[Federal Register Volume 61, Number 102 (Friday, May 24, 1996)]
[Notices]
[Pages 26182-26186]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-13106]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94D-0401]
Bioequivalence Guidance, 1996; 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 the revised guidance document entitled ``Bioequivalence
Guidance, 1996'' prepared by the Center for Veterinary Medicine (CVM).
The availability of a draft guideline entitled ``Bioequivalence
Guideline (Draft) 1994'' was announced in the Federal Register of March
1, 1995 (60 FR 11097) (hereinafter referred to as the 1994 draft
guideline). The 1994 draft guideline was a revision of the 1990 version
and covered the following areas: General considerations, blood level
studies, pharmacologic endpoints, clinical endpoints, and human food
safety. The guidance is intended to assist sponsors of new animal drug
applications (NADA's) in the design and analysis of in vivo
bioequivalence studies. This notice addresses comments submitted on the
1994 draft guideline.
DATES: Written comments on the guidance document may be submitted at
any time.
ADDRESSES: Submit written requests for single copies of the guidance
document entitled ``Bioequivalence Guidance, 1996'' to the
Communications and Education Branch (HFV-12), Center for Veterinary
Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville,
MD 20855, 301-594-1755. Send two self-addressed adhesive labels to
assist that office in processing your requests. Submit written comments
on the guidance document to the Dockets Management Branch (HFA-305),
Food
[[Page 26183]]
and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD
20857. Requests and comments should be identified with the docket
number found in brackets in the heading of this document. A copy of the
guidance document and received comments may be seen at the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
FOR FURTHER INFORMATION CONTACT: Melanie R. Berson, Center for
Veterinary Medicine (HFV-135), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1643.
SUPPLEMENTARY INFORMATION: FDA is announcing the availability of the
revised guidance entitled ``Bioequivalence Guidance, 1996''. The
guidance may be used by sponsors of NADA's for the design and analysis
of in vivo bioequivalence studies.
In a notice published in the Federal Register of March 1, 1995 (60
FR 11097), FDA announced the availability of the 1994 draft guideline
entitled ``Bioequivalence Guideline (Draft) 1994''. The 1994 draft
guideline was based on an April 1990 bioequivalence guidance and
reports from panel presentations at the 1993 Veterinary Drug
Bioequivalence Workshop held in Rockville, MD. New topics addressed in
the 1994 draft guideline included: Bioequivalence overdose studies,
testing for multiple strength solid oral dosage forms, assay
considerations, area under the curve and maximum blood concentration as
pivotal parameters, and blood level studies with good laboratory
practice tissue residue depletion studies for generic products for food
animals. Interested persons were given until May 30, 1995, to comment
on the 1994 draft guideline.
Comments on the 1994 draft guideline were received from a
pharmaceutical company and an industry group. The 1994 draft guideline
has been revised as a result of these comments and from internal
discussions within CVM. In the following section on received comments
and CVM responses, the page numbers and sections refer to those found
in the 1994 draft guideline.
1. Section II.E. Dose Selection. The comment objected to the use of
the term ``overdose bioequivalence study'' since ``overdose'' has
toxicological connotations.
CVM accepts the comments and will change the wording from
``overdose'' to ``higher than approved dose.''
2. Section II.F. Multiple Strengths of Solid Oral Dosage Forms. One
comment asked for the rationale for requiring two bioequivalence
studies in order to obtain approval when there are more than three
strengths of exactly proportional formulations.
CVM accepts the comment and has modified the guidance to allow more
flexibility in the determination of the need for more than one
bioequivalence study for multiple strengths of solid oral dosage forms.
The guidance has been modified to read as follows:
The generic sponsor should discuss with CVM the appropriate in
vivo bioequivalence testing and in vitro dissolution testing to
obtain approval for multiple strengths (or concentrations) of solid
oral dosage forms.
CVM will consider the ratio of active to inactive ingredients
and the in vitro dissolution profiles of the different strengths,
the water solubility of the drug, and the range of strengths for
which approval is sought.
One in vivo bioequivalence study with the highest strength
product may suffice, if the multiple strength products have the same
ratio of active to inactive ingredients and are otherwise identical
in formulation.
In vitro dissolution testing should be conducted, using an FDA
approved method, to compare each strength of the generic product to
the corresponding strength of the reference product.
