Assessing the Effects of  
Food on Drugs in INDs  
and NDAs    Clinical  
Pharmacology 
Considerations  
Guidance for Industry  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S.Department of Health and Human Services  
Food and Drug Administration  
Center for Drug  Evaluation and Research (CDER)  
 
June  2022  
Clinical Pharmacology  
 
    
Assessing the Effects of  
Food on Drugs in INDs  
and NDAs   Clinical  
Pharmacology 
Considerations  
Guidance for Industry 
 
Additional copies are available from:  
Office of Communications,  Division of Drug Information   
Center for Drug Evaluation and Research  
Food and Drug Administration  
10001  New Hampshire Ave., Hillandale Bldg., 4th  Floor   
Silver Spring, MD 20993-0002   
Phone:  855-543-3784 or  301-796-3400; Fax:  301-431-6353  
Email:  druginfo@fda.hhs.gov   
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs  
 
 
 
 
 
 
 
U.S.Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
June 2022 
Clinical Pharmacology  
 
  Contains Nonbinding Recommendations  
 
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION.............................................................................................................  1  
II.   BACKGROUND  ...............................................................................................................  2  
III.   RECOMMENDATIONS  FOR FE STUDIES ................................................................  3  
IV.   CONSIDERATIONS FOR DESIGNING FE STUDIES...............................................  4  
A.    Pilot Studies .................................................................................................................................... 4  
B.    Definitive Studies  ........................................................................................................................... 4  
C.    Types  of Meals to Evaluate  ........................................................................................................... 5  
D.    Subject Selection  ............................................................................................................................ 5  
E.    Test Doses  ....................................................................................................................................... 6  
F.    Administration ............................................................................................................................... 6  
G.   Sample Collection........................................................................................................................... 7  
V.   OTHER CONSIDERATIONS .........................................................................................  7  
A.    FE Study Waivers .......................................................................................................................... 7  
B.    Model-Informed Drug  Development Approaches  ...................................................................... 7  
C.    Drug Products Labeled for Administration With Soft Foods .................................................... 7  
D.    Drug Products Labeled  for Administration  With Special  Vehicles  .......................................... 8  
E.    Specific Populations ....................................................................................................................... 8  
F.    Fixed-Combination Drug Products .............................................................................................. 9  
VI.   DATA ANALYSIS AND LABELING  ..........................................................................  10  
A.   Data Analyses  ............................................................................................................................... 10  
B.    Labeling  ....................................................................................................................................... 11  
APPENDIX 1.  COMPOSITION OF A HIGH-FAT MEAL ..................................................  12  
APPENDIX 2.  COMPOSITION OF A LOW-FAT MEAL ...................................................  13  
APPENDIX 3.  LABELING EXAMPLES  ...............................................................................  14  
 
 
   
 
i   Contains Nonbinding Recommendations  
 
Assessing the Effects of  Food on Drugs in INDs and  NDAs    
Clinical Pharmacology Considerations  
Guidance for Industry1  
 
 
This guidance represents the current thinking of the  Food and Drug Administration (FDA or Agency) on 
this topic.  It does not  establish  any rights for any person and is not binding on FDA or the  public.  You 
can use an  alternative approach if  it  satisfies the requirements of the applicable statutes and  regulations.   
To  discuss an  alternative approach,  contact the FDA  office  responsible for this  guidance  as listed on the 
title page.   
 
 
 
 
I.   INTRODUCTION  
 
This  guidance  provides  recommendations  to  sponsors  planning to  conduct food-effect (FE)  
studies  for orally  administered drug products  under investigational  new drug applications  
(INDs) to support new drug applications (NDAs)  and supplements  to  these  applications  for 
drugs being developed under section 505 of the  Federal  Food, Drug, and Cosmetic Act (21 
U.S.C. 355).  This guidance revises and replaces part of the 2002 FDA  guidance entitled Food-
Effect Bioavailability and Fed Bioequivalence Studies (December 2002).2  Information on fed  
bioequivalence (BE) studies to be submitted in abbreviated new drug applications (ANDAs)  is 
now found in the FDA guidance entitled  Bioequivalence Studies with Pharmacokinetic  
Endpoints for Drugs Submitted Under an ANDA (August 2021).3   Specific recommendations  
concerning fed comparability studies are now described in the FDA guidance  entitled  
Bioavailability Studies Submitted in NDAs or INDs   General  Considerations (April 2022).  
 
The contents of this document do not have the force and effect of law  and are not meant  
to bind the public in any way, unless specifically incorporated into a contract.  This  
document is intended only to provide clarity to the public regarding existing requirements  
under the law.  FDA guidance documents, including this guidance, should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The 
use of the word should in Agency guidance means that something is suggested or  
recommended, but not required. 
 
