Guidance for Industry
Bioavailability and Bioequivalence Studies for Orally Administered
Drug Products — General Considerations
(PDF version of this document)
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
March 2003
BP
Revision 1
Guidance for Industry
Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products — General Considerations
Additional copies are available from:
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
March 2003
BP
Revision 1
Guidance for IndustryBA and BE Studies for Orally Administered Drug Products —
General Considerations
This guidance represents the Food
and Drug Administration's (FDA's) current thinking on this topic.
It does not create or confer any rights for or on any person and
does 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.
This guidance is intended to provide
recommendations to sponsors and/or applicants planning to include
bioavailability (BA) and bioequivalence (BE) information for orally
administered drug products in investigational new drug applications
(INDs), new drug applications (NDAs), abbreviated new drug
applications (ANDAs), and their supplements. This guidance contains
advice on how to meet the BA and BE requirements set forth in part
320 (21 CFR part 320) as they apply to dosage forms intended for
oral administration.
The guidance is also generally applicable to nonorally administered
drug products where reliance on systemic exposure measures is
suitable to document BA and BE (e.g., transdermal delivery systems
and certain rectal and nasal drug products). We believe that the
guidance will be useful for applicants planning to conduct BA and BE
studies during the IND period for an NDA, BE studies intended for
submission in an ANDA, and BE studies conducted in the postapproval
period for certain changes in both NDAs and ANDAs.
This guidance revises the October 2000
guidance. We have revised our recommendations regarding (1) study
design and dissolution methods development, (2) comparisons of BA
measures, (3) the definition of proportionality, and (4) waivers for
bioequivalence studies. The guidance also makes other revisions for
clarification. We believe that these revisions provide clear
guidance to sponsors conducting BA and BE studies for orally
administered drug products.
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
Studies to measure BA and/or establish BE of a
product are important elements in support of INDs, NDAs, ANDAs, and
their supplements. As part of INDs and NDAs for orally administered
drug products, BA studies focus on determining the process by which
a drug is released from the oral dosage form and moves to the site
of action. BA data provide an estimate of the fraction of the drug
absorbed, as well as its subsequent distribution and elimination.
BA can be generally documented by a systemic exposure profile
obtained by measuring drug and/or metabolite concentration in the
systemic circulation over time. The systemic exposure profile
determined during clinical trials in the IND period can serve as a
benchmark for subsequent BE studies.
Studies to establish BE between two products
are important for certain changes before approval for a pioneer
product in NDA and ANDA submissions and in the presence of certain
postapproval changes in NDAs and ANDAs. In BE studies, an applicant
compares the systemic exposure profile of a test drug product to
that of a reference drug product (RLD). For two orally administered
drug products to be bioequivalent, the active drug ingredient or
active moiety in the test product must exhibit the same rate and
extent of absorption as the reference drug product (see 21 CFR
320.1(e) and 320.23(b)).
Both BA and BE studies are required by
regulations, depending on the type of application being submitted.
Under § 314.94, BE information is required to ensure therapeutic
equivalence between a pharmaceutically equivalent test drug product
and a reference listed drug. Regulatory requirements for
documentation of BA and BE are provided in part 320, which contains
two subparts. Subpart A covers general provisions, while subpart B
contains 18 sections delineating the following general BA/BE
requirements:
·
Requirements for submission of BA and BE data (§
320.21)
·
Criteria for waiver of an in vivo BA or BE study (§
320.22)
·
Basis for demonstrating in vivo BA or BE (§ 320.23)
·
Types of evidence to establish BA or BE (§ 320.24)
·
Guidelines for conduct of in vivo BA studies (§
320.25)
·
Guidelines on design of single-dose BA studies (§
320.26)
·
Guidelines on design of multiple-dose in vivo BA
studies (§ 320.27)
·
Correlations of BA with an acute pharmacological
effect or clinical evidence
(§ 320.28)
·
Analytical methods for an in vivo BA study (§ 320.29)
·
Inquiries regarding BA and BE requirements and review
of protocols by FDA
(§ 320.30)
·
Applicability of requirements regarding an IND
application (§ 320.31)
·
Procedures for establishing and amending a BE
requirement (§ 320.32)
·
Criteria and evidence to assess actual or potential BE
problems (§ 320.33)
·
Requirements for batch testing and certification by
FDA (§ 320.34)
·
Requirements for in vitro batch testing of each batch
(§ 320.35)
·
Requirements for maintenance of records of BE testing
(§ 320.36)
·
Retention of BA samples (§ 320.38)
·
Retention of BE samples (§ 320.63)
Bioavailability is defined in § 320.1 as:
the rate and extent to which the
active ingredient or active moiety is absorbed from a drug product
and becomes available at the site of action. For drug products that
are not intended to be absorbed into the bloodstream,
bioavailability may be assessed by measurements intended to reflect
the rate and extent to which the active ingredient or active moiety
becomes available at the site of action.
This
definition focuses on the processes by which the active ingredients
or moieties are released from an oral dosage form and move to the
site of action.
From a pharmacokinetic perspective, BA data for
a given formulation provide an estimate of the relative fraction of
the orally administered dose that is absorbed into the systemic
circulation when compared to the BA data for a solution, suspension,
or intravenous dosage form (21 CFR 320.25(d)(2) and (3)). In
addition, BA studies provide other useful pharmacokinetic
information related to distribution, elimination, the effects of
nutrients on absorption of the drug, dose proportionality, linearity
in pharmacokinetics of the active moieties and, where appropriate,
inactive moieties. BA data can also provide information indirectly
about the properties of a drug substance before entry into the
systemic circulation, such as permeability and the influence of
presystemic enzymes and/or transporters (e.g., p-glycoprotein).
BA for orally administered drug products can be
documented by developing a systemic exposure profile. A profile can
be obtained by measuring the concentration of active ingredients
and/or active moieties and, when appropriate, its active metabolites
over time in samples collected from the systemic circulation.
