U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2002
BP
Guidance for Industry
Food-Effect Bioavailability and
Fed Bioequivalence Studies
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(Internet)
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)
December 2002
BP
Guidance For Industry
Food-Effect Bioavailability and Fed Bioequivalence Studies
This guidance provides recommendations to
sponsors and/or applicants planning to conduct food-effect
bioavailability (BA) and fed bioequivalence (BE) studies for
orally administered drug products as part of investigational new
drug applications (INDs), new drug applications (NDAs),
abbreviated new drug applications (ANDAs), and supplements to
these applications. This guidance applies to both
immediate-release and modified-release drug products. The
guidance addresses how to meet the BA and BE requirements in 21
CFR 320, 314.50 (d) (3), and 314.94 (a) (7) as they apply to oral
dosage forms. This guidance provides recommendations for
food-effect BA and fed BE study designs,
data analysis, and product labeling. It also provides information
on when food-effect BA and fed BE studies should be performed.
Food effect BA studies are usually conducted
for new drugs and drug products during the IND period to assess
the effects of food on the rate and extent of absorption of a drug
when the drug product is administered shortly after a meal (fed
conditions), as compared to administration under fasting
conditions. Fed BE studies, on the other hand, are conducted for
ANDAs to demonstrate their bioequivalence to the reference listed
drug (RLD) under fed conditions.
Food can change the BA of a drug and can
influence the BE between test and reference products. Food effects
on BA can have clinically significant consequences. Food can
alter BA by various means, including:
-
Delay gastric emptying
-
Stimulate bile flow
-
Change gastrointestinal (GI) pH
-
Increase splanchnic blood flow
-
Change luminal metabolism of a drug substance
-
Physically or chemically interact with a dosage form or a drug
substance
Food effects on BA are generally greatest
when the drug product is administered shortly after a meal is
ingested. The nutrient and caloric contents of the meal, the meal
volume, and the meal temperature can cause physiological changes
in the GI tract in a way that affects drug product transit time,
luminal dissolution, drug permeability, and systemic availability.
In general, meals that are high in total calories and fat content
are more likely to affect the GI physiology and thereby result in
a larger effect on the BA of a drug substance or drug product. We
recommend use of high-calorie and high-fat meals during
food-effect BA and fed BE studies.
Administration of a drug product with food
may change the BA by affecting either the drug substance or the
drug product. In practice, it is difficult to determine the exact
mechanism by which food changes the BA of a drug product without
performing specific mechanistic studies.
Important food effects on BA are least likely to occur with
many rapidly dissolving, immediate-release drug products
containing highly soluble and highly permeable drug substances (BCS
Class I) because absorption of the drug substances in Class I is
usually pH- and site-independent and thus insensitive to
differences in dissolution.
[3] However, for some drugs in this class,
food can influence BA when there is a high first-pass effect,
extensive adsorption, complexation, or instability of the drug
substance in the GI tract. In some cases, excipients or
interactions between excipients and the food-induced changes in
gut physiology can contribute to these food effects and influence
the demonstration of BE. For rapidly dissolving formulations of
BCS Class I drug substances, food can affect Cmax and
the time at which this occurs (Tmax) by delaying
gastric emptying and prolonging intestinal transit time. However,
we expect the food effect on these measures to be similar for test
and reference products in fed BE studies.
For other immediate-release drug products (BCS
Class II, III, and IV) and for all modified-release drug products,
food effects are most likely to result from a more complex
combination of factors that influence the in vivo dissolution of
the drug product and/or the absorption of the drug substance. In
these cases, the relative direction and magnitude of food effects
on formulation BA and the effects on the demonstration of BE are
difficult, if not impossible, to predict without conducting a fed
BE study.
This section of the guidance provides
recommendations on when food-effect BA studies should be conducted
as part of INDs and NDAs and when fed BE studies should be
conducted as part of ANDAs. For postapproval changes in an
approved immediate- or modified-release drug product that requires
in vivo redocumentation of BE under fasting conditions, fed BE
studies are generally unnecessary.
1. INDs/NDAs
We recommend that a
food-effect BA study be conducted for all new chemical entities (NCEs)
during the IND period.
Food-effect BA studies should be conducted early in the drug
development process to guide and select formulations for further
development. Food-effect BA information should be available to
design clinical safety and efficacy studies and to provide
information for the CLINICAL PHARMACOLOGY and/or DOSAGE AND
ADMINISTRATION sections of product labels. If a sponsor makes
changes in components, composition, and/or method of manufacture
in the clinical trial formulation prior to approval, BE should be
demonstrated between the to-be-marketed formulation and the
clinical trial formulation.
