[Federal Register Volume 79, Number 141 (Wednesday, July 23, 2014)]
[Notices]
[Pages 42800-42801]
[FR Doc No: 2014-17293]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2007-D-0369]

Draft and Revised Draft Guidances for Industry Describing
Product-Specific Bioequivalence Recommendations; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of additional draft and revised draft product-specific
bioequivalence (BE) recommendations. The recommendations provide
product-specific guidance on the design of BE studies to support
abbreviated new drug applications (ANDAs). In the Federal Register of
June 11, 2010, FDA announced the availability of a guidance for
industry entitled ``Bioequivalence Recommendations for Specific
Products,'' which explained the process that would be used to make
product-specific BE recommendations available to the public on FDA's
Web site. The BE recommendations identified in this notice were
developed using the process described in that guidance.

DATES: Although you can comment on any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the Agency considers your comments on
these draft and revised draft guidances before it begins work on the
final versions of the guidances, submit either electronic or written
comments on the draft and revised draft product-specific BE
recommendations listed in this notice by September 22, 2014.

ADDRESSES: Submit written requests for single copies of the individual
BE guidances to the Division of Drug Information, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002. Send
one self-addressed adhesive label to assist that office in processing
your requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the draft guidance recommendations.
    Submit electronic comments on the draft product-specific BE
recommendations 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.

FOR FURTHER INFORMATION CONTACT: Kris Andr[eacute], Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 75, rm. 1615, Silver Spring, MD 20993-0002, 240-
402-7959.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 11, 2010 (75 FR 33311), FDA
announced the availability of a guidance for industry entitled
``Bioequivalence Recommendations for Specific Products'' which
explained the process that would be used to make product-specific BE
recommendations available to the public on FDA's Web site at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
    As described in that guidance, FDA adopted this process as a means
to develop and disseminate product-specific BE recommendations and
provide a meaningful opportunity for the public to consider and comment
on those recommendations. Under that process, draft recommendations are
posted on FDA's Web site and announced periodically in the Federal
Register. The public is encouraged to submit comments on those
recommendations within 60 days of their announcement in the Federal
Register. FDA considers any comments received, and either publishes
final recommendations or publishes revised draft recommendations for
comment. Recommendations were last announced in the Federal Register on
April 2, 2014 (79 FR 18561). This notice announces draft product-
specific recommendations, either new or revised, that are posted on
FDA's Web site.

II. Drug Products for Which New Draft Product-Specific BE
Recommendations Are Available

    FDA is announcing the availability of a new draft guidance for
industry on product-specific BE recommendations for drug products
containing the following active ingredients:

Table 1--New Draft Product-Specific Be Recommendations for Drug Products
------------------------------------------------------------------------

------------------------------------------------------------------------
A............................  Alogliptin benzoate.
                               Alogliptin benzoate; Metformin
                                hydrochloride (HCl).
                               Alogliptin benzoate; Pioglitazone HCl.
                               Amoxicillin (multiple reference listed
                                drugs).
                               Atenolol; Chlorthalidone.
C............................  Canagliflozin.
                               Carbidopa.
                               Carbinoxamine maleate.

                               Cefixime.
                               Colestipol HCl.
                               Crizotinib.
D............................  Daunorubicin citrate.
                               Diflorasone diacetate.
                               Dimethyl fumarate.
                               Diphenhydramine HCl.
                               Doxycycline (multiple reference listed
                                drugs).
                               Doxylamine succinate; Pyridoxine HCl.
E............................  Esomeprazole strontium.
                               Ethinyl estradiol; Levonorgestrel and
                                Ethinyl estradiol.
                               Ethinyl estradiol; Norethindrone acetate.
F............................  Fosfomycin tromethamine.
G............................  Gentamicin sulfate.
H............................  Hydromorphone HCl.
L............................  Lanreotide acetate.
                               Linagliptin; Metformin HCl.
                               Lomustine.
M............................  Menthol; Methyl salicylate.
                               Metformin HCl; Sitagliptin phosphate.
O............................  Ospemifene.
                               Oxcarbazepine.
P............................  Paroxetine mesylate.
                               Promethazine (multiple reference listed
                                drugs and strengths).
                               Propranolol HCl.
R............................  Ropinirole HCl.
S............................  Sucralfate (multiple reference listed
                                drugs and dosage forms).
T............................  Tacrolimus.
Z............................  Zolmitriptan.
------------------------------------------------------------------------