3. Section II.G. Manufacturing of Pilot Batch (``Biobatch''). One
comment requested that terms such as `pilot' and `biobatch' need to be
precisely defined in this document or reference made to the
manufacturing guidelines.
CVM refers the reader to CVM's ``Animal Drug Manufacturing
Guidelines, 1994'' for definition of terms.
4. Section III.A. Assay Considerations. One comment requests that
CVM should adopt the same guidance as established in the joint
industry/academia conference on ``Analytical Methods Validation:
Bioavailability, Bioequivalence, and Pharmacokinetics Studies''
published in several journals including the Journal of Pharmaceutical
Sciences, 81(3), 309-312, 1992.
CVM does not agree with this comment. The substance of CVM's
guidance does not differ substantially from those used by CDER. Any
difference is the result of CVM's interest in maintaining consistency
among its analytical criteria for drug residues in the edible tissues.
Drug residue measurement in edible tissues is specific to animal drugs
and is not applicable to CDER (human drugs).
5. Section III.C.6.a. Area Under the Curve (AUC) Estimates. One
comment questioned whether AUC by the linear trapezoidal rule is the
preferred method to estimate AUC, and noted that the method is subject
to substantial error when data points are widely spaced (e.g., during
the terminal exponential disposition phase).
CVM accepts the comment and will modify the wording in the guidance
to acknowledge that methods other than the linear trapezoidal rule may
be used for estimating AUC, but the alternative method should be
accompanied by appropriate references.
6. Section III.C.6.a. One comment questioned the reason to equate
AUC over a dosing interval at steady-state to single-dose AUC zero to
infinity. The comment stated that this relationship only holds if
pharmacokinetics are linear over the relevant dose range and one of the
prime reasons for doing a multiple-dose bioequivalence study is when
kinetics are nonlinear.
CVM has modified the guidance to read as follows:
Under steady state conditions, AUC0-t equals the full
extent of bioavailability of the individual dose (AUC0-INF),
assuming linear kinetics. For drugs which are known to follow
nonlinear kinetics, the sponsor should consult with CVM to determine
the appropriate parameters for the bioequivalence determination.
7. Section III.C.6.c. Determination of Product Bioequivalence. One
comment requested that the sponsor should be allowed to extend the
range of acceptable bioequivalence limits for drugs exhibiting highly
variable pharmacokinetics, if adequate justification is provided.
CVM accepts the comment and has modified the guidance to include
the following statement:
The sponsor and CVM should agree to the acceptable bounds for
the confidence limits for the particular drug and formulation during
protocol development. If studies or literature demonstrate that the
pioneer drug product exhibits highly variable kinetics, then the
generic drug sponsor may propose alternatives to the generally
acceptable bounds for the confidence limits.
8. One comment requested that the repeated references to flip-flop
kinetics should be replaced by the more general term ``prolonged
absorption.''
CVM accepts the comment and has replaced the term ``flip-flop
kinetics'' with ``sustained or prolonged absorption.''
9. One comment requested that the Bioequivalence Guidance provide
more detail on evaluation of Production Drugs and Short Term
Therapeutic Treatments in Feed (Staff Manual Guide 1240.4145).
CVM does not agree with the request to elaborate on combination
drugs for use in feed. The focus of the Bioequivalence Guidance is the
approval of generic animal drugs, although many of the principles may
be applied to blood level studies conducted for other purposes. CVM
considers it beyond the scope and intent of this guidance to discuss
combination approvals for feeds.
10. Page 1, section I. INTRODUCTION, fifth paragraph. One
[[Page 26184]]
comment requested insertion of the following paragraph:
Tissue residue studies will not normally be required if blood
concentration curve shape and depletion time through the reference
product's withdrawal time are the same for generic and reference
products. Tissue residue studies will normally be required where the
blood levels cannot be measured prior to the elapse of the reference
product's withdrawal period.
CVM does not agree with the change proposed by this comment. The
pivotal parameters for the drug concentration versus time curve are AUC
and CMAX. CVM does not intend to evaluate curve shape and
depletion time as pivotal parameters. For clarity, however, the
guidance has been modified to read as follows:
The Center has concluded that the tissue residue depletion of
the generic product is not adequately addressed through
bioequivalence studies. Therefore, ANADA's for drug products for
food-producing animals will generally be required to include
bioequivalence and tissue residue studies. A tissue residue study
will generally be required to accompany clinical end-point and
pharmacologic end-point bioequivalence studies, and blood level
bioequivalence studies that can not quantify the concentration of
the drug in blood throughout the established withdrawal period.