Systemic exposure patterns reflect both release of the drug
substance from the drug product and a series of possible presystemic/systemic
actions on the drug substance after its release from the drug
product. We recommend that additional comparative studies be
performed to understand the relative contribution of these processes
to the systemic exposure pattern.
One regulatory
objective is to assess, through appropriately designed BA studies,
the performance of the formulations used in the clinical trials that
provide evidence of safety and efficacy (21 CFR 320.25(d)(1)).
Before marketing a drug product, the performance of the clinical
trial dosage form can be optimized, in the context of demonstrating
safety and efficacy. The systemic exposure profiles of clinical
trial material can be used as a benchmark for subsequent formulation
changes and can be useful as a reference for future BE studies.
Although BA
studies have many pharmacokinetic objectives beyond formulation
performance as described above, we note that subsequent sections of
this guidance focus on using relative BA (referred to as product
quality BA) and, in particular, BE studies as a means to document
product quality. In vivo performance, in terms of BA/BE, can be
considered to be one aspect of product quality that provides a link
to the performance of the drug product used in clinical trials and
to the database containing evidence of safety and efficacy.
Bioequivalence
is defined in § 320.1 as:
the absence of a significant
difference in the rate and extent to which the active ingredient or
active moiety in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when
administered at the same molar dose under similar conditions in an
appropriately designed study.
As noted in
the statutory definitions, both BE and product quality BA focus on
the release of a drug substance from a drug product and subsequent
absorption into the systemic circulation. As a result, we recommend
that similar approaches to measuring BA in an NDA generally be
followed in demonstrating BE for an NDA or an ANDA. Establishing
product quality BA is a benchmarking effort with comparisons to an
oral solution, oral suspension, or an intravenous formulation. In
contrast, demonstrating BE is usually a more formal comparative test
that uses specified criteria for comparisons and predetermined BE
limits for such criteria.
BE documentation
can be useful during the IND or NDA period to establish links
between (1) early and late clinical trial formulations; (2)
formulations used in clinical trial and stability studies, if
different; (3) clinical trial formulations and to-be-marketed drug
product; and (4) other comparisons, as appropriate. In each
comparison, the new formulation or new method of manufacture is the
test product and the prior formulation or method of manufacture is
the reference product. We recommend that the determination to
redocument BE during the IND period be generally left to the
judgment of the sponsor, who can wish to use the principles of
relevant guidances (in this guidance, see sections II.C.3,
Postapproval Changes, and III.D, in Vitro Studies) to determine when
changes in components, composition, and/or method of manufacture
suggest further in vitro and/or in vivo studies be performed.
A test product can
fail to meet BE limits because the test product has higher or lower
measures of rate and extent of absorption compared to the reference
product or because the performance of the test or reference product
is more variable. In some cases, nondocumentation of BE can arise
because of inadequate numbers of subjects in the study relative to
the magnitude of intrasubject variability, and not because of either
high or low relative BA of the test product. Adequate design and
execution of a BE study will facilitate understanding of the causes
of nondocumentation of BE.
Where the test
product generates plasma levels that are substantially above those
of the reference product, the regulatory concern is not therapeutic
failure, but the adequacy of the safety database from the test
product. Where the test product has levels that are substantially
below those of the reference product, the regulatory concern becomes
therapeutic efficacy. When the variability of the test product
rises, the regulatory concern relates to both safety and efficacy,
because it may suggest that the test product does not perform as
well as the reference product, and the test product may be too
variable to be clinically useful.
Proper mapping of
individual dose-response or concentration-response curves is useful
in situations where the drug product has plasma levels that are
either higher or lower than the reference product and are outside
usual BE limits. In the absence of individual data, population
dose-response or concentration-response data acquired over a range
of doses, including doses above the recommended therapeutic doses,
may be sufficient to demonstrate that the increase in plasma levels
would not be accompanied by additional risk. Similarly, population
dose- or concentration-response relationships observed over a lower
range of doses, including doses below the recommended therapeutic
doses, may be able to demonstrate that reduced levels of the test
product compared to the reference product are associated with
adequate efficacy. In either event, the burden is on the sponsor to
demonstrate the adequacy of the clinical trial dose-response or
concentration-response data to provide evidence of therapeutic
equivalence. In the absence of this evidence, failure to document
BE may suggest the product should be reformulated, the method of
manufacture for the test product be changed, and/or the BE study be
repeated.
BE studies are a
critical component of ANDA submissions. The purpose of these
studies is to demonstrate BE between a pharmaceutically equivalent
generic drug product and the corresponding reference listed drug (21
CFR 314.94 (a)(7)). Together with the determination of
pharmaceutical equivalence, establishing BE allows a regulatory
conclusion of therapeutic equivalence.
Information on the
types of in vitro dissolution and in vivo BE studies that we
recommend be conducted for immediate-release and modified-release
drug products approved as either NDAs or ANDAs in the presence of
specified postapproval changes is provided in the FDA guidances for
industry entitled SUPAC-IR: Immediate Release Solid Oral Dosage
Forms: Scale-Up and Post-Approval Changes: Chemistry,
Manufacturing, and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation; and SUPAC-MR: Modified
Release Solid Oral Dosage Forms: Scale-Up and Post-Approval
Changes: Chemistry, Manufacturing, and Controls, In Vitro
Dissolution Testing, and In Vivo Bioequivalence Documentation.
In the presence of certain major changes in components, composition,
and/or method of manufacture after approval, we recommend that in
vivo BE be redemonstrated. For approved NDAs, we also recommend
that the drug product after the change be compared to the drug
product before the change. For approved ANDAs, we also recommend
that the drug product after the change be compared to the reference
listed drug. Under section 506A(c)(2)(B) of the Federal Food, Drug,
and Cosmetic Act (the Act) (21 U.S.C. 356a(c)(2)(B)), postapproval
changes requiring completion of studies in accordance with part 320
must be submitted in a supplement and approved by FDA before
distributing a drug product made with the change.