1  This guidance has been prepared by the Office  of Clinical Pharmacology in the Center for Drug Evaluation and 
Research at  the Food and Drug Administration.   
 
2  We update guidances periodically.   To make sure you have  the most recent version of guidance, check the  FDA 
Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  or 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
3  When final, this guidance will represent the FDAs current thinking on this topic.  
 
  1  Contains Nonbinding Recommendations  
 
 
 
II.   BACKGROUND  
 
Food-drug interactions can have  a significant impact on the safety and efficacy of  orally  
administered drug  products.  These effects can manifest  in different ways.  In some cases,  co-
administration  of an orally administered  drug with food can increase the systemic exposure of  
the drug, potentially leading to an increased pharmacologic effect impacting efficacy and/or  
safety findings.   In other  cases, administration of an orally administered  drug with food can 
lower the systemic absorption of a drug, thereby reducing the efficacy.  Hence, assessing the  
effect  of food on the  absorption of an orally administered  drug contributes  to the optimization 
of  the safety and efficacy of the product  and helps  provide adequate  instructions for drug 
administration in relation to food.  Because diets vary  with respect  to the amount and type of  
food,  and maintaining strict control over the daily content of food can be difficult, developing 
drug formulations that are not affected by food is  strongly encouraged.  However, when 
developing such formulations is not possible, well-conducted FE  studies  can inform how, 
when, and why drugs should or should not be administered with food.   During new drug 
development, pharmacokinetic studies to assess the effect of  food on the systemic exposure of  
the drug are conducted to determine:  (1) if, and to what extent, food impacts the systemic  
exposure of the drug; (2)  whether food changes  the variability of the systemic exposure of the  
drug; and (3) if the  effect of food is different across meals with different  fat or caloric  
contents.  
 
Understanding the  exposure-response relationships  of the drug can be informative in  assessing  
the implications  of FE studies.  Additionally, the impact of  various clinical dosing scenarios  
(e.g.,  under fed or fasted conditions, types of food,  duration of fasting)  is  important to provide  
adequate instructions for  use of the drug.  In  some cases, the clinical pharmacology 
characteristics of the drug  could  suggest that it should be administered only under fasted  
conditions (e.g., when higher exposures under  fed conditions raise the risk of a clinically 
significant adverse reaction).  In such cases, the drug should be administered without food in  the  
clinical trials.  In these trials,  the sponsor should include  a realistic interval  between drug  
administration and food  to include in the product labeling  that patients can  practically  
implement.   In other examples, some drugs  cause  adverse reactions  that can be alleviated when  
taken with a meal.  For example, drugs  that  cause gastric irritation can  adversely impact patient  
compliance or lead to loss of the  administered  dose from vomiting.   In such cases, the drug could 
be administered  with food.  The  sponsor should determine the impact of  food, and when 
necessary, the impact of the type of food, on the  pharmacokinetics  (PK)  of  the drug.  Lastly, in 
some circumstances, co-administration of a drug with food could  be the only practical means of  
ensuring adequate systemic  availability  for the drug to be effective in patients (e.g., food could 
increase the absorption).  In such cases, the drug should be administered with food, and the  
sponsor  should  determine the attributes of the  food that will ensure adequate systemic  
availability to inform the labeling.  
 
Sometimes, the observed increase or decrease in the systemic exposures of some drugs in the  
presence of food might  not be clinically relevant based on  exposure-response information.  If  
appropriately conducted FE studies indicate that food  does not have a  clinically significant 
  2  Contains Nonbinding Recommendations  
 
impact on the  PK  of the  drug, the sponsor can conduct pivotal safety and  efficacy  trials  
without regard to food,  and the labeling can state that the drug can be taken with or without  
food.  
 
The composition of the meal itself can influence  the absorption of a drug.  The physiological  
conditions induced by a  high-fat meal  generally  provide  the  greatest  effects  on gastrointestinal  
physiology  and the maximum effects on the  systemic  availability of the drug.   The 
investigation of the effect of food  on a new drug should include a study with a  high-fat meal.  
For some drugs, the absorption can increase when the drug is given with a high-fat meal, but a 
low-fat meal  could  have inconsequential effects on the absorption of the same drug.  To  
provide dosing instructions in relation to food, FE studies that include additional meal types  
that do  not result in a clinically relevant  effect of food  can be beneficial  and provide useful  
labeling information.  When  drug administration with a high-fat meal causes unacceptable 
increases in PK,  toxicity,  or a loss of  drug efficacy,  it is possible that  a low-fat meal can  have 
less or  no impact  on systemic exposures, improve  patient compliance, and alleviate gastric 
irritation.   In these circumstances,  evaluating the  effect of  additional meal types on the PK of  
the drug can  be helpful.   
 
 
III.   RECOMMENDATIONS FOR FE STUDIES  
 
Generally, sponsors should conduct FE  studies  for new  orally administered drug  products  
including immediate-release products, modified-release products,  and fixed-combination 
products of new,  or  in some cases, previously  approved drugs.   Sponsors are encouraged to 
engage  FDA staff early in the development  of a new drug  regarding the strategy and details  of FE  
studies.  The general recommendations for these  FE studies are as follows:  
 
   Sponsors  should assess the effect of  a high-fat meal on the PK of a new  drug product  
early in  development  to inform the  appropriate dose and administration throughout  
clinical development  and product labeling.   If  an important drug-food interaction is seen 
with a  high-fat  meal,  assessing the interaction with  a lower-fat meal  could  be useful.   
 
   Sponsors should test the effect of food  on a new drug  product  in clinical trials (see  
section IV)  before  conducting the pivotal safety and efficacy trials  to provide  rational 
decisions regarding dosing with respect to food.  Preliminary  assessments  of  the effects  
of food on a new drug in pilot  studies  (e.g.,  as part of the first-in-human trials (see section  
IV))  help determine  whether a drug should be administered with food in clinical trials  
until a to-be-marketed formulation is identified.  
 
   The sponsor should conduct a definitive FE  study  using the  final to-be-marketed  oral  
formulation.  In  cases where the  clinical trial formulation had no significant effect  of 
food,  and the to-be-marketed formulation is not significantly different  from the clinical 
trial formulation,  (see the FDA guidances entitled  SUPAC-MR: Modified Release Solid 
Oral Dosage Forms Scale-Up and Postapproval  Changes: Chemistry, Manufacturing, 
and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation 
(October 1997) and SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up  
  3  Contains Nonbinding Recommendations  
 
and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro 
Dissolution Testing, and In Vivo Bioequivalence  Documentation  (November 1995))  an  
FE study with the to-be-marketed formulation might not be necessary.  Further, an  FE  
study with the to-be-marketed formulation might  not be necessary  in a  situation where a 
biowaiver is accepted for a formulation change  (see the FDA guidance entitled M9  
Biopharmaceutics Classification System-Based Biowaivers  (May 2021)).   The  sponsor  
should discuss  the approach  with the relevant FDA review division.  In cases where the 
clinical trial formulation  is significantly different from the final to-be-marketed  
formulation, the sponsor should conduct a relative bioavailability study to compare the  
systemic exposures and an FE assessment using the to-be-marketed  formulation, if  
appropriate  (for more information refer to the FDA guidance  entitled Bioavailability  
Studies Submitted in NDAs or INDs    General Considerations  (April  2022)).   
 
   When the efficacy or safety of a  new drug  is adversely impacted by food, and fasted  
dosing is necessary, the sponsor should conduct FE  studies  to determine a practical  
interval  of time  between drug administration and food.  The choice of the interval of time  
for dosing should be guided by the  pharmacokinetic  characteristics of the drug.    
 
 
IV.   CONSIDERATIONS FOR DESIGNING FE STUDIES  
 
This  section  provides  general  considerations  for designing  FE  studies.   Sponsors can  propose  
alternative  study  designs and  data  analyses.   The sponsor should provide the  scientific  rationale  
and justifications  for any alternative  study  designs and  data analyses  in  the  study  protocol.  
 
A.    Pilot  Studies  
 
Early in development, the sponsor should  consider  conducting  a pilot  study to provide a  
preliminary assessment of the  effect of  a high-fat meal  on the systemic exposure of the drug.  To  
ensure the safety of the subject population, sponsors should carefully choose the  dose for the FE  
assessment to  account for  any potential significant effects  of food on the  exposure  of the  drug  
that might  increase the number or severity of  adverse events.    
 
B.   Definitive Studies  
 
The sponsor should  generally  use a randomized,  balanced,  single-dose,  two-treatment  (i.e., fed  
versus  fasted),  two-period,  crossover design  to  study  the  effects  of food on the orally 
administered  drug product.  A three-way crossover study can  be conducted if the bioavailability 
of two formulations  is  being assessed  in the same  study  (refer to the  FDA guidance entitled  
Bioavailability Studies Submitted in NDAs or INDs   General  Considerations  (April  2022)).   
The  formulation  to  be  tested  should  be administered  on an  empty  stomach  during  one  period  and  
with  the  high-fat test  meal  during  the  alternate period.  For other types of  food, see section C  
below.   A washout period of  three  to five  elimination half-lives  of the drug  should separate the  
treatments in  the FE  study.  
 
  4  Contains Nonbinding Recommendations  
 
For drugs with long elimination half-lives (i.e., longer than 24 hours), a single-dose, parallel  
study design can be more practical.   In these studies, the sponsor should administer  each  
treatment (i.e., fasted  and  fed) to a separate group of subjects with similar demographics.   
 