11. Page 2, section II.A. Selection of Reference Product for
Bioequivalence Testing, second paragraph. One comment suggested that
the paragraph should read ``but remains eligible to be copied, then the
first approved and available generic copy of the pioneer should be used
* * *.''
CVM accepts the comment and has reworded the paragraph.
12. Page 5, first full paragraph. One comment suggests that
multiple bioequivalence studies at different doses should only be
required if the pharmacokinetics are not linear.
CVM accepts the recommendation and has modified the guidance to
read as follows:
For products labeled for multiple claims involving different
pharmacologic actions at a broad dose range (e.g., therapeutic and
production claims), a single bioequivalence study at the highest
approved dose will usually be adequate. However, multiple
bioequivalence studies at different doses may be needed if the drug
is known to follow nonlinear kinetics. The sponsor should consult
with CVM to discuss the bioequivalence study or studies appropriate
to a particular drug.
13. Page 6, section III.A.1. Concentration Range and Linearity. One
comment proposed that ``at least 5-8 concentrations'' is vague and
suggested ``at least 5 concentrations.''
CVM accepts the comment and has changed the wording to ``at least 5
concentrations.''
14. Page 7, section III.A.4. Specificity. One comment requested
that CVM provide further detail on statistical methods for
demonstrating ``parallelism and superimposability.'' Analysis of
variance is used to compare means but could be used to compare slopes
in this case. This is computationally straightforward for linear curves
but nonlinear curves (e.g., microbiological assays) pose unique
problems.
CVM's response is that the type of statistical procedure used to
process data demonstrating parallelism and superimposability of curves
depends on the nature of the experimental data. CVM is allowing the
sponsor the flexibility to determine the algorithm used to evaluate
data. Whatever statistical procedure is used should be justified by the
sponsor.
The use of microbiological assays for drug analysis will be
addressed in a future CVM guidance.
15. Page 8, sections III.A.5. Accuracy (Recovery) and III.A.6.
Precision. One comment requested that ``replicate injections'' be
changed to ``replicates.''
CVM accepts the comment.
16. Page 8, section III.A.6. Precision. One comment stated that the
suggested coefficient of variation of 10 percent for
concentrations at or above 0.1 micrograms per milliliter (mL) is too
stringent. The comment suggested 15 percent as an
alternative coefficient of variation to target.
CVM does not agree with this comment. In light of today's
analytical technology, 10 percent coefficient of variation
is not unreasonable and is consistent with CVM policy in other
analytical areas. In addition, CVM does not believe anything is gained
by a detailed analysis of the sources of variation in analytical
results.
17. Page 8, section III.A.7. Analyte Stability, second paragraph.
One comment recommended that stability samples at only two
concentrations are necessary, rather than three as suggested in the
1994 draft guideline. It is critically important to validate the assay
before conduct of the bioequivalence study. However, analyte stability
cannot be done without the use of more animals than required by the
bioequivalence study so as to have a valid method in place prior to
study initiation. It is impossible to store and begin analyzing
stability samples throughout the duration of the bioequivalence study
analysis phase unless the method has been validated prior to that
study's initiation.
CVM does not agree with this comment. No study should be undertaken
until the analytical methods that will be used to develop the data are
properly validated and shown to be operating in a state of control in
the laboratory. This means that after the method is validated, the
laboratory intending to use the method for a study, must practice with
the method to assure full familiarization with technical details. CVM
does not make any recommendation on how much practice is required. This
depends on the complexity of the method and on the experience of the
laboratory.
18. Page 8, section III.A.8. Analytical System Stability. One
comment stated that it was unclear how the use of standards (of
multiple concentrations) repetitively run to assure analytical system
stability differs from quality control methods of assuring the same
thing.
CVM accepts the comment that the wording on the use of standards
may be unclear. The guidance section on ``Assay Considerations'' has
been extensively reworded for clarity.
19. Page 9, section III.B.1. Dosing by Labeled Concentration. One
comment asked how the assay prior to study will be used to ensure
specifications. What actions can the sponsor take if the pioneer assays
at -5 percent while the generic assays at +5 percent.