As noted in § 320.24, several in vivo and in
vitro methods can be used to measure product quality BA and to
establish BE. In descending order of preference, these include
pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.
These general approaches are discussed in the following sections of
this guidance. Product quality BA and BE frequently rely on
pharmacokinetic measures such as AUC and Cmax that are reflective of
systemic exposure.
The statutory
definitions of BA and BE, expressed in terms of rate and extent of
absorption of the active ingredient or moiety to the site of action,
emphasize the use of pharmacokinetic measures in an accessible
biological matrix such as blood, plasma, and/or serum to indicate
release of the drug substance from the drug product into the
systemic circulation.
This approach rests on an understanding that measuring the active
moiety or ingredient at the site of action is generally not possible
and, furthermore, that some relationship exists between the
efficacy/safety and concentration of active moiety and/or its
important metabolite or metabolites in the systemic circulation. To
measure product quality BA and establish BE, reliance on
pharmacokinetic measurements may be viewed as a bioassay that
assesses release of the drug substance from the drug product into
the systemic circulation. A typical study is conducted as a
crossover study. In this type of study, clearance, volume of
distribution, and absorption, as determined by physiological
variables (e.g. gastric emptying, motility, pH), are assumed to have
less interoccasion variability compared to the variability arising
from formulation performance. Therefore, differences between two
products because of formulation factors can be determined.
If the sponsor
chooses, a pilot study in a small number of subjects can be carried
out before proceeding with a full BE study. The study can be used
to validate analytical methodology, assess variability, optimize
sample collection time intervals, and provide other information.
For example, for conventional immediate-release products, careful
timing of initial samples may avoid a subsequent finding in a
full-scale study that the first sample collection occurs after the
plasma concentration peak. For modified-release products, a pilot
study can help determine the sampling schedule to assess lag time
and dose dumping. A pilot study that documents BE can be
appropriate, provided its design and execution are suitable and a
sufficient number of subjects (e.g., 12) have completed the study.
General
recommendations for a standard BE study based on pharmacokinetic
measurements are provided in Attachment A.
Nonreplicate crossover study designs
are recommended for BE studies of immediate-release and
modified-release dosage forms. However, sponsors and/or applicants
have the option of using replicate designs for BE studies for these
drug products. Replicate study designs may offer several scientific
advantages compared to nonreplicate designs. The advantages of
replicate study designs may be that they (1) allow comparisons of
within-subject variances for the test and reference products, (2)
provide more information about the intrinsic factors underlying
formulation performance, and (3) reduce the number of subjects
participating in the BE study. The recommended method of analysis
of nonreplicate or replicate studies to establish BE is average
bioequivalence, as discussed in section IV. General recommendations
for nonreplicate study designs are provided in Attachment A.
Recommendations for replicate study designs can be found in the
guidance for industry Statistical Approaches to Establishing
Bioequivalence.
5. Study Population
We recommend that, unless otherwise
indicated by a specific guidance, subjects recruited for in vivo BE
studies be 18 years of age or older and capable of giving informed
consent. This guidance recommends that in vivo BE studies be
conducted in individuals representative
of the general population, taking into account age, sex, and race.
We recommend that if the drug product is intended for use in both
sexes, the sponsor attempt to include similar proportions of males
and females in the study. If the drug product is to be used
predominantly in the elderly, we also recommend that the sponsor
attempt to include as many subjects of 60 years of age or older as
possible. We recommend that the total number of subjects in the
study provide adequate power for BE demonstration, but it is not
expected that there will be sufficient power to draw conclusions for
each subgroup. Statistical analysis of subgroups is not
recommended. We recommend that restrictions on admission into the
study generally be based solely on safety considerations. In some
instances, it may be useful to admit patients into BE studies for
whom a drug product is intended. In this situation, we recommend
that sponsors and/or applicants attempt to enter patients whose
disease process is stable for the duration of the BE study. In
accordance with § 320.31, for some products that will be submitted
in ANDAs, an IND may be required for BE studies to ensure
patient safety.
Instances where
multiple-dose studies can be useful are defined under §
320.27(a)(3). However, this guidance generally recommends
single-dose pharmacokinetic studies for both immediate- and
modified-release drug products to demonstrate BE because they are
generally more sensitive in assessing release of the drug
substance from the drug product into the systemic circulation (see
section V). We recommend that if a multiple-dose study design is
important, appropriate dosage administration and sampling be carried
out to document attainment of steady state.
We recommend sponsors
ensure that bioanalytical methods for BA and BE studies are
accurate, precise, selective, sensitive, and reproducible. A
separate FDA guidance entitled Bioanalytical Method Validation
is available to assist sponsors in validating bioanalytical
methods.
Both direct (e.g.,
rate constant, rate profile) and indirect (e.g., Cmax, Tmax, mean
absorption time, mean residence time, Cmax normalized to AUC)
pharmacokinetic measures are limited in their ability to assess rate
of absorption. This guidance, therefore, recommends a change in
focus from these direct or indirect measures of absorption rate to
measures of systemic exposure. Cmax and AUC can continue to be used
as measures for product quality BA and BE, but more in terms of
their capacity to assess exposure than their capacity to reflect
rate and extent of absorption. We recommend that reliance on
systemic exposure measures reflect comparable rate and extent of
absorption, which in turn would achieve the underlying statutory and
regulatory objective of ensuring comparable therapeutic effects.
Exposure measures are defined relative to early, peak, and total
portions of the plasma, serum, or blood concentration‑time profile,
as follows:
a.
Early Exposure
For orally administered immediate-release drug products, BE can
generally be demonstrated by measurements of peak and total
exposure. An early exposure measure may be informative on the basis
of appropriate clinical efficacy/safety trials and/or
pharmacokinetic/pharmacodynamic studies that call for better control
of drug absorption into the systemic circulation (e.g., to ensure
rapid onset of an analgesic effect or to avoid an excessive
hypotensive action of an antihypertensive). In this setting, the
guidance recommends use of partial AUC as an early exposure measure.