III. Drug Products for Which Revised Draft Product-Specific BE
Recommendations Are Available

    FDA is announcing the availability of a revised draft guidance for
industry on product-specific BE recommendations for drug products
containing the following active ingredients:

   Table 2--Revised Draft Product-Specific BE Recommendations for Drug
                                Products
------------------------------------------------------------------------

------------------------------------------------------------------------
D............................  Dronedarone HCl.
                               Duloxetine HCl.
E............................  Ergocalciferol
                               Esomeprazole magnesium.
F............................  Fluorouracil.
H............................  Hydrochlorothiazide; Moexipril HCl.
I............................  Imatinib mesylate.
L............................  Lansoprazole.
M............................  Mesalamine (multiple reference listed
                                drugs).
N............................  Nevirapine.
                               Nilotinib HCl monohydrate.
P............................  Pentosan polysulfate sodium.
------------------------------------------------------------------------

    For a complete history of previously published Federal Register
notices related to product-specific BE recommendations, please go to
http://www.regulations.gov and enter Docket No. FDA-2007-D-0369.
    These draft and revised draft guidances are being issued consistent
with FDA's good guidance practices regulation (21 CFR 10.115). These
guidances represent the Agency's current thinking on product-specific
design of BE studies to support ANDAs. They do not create or confer any
rights for or on any person and do not operate to bind FDA or the
public. An alternative approach may be used if such approach satisfies
the requirements of the applicable statutes and regulations.

IV. Comments

    Interested persons may submit either electronic comments on any of
the specific BE recommendations posted on FDA's Web site to http://www.regulations.gov or written comments to the Division of Dockets
Management (see ADDRESSES). 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. The guidances, notices, and 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.

V. Electronic Access

    Persons with access to the Internet may obtain the document at
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: July 17, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-17293 Filed 7-22-14; 8:45 am]
BILLING CODE 4164-01-P


Assessing the Effect of Five Gasoline Properties on Exhaust Emissions from Light-Duty Vehicles certified to Tier-2 Standards

                       Analysis of Data from EPA Phase 3

                                (EPAct/V2/E-89)

                                 Appendix H.4
                              Final Model Fitting
                         Carbon Monoxide (CO) (Bag 2)

No. Observations:			956
No. Vehicles:		  		  15
No. censored measurements:		    0
No. missing measurements:		    0
No. measurements removed:		    0
Model Type:				Mixed model

H.4.1   Model fitting with respect to the 11-term design model.
Design Model (11-terms):  Bayesian Information Criterion (BIC) vs. number of terms in model (p) for all possible models respecting hierarchy.

Design Model (11-terms):  Bayesian Information Criterion (BIC) vs. number of terms in model (p) for all possible models respecting hierarchy (CLOSEUP of previous figure).

CO (Bag 2):  Number of terms (p), Goodness-of-fit (BIC) and terms included in the 35 best-fitting candidate models (out of a total of 294 possible models with hierarchy).  (Terms included in models ranked 1-5 comprise the "superset" for final model-fitting).

      Models fit for CO (Bag 2): (all models include an intercept term).
Model Term
                                   Notation
                                     Model

                                   Superset
                                    SM3[1]
                                      SM4
                                     etOH
Ze
                                      ●
                                      ●
                                      x
                                     Arom
Za
                                      ●
                                      ●
                                      ●
                                      RVP
Zr
                                      ●
                                      ●
                                      ●
                                      T50
Z5
                                      ●
                                      ●
                                      ●
                                      T90
Z9
                                      ●
                                      ●
                                      ●
                                 etOH x etOH
ZZee
                                      ●
                                      x

                                  T50 x T50
ZZ55
                                      ●
                                      x

                                 etOH x Arom
ZZea
                                      ---
                                      ---
                                      ---
                                  etOH x RVP
ZZer
                                      ---
                                      ---
                                      ---
                                  etOH x T50
ZZe5
                                      ---
                                      ---
                                      ---
                                  etOH x T90
ZZe9
                                      ●
                                      x

[1] Represents "Superset minus 3," etc.