CVM's response is that the pioneer and generic products should be
assayed to determine that the particular lots are within
specifications. No action can be taken if the pioneer assays at -5
percent while the generic assays at +5 percent.
For clarity, the guidance has been reworded to read as follows:
``To maximize the ability to demonstrate bioequivalence, the Center
recommends that the potency of the pioneer and generic lots should
differ by no more than 5% for dosage form products.''
20. Page 10, section III.B.2. Single Dose vs Multiple Dose Studies.
One comment questioned whether documentation of flip-flop kinetics is
necessary.
CVM agrees with this comment and has modified the guidance to read
as follows:
A multiple dose study may also be needed when assay sensitivity
is inadequate to permit drug quantitation out to 3 terminal
elimination half-lives beyond the time when maximum blood
concentrations (Cmax) are achieved, or in cases where prolonged
or delayed absorption2 exist. The determination of prolonged or
delayed absorption (i.e., flip-flop kinetics) may be made from pilot
data, from the literature, or from the CVM database on the
particular drug or family of drugs.
21. Page 11, section III.B.4. Fed vs Fasted State, last paragraph.
One comment stated that it was unclear whether studies in both the fed
and fasted states should be required for enteric-coated or sustained
release oral
[[Page 26185]]
products. If the referenced product is limited to administration either
in the fed or the fasted state, then the test formulation should also
be administered in the same situation conforming to the reference
product's label.
CVM agrees with this comment and has modified the guidance as
follows:
If a pioneer product label indicates that the product is limited
to administration either in the fed or fasted state, then the
bioequivalence study should be conducted accordingly. If the
bioequivalence study parameters pass the agreed upon confidence
intervals, then the single study is acceptable as the basis for
approval of the generic product.
However, for certain product classifications or drug entities,
such as enteric coated and oral sustained release products,
demonstration of bioequivalence in both the fasted and fed states
may be necessary, if the drug is highly variable under feeding
conditions, as determined from the literature or from pilot data. A
bioequivalence study conducted under fasted conditions may be
necessary to pass the confidence intervals. A second smaller study
may be necessary to examine meal effects. CVM will evaluate the
smaller study with respect to the means of the pivotal parameters
(AUC, CMAX). The sponsor should consult with CVM prior to
conducting the studies.
22. Page 12, section III.C.2. Protein Binding. One comment stated
that it is not clear from the 1994 draft guideline to what extent the
protein binding must be nonlinear within the therapeutic dosing range,
nor how determination of linearity is to be conducted. If it is a
judgment and not a statistical criterion, then the parameters within
which that judgment is made need to be determined prior to embarking
upon the abbreviated NADA. In addition, the type of blood protein to
which the drug binds is only pertinent in very unique situations (i.e.,
low capacity protein binding situations). These determinations of the
type of blood protein to which the drug binds are very tedious, time-
consuming and expensive technical studies that may only rarely be
relevant, whereas the magnitude of protein binding is critical. The
type of blood protein to which the drug binds is only a consideration
if prior data indicate it is a concern. There are numerous instances
where CVM requires additional studies ``if ------------------ is known
to occur.'' What are the criteria for knowing? This general statement
could lead to intractable situations. Specifically for this section,
the wording allows CVM to require protein binding studies for all
approvals. A proposal would be to first evaluate the blood profiles
observed in the pilot studies to see if there is evidence of such
binding (multicompartment phenomena). If not, then eliminate the need
for further studies. For combination approvals, the necessary
fractionation and assessment of matrix effects using micro methods
would be a formidable task.
CVM notes that the Bioequivalence Guidance is not intended to
address combination drug approvals. The issue of protein binding for
generic approvals would be addressed only if literature or pilot data
indicate that protein binding is significant to the drug in question.
For clarity, however, the guidance has been modified to read as
follows:
However, if nonlinear protein binding is known to occur within
the therapeutic dosing range (as determined from literature or pilot
data), then sponsors may need to submit data on both the free and
total drug concentrations for the generic and pioneer products.
23. Page 14, section III.C.4. Cross-over and Parallel Design
Considerations, last sentence. One comment proposed that the pilot data
be used in support of alternative study designs during discussions with
CVM.