We recommend that the partial area be truncated at the population
median of Tmax values for the reference formulation. We also
recommend that at least two quantifiable samples be collected before
the expected peak time to allow adequate estimation of the partial
area.
b. Peak
Exposure
We recommend that peak exposure be assessed
by measuring the peak drug concentration (Cmax) obtained directly
from the data without interpolation.
c. Total Exposure
For single-dose studies, we recommend that
the measurement of total exposure be:
·
Area under the plasma/serum/blood concentration-time
curve from time zero to time t (AUC0-t), where t is the
last time point with measurable concentration for individual
formulation.
·
Area under the plasma/serum/blood concentration-time
curve from time zero to time infinity (AUC0-¥),
where AUC0-¥ =
AUC0-t + Ct/lz,
Ct is the last measurable drug concentration and
lz is the
terminal or elimination rate constant calculated according to an
appropriate method. We recommend that the terminal half-life (t1/2)
of the drug also be reported.
For steady-state
studies, we recommend that the measurement of total exposure be the
area under the plasma, serum, or blood concentration-time curve from
time zero to time tau over a dosing interval at steady state (AUC0-tau),
where tau is the length of the dosing interval.
Pharmacodynamic studies are not recommended for orally administered
drug products when the drug is absorbed into the systemic
circulation and a pharmacokinetic approach can be used to assess
systemic exposure and establish BE. However, in those instances
where a pharmacokinetic approach is not possible, suitably validated
pharmacodynamic methods can be used to demonstrate BE.
Where there
are no other means, well-controlled clinical trials in humans can be
useful to provide supportive evidence of BA or BE. However, we
recommend that the use of comparative clinical trials as an approach
to demonstrate BE generally be considered insensitive and be avoided
where possible (21 CFR 320.24). The use of BE studies with clinical
trial endpoints can be appropriate to demonstrate BE for orally
administered drug products when measurement of the active
ingredients or active moieties in an accessible biological fluid
(pharmacokinetic approach) or pharmacodynamic approach is
infeasible.
Under certain circumstances, product quality BA
and BE can be documented using in vitro approaches (21 CFR
320.24(b)(5) and 21 CFR 320.22(d)(3)). For highly soluble, highly
permeable, rapidly dissolving, and orally administered drug
products, documentation of BE using an in vitro approach
(dissolution studies) is appropriate based on the biopharmaceutics
classification system.
This approach may also be suitable under some circumstances in
assessing BE during the IND period, for NDA and ANDA submissions,
and in the presence of certain postapproval changes to approved NDAs
and ANDAs. In addition, in vitro approaches to documenting BE for
nonbioproblem drugs approved before 1962 remain appropriate
(21 CFR 320.33).
Dissolution testing is also used to assess
batch-to-batch quality, where the dissolution tests, with defined
procedures and acceptance criteria, are used to allow batch release.
We recommend that dissolution testing is also used to (1) provide
process control and quality assurance, and (2) assess whether
further BE studies relative to minor postapproval changes be
conducted, where dissolution can function as a signal of
bioinequivalence. In vitro dissolution characterization is
encouraged for all product formulations investigated (including
prototype formulations), particularly if in vivo absorption
characteristics are being defined for the different product
formulations. Such efforts may enable the establishment of an in
vitro-in vivo correlation. When an in vitro-in vivo correlation or
association is available (21 CFR 320.24(b)(1)(ii)), the in vitro
test can serve not only as a quality control specification for the
manufacturing process, but also as an indicator of how the product
will perform in vivo. The following guidances provide
recommendations on the development of dissolution methodology,
setting specifications, and the regulatory applications of
dissolution testing: (1) Dissolution Testing of Immediate
Release Solid Oral Dosage Forms; and (2) Extended Release
Oral Dosage Forms: Development, Evaluation, and Application of In
Vitro/In Vivo Correlations.
We recommend that the following information
generally be included in the dissolution method development report
for solid oral dosage forms:
For an NDA:
·
The pH solubility profile of the drug substance
·
Dissolution profiles generated at different agitation
speeds (e.g., 100 to 150 revolutions per minute (rpm) for U.S.
Pharmacopeia (USP) Apparatus I (basket), or 50 to 100 rpm for USP
Apparatus II (paddle))
·
Dissolution profiles generated on all strengths in at
least three dissolution media (e.g., pH 1.2, 4.5, and 6.8 buffer).
Water can be used as an additional medium. If the drug being
considered is poorly soluble, appropriate concentrations of
surfactants are recommended.
It is recommended that the sponsor select the
agitation speed and medium that provide adequate discriminating
ability, taking into account all the available in vitro and in vivo
data.
For ANDAs:
·
For immediate-release drug products, we recommend that
the appropriate USP method be submitted. If there is no USP method
available, we recommend that the FDA method for the reference listed
drug be used. If the USP and/or FDA methods are not available, we
recommend that the dissolution method development report described
above be submitted.
·
For modified-release products, dissolution profiles
using the appropriate USP method (if available) can be submitted. If
there is no USP method available, we recommend that the FDA method
for the reference listed drug be used. In addition, we recommend
that profiles using at least three other dissolution media (e.g., pH
1.2, 4.5, and 6.8 buffer) and water be submitted.
This guidance recommends that dissolution data
from three batches for both NDAs and ANDAs be used to set
dissolution specifications for modified-release dosage forms,
including extended-release dosage forms.
An equivalence approach has been and continues
to be recommended for BE comparisons. The recommended approach
relies on (1) a criterion to allow the comparison, (2) a confidence
interval for the criterion, and (3) a BE limit. Log-transformation
of exposure measures before statistical analysis is recommended. BE
studies are performed as single-dose, crossover studies. To compare
measures in these studies, data have been analyzed using an average
BE criterion. This guidance recommends continued use of an average
BE criterion to compare BA measures for replicate and nonreplicate
BE studies of both immediate- and modified-release products.