The sponsor should enroll an adequate number of  subjects to sufficiently characterize the effect  
of food on the PK of the  drug.  The sample size for each group will depend on the  
pharmacokinetic  variability of the drug.   
 
C.   Types of Meals to Evaluate  
 
For all orally administered drugs under development, an  FE  study with a  high-fat  meal  should be  
conducted.  Sponsors should also consider FE studies with a low-fat meal when administration of  
the oral product with a high-fat meal in the indicated patient population cannot be tolerated.  
Table  1 provides the definition of  various test meals:  
 
Table 1.  Test Meal Definitions  
 
Fat  
Meal Type   Total Kcal  
Kcal   Grams   Percent  
High-Fat4   800-1000   500-600   55-65   >50  
Low-Fat5   400-500   100-125    11-14   25  
 
The sponsor should provide a description of the meal  as well as  the caloric and content  
breakdown (carbohydrates, proteins, and fat) in the study report.  Data collected on the type of  
fat (e.g., percent  saturated fat and percent unsaturated fat)  can be helpful.  Examples of high- and 
low-fat meals are provided in the Appendices and can help guide study design and product  
labeling. 
 
D.   Subject Selection  
 
Sponsors can conduct  FE  studies in  healthy adult  subjects.  Subjects  from  the  patient  population  
can  also  be  appropriate if  safety  concerns preclude  the  enrollment  of healthy  subjects, or if  
differential  effects of food on the drug are expected in the target patient population as compared 
to healthy subjects because of the underlying disease condition.  
 
The sponsor should enroll both male and female subjects  in the FE study unless the indication is  
specific to one sex  (e.g., oral contraceptives), or  if  safety concerns preclude the enrollment of  
one  sex (e.g., if the drug is a  teratogen, women of  child-bearing  age should be excluded).   
Subjects  in FE studies should have normal renal and hepatic function.  Sponsors should exclude  
 
4  See Appendix 1:  Composition of a High-Fat Meal.  The definitions of high-fat and low-fat presented in this  
guidance are intended only for purposes of this guidance.    
 
5  See Appendix 2:  Composition of a  Low-Fat Meal.  The  definitions of high-fat and low-fat presented in this  
guidance are intended only for purposes of this guidance.    
  5  Contains Nonbinding Recommendations  
 
subjects if they cannot refrain from  using  concomitant drugs that  could  confound the  results of 
the  FE study (e.g.,  drugs that  can  alter  the  absorption of other drugs by affecting gastrointestinal 
motility or  by changing the gastric pH  as well as  drugs that  can  increase or  decrease the 
metabolism and excretion of the investigational drug).   
 
E.   FE Study  Doses  
 
The sponsor should use the clinically recommended dose in the  definitive  FE study.  When 
several doses of a drug that exhibit linear PK will be marketed, the sponsor should use the  
highest clinically recommended dose unless safety concerns necessitate a lower dose.  When it  
is unsafe to administer the  highest  dose to healthy subjects, the sponsor can  conduct the study 
in patients or  test the highest strength of the drug product  in lieu of the highest dose  in healthy 
subjects, as long as the PK of the drug over the therapeutic  range  is  linear.   For drugs with 
nonlinear  PK across the therapeutic dose range, the sponsor should conduct single-dose FE 
studies  using both the  high and low doses  listed in  the  proposed  product  labeling.    
 
F.   Administration  
 
1.        Fasted Conditions  
 
Following  an  overnight  fast  of at  least  10 hours, investigators should administer  the  drug product  
to study subjects  with  240 mL  (i.e., 8 fluid  ounces)  of water.   Additional water is permitted  ad lib  
except for the period 1 hour before  until  1 hour after  administration of the  drug product.   The 
study subjects should not consume any food  for at  least  4 hours after the dose.  Subjects  should  
receive  standardized  meals  scheduled  at the  same  time  throughout the  study.  
 
2.        Fed Conditions  
 
Following  an  overnight  fast  of at  least  10 hours, the study subjects  should  start  the recommended  
meal  30 minutes  before  administration  of the  drug product.   Study  subjects  should eat  this  meal  
in  30 minutes  or less.  The study subjects should take the  drug product  with  240 mL  (8 fluid  
ounces)  of water.   Additional  water  is  allowed  ad lib  except  for  the period  1 hour before  until 1  
hour after  drug administration.  No food is  allowed  for at  least  4 hours  after the dose.    
 