CVM agrees with the comment. The guidance statement has been
modified to read as follows: ``The use of alternative study designs
should be discussed with CVM prior to conducting the bioequivalence
study. Pilot data or literature may be used in support of alternative
study designs.''
24. Page 15, top paragraph. One comment regarding the duration of
washout time was that prolonged tissue binding may not be a consequence
if drug concentrations in plasma are less than the limit of detection.
The onus is on the sponsor for having a sufficiently long washout
period to allow the second period of the cross-over study to be
applicable in the statistical analysis. If sequence effects are noted,
it must be emphasized that at the very minimum the same data from the
first period alone can be evaluated as a parallel design study.
CVM agrees with the comments and has modified the paragraph in the
guidance to read as follows:
The washout period should be sufficiently long to allow the
second period of the cross-over study to be applicable in the
statistical analysis. However, if sequence effects are noted, the
data from the first period may be evaluated as a parallel design
study.
25. Page 15, section III.C.6.a., AUC Estimate. One comment stated
that it is implied from the discussions regarding AUC and CMAX
that ratio testing (the ratio of the test versus the reference product)
is considered to be the more appropriate comparison rather than the
difference between the test and the reference product. This is not
universally accepted as the case. The responsibility for whether the
difference between the two is used or the ratio of the two is used
should be placed upon the sponsor and should be concurred with by CVM
prior to conduct of the study.
CVM does not agree with nor completely understand the comment's
interpretation of the guidance. CVM has, however, changed the word
``ratio'' to ``comparison'' in the following sentence:
The comparison of the test and reference product value for this
noninfinity estimate provides the closest approximation of the
measure of uncertainty (variance) and the relative bioavailability
estimate associated with AUC0-INF' the full extent of product
bioavailability.
26. Page 15, section III.C.6.a. One comment stated that AUC0-
INF is an estimated value and questioned how CVM intends this to be
derived using ``model independent methods?''
CVM has added the following statement to the guidance: ``The method
for estimating the terminal elimination phase should be described in
the protocol and the final study report.''
27. Page 16, section III.C.6.b. Rate of Absorption. One comment
requested that the revised guidance define CMIN. The 1994 draft
guideline stated that three successive CMIN values should be
provided. The comment proposes that to determine a steady state
concentration, the values should be regressed over time and the
resultant slope should be tested as being different from zero.
CVM agrees with the comment and has modified the guidance to read
as follows:
When conducting a steady-state investigation, data on the
minimum drug concentrations (trough values) observed during a single
dosing interval (CMIN) should also be collected. Generally,
three successive CMIN values should be provided to verify that
steady-state conditions have been achieved. Although CMIN most
frequently occurs immediately prior to the next successive dose,
situations do occur with CMIN observed subsequent to dosing. To
determine a steady state concentration, the CMIN values should
be regressed over time and the resultant slope should be tested for
its difference from zero.
28. Page 16, section III.C.6.c. Determination of Product
Bioequivalence. One comment states that for multiple dose studies,
CMAX and AUCO-t are applicable only if done at steady state.
It is not clear from the current description that these must be steady
state values to have the appropriate interpretation for bioequivalence
testing.
CVM does not agree with the comment because a multiple dose
bioequivalence study could be conducted with a drug that never achieves
steady-state. However, the pioneer and generic products CMAX and
[[Page 26186]]
AUCO-t should be equivalent at any dosing interval whether or not
steady-state is achieved.
29. Page 17, section III.D. Statistical Analysis, second paragraph.
The choice of whether to use untransformed data should be made by the
sponsor based on whether transformation is necessary to allow for
homogeneity of variance. It should not be determined prior to the study
because the data should dictate which transformation, if any, is
required.
CVM does not agree with this recommendation. The sponsor has the
option to use untransformed or log transformed data, but the decision
should be made prior to conducting the study.
30. Page 19, section III.D., second from the last paragraph
relating to selection of confidence interval. One comment noted that
CVM states that in general the confidence interval for untransformed
data should be 80 to 120. Firstly, percent should be specified.
Secondly, emphasis should be added that these are general rather than
the adamant and steadfast specifications of CVM. The opinion of many
statisticians with considerable experience in this field is that the
20 percent interval is entirely too restrictive. In the
animal health market, the potential cost to evaluate generics or
combinations may be so great as to preclude bringing a useful drug/
combination to the market.