An in vivo study is generally recommended for
all solid oral dosage forms approved after 1962 and for
bioproblem drug products approved before 1962. Waiver of in
vivo studies for different strengths of a drug product can be
granted under § 320.22(d)(2) when (1) the drug product is in the
same dosage form, but in a different strength; (2) this different
strength is proportionally similar in its active and inactive
ingredients to the strength of the product for which the same
manufacturer has conducted an appropriate in vivo study; and (3) the
new strength meets an appropriate in vitro dissolution test. This
guidance defines proportionally similar in the following
ways:
·
All active and inactive ingredients are in exactly the
same proportion between different strengths (e.g., a tablet of 50-mg
strength has all the inactive ingredients, exactly half that of a
tablet of 100-mg strength, and twice that of a tablet of 25-mg
strength).
·
Active and inactive ingredients are not in exactly the
same proportion between different strengths as stated above, but
the ratios of inactive ingredients to total weight of the dosage
form are within the limits defined by the SUPAC-IR and SUPAC-MR
guidances up to and including Level II.
·
For high potency drug substances, where the amount of
the active drug substance in the dosage form is relatively low, the
total weight of the dosage form remains nearly the same for all
strengths (within + 10 % of the total weight of the strength
on which a biostudy was performed), the same inactive ingredients
are used for all strengths, and the change in any strength is
obtained by altering the amount of the active ingredients and one or
more of the inactive ingredients. The changes in the inactive
ingredients are within the limits defined by the SUPAC-IR and
SUPAC-MR guidances up to and including Level II.
Exceptions to the above definitions may be
possible, if adequate justification is provided.
For oral
solutions, elixirs, syrups, tinctures, or other solubilized forms,
in vivo BA and/or BE can be waived (21 CFR 320.22(b)(3)(i)).
Generally, in vivo BE studies are waived for solutions on the
assumption that release of the drug substance from the drug product
is self-evident and that the solutions do not contain any excipient
that significantly affects drug absorption (21 CFR
320.22(b)(3)(iii)). However, there are certain excipients, such as
sorbitol or mannitol, that can reduce the bioavailability of drugs
with low intestinal permeability in amounts sometimes used in oral
liquid dosage forms.
We recommend
that BA and BE for a suspension generally be established for
immediate-release solid oral dosage forms, and both in vivo and in
vitro studies are recommended.
For product quality BA
and BE studies, we recommend that where the focus is on release of
the drug substance from the drug product into the systemic
circulation, a single-dose, fasting study be performed. We also
recommend that in vivo BE studies be accompanied by in vitro
dissolution profiles on all strengths of each product. For ANDAs,
we also recommend that the BE study be conducted between the test
product and reference listed drug using the strength(s) specified in
Approved Drug Products with Therapeutic Equivalence Evaluations
(Orange Book).
a. INDs, NDAs, and ANDAs: Preapproval
When the drug product
is in the same dosage form, but in a different strength, and is
proportionally similar in its active and inactive ingredients to the
strength on which BA or BE testing has been conducted, an in vivo BE
demonstration of one or more lower strengths can be waived based on
dissolution tests and an in vivo study on the highest strength.
For an NDA,
biowaivers of a higher strength will be determined to be appropriate
based on (1) clinical safety and/or efficacy studies including data
on the dose and the desirability of the higher strength, (2) linear
elimination kinetics over the therapeutic dose range, (3) the higher
strength being proportionally similar to the lower strength, and (4)
the same dissolution procedures being used for both strengths and
similar dissolution results obtained. We recommend that a
dissolution profile be generated for all strengths.
If an appropriate
dissolution method has been established (see section III.D.), and
the dissolution results indicate that the dissolution
characteristics of the product are not dependent on the product
strength, then dissolution profiles in one medium are usually
sufficient to support waivers of in vivo testing. Otherwise,
dissolution data in three media (pH 1.2, 4.5, and 6.8) are
recommended.
We recommend that the
f2 test be used to compare profiles from the different
strengths of the product. An f2 value > 50
indicates a sufficiently similar dissolution profile such that
further in vivo studies are not needed. For an f2 value
< 50, further discussions with CDER review staff may help to
determine whether an in vivo study is appropriate (21 CFR
320.22(d)(2)(ii)). The f2 approach is not suitable for
rapidly dissolving drug products (e.g., > 85% dissolved in 15
minutes or less).
For an ANDA,
conducting an in vivo study on a strength that is not the highest
may be appropriate for reasons of safety, subject to approval by the
Division of Bioequivalence, Office of Generic Drugs, and provided
that the following conditions are met:
·
Linear elimination kinetics has been shown over the
therapeutic dose range.
·
The higher strengths of the test and reference
products are proportionally similar to their corresponding lower
strength.
·
Comparative dissolution testing on the higher strength
of the test and reference products is submitted and found to be
appropriate.
b. NDAs and ANDAs: Postapproval
Information on the
types of in vitro dissolution and in vivo BE studies for
immediate-release drug products approved as either NDAs or ANDAs in
the presence of specified postapproval changes are provided in an
FDA guidance for industry entitled SUPAC-IR: Immediate Release
Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes:
Chemistry, Manufacturing, and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation. For
postapproval changes, we recommend that the in vitro comparison be
made between the prechange and postchange products. In instances
where dissolution profile comparisons are suggested, we also
recommend an f2 test be used. An f2 value of
> 50 suggests a sufficiently similar dissolution profile and
no further in vivo studies are needed. When in vivo BE studies are
called for, we recommend that the comparison be made for NDAs
between the prechange and postchange products, and for ANDAs between
the postchange and reference listed drug products.
Modified-release products include
delayed-release products and extended- (controlled) release
products.
As defined in the USP, delayed-release drug
products are dosage forms that release the drugs at a time later
than immediately after administration (i.e., these drug products
exhibit a lag time in quantifiable plasma concentrations).
