD 20855. Parking is free. in vitro BE approach may be considered
and currently paid by providers for a drug
marketed or sold by a particular
Contact Person: Aleta Sindelar, CVM, when blood level BE studies are either
manufacturer or labeler in the package size Food and Drug Administration, 7519 not feasible or not appropriate, and
of drug most frequently purchased by Standish Pl., Rm. 144, Rockville, MD when products do not meet the criteria
providers.’’ 20855, 240–276–9230, FAX: 240–276– for applying a Guidance #171-based
In the event that CMS and the state come 9241, email: BioequivalencePublic biowaiver.
to agreement on resolution of the issues MeetingRegistration@fda.hhs.gov. The assumption underlying the
which formed the basis for disapproval, this Registration: Registration is free and application of the in vitro BE approach
SPA may be moved to approval prior to the available on a first-come, first-served is that equivalence in product
scheduled hearing. basis. Persons interested in requesting physicochemical attributes and in vitro
Sincerely, an opportunity to speak during the open product performance translates to
Andrew M. Slavitt public comment period must register by equivalence in product in vivo behavior.
Section 1116 of the Social Security Act (42 April 8, 2015, and must include a brief For sponsors with a right of reference to
U.S.C. 1316; 42 CFR 430.18) (Catalog of summary of comments with their underlying safety and effectiveness data,
Federal Domestic Assistance program No. registration. Those individuals will be the criteria for similarity of
13.714. Medicaid Assistance Program.) contacted prior to the meeting regarding physicochemical attributes would be
Dated: March 13, 2015. their participation. Persons interested in defined on the basis of the underlying
Andrew M. Slavitt, attending this meeting who are not dataset to confirm the comparability of
Acting Administrator, Centers for Medicare
requesting an opportunity to speak at the original formulation and pre- and
& Medicaid Services. the meeting must register by April 14, post-approval changes in formulation or
[FR Doc. 2015–06226 Filed 3–17–15; 8:45 am]
2015. For general questions about the method of product manufacture. In the
meeting, for assistance registering for case of generic products, a more rigid
BILLING CODE 4120–01–P
the meeting, to request an opportunity approach to sameness would be used in
to make an oral presentation, or to terms of product composition and
DEPARTMENT OF HEALTH AND request special accommodations due to physicochemical characteristics. In both
HUMAN SERVICES a disability, contact Aleta Sindelar (see situations, physicochemical
Contact Person). Please include your comparisons would be based upon a
Food and Drug Administration name, organization, and contact battery of in vitro test procedures,
information. Early registration for the including a comparison of in vitro
[Docket No. FDA–2015–N–0684] meeting is encouraged due to limited dissolution behavior under a range of
time and space. physiologically-relevant conditions.
Identification of Alternative In Vitro SUPPLEMENTARY INFORMATION: Examples of the kinds of products
mstockstill on DSK4VPTVN1PROD with NOTICES
Bioequivalence Pathways Which Can where in vitro bioequivalence concepts
I. Background can potentially be applied include some
Reliably Ensure In Vivo Bioequivalence
of Product Performance and Quality of Given the imprecision and logistic orally administered products (e.g., Type
Non-Systemically Absorbed Drug challenges associated with clinical A medicated articles), solutions,
Products for Animals; Public Meeting endpoint BE studies, FDA is exploring emulsions, ointments, creams,
alternative pathways that can be applied suspensions, transdermal products, and
AGENCY: Food and Drug Administration, to help ensure the equivalence of intra-mammary formulations. Due to
HHS. product performance and quality for unique issues raised by products
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![Federal Register / Vol. 80, No. 52 / Wednesday, March 18, 2015 / Notices 14147
employing modified release Administration, 5630 Fishers Lane, Rm. Dated: March 12, 2015.
technologies, only immediate release 1061, Rockville, MD 20852. It is only Leslie Kux,
formulations would be candidates for necessary to send one set of comments. Associate Commissioner for Policy.
the in vitro BE assessment. For orally Identify comments with the docket [FR Doc. 2015–06119 Filed 3–17–15; 8:45 am]
administered products, in vitro BE number found in brackets in the BILLING CODE 4164–01–P
would be limited to disintegrated heading of this document. Received
dosage forms. In cases when the comments may be seen in the Division
administered drug acts both locally and of Dockets Management between 9 a.m.
systemically, blood level data may be and 4 p.m., Monday through Friday, and
used to confirm drug product BE of the DEPARTMENT OF HOMELAND
will be posted to the docket at http:// SECURITY
systemic effects (and to confirm
www.regulations.gov.