CVM has made the requested editorial changes. However, CVM will
continue to accept 20 percent as the acceptable confidence
interval for the pivotal parameters. CVM invites sponsors to submit
data to justify broadening the confidence interval for a particular
drug.
31. Page 20, section IV.B. Statistical Analysis. One comment noted
that for pharmacologic endpoint studies as described, it appears that
these studies described are evaluating significant differences rather
than statistical equivalence. As such, these pharmacological endpoint
studies are not as rigorously designed from a statistical standpoint as
classic bioequivalence plasma level studies, inasmuch as differences
are being evaluated rather than equivalence. The comment suggested that
pharmacological endpoint studies should also be evaluating statistical
equivalence, rather than significant differences. In fact, a comparable
equivalence testing is alluded to on page 22 regarding clinical
endpoint studies, studies which would be expected to be less able to
prove equivalence than pharmacologic endpoint studies.
CVM agrees with the comment and has modified the guidance to read
as follows:
For parameters which can be measured over time, a time vs effect
profile is generated, and equivalence is determined with the method
of statistical analysis essentially the same as for the blood level
bioequivalence study.
For pharmacologic effects for which effect vs time curves can
not be generated, then alternative procedures for statistical
analysis should be discussed with CVM prior to conducting the study.
32. Page 23, section VI. Human Food Safety Considerations. One
comment asked if there is a need for determining a full depletion
profile for the generic? The sponsor proposed that a single point
tissue residue study completed out to the withdrawal time of the
pioneer would be sufficient.
The Center does not agree with the use of a single point tissue
residue study at the withdrawal time of the pioneer as a general
practice.
A traditional tissue residue depletion study has always been
required for generic products where bioequivalence is determined with a
pharmacological or clinical endpoint study. The need for a traditional
tissue residue depletion profile is expanded in the revised guidance to
include blood level bioequivalence studies, because the Center has
concluded that, with the exception of those examples listed in section
VI. of the guidance, the tissue residue depletion of the generic
product is not adequately addressed through bioequivalence studies.
The use of the traditional tissue residue depletion study provides
the Center with the data needed to compute a withdrawal period for the
drug product in question, using our statistical tolerance limit model,
whereby the 99th percentile is calculated with 95 percent confidence.
Use of a single point tissue residue study ordinarily would not provide
the data needed to use our current model, since the single-point study
would not contain sufficient information regarding the variability of
the residue depletion profile. Additionally, since the analytical
methods approved for regulatory purposes can rarely measure the marker
residue at the withdrawal time, a single point residue study at the
pioneer withdrawal time would be limited by the efficiency of the
regulatory analytical method at the drug concentrations typically seen
at the pioneer withdrawal time. When the tissue residue values include
negative or zero values (i.e., values below the limit of quantitation
for the assay), the number of animals needed in the study will depend
on the method variance and the number of zero values, and will vary
from drug to drug. It is not possible to predict, a priori, the number
of animals that will be needed to provide data of sufficient confidence
for a single point tissue residue depletion study to obtain the
confidence similar to that seen for the pioneer drug using our
traditional residue depletion study design.
The Center will consider the use of a single point tissue residue
depletion study in those cases where the regulatory analytical method
can be validated and demonstrated to measure reliably residues in the
treated animals at the pioneer withdrawal time so that a 99th
percentile statistical tolerance limit with 95 percent confidence can
be calculated.
A person may follow the guidance or may choose to follow alternate
procedures or practices. If a person chooses to use alternate
procedures or practices, that person may wish to discuss the matter
further with the agency to prevent an expenditure of money and effort
on activities that may later be determined to be unacceptable to FDA.
Although this guidance document does not bind the agency or the public,
and it does not create or confer any rights, privileges, or benefits
for or on any person, it represents FDA's current thinking on
bioequivalence testing for animal drugs. When a guidance document
states a requirement imposed by statute or regulation, the requirement
is law and its force and effect are not changed in any way by virtue of
its inclusion in the guidance.
Interested persons may, at any time, submit to the Dockets
Management Branch (address above) written comments on the document. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. The documents and
received comments are available for public examination in the Dockets
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.
Dated: May 17, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-13106 Filed 5-23-96; 8:45 am]
BILLING CODE 4160-01-F