Sponsors may wish
to use relevant principles described in the guidance for industry
on 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 (SUPAC-IR guidance) to determine if in vivo BE
studies are recommended. These BE studies, if indicated, should
generally be conducted under fasting conditions.
2. ANDAs
In addition to a BE
study under fasting conditions, we recommend a BE study under fed
conditions for all orally administered immediate-release drug
products, with the following exceptions:
·
When both test product and RLD are rapidly
dissolving, have similar dissolution profiles, and contain a drug
substance with high solubility and high permeability (BCS Class I)
(see footnote 3), or
·
When the DOSAGE AND ADMINISTRATION section of the
RLD label states that the product should be taken only on an empty
stomach, or
·
When the RLD label does not make any statements
about the effect of food on absorption or administration.
We recommend that
food-effect BA and fed BE studies be performed for all
modified-release dosage forms.
1. INDs/NDAs
We recommend a
study comparing the BA under fasting and fed conditions for all
orally administered modified-release drug products.
When changes occur
in components, composition, and/or method of manufacture between
the to-be-marketed formulation and the primary clinical trial
material, the sponsor may wish to use relevant principles
described in the guidance for industry on 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 (SUPAC-MR
guidance) to determine if documentation of in vivo BE is
recommended. These BE studies, if indicated, should generally be
conducted under fasting conditions.
2. ANDAs
In addition to a BE
study under fasting conditions, a BE study under fed conditions
should be conducted for all orally administered modified-release
drug products.
This section provides general considerations
for designing food effect BA and fed BE studies. A sponsor
may propose alternative study designs and data analyses.
The scientific rationale and justification for these study
designs and analyses should be provided in the study protocol.
Sponsors may choose to conduct additional studies for a better
understanding of the drug product and to provide optimal labeling
statements for dosage and administration (e.g. different meals and
different times of drug intake in relation to meals). In studying
modified-release dosage forms, consideration should be given to
the possibility that co-administration with food can result in
dose dumping, in which the complete dose may be more rapidly
released from the dosage form than intended, creating a potential
safety risk for the study subjects.
We recommend a randomized, balanced,
single-dose, two-treatment (fed vs. fasting), two-period,
two-sequence crossover design for studying the effects of food on
the BA of either an immediate-release or a modified-release drug
product. The formulation to be tested should be administered on
an empty stomach (fasting condition) in one period and following a
test meal (fed condition) in the other period. We recommend a
similar, two-treatment, two-period, two-sequence crossover design
for a fed BE study except that the treatments should consist of
both test and reference formulations administered following a test
meal (fed condition). An adequate washout period should separate
the two treatments in food-effect BA and fed BE studies.
Both food-effect BA and fed BE studies can be
carried out in healthy volunteers drawn from the general
population. Studies in the patient population are also
appropriate if safety concerns preclude the enrollment of healthy
subjects. A sufficient number of subjects should complete the
study to achieve adequate power for a statistical assessment of
food effects on BA to claim an absence of food effects, or to
claim BE in a fed BE study (see DATA ANALYSIS AND LABELING
section). A minimum of 12 subjects should complete the
food-effect BA and fed BE studies.
In general, the highest strength of a drug
product intended to be marketed should be tested in food-effect BA
and fed BE studies. In some cases, clinical safety concerns can
prevent the use of the highest strength and warrant the use of
lower strengths of the dosage form. For ANDAs, the same lot and
strength used in the fasting BE study should be tested in the fed
BE study. For products with multiple strengths in ANDAs, if a fed
BE study has been performed on the highest strength, BE
determination of one or more lower strengths can be waived based
on dissolution profile comparisons (for details see the guidance
on Bioavailablity and Bioequivalence Studies for Orally
Administered Drug Products - General Considerations.
We recommend that food-effect BA and fed BE
studies be conducted using meal conditions that are expected to
provide the greatest effects on GI physiology so that systemic
drug availability is maximally affected. A high-fat
(approximately 50 percent of total caloric content of the meal)
and high-calorie (approximately 800 to 1000 calories) meal is
recommended as a test meal for food-effect BA and fed BE studies.
This test meal should derive approximately 150, 250, and 500-600
calories from protein, carbohydrate, and fat, respectively.