3.        Modified Fasted Condition  
 
When  fasted dosing is necessary because food can significantly increase or  decrease the exposure 
of the drug, the standard, overnight,  fasted test condition  might  not  be practical for  patient 
treatment.   Furthermore, the results of the overnight,  fasted condition might  not be applicable to 
shorter periods of  fasting in patients.  To provide  food-drug labeling instructions  (e.g., do not 
consume  food within  X hours before  or Y hours after  drug administration) for such products,  the 
sponsor should conduct FE studies with appropriate separation times between drug 
administration and food consumption.  The sponsor should provide pharmacokinetic data to 
support pragmatic labeling instructions to prevent food-drug interactions, taking into 
consideration the frequency of dosing, the patient  demographics, the disease condition, and any 
other relevant factors.  
  6  Contains Nonbinding Recommendations  
 
 
G.   Sample Collection  
 
For both  fasted  and  fed  treatment  periods,  the  sponsor should collect  samples  in  a suitable 
biological  matrix (e.g.,  plasma)  from  the  study subjects.  To  characterize the  complete  
concentration  versus  time  profile  for the  drug, the  total duration of sampling should cover at least  
three  to five  elimination half-lives  (e.g., 12  to  18 samples per subject per period).   The sponsor  
can use different sample collection times for the fasted and fed treatments  when co-
administration  of a  drug  with  food is expected to alter the time course of  drug concentrations.  To 
determine whether to  measure  other  moieties  in addition to the parent drug  in  the  biological  
matrix,  such as active  metabolites,  sponsors should  refer  to  the  FDA guidance  entitled  
Bioavailability Studies Submitted in NDAs or INDs    General Considerations  (April  2022).  
 
 
V.   OTHER CONSIDERATIONS  
 
A.    FE Study Waivers  
 
Biopharmaceutics  Classification  System class  1 (BCS class 1) drug products  are highly 
soluble, highly permeable, and rapidly dissolving products  that are in most  cases  unaffected by 
food.  Based on FDA experience,  more than 80 percent of BCS class 1 immediate-release drug  
products  are not affected  by high-fat meals; therefore, the labeling for these drug products  
states that they can be administered with  or without  food.  The remaining BCS class 1 drug 
products  are subject to high first-pass metabolism effects or luminal degradation and can be 
affected by meals.  The FDA  may  waive an  FE study for drug products  that are designated as  
BCS class 1 (i.e., high solubility, high permeability),  immediate-release drug  products  as  
defined in the FDA guidance entitled M9 Biopharmaceutics Classification System-Based 
Biowaivers  (May 2021)  that also have a high bioavailability (F  0.85).  Sponsors should 
consult the FDA regarding the feasibility of an  FE  study waiver.  
 
B.   Model-Informed Drug Development Approaches  
 
In conjunction with FE data in subjects, physiologically based pharmacokinetic (PBPK)  
analyses  can  sometimes  be used to further assess the effects of food on a drug.  For  example, 
PBPK models can guide in vitro experimental  designs to generate data that can be used to  
further support PBPK model development, and to  identify and optimize parameters that  are 
important to understanding  and predicting  food-drug interactions in conjunction with FE data.  
PBPK approaches can also be useful to guide clinical study designs.  However, PBPK  
modeling is still evolving, and new  applications of  PBPK  simulation  are continuously being 
evaluated  by the  FDA.   Sponsors are  encouraged to consult the appropriate  review division  
regarding the suitability of the  PBPK  approach.  
 
C.    Drug Products  Intended  for Administration With  Soft Foods  
 
The  labeling  of some orally administered drugs  (e.g.,  oral granules, or extended-release capsules)  
include recommendations for use of the drug product  with  qualified soft food vehicles  (e.g., 
  7  Contains Nonbinding Recommendations  
 
applesauce, pudding).   Soft foods for   use as vehicles  should be identified  and qualified  by in vitro  
assessments to demonstrate  a lack of potential  physicochemical interactions  between the soft  food  and  the  
drug product  (intact or manipulated),  including interactions of  the drug substance  or excipients  with the  
vehicle.  For recommendations on in vitro assessments to select appropriate soft food vehicles for  
drug administration,  refer to the FDA draft  guidance  entitled  Use of Liquids and/or Soft Foods as  
Vehicles for Drug Administration: General Considerations for Selection and In Vitro Methods  
for Product Quality Assessments  (July 2018).6   In vitro  assessments are used to identify and 
qualify potential vehicles but do not replace the need for  an  in vivo evaluation to permit  
instructions for  drug administration with qualified  soft food vehicles  in  labeling.  For the  labeling  
to  indicate  that  the  drug can  be  sprinkled on soft foods, the sponsor should perform additional  in  
vivo,  relative  bioavailability studies using the soft foods listed  as vehicles  in the proposed 
labeling.  A sponsor should provide in vitro study results for all proposed soft food vehicles  and 
should discuss with the relevant  FDA review division to determine if relative bioavailability  
assessment of one soft food vehicle can  be extended to similar  soft food vehicles  (see Pediatrics  
Section below).  
 
D.    Drug Products  Intended  for Intact Administration  
 
Some drug products  should be  swallowed without  chewing.   When the product is to be labeled for  
administration as an intact  dosage  form (tablets, capsules),  a new formulation that is intended to  
be opened, diluted, chewed,  or crushed  should be  compared to the original  formulation  
administered  as  the  intact  form taken with food,  if the  effect of food  on the formulation has not  
already be been  tested.    
 
E.   Drug Products  Intended  for Administration With  Liquids as  Vehicles    
 
The  labeling  of  certain  oral  products  (e.g.,  cyclosporine  oral  solution)  recommends  that  the  
product  be  mixed  with  a  liquid vehicle (e.g.,  beverage)  before  administration.   The 
bioavailability  of these  products  can  change  when mixed  with  different  liquid vehicles  because 
of  the  formation  of complex  mixtures  and  other  physical, chemical,  or  physiological  factors.   
The  qualification of liquids  for their  use as vehicles  should include  an assessment and demonstration of  
lack of  a potential interaction between the liquid  and  the drug product  (intact  or manipulated), including  
interactions of  the drug substance  or excipients with the vehicle.  For recommendations on in vitro 
assessments to select appropriate liquid  vehicles for drug administration, refer to the FDA 
draft  guidance entitled  Use of Liquids and/or Soft  Foods as Vehicles for Drug 
Administration: General Considerations for Selection and In Vitro Methods for Product  
Quality Assessments (July 2018).7   Sponsors should contact the FDA to determine what data  
should  be  submitted  to  support  proposed labeling instructions regarding the  use of  specific 
liquids as qualified vehicles for drug administration.  
  
F.   Specific Populations  
 
 
6  When final, this guidance will represent the FDAs current thinking on this topic.  
 
7  When final, this guidance will represent the FDAs current thinking on this topic.  
  8  Contains Nonbinding Recommendations  
 
1.   Geriatric  Patients  
 
The FDA does not recommend a  dedicated  FE  study  in geriatric patients  (i.e., patients  aged  
65 years  and over).   The  prevalence of  certain diseases (e.g.,  gastro-esophageal reflux  
disease) that  can alter the bioavailability of drugs  increases with age.  However, these  
diseases  do not influence  the effect of food on the bioavailability  of the drug in an  age-
dependent  manner.  
 
2.   Pediatric  Patients  
 
When a new  age-appropriate pediatric formulation is developed, the sponsor should conduct  a 
new  FE  study  with the pediatric formulation in adults.  These results can then be applied to  
the pediatric population.  Sponsors can use foods  and quantities of food that are commonly 
consumed with drugs in a  particular pediatric population (e.g., formula  or milk  for infants  as  
well as  jelly, pudding, or apple sauce  for toddlers).   The outcomes of  FE studies conducted 
with one  soft food vehicle  could  be extrapolated to other  similar soft food  vehicles  (e.g.,  same 
fat,  protein,  and  carbohydrate content)  and could  support proposed labeling instructions. 
However, such extrapolation should be supported by  in vitro data  which demonstrates  a  lack  
of interaction between the  drug product  (intact or manipulated), including lack of interaction with the  
drug substance or  excipients, with  other  similar  soft  food  vehicles  (see section  V(C)).   For  
products intended to be used in pediatric populations with modified diets, discuss  plans  with  
the relevant  FDA review division prior to undertaking a FE study.  
 
Small quantities of  liquids or soft  foods (e.g.,  5-15 mL)  used as vehicles for pediatric drug 
delivery should adhere to the principles described in the FDA draft  guidance  entitled  Use of  
Liquids and/or Soft Foods as Vehicles for Drug Administration: General Considerations for  
Selection and In Vitro Methods for Product Quality Assessments  (July 2018).8  
   
When  a formulation that is approved for use in adults is approved for use in a pediatric  
population  (12 years old),  a separate FE  study  is not necessary.   Furthermore, a separate FE  
study  might  not be necessary if a pediatric formulation is very similar to the adult formulation,  
and if the pediatric formulation is  approved based on a biowaiver  approach.  
 
G.   Fixed-Combination Drug  Products  
 
Fixed-combination drug products  are products with two or more active ingredients combined at a  
fixed dosage in a single dosage form.  Such fixed-combination  drug products  can  exhibit  
different  effects of food compared to  when  each active drug ingredient  is administered alone.   
Therefore, the sponsor should assess the effect of  food on the various active ingredients of the  
fixed-combination drug product after administration of the combination drug product.   An  FE  
study might  not be necessary if neither drug  product  when given alone is affected by food, and 
the sponsor can provide an adequate justification that the  fixed-combination  drug  product  would 
be unaffected by food.  
 