Typically, coatings (e.g., enteric coatings) are intended to delay
the release of medication until the dosage form has passed through
the acidic medium of the stomach. In vivo tests for delayed-release
drug products are similar to those for extended-release drug
products. We recommend that in vitro dissolution tests for these
products document that they are stable under acidic conditions and
that they release the drug only in a neutral medium (e.g., pH 6.8).
Extended-release drug products are dosage forms
that allow a reduction in dosing frequency as compared to when the
drug is present in an immediate-release dosage form. These drug
products can be developed to reduce fluctuations in plasma
concentrations. Extended-release products can be capsules, tablets,
granules, pellets, and suspensions. If any part of a drug product
includes an extended-release component, the following
recommendations apply.
An NDA can be
submitted for a previously unapproved new molecular entity, new
salt, new ester, prodrug, or other noncovalent derivative of a
previously approved new molecular entity formulated as a
modified-release drug product. We recommend that the first
modified-release drug product for a previously approved
immediate-release drug product be submitted as an NDA. We also
recommend that subsequent modified-release products that are
pharmaceutically equivalent and bioequivalent to the listed drug
product be submitted as ANDAs. BA requirements for the NDA of an
extended-release product are listed in § 320.25(f). The purpose of
an in vivo BA study for which a controlled-release claim is made is
to determine if all of the following conditions are met:
·
The drug product meets the controlled-release claims
made for it.
·
The BA profile established for the drug product rules
out the occurrence of any dose dumping.
·
The drug product’s steady-state performance is
equivalent to a currently marketed noncontrolled release or
controlled-release drug product that contains the same active drug
ingredient or therapeutic moiety and that is subject to an approved
full NDA.
·
The drug product’s formulation provides consistent
pharmacokinetic performance between individual dosage units.
As noted in §
320.25(f)(2), “the reference material(s) for such a bioavailability
study shall be chosen to permit an appropriate scientific evaluation
of the controlled release claims made for the drug product,” such
as:
·
A solution or suspension of the active drug ingredient
or therapeutic moiety
·
A currently marketed noncontrolled-release drug
product containing the same active drug ingredient or therapeutic
moiety and administered according to the dosage recommendations in
the labeling
·
A currently marketed controlled-release drug product
subject to an approved full NDA containing the same active drug
ingredient or therapeutic moiety and administered according to the
dosage recommendations in the labeling
This guidance
recommends that the following BA studies be conducted for an
extended-release drug product submitted as an NDA:
·
A single-dose, fasting study on all strengths of
tablets and capsules and highest strength of beaded capsules
·
A single-dose, food-effect study on the highest
strength
·
A steady-state study on the highest strength
BE studies are
recommended when substantial changes in the components or
composition and/or method of manufacture for an extended-release
drug product occur between the to-be-marketed NDA dosage form and
the clinical trial material.
For
modified-release products submitted as ANDAs, the following studies
are recommended: (1) a single-dose, nonreplicate, fasting study
comparing the highest strength of the test and reference listed drug
product and (2) a food-effect, nonreplicate study comparing the
highest strength of the test and reference product (see section VI.A).
Because single-dose studies are considered more sensitive in
addressing the primary question of BE (i.e., release of the drug
substance from the drug product into the systemic circulation),
multiple-dose studies are generally not recommended, even in
instances where nonlinear kinetics are present.
a. Beaded Capsules — Lower Strength
We recommend that for
modified-release beaded capsules where the strength differs only in
the number of beads containing the active moiety, a single-dose,
fasting BE study be carried out only on the highest strength, with
waiver of in vivo studies for lower strengths based on dissolution
profiles. A dissolution profile can be generated for each strength
using the recommended dissolution method. The f2 test
can be used to compare profiles from the different strengths of the
product. An f2 value of > 50 can be used to
confirm that further in vivo studies are not needed.
b. Tablets — Lower Strength
For modified-release
tablets, when the drug product is in the same dosage form but in a
different strength, when it is proportionally similar in its active
and inactive ingredients, and when it has the same drug release
mechanism, an in vivo BE determination of one or more lower
strengths can be waived based on dissolution profile comparisons,
with an in vivo study only on the highest strength. We recommend
that the drug products exhibit similar dissolution profiles between
the highest strength and the lower strengths based on the f2
test in at least three dissolution media (e.g., pH 1.2, 4.5 and
6.8). We recommend that the dissolution profile be generated on the
test and reference products of all strengths.
Information on the
types of in vitro dissolution and in vivo BE studies for
extended-release drug products approved as either NDAs or ANDAs in
the presence of specified postapproval changes are provided in an
FDA guidance for industry entitled SUPAC-MR: Modified Release
Solid Oral Dosage Forms: Scale-Up and Post-Approval Changes:
Chemistry, Manufacturing, and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation. We recommend
that for postapproval changes, the in vitro comparison be made
between the prechange and postchange products. In instances where
dissolution profile comparisons are recommended, an f2
test can be used. An f2 value of > 50 suggests a
similar dissolution profile. A failure to demonstrate similar
dissolution profiles may indicate an in vivo BE study be performed.
When in vivo BE studies are conducted, we recommend that the
comparison be made for NDAs between the prechange and postchange
products, and for ANDAs between the postchange product and reference
listed drug.
We recommend that rapidly dissolving drug
products, such as buccal and sublingual dosage forms (and chewable
tablets), be tested for in vitro dissolution and in vivo BA and/or
BE. We recommend that chewable tablets (as a whole) be subject to in
vitro dissolution testing because they might be swallowed by a
patient without proper chewing. In general, we recommend that in
vitro dissolution test conditions for chewable tablets be the same
as for nonchewable tablets of the same active ingredient or moiety.
Infrequently, different test conditions or acceptance criteria can
be indicated for chewable and nonchewable tablets, but we recommend
these differences, if they exist, be resolved with the appropriate
review division.
