1. Guided by : Dr. Dhaivat Parikh
Prepared by: Dhara Patel
14MPH103
2. • 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.
• This guidance provides recommendations for food-effect BA and
fed BE study designs, data analysis, and product labelling .
• It also provides information on when food-effect BA and fed BE
studies should be performed.
INTRODUCTION
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3. • 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
POTENTIAL MECHANISMS OF FOOD EFFECTS ON BA
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4. • Case 1: Food Prolongs Absorption Rate
• Case 2: Food Decreases Absorption
• Case 3: Food Increases Absorption
• Case 4: No Food Effect
FOOD EFFECTS ON BA OF DRUG SUBSTANCE
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5. • Commonly seen with highly soluble, highly permeable, rapidly
absorbed drug substances
• Major mechanism : Delayed gastric emptying
CASE 1: FOOD PROLONGS ABSORPTION RATE
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7. • Mechanisms include
– Instability in gastric acids;
– Physical/chemical binding with food components;
– Increased first-pass metabolism & clearance.
• Can result in decreased efficacy
CASE 2: FOOD DECREASES ABSORPTION
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10. • Mechanisms include
– Inhibition of first-pass effect;
– Physicochemical/physiological effects;
– Increased bile release; or
– Longer gastric residence time
• Food can affect efficacy or safety
CASE 3: FOOD INCREASES ABSORPTION
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13. • Mechanisms include
• –Relatively insensitive to changes in GI tract
• –Rapidly, completely absorbed
• –Well-absorbed from both large & small intestine
CASE 4: NO FOOD EFFECT
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16. • Often seen with MR formulations.
• Release-controlling excipients depend on environmental
conditions of GI tract.
• Food can affect drug absorption from MR formulations by
changing physiological conditions in GI tract.
FOOD-FORMULATION INTERACTIONS
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17. • Defined as the rapid release of the active ingredient from a MR
formulation.
• First characterized in the 1980s in studies of theophylline MR
formulations.
• Administration with food caused dose-dumping from some
theophylline products.
• This was a serious safety issue because theophylline has a
narrow therapeutic index.
ILLUSTRATION OF A FOOD-FORMULATION
INTERACTION: THEOPHYLLINE DOSE-DUMPING
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18. • Food can have different effects on drug BA from IR versus MR
formulations.
• Food increased Cmax by 23%, had no effect on AUC from IR
azithromycin (Zithromax®).
• However, food increased Cmax by 115% and AUC by 23% from MR
azithromycin (Zmax®).
COMPARING FOOD EFFECTS ON IR AND MR
FORMULATIONS
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19. • For some products, delayed-release (DR) and/or extended-
release (ER) formulations are developed after IR formulation
approval.
• FDA requests new food-effect BA studies on the new MR
formulation.
CHARACTERIZING FOOD-FORMULATION
INTERACTIONS FOR NDA’S
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20. • Under Food and Drug laws and FDA’s regulations, a generic drug
product’s formulation/release mechanism can differ from those
of the reference.
• Fed BE studies are designed to show whether the generic
formulation performs the same as the reference formulation
when products are given with food.
• The generic must be bioequivalent to the reference when given
with food.
CHARACTERIZING FOOD-FORMULATION
INTERACTIONS FOR ANDAS
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21. • Acceptance criteria for fed BE studies are that the 90%
confidence intervals of the test/reference AUC and Cmax ratios
must fall within limits of 80-125%.
• FDA generally requests fed BE studies for generic IR solid oral
dosage forms except for products which
• –Are BCS Class 1 drugs
• –Must be taken on an empty stomach
• FDA generally requests fed BE studies for generic MR solid oral
dosage forms with very few exceptions.
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22. • FDA uses label information in deciding when to request fed BE
studies
• Such information includes
• Information about high in vivo permeability
• -Potential BCS Class 1 biowaiver
• Whether to take on an empty stomach
• Safety information
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24. • A. General Design
• B. Subject Selection
• C. Dosage Strength
• D. Test Meal
• E. Administration
• F. Sample Collection
STUDY CONSIDERATIONS
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25. • FDA recommends 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.
A. GENERAL DESIGN
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26. • FDA recommends 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.
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27. • 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.
• A minimum of 12 subjects should complete the food-effect BA
and fed BE studies.
B. SUBJECT SELECTION
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28. • 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.
C. DOSAGE STRENGTH
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29. • FDA recommends 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.
D. TEST MEAL
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30. • 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.
E. ADMINISTRATION
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31. •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.
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32. • 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.
F. SAMPLE COLLECTION
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33. • The following exposure measures and pharmacokinetic parameters should
be obtained:
• 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.
DATA ANALYSIS
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34. • For new solid oral dosage forms
• –Food-effect BA studies should be conducted early in drug
development
• –Study results should be summarized in label
• –Label should describe relationship of food to drug
administration
SUMMARY AND CONCLUSIONS
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35. • For generic drug IR and MR solid oral formulations, fed BE
studies generally should be conducted, in addition to fasting BE
studies (with some exceptions)
• For a generic drug formulation to be deemed bioequivalent to
the reference formulation, both fed and fasting BE studies must
be acceptable
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36. • Crossover study designs are optimal for food-effect BA and fed
BE studies
• Food effects should generally be studied with a high-fat, high-
calorie meal
• Acceptable sprinkle relative BA (for NDAs) or BE (for ANDAs)
studies should be conducted in certain circumstances
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37. • CDER Guidance for Industry. Food-Effect Bioavailability and Fed
Bioequivalence Studies, December 2002.
• CDER Guidance for Industry, Individual Product Bioequivalence
Recommendations.
• Davit BM & Conner DP. Food Effects on Drug Bioavailability.
• U.S. Department of Health and Human services
• Food and Drug Administration
REFERENCE
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