The caloric breakdown of the test meal should be provided in the
study report. If the caloric breakdown of the meal is
significantly different from the one described above, the sponsor
should provide a scientific rationale for this difference. In
NDAs, it is recognized that a sponsor can choose to conduct
food-effect BA studies using meals with different combinations of
fats, carbohydrates, and proteins for exploratory or label
purposes. However, one of the meals for the food-effect BA
studies should be the high-fat, high-calorie test meal described
above.
Fasted Treatments: Following an
overnight fast of at least 10 hours, subjects should be
administered the drug product with 240 mL (8 fluid ounces) of
water. No food should be allowed for at least 4 hours post-dose.
Water can be allowed as desired except for one hour before and
after drug administration. Subjects should receive standardized
meals scheduled at the same time in each period of the study.
Fed Treatments: Following an
overnight fast of at least 10 hours, subjects should start the
recommended meal 30 minutes prior to administration of the drug
product. Study subjects should eat this meal in 30 minutes or
less; however, the drug product should be administered 30 minutes
after start of the meal. The drug product should be administered
with 240 mL (8 fluid ounces) of water. No food should be
allowed for at least 4 hours post-dose. Water can be allowed as
desired except for one hour before and after drug administration.
Subjects should receive standardized meals scheduled at the same
time in each period of the study.
For both fasted and fed treatment periods,
timed samples in biological fluid, usually plasma, should be
collected from the subjects to permit characterization of the
complete shape of the plasma concentration-time profile for the
parent drug. It may be advisable to measure other moieties in the
plasma, such as active metabolites, and sponsors should refer to
the guidance on Bioavailability and Bioequivalence Studies for
Orally Administered Drug Products — General Considerations for
recommendations on these issues. Consideration should be given to
the possibility that co-administration of a dosage form with food
can alter the time course of plasma drug concentrations so that
fasted and fed treatments can have different sample collection
times.
Food-effect BA studies may be exploratory and
descriptive, or a sponsor may want to use a food-effect BA study
to make a label claim.
The following exposure measures and pharmacokinetic parameters
should be obtained from the resulting concentration-time curves
for the test and reference products in food-effect BA and fed BE
studies:
-
Total exposure, or area under the concentration-time
curve (AUC0-inf, AUC0-t)
-
Peak exposure (Cmax)
-
Time to peak exposure (Tmax)
-
Lag-time (tlag) for modified-release
products, if present
-
Terminal elimination half-life
-
Other relevant pharmacokinetic parameters
Individual subject measurements, as well as
summary statistics (e.g., group averages, standard deviations,
coefficients of variation) should be reported. An equivalence
approach is recommended for food-effect BA (to make a claim of no
food effects) and fed BE studies, analyzing data using an average
criterion. Log-transformation of exposure measurements (AUC and Cmax
) prior to analysis is recommended. The 90 percent CI for the
ratio of population geometric means between test and reference
products should be provided for AUC0-inf, AUC0-t,
and Cmax (see guidance for industry on Statistical
Approaches to Establishing Bioequivalence). For IND or NDA
food-effect BA studies, the fasted treatment serves as the
reference. For ANDA fed BE studies, the RLD administered under
fed condition serves as the reference treatment.
The effect of food on the absorption and BA of a drug product
should be described in the CLINICAL PHARMACOLOGY section of the
labeling. In addition, the DOSAGE AND ADMINISTRATION section of
the labeling should provide instructions for drug administration
in relation to food based on clinical relevance (i.e.,
whether or not the changes in systemic exposure caused by
co-administration with food results in safety or efficacy
concerns, or when there is no important change in systemic
exposure but there is a possibility that the drug substance causes
GI irritation when taken without food).