Co-administration of food with oral drug
products may influence drug BA and/or BE. Food-effect BA studies
focus on the effects of food on the release of the drug substance
from the drug product as well as the absorption of the drug
substance. BE studies with food focus on demonstrating comparable
BA between test and reference products when coadministered with
meals. Usually, a single-dose, two-period, two-treatment,
two-sequence crossover study is recommended for both food-effect BA
and BE studies.
The moieties to be
measured in biological fluids collected in BA and BE studies are
either the active drug ingredient or its active moiety in the
administered dosage form (parent drug) and, when appropriate, its
active metabolites (21 CFR 320.24(b)(1)(i)).
This guidance recommends the following approaches for BA and BE
studies.
For BA studies (see
section II.B), we recommend that determination of moieties to be
measured in biological fluids take into account both concentration
and activity. Concentration refers to the relative quantity
of the parent drug or one or more metabolites in a given volume of
an accessible biological fluid such as blood or plasma. Activity
refers to the relative contribution of the parent drug and its
metabolite(s) in the biological fluids to the clinical safety and/or
efficacy of the drug. For BA studies, we also recommend that both
the parent drug and its major active metabolites be measured, if
analytically feasible.
For BE studies,
measurement of only the parent drug released from the dosage form,
rather than the metabolite, is generally recommended. The rationale
for this recommendation is that concentration-time profile of the
parent drug is more sensitive to changes in formulation performance
than a metabolite, which is more reflective of metabolite formation,
distribution, and elimination. The following are exceptions to this
general approach.
·
Measurement of a metabolite may be preferred when
parent drug levels are too low to allow reliable analytical
measurement in blood, plasma, or serum for an adequate length of
time. We recommend that the metabolite data obtained from these
studies be subject to a confidence interval approach for BE
demonstration. If there is a clinical concern related to efficacy
or safety for the parent drug, we also recommend that sponsors
and/or applicants contact the appropriate review division to
determine whether the parent drug should be measured and analyzed
statistically.
·
A metabolite may be formed as a result of gut wall or
other presystemic metabolism. If the metabolite contributes
meaningfully to safety and/or efficacy, we also recommend that the
metabolite and the parent drug be measured. When the relative
activity of the metabolite is low and does not contribute
meaningfully to safety and/or efficacy, it does not have to be
measured. We recommend that the parent drug measured in these BE
studies be analyzed using a confidence interval approach. The
metabolite data can be used to provide supportive evidence of
comparable therapeutic outcome.
For BA studies,
measurement of individual enantiomers may be important. For BE
studies, this guidance recommends measurement of the racemate using
an achiral assay. Measurement of individual enantiomers in BE
studies is recommended only when all of the following conditions are
met: (1) the enantiomers exhibit different pharmacodynamic
characteristics, (2) the enantiomers exhibit different
pharmacokinetic characteristics, (3) primary efficacy and safety
activity resides with the minor enantiomer, and (4) nonlinear
absorption is present (as expressed by a change in the enantiomer
concentration ratio with change in the input rate of the drug) for
at least one of the enantiomers. In such cases, we recommend that
BE factors be applied to the enantiomers separately.
Certain drug
products may contain complex drug substances (i.e., active moieties
or active ingredients that are mixtures of multiple synthetic and/or
natural source components). Some or all of the components of these
complex drug substances cannot be characterized with regard to
chemical structure and/or biological activity. Quantification of
all active or potentially active components in pharmacokinetic
studies to document BA and BE is neither encouraged nor desirable.
Rather, we recommend that BA and BE studies be based on a small
number of markers of rate and extent of absorption. Although a
case-by-case determination, criteria for marker selection include
amount of the moiety in the dosage form, plasma or blood levels of
the moiety, and biological activity of the moiety relative to other
moieties in the complex mixture. Where pharmacokinetic approaches
are infeasible to assess rate and extent of absorption of a drug
substance from a drug product, in vitro approaches may be
preferred. Pharmacodynamic or clinical approaches may be called for
if no quantifiable moieties are available for in vivo
pharmacokinetic or in vitro studies.
In a BA or pharmacokinetic study involving an
oral product with a long half-life drug, adequate characterization
of the half-life calls for blood sampling over a long period of
time. For a BE determination of an oral product with a long
half-life drug, a nonreplicate, single-dose, crossover study can be
conducted, provided an adequate washout period is used. If the
crossover study is problematic, a BE study with a parallel design
can be used. For either a crossover or parallel study, we recommend
that sample collection time be adequate to ensure completion of
gastrointestinal transit (approximately 2 to 3 days) of the drug
product and absorption of the drug substance. Cmax and a suitably
truncated AUC can be used to characterize peak and total drug
exposure, respectively. For drugs that demonstrate low intrasubject
variability in distribution and clearance, an AUC truncated at 72
hours (AUC0-72 hr) can be used in place of AUC0-t
or AUC0-¥.
For drugs demonstrating high intrasubject variability in
distribution and clearance, AUC truncation warrants caution. In
such cases, we also recommend that sponsors and/or applicants
consult the appropriate review staff.
The first
point of a concentration-time curve in a BE study based on blood
and/or plasma measurements is sometimes the highest point, which
raises a question about the measurement of true Cmax because of
insufficient early sampling times. A carefully conducted pilot
study may avoid this problem. Collection of an early time point
between 5 and 15 minutes after dosing followed by additional sample
collections (e.g., two to five) in the first hour after dosing may
be sufficient to assess early peak concentrations. If this sampling
approach is followed, we recommend that data sets be considered
adequate, even when the highest observed concentration occurs at the
first time point.
Documentation
of product quality BA for NDAs where the drug substance produces its
effects by local action in the gastrointestinal tract can be
achieved using clinical efficacy and safety studies and/or suitably
designed and validated in vitro studies. Similarly, documentation
of BE for ANDAs, and for both NDAs and ANDAs in the presence of
certain postapproval changes, can be achieved using BE studies with
clinical efficacy and safety endpoints and/or suitably designed and
validated in vitro studies, if the latter studies are either
reflective of important clinical effects or are more sensitive to
changes in product performance compared to a clinical study. To
ensure comparable safety, additional studies with and without food
may help to understand the degree of systemic exposure that occurs
following administration of a drug product intended for local action
in the gastrointestinal tract.