 
8  When final, this guidance will represent the FDAs current thinking on this topic.  
  9  Contains Nonbinding Recommendations  
 
 
VI.   DATA ANALYSIS AND LABELING  
 
A.   Data Analyses  
 
The  following  exposure  measures  and  pharmacokinetic parameters  should  be derived  from  all  FE  
studies  and reported:  
 
   The total  exposure  of the drug  or area  under  the  concentration-time  curve  (AUC ,  
0-INF
AUC )  
0-t
 
   The peak  concentration of the drug  (C )  
max
 
   The time  to  the peak  concentration of the drug  (T )  
max
 
   The time taken for the drug to appear in the systemic circulation following administration  
(Tlag), when applicable  
 
   The elimination  half-life  of the drug (t )  
1/2
 
   The apparent clearance (Cl/F)   
 
   The apparent volume of  distribution (Vd/F)  
 
Individual subject measurements  as well as summary statistics (e.g., group averages, standard 
deviations, coefficients of variation, ranges) should be reported.  
 
For new  orally administered drugs, the  exposure-response relationships for  safety and efficacy 
should be considered when available to assess the clinical impact of  the effect of food.  When a  
fed  bioavailability  study is conducted to assess changes in formulations, an equivalence approach 
is recommended  (refer to the FDA guidance  for industry  entitled  Bioavailability  Studies  
Submitted in NDAs or INDsGeneral  Considerations  (April  2022)).   To  include a statement in  
the labeling  of no effect  of food, the  data should be analyzed using an average criterion, with the 
fasted treatment arm serving as the reference.   
 
Exposure measurements  (AUC and C ) should be log-transformed  before  statistical analysis.  
max
The 90 percent confidence interval  for the ratio of the population geometric means between the 
fed and fasted conditions  should be provided for  AUC , AUC , and C .  An absence of  an 
0-INF 0-t max
effect of food on bioavailability is established if the 90 percent confidence interval  for the  ratio  
of the population geometric means between fed and fasted treatments, constructed based on log-
transformed  data, is contained in the equivalence limits of 80-125 percent  for AUC (AUC
0-INF   0-t 
when appropriate)  and C , unless other criteria based on the established exposure-response  
max
relationships for the drug are more appropriate  (refer to the  FDA guidance entitled  Statistical 
Approaches to Establishing Bioequivalence  (February 2001)).  When the 90 percent  confidence 
interval  for the  ratio of the population geometric  means of either  AUC (AUC when 
0-INF   0-t 
appropriate)  or C  between fed  and fasted treatments fails to meet the limits of 80-125 percent, 
max 
  10   Contains Nonbinding Recommendations  
 
the sponsor should provide specific  recommendations on the clinical significance of the effect of 
food  based on what is known about  the exposure-response  relationships of the drug and the  
totality of the clinical information.  The clinical relevance of any difference in T  and T  
max  lag 
should also be indicated by the sponsor.  
 
B.    Labeling  Recommendations  
 
Labeling should include  a summary of essential information pertaining to the effect of  food on 
the PK and  pharmacodynamics  of an  orally administered  drug (if known) that is needed for the  
safe and  effective use of  the drug.   See the FDA  guidance entitled  Clinical Pharmacology  
Section of Labeling for Human Prescription Drug and Biological Products    Content and 
Format  (December 2016)  for more information.  The effect of  food on the  absorption of orally 
administered drugs should be described under  a subheading called Effect of Food under the  
Absorption  heading  in the  Pharmacokinetics  subsection of the CLINICAL  
PHARMACOLOGY section.  The Effect of  Food  subheading should include detailed 
information that informs actionable recommendations.   The specific dosing instructions related 
to food should be  described  in the DOSAGE AND ADMINISTRATION section of labeling  with  
a cross-reference  to the CLINICAL PHARMACOLOGY section.9   Other  FE information in  
labeling should be included in other sections of labeling as  appropriate  (e.g., WARNINGS AND 
PRECAUTIONS, PATIENT COUNSELING INFORMATION).   Orally administered drugs that 
are unaffected by food should be labeled as take with or without  food  in the DOSAGE  AND 
ADMINISTRATION section.   See Appendix 3 of  this guidance for examples of incorporating 
FE information in labeling.  
 
When the DOSAGE AND ADMINISTRATION section of labeling  provides an actionable 
recommendation that is not the result of a pharmacokinetic or pharmacodynamic effect (e.g., 
dosing with food to reduce  nausea),  the  rationale  for the recommendation should be stated and 
the appropriate section with the rationale should be cross-referenced.  
 
9  See the FDA guidance entitled  Dosage and Administration Section of Labeling for Human Prescription Drug and 
Biological Products  - Content and Format  (March 2010).  
 