comparability of in vivo product
disintegration in cases where multiple Coast Guard
III. Comments, Transcripts, and
drugs are combined in a single solid oral Recorded Video
dosage forms), while the additional in [USCG–2014–0941]
vitro dissolution data could be used to Information and data submitted
support the comparability of the local voluntarily to FDA during the public Port Access Route Study: In the
actions. meeting will become part of the Chukchi Sea, Bering Strait and Bering
The in vitro BE approach should not administrative record for the rulemaking Sea
be construed as a biowaiver, but rather and will be accessible to the public at
as an alternative set of tests that would http://www.regulations.gov. The AGENCY: Coast Guard, DHS.
be handled in a manner consistent with transcript of the proceedings from the ACTION: Notice; withdrawal.
that of an in vivo BE study. Specifically, public meeting will become part of the
(1) because an in vitro BE approach is administrative record for the SUMMARY: The Coast Guard published a
not a biowaiver, sponsors would still rulemaking. Please be advised that as
need to meet the same environmental document in the Federal Register of
soon as a transcript is available, it will February 19, 2015, (80 FR 8892)
safety and human food safety
be accessible at http:// concerning the Port Access Route Study
requirements associated with products
undergoing in vivo BE studies; (2) one www.regulations.gov under the docket (PARS) in the Chukchi Sea, Bering Strait
in vitro study may not suffice when number found in brackets in the and Bering Sea. The February 19, 2015,
there are multiple product strengths heading of this document, and at FDA’s PARS document was erroneously
(e.g., varying concentrations of an intra- Web site at http://www. fda. gov/ published and should be disregarded in
mammary infusion); and (3) the in vitro AnimalVeterinary/NewsEvents/ its entirety.
method could be applied both to fully WorkshopsConferencesMeetings/
ucm435459.htm. It may also be viewed FOR FURTHER INFORMATION CONTACT: If
soluble and poorly soluble compounds.
at the Division of Dockets Management you have questions on this notice of
In vitro BE determinations would be
based upon a battery of in vitro (HFA–305), Food and Drug study or any of the meetings, call or
dissolution studies and Administration, 5630 Fishers Lane, Rm. email LT Kody Stitz, Seventeenth Coast
physicochemical tests. Links to 1061, Rockville, MD 20852. A transcript Guard District (dpw); telephone (907)
additional background material are will also be available in either hardcopy 463–2270; email Kody.J.Stitz@uscg.mil
provided on the Agency’s Web site at: or on CD–ROM, after submission of a or Mr. David Seris, Seventeenth Coast
http://www.fda.gov/AnimalVeterinary/ Freedom of Information request. Written Guard District (dpw); telephone (907)
NewsEvents/WorkshopsConferences requests are to be sent to the Division 463–2267; email David.M.Seris@
Meetings/ucm435459.htm. of Freedom of Information (ELEM– uscg.mil.
To assist FDA in developing guidance
1029), Food and Drug Administration, SUPPLEMENTARY INFORMATION: For
for demonstrating in vitro BE, with this
12420 Parklawn Dr., Element Bldg., correct information on the Port Access
notice the Agency is convening an open
forum, providing a summary of what the Rockville, MD 20857. Route Study please see the Notice of
Agency envisions as considerations Additionally, the public can access Study published in the Federal Register
pivotal to the BE assessment and the meeting remotely by using the on December 5, 2014 (79 FR 72157); and
inviting public comment on the various following Adobe Connect link: https:// the Notice of Public Meetings published
components of an in vitro BE collaboration. fda. gov/cvm_ in the Federal Register on February 25,
determination. bioequivalence_meeting/. The link will 2015 (80 FR 10137).
II. Participation in a Public Meeting become active shortly before the To electronically access all
meeting begins at 9 a.m. on April 16, information referenced in this notice of
While oral presentations from specific 2015. Anyone interested in viewing the
individuals and organizations may be correction visit http://
meeting remotely using this link will www.regulations.gov and search for
limited due to time constraints during need to register as a guest using the
the public meeting, stakeholders may ‘‘USCG–2014–0941’’.
registration information in this
submit electronic or written comments Dated: March 3, 2015.
document. The Agency will be
discussing any issues of concern to the D.B. Abel,
recording the meeting for subsequent
mstockstill on DSK4VPTVN1PROD with NOTICES
administrative record (the docket) for Rear Admiral, U.S. Coast Guard, Commander,
the rulemaking. All relevant data and viewing by the public. Once the
recording has been made 508 compliant, Seventeenth Coast Guard District.
documentation should be submitted
it will be accessible at FDA’s CVM Web [FR Doc. 2015–05372 Filed 3–17–15; 8:45 am]
with the comments. Submit electronic
comments to http:// site at http://www. fda. gov/ BILLING CODE 9110–04–P
www.regulations.gov. Submit written Animal Veterinary/News Events/
comments to the Division of Dockets WorkshopsConferences Meetings/
Management (HFA–305), Food and Drug ucm435459.htm.
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Document Created: 2018-02-21 09:39:38
Document Modified: 2018-02-21 09:39:38
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notification of public meeting; request for comments. | |
| FR Citation | 80 FR 14146 |
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