This guidance defines narrow therapeutic
range
drug products as containing certain drug substances subject to
therapeutic drug concentration or pharmacodynamic monitoring, and/or
where product labeling indicates a narrow therapeutic range
designation. Examples include digoxin, lithium, phenytoin,
theophylline, and warfarin. Because not all drugs subject to
therapeutic drug concentration or pharmacodynamic monitoring are
narrow therapeutic range drugs, sponsors and/or applicants can
contact the appropriate review division at CDER to determine whether
a drug can or cannot be considered to have a narrow therapeutic
range.
This guidance recommends that sponsors consider
additional testing and/or controls to ensure the quality of drug
products containing narrow therapeutic range drugs. The approach is
designed to provide increased assurance of interchangeability for
drug products containing specified narrow therapeutic range drugs.
It is not designed to influence the practice of medicine or
pharmacy.
Unless otherwise indicated by a specific
guidance, this guidance recommends that the traditional BE limit of
80 to 125 percent for non-narrow therapeutic range drugs remain
unchanged for the bioavailability measures (AUC and Cmax) of narrow
therapeutic range drugs.
For both replicate and nonreplicate, in vivo
pharmacokinetic BE studies, the following general approaches are
recommended, recognizing that the elements can be adjusted for
certain drug substances and drug products.
Study conduct:
·
The test or reference products can be administered
with about 8 ounces (240 milliliters) of water to an appropriate
number of subjects under fasting conditions, unless the study is a
food-effect BA and BE study.
·
Generally, the highest marketed strength can be
administered as a single unit. If warranted for analytical reasons,
multiple units of the highest strength can be administered,
providing the total single-dose remains within the labeled dose
range.
·
An adequate washout period (e.g., more than 5 half
lives of the moieties to be measured) would separate each treatment.
·
The lot numbers of both test and reference listed
products and the expiration date for the reference product would be
stated. The drug content of the test product cannot differ from
that of the reference listed product by more than 5 percent. The
sponsor can include a statement of the composition of the test
product and, if possible, a side-by-side comparison of the
compositions of test and reference listed products. In accordance
with § 320.38, samples of the test and reference listed product must
be retained for 5 years.
·
Before and during each study phase, we recommend that
subjects (1) be allowed water as desired except for 1 hour
before and after drug administration, (2) be provided standard meals
no less than 4 hours after drug administration, and (3) abstain from
alcohol for 24 hours before each study period and until after the
last sample from each period is collected.
Sample collection and sampling times:
·
We recommend that under normal circumstances, blood,
rather than urine or tissue, be used. In most cases, drug, or
metabolites are measured in serum or plasma. However, in certain
cases, whole blood may be more appropriate for analysis. We
recommend that blood samples be drawn at appropriate times to
describe the absorption, distribution, and elimination phases of the
drug. For most drugs, we recommend that 12 to 18 samples, including
a predose sample, be collected per subject per dose. This sampling
can continue for at least three or more terminal half lives of the
drug. The exact timing for sample collection depends on the nature
of the drug and the input from the administered dosage form. The
sample collection can be spaced in such a way that the maximum
concentration of the drug in the blood (Cmax) and terminal
elimination rate constant (lz)
can be estimated accurately. At least three to four samples can be
obtained during the terminal log-linear phase to obtain an accurate
estimate of lz
from linear regression. We recommend that the actual clock time when
samples are drawn as well as the elapsed time related to drug
administration be recorded.
Subjects with predose plasma concentrations:
·
If the predose concentration is
£ 5 percent of Cmax value
in that subject, the subject’s data without any adjustments can be
included in all pharmacokinetic measurements and calculations. We
recommend that if the predose value is > than 5 percent of Cmax, the
subject be dropped from all BE study evaluations.
Data deletion due to vomiting:
·
We recommend that data from subjects who experience
emesis during the course of a BE study for immediate-release
products be deleted from statistical analysis if vomiting occurs at
or before 2 times median Tmax. In the case of modified-release
products, the data from subjects who experience emesis any time
during the labeled dosing interval can be deleted.
The following pharmacokinetic information is
recommended for submission:
·
Plasma concentrations and time points
·
Subject, period, sequence, treatment
·
AUC0-t, AUC0-¥,
Cmax, Tmax, lz ,
and t1/2
·
Intersubject, intrasubject, and/or total variability,
if available
·
Cmin (concentration at the end of a dosing interval),
Cav (average concentration during a dosing interval), degree of
fluctuation [(Cmax-Cmin)/Cav], and swing [(Cmax-Cmin)/Cmin] if
steady-state studies are employed
·
Partial AUC, requested only as discussed in section
III. A.9.a.
In addition, we recommend that the following
statistical information be provided for AUC0-t, AUC0-¥,
and Cmax:
·
Geometric mean
·
Arithmetic mean
·
Ratio of means
·
Confidence intervals
We also recommend that logarithmic
transformation be provided for measures used for BE demonstration.
Rounding off of confidence interval values:
·
We recommend that confidence interval (CI) values not
be rounded off; therefore, to pass a CI limit of 80 to125, the value
would be at least 80.00 and not more than 125.00.
A dosage form contains active and, usually, inactive
ingredients. The active ingredient may be a prodrug that
becomes active with further in vivo transformation. An active
moiety is the molecule or ion, excluding those appended portions
of the molecule that cause the drug to be an ester, salt, or
other noncovalent derivative of the molecule, responsible for
the physiological or pharmacological action of the drug
substance.
Back
to Top
Back to Guidance Page
PDF requires the free Adobe
Acrobat Reader
Date created: March 15, 2006 |