Food Effect Studies
Food Effect Studies are necessary as food may affect drug Bioavailability by delaying gastric emptying, physically or chemically interacting with a drug, altering the gastrointestinal pH, stimulating bile flow, increasing splanchnic blood flow, and altering luminal drug metabolism. Another level of complexity is added by the fact that the volume, temperature, nutrients, and calories of a meal all influence its potential effect on drug bioavailability. The most pronounced food effects are observed when a drug is administered briefly after a meal, especially when consumed by a high-calorie or high-fat meal.
Food Effect Studies Key Component of Clinical Drug Development
Due to the potential for a pronounced influence of food on drug bioavailability, food effect studies have become an essential component of clinical drug development. Food effect studies evaluate the effects of food on the bioavailability (defined by the extent and rate of absorption) of orally administered New Chemical Entities (NCEs) or New Investigational Medicinal Products (IMPs).
In other words, food effect studies compare the bioavailability of NCEs and IMPs administered soon after a meal (under fed conditions) to their bioavailability when administered under fasting conditions. Key pharmacokinetic parameters are examined, including the total exposure, peak exposure, time to peak exposure, lag-time for modified-release products, and terminal elimination half-life of particular drug formulations. When generic drugs or drugs with modified formulations are evaluated, food effect studies to assess their bioequivalence to reference drugs under fed conditions are generally required.
The Significance of Initiating Food Effect Studies Early
When indicated, food effect studies should be completed before submitting a new drug application (NDA) or an abbreviated new drug application (ANDA) when it’s applicable. However, initiating food effect studies early during the clinical drug development process is advantageous because it enables the selection and, if needed, modification of drug formulations used in advanced clinical trials.
Challenges Associated with Food Effect Studies
The design and performance of food effect studies are associated with several significant challenges.
Close safety monitoring
The participants’ safety should be monitored closely during food effect studies. The safety monitoring strategy should include a baseline set of safety assessments, the safety profile when the drug given without food. An adaptive design may be responsive to the emerging study data, and, if necessary, additional safety measures to specifically address safety signals detected in the preclinical program or relevant to the pharmacology or therapeutic targets of the NCE or IMP.
Ensuring participants’ compliance with the study protocol, including meal consumption
High-calorie and high-fat meals are generally used in food effect studies. The complete consumption of the test meal and compliance with the fasting period should be ensured to appropriately examine the food effect on drug bioavailability.
Selection of the most appropriate drug formulation
In general, the highest-strength formulation of an NCE or IMP should be tested in food effect studies. However, in certain cases, clinical safety concerns may warrant using a drug formulation with lower strength. In addition, for ANDAs, the fasting and fed bioequivalence studies should use the same strength and a lot of a dosage form.
Designing an appropriate schedule for pharmacokinetic blood sampling
Food consumption may affect key pharmacokinetic parameters, including reducing the peak exposure and a delay in the time to peak exposure under fed conditions. Therefore, developing an appropriate pharmacokinetic protocol and an optimal pharmacokinetic blood sampling schedule is essential to generating a complete pharmacokinetic profile of the NCE or IMP. This, in turn, enables the determination of potential food effects. Since the food effect study comparing the drug’s bioavailability with (fed) or without food (fasting), so different sampling schedule in food effect study may be necessary if food expected to alter the time to reach the peak plasma level.
Correctly predicting the solubility & permeability of NCEs or IMPs administered with food
The solubility and permeability of NCEs or IMPs should be properly evaluated to predict/assess the potential safety of drug administration with food.
Careful statistical aspect planning of the study
Ensuring sufficient power of the food effect study is a prerequisite for the acquisition of valid study data. Moreover, the statistical analysