Guidance for Industry
`
`Food-Effect Bioavailability and
`Fed Bioequivalence Studies
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`December 2002
`BP
`
`Grün. Exhibit 1082
`Grünenthal v. Antecip
`PGR2017-00022
`
`

`

`Guidance for Industry
`
`Food-Effect Bioavailability and
`Fed Bioequivalence Studies
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Drug Information, HFD-240
`5600 Fishers Lane
`Rockville, MD 20857
`
`(Tel) 301-827-4573
`(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
`
`

`

`Table of Contents
`
`I.
`
`INTRODUCTION................................................................................................................. 1
`
`II. BACKGROUND ................................................................................................................... 1
`
`A. Potential Mechanisms of Food Effects on BA ............................................................................. 1
`
`B. Food Effects on Drug Products..................................................................................................... 2
`
`III. RECOMMENDATIONS FOR FOOD-EFFECT BA AND FED BE STUDIES ............. 3
`
`A.
`
`Immediate-Release Drug Products............................................................................................... 3
`
`B. Modified-Release Drug Products.................................................................................................. 4
`
`IV. STUDY CONSIDERATIONS.............................................................................................. 4
`
`A. General Design ............................................................................................................................... 4
`
`B. Subject Selection ............................................................................................................................ 5
`
`C. Dosage Strength ............................................................................................................................. 5
`
`D. Test Meal ........................................................................................................................................ 5
`
`E. Administration ............................................................................................................................... 6
`
`F. Sample Collection........................................................................................................................... 6
`
`V. DATA ANALYSIS AND LABELING ................................................................................ 6
`
`VI. OTHER CONSIDERATIONS............................................................................................. 8
`
`A. Sprinkles ......................................................................................................................................... 8
`
`B. Special Vehicles .............................................................................................................................. 8
`
`

`

`Guidance For Industry1
`
`Food-Effect Bioavailability and Fed Bioequivalence Studies
`
`This guidance represents the Food and Drug Administration•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.
`
`I.
`
`INTRODUCTION
`
`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. 2
`
`II.
`
`BACKGROUND
`
`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.
`
`A.
`
`Potential Mechanisms of Food Effects on BA
`
`1
`
`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).
`
`2
`
`See also the guidance for industry on Bioavailablity and Bioequivalence Studies for Orally Administered Drug
`Products • • General Considerations.
`
`1
`
`

`

`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
`
`(cid:120) Delay gastric emptying
`(cid:120) Stimulate bile flow
`(cid:120) Change gastrointestinal (GI) pH
`(cid:120)
`Increase splanchnic blood flow
`(cid:120) Change luminal metabolism of a drug substance
`(cid:120) 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.
`
`B.
`
`Food Effects on Drug Products
`
`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.
`
`3
`
`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.
`
`2
`
`

`

`III. RECOMMENDATIONS FOR FOOD-EFFECT BA AND FED BE STUDIES
`
`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.
`
`A.
`
`Immediate-Release Drug Products
`
`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:
`
`(cid:120) 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
`
`(cid:120) When the DOSAGE AND ADMINISTRATION section of the RLD label states that
`the product should be taken only on an empty stomach, or
`
`3
`
`

`

`(cid:120) When the RLD label does not make any statements about the effect of food on
`absorption or administration.
`
`B. Modified-Release Drug Products
`
`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.
`
`IV.
`
`STUDY CONSIDERATIONS
`
`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.
`
`A.
`
`General Design
`
`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
`
`4
`
`

`

`(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.
`
`B.
`
`Subject Selection
`
`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.
`
`C.
`
`Dosage Strength
`
`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.
`
`D.
`
`Test Meal
`
`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.4 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.
`
`4 An example test meal would be two eggs fried in butter, two strips of bacon, two slices of toast with butter, four
`ounces of hash brown potatoes and eight ounces of whole milk. Substitutions in this test meal can be made as long as
`the meal provides a similar amount of calories from protein, carbohydrate, and fat and has comparable meal volume
`and viscosity.
`
`5
`
`

`

`E.
`
`Administration
`
`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.
`
`F.
`
`Sample Collection
`
`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.
`
`V.
`
`DATA ANALYSIS AND LABELING
`
`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.5 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:
`
`(cid:120) Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t)
`(cid:120) Peak exposure (Cmax)
`(cid:120) Time to peak exposure (Tmax)
`(cid:120) Lag-time (tlag) for modified-release products, if present
`(cid:120) Terminal elimination half-life
`(cid:120) 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
`
`5 Regulations on labeling requirements for a drug product submitted in an NDA can be found in 21 CFR part 201.
`
`6
`
`

`

`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
`
`7
`
`

`

`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.
`
`VI. OTHER CONSIDERATIONS
`
`A.
`
`Sprinkles
`
`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.
`
`B.
`
`Special Vehicles
`
`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
`
`8
`
`

`

`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.
`
`9
`
`