  CO (Bag 2): Model fitting history, starting with the 8-term superset model.
                                Fit Parameters

                             Test with respect to
                                Previous Model
Model
                                                                              p
-2lnL
BIC[1]

                                                                           Dev.
                                                                              d
                                                                    Pr>χ[2]
Superset
                                                                              9
828.049
857.838

SM3
                                                                              6
831.913
853.577

                                                                          3.864
                                                                              3
                                                                          0.277
SM4[2]
                                                                              5
832.664
851.620

                                                                          0.751
                                                                              1
                                                                          0.386

[1] A lower value indicates a better fit.
[2] Best fit with respect to the 11-term design model.

CO (Bag 2): Coefficients  and Tests of Effect for the Superset and Reduced Models, with respect to the 11-term design model.

H.4.2	Model Fitting with respect to the 16-term extended Model.
Extended Model (16-terms):  Bayesian Information Criterion (BIC) vs. number of terms in model (p) for all possible models respecting hierarchy.

Extended Model (16-terms):  Bayesian Information Criterion (BIC) vs. number of terms in model (p) for subset of models respecting hierarchy (CLOSEUP of previous figure).

CO (Bag 2):  Number of terms (p), Goodness-of-fit (BIC) and terms included in the 35 best-fitting candidate models (out of a total of 2,964 possible models with hierarchy).  (Terms included in models ranked 1-5 comprise the "superset" for final model-fitting).

      Models fit for CO (Bag 2): (all models include an intercept term).
Model Term
                                   Notation
                                     Model

                                   Superset
                                    SM3[1]
                                      SM4
                                     etOH
Ze
                                      ●
                                      ●
                                      x
                                     Arom
Za
                                      ●
                                      ●
                                      ●
                                      RVP
Zr
                                      ●
                                      ●
                                      ●
                                      T50
Z5
                                      ●
                                      ●
                                      ●
                                      T90
Z9
                                      ●
                                      ●
                                      ●
                                 etOH x etOH
ZZee
                                      ●
                                      x

                                  T50 x T50
ZZ55
                                      ●
                                      x

                                 etOH x Arom
ZZea
                                      ---
                                      ---
                                      ---
                                  etOH x RVP
ZZer
                                      ---
                                      ---
                                      ---
                                  etOH x T50
ZZe5
                                      ---
                                      ---
                                      ---
                                  etOH x T90
ZZe9
                                      ---
                                      ---
                                      ---

                                  Arom x RVP
ZZar
                                      ---
                                      ---
                                      ---
                                  Arom x T50
ZZa5
                                      ---
                                      ---
                                      ---
                                  Arom x T90
ZZa9
                                      ---
                                      ---
                                      ---
                                  T50 x T90
ZZ59
                                      ●
                                      ●
                                      ●
                                  RVP x T90
ZZr9
                                      ●
                                      x

[1] denotes "Superset minus 3, etc."

CO (Bag 2): Model fitting history, starting with the 9-term superset model.
                                Fit Parameters

                             Test with respect to
                                Previous Model
Model
                                                                              p
-2lnL
BIC[1]

                                                                           Dev.
                                                                              d
                                                                    Pr>χ[2]
Superset
                                                                             10
826.828
859.325

SM3
                                                                              7
828.868
853.241

                                                                          2.040
                                                                              3
                                                                          0.564
SM4[2]
                                                                              6
829.667
851.331

                                                                          0.798
                                                                              1
                                                                           0.37

[1] A lower value indicates a better fit.
[2] Best fit with respect to the 16-term extended model.

CO (Bag 2): Coefficients  and Tests of Effect for the Superset and Reduced Models, with respect to the 16-term extended model.