For an NDA, an absence of food effect on BA
is not established if the 90 percent CI for the ratio of
population geometric means between fed and fasted treatments,
based on log-transformed data, is not contained in the equivalence
limits of 80-125 percent for either AUC0-inf (AUC0-t
when appropriate) or Cmax. When the 90
percent CI fails to meet the limits of 80-125 percent, the sponsor
should provide specific recommendations on the clinical
significance of the food effect based on what is known from the
total clinical database about dose-response (exposure-response)
and/or pharmacokinetic-pharmacodynamic relationships of the drug
under study. The clinical relevance of any difference in Tmax
and tlag should also be indicated by the sponsor. The
results of the food-effect BA study should be reported factually
in the CLINICAL PHARMACOLOGY section of the labeling and should
form the basis for making label recommendations (e.g., take
only on an empty stomach) in the DOSAGE AND ADMINISTRATION
section of the labeling. The following are examples of language
for the package insert:
A food-effect
study involving administration of [the drug product] to healthy
volunteers under fasting conditions and with a high-fat meal
indicated that the Cmax and AUC were increased 57% and
45%, respectively, under fed conditions. This increase in exposure
can be clinically significant, and therefore [the drug] should be
taken only on an empty stomach (1 hour before or 2 hours after a
meal)
A food-effect study involving administration of [the drug
product] to healthy volunteers under fasting conditions and with a
high-fat meal indicated that the Cmax was decreased 15%
while the AUC remained unchanged. This decrease in exposure is not
clinically significant, and therefore [the drug] could be taken
without regards to meals.
An absence of food effect on BA is indicated
when the 90 percent CI for the ratio of population geometric means
between fed and fasted treatments, based on log-transformed data,
is contained in the equivalence limits of 80-125 percent for AUC0-inf
(AUC0-t when appropriate) and Cmax.
In this case, a sponsor can make a specific claim in the CLINICAL
PHARMACOLOGY or DOSAGE AND ADMINISTRATION section of the label
that no food effect on BA is expected provided that the Tmax
differences between the fasted and fed treatments are not
clinically relevant. The following is an example of language for
the package insert:
The Cmax
and AUC data from a food-effect study involving administration of
[the drug product] to healthy volunteers under fasting conditions
and with a high-fat meal indicated that exposure to the drug is
not affected by food. Therefore, [the drug product] may be taken
without regard to meals.
For an ANDA, BE of a test product to the
RLD product under fed conditions is concluded when the
90 percent CI for the ratio of population geometric means between
the test and RLD product, based on log-transformed data, is
contained in the BE limits of 80-125 percent for AUC and Cmax.
Although no criterion applies to Tmax, the Tmax
values for the test and reference products are expected to be
comparable based on clinical relevance. The conclusion of BE
under fed conditions indicates that with regard to food, the
language in the package insert of the test product can be the same
as the reference product.
In NDAs, the labeling of certain drug
products (e.g., controlled-release capsules containing beads) can
recommend that the product be sprinkled on soft foods, such as
applesauce, and swallowed without chewing. For the labeling to
indicate that the drug product can be sprinkled on soft foods,
additional in vivo relative BA studies should be performed by
sprinkling the product on the soft foods to be listed in the
labeling (test treatment) and comparing it to the product
administered in the intact form (reference treatment), then
administering both on an empty stomach.
In ANDAs, BE of the test to the RLD is
demonstrated in a single dose crossover study. Both treatments
should be sprinkled on one of the soft foods mentioned in the
labeling, usually applesauce. The BE data should be analyzed
using average BE and the 90 percent CI criteria should be used to
declare BE. If there are questions about other foods, the design,
or the analysis of such BE studies, the sponsors and/or applicants
should contact the Office of Generic Drugs.
For NDAs, the
labeling for certain oral solution products (e.g., cyclosporine
oral solution, modified) recommends that the solution be mixed
with a beverage prior to administration. The BA of these products
can change when mixed with different beverages due to the
formation of complex mixtures and other physical-chemical and/or
physiological factors. NDA sponsors should contact the Office of
Clinical Pharmacology and Biopharmaceutics to determine what data
should be submitted to support labeling.
In ANDAs, BE of the test to the RLD is
demonstrated in a single-dose crossover study. Both treatments
should be mixed with one of the beverages mentioned in the
labeling. Sponsors should provide evidence that BE differences
would not be expected from the use of other listed vehicles. The
BE data should be analyzed using average BE, and the 90 percent CI
criteria should be used to declare BE. If there are questions
about other vehicles, or the design or analysis of such BE
studies, the sponsors and/or applicants should contact the Office
of Generic Drugs.
This guidance has been
prepared by the Food Effect Working Group of the
Biopharmaceutics Coordinating Committee in the Office of
Pharmaceutical Science, Center for Drug Evaluation and
Research (CDER) at the Food and Drug Administration (FDA).
See also the guidance
for industry on Bioavailablity and Bioequivalence Studies
for Orally Administered Drug Products
C General
Considerations.
See the guidance for
industry on Waiver of In Vivo Bioavailability and
Bioequivalence Studies for Immediate Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System.