  11   Contains Nonbinding Recommendations  
 
APPENDIX 1.  COMPOSITION OF A HIGH-FAT MEAL*   
 
Total Calories   800-1000 
 
 
Calories from Protein   150 
 
 
Calories from  
250 
Carbohydrates  
 
 
Calories from Fat   500-600 
 
 
Percent Calories from  
>50 
Fat  
 
 
   Two eggs fried in butter  
An Example of a  High-    Two strips of bacon  
Fat Breakfast      Two slices of  toast with butter  
     Four ounces of hash brown potatoes  
   Eight ounces of whole milk 
 
*50 percent of calories are  derived from fat.  Substitutions can be made to this  meal if  the content, volume, and 
viscosity are  maintained.  
  12   Contains Nonbinding Recommendations  
 
APPENDIX 2.   COMPOSITION OF A LOW-FAT MEAL  
 
Total Calories   400-500  
 
 
Calories from  Fat    100-125  
 
 
Percent Calories from  
25  
Fat  
 
 
An Example of a Low-    Eight ounces milk (1 percent fat)  
Fat Breakfast*      One boiled egg  
     One packet flavored instant oatmeal made with  water  
 
*This low-fat breakfast contains 387 calories and has 10 grams of fat. 
  13   Contains Nonbinding Recommendations  
 
APPENDIX 3.  LABELING EXAMPLES  
 
The following are  examples of incorporating food-effect information in the DOSAGE AND 
ADMINISTRATION section of labeling and the  Pharmacokinetics subsection in the CLINICAL  
PHARMACOLOGY section of labeling for DRUG-X (drugoxide tablets).  
 
Example 1 
2 DOSAGE AND ADMINISTRATION  
2.1 Recommended Dosage  and Administration  
The  recommended dosage of  DRUG-X is 500 mg orally once daily.  Take daily on 
an empty stomach at least  2  hours before or  1 hour after  food  [see Clinical 
Pharmacology (12.3)].  
 
12 CLINICAL PHARMACOLOGY  
... 
12.3 Pharmacokinetics  
Absorption  
Effect of Food  
Drugoxide  Cmax  increased  57%, and  the  AUC  increased  45%  with  a  high-fat  
meal  (1000 calories, 50% fat)  compared to fasted conditions  following 
administration  of  DRUG-X  to  healthy  subjects.    
 
 
Example 2 
2 DOSAGE AND ADMINISTRATION  
2.1 Recommended Dosage  and Administration  
The  recommended dosage of  DRUG-X is 250 mg orally twice daily.  Take with a  
low-fat  meal  (e.g., meals with 400 calories, 25%  fat  or  less) or on an empty 
stomach  [see Clinical Pharmacology (12.3)].  
 
12 CLINICAL PHARMACOLOGY  
... 
12.3 Pharmacokinetics  
Absorption  
Effect of Food  
Drugoxide  Cmax  and  AUC  increased  74% and  87%, respectively,  with  a  high-fat  
meal  (1000 calories, 50% fat)  compared to fasted conditions.   No clinically  
significant differences in  drugoxide  pharmacokinetics were observed  following  
administration  of  DRUG-X  with  a low-fat  meal (400 calories, 25% fat)  to  healthy  
subjects.     
 
 
Example 3 
2 DOSAGE AND ADMINISTRATION  
2.1 Recommended Dosage  and Administration  
The recommended dosage of DRUG-X is 400 mg orally once daily.  Take  with a meal  
containing 400-1000 calories, 25-50% fat  [see Clinical Pharmacology  (12.3)].  
 
12 CLINICAL PHARMACOLOGY  
  14   Contains Nonbinding Recommendations  
 
... 
12.3 Pharmacokinetics  
Absorption  
Effect of Food  
Drugoxide  Cmax and AUC  increased  15% and  65%  with a low-fat meal (400 
calories, 25% fat)  and 17% and 73%  with a  high-fat meal  (1000 calories, 50% fat), 
respectively,  following administration  of  DRUG-X to  healthy subjects  compared 
to fasted conditions.      
 
 
Example 4 
2 DOSAGE AND ADMINISTRATION  
2.1 Recommended Dosage  and Administration  
The recommended dosage of DRUG-X is 800 mg orally twice daily.  Take  with or  
without food  [see Clinical Pharmacology  (12.3)].  
 
12 CLINICAL PHARMACOLOGY  
... 
12.3 Pharmacokinetics  
Absorption  
Effect of Food  
No clinically significant differences in  drugoxide  pharmacokinetics were 
observed following administration of a high-fat meal (1000 calories, 50% fat) to  
healthy subjects.  
 
 
Example 5 
2 DOSAGE AND ADMINISTRATION  
2.1 Recommended Dosage  and Administration  
The  recommended dosage of  DRUG-X is 400 mg orally once daily with food [see Warnings 
and Precautions (5.x)]  (see SECTION X).  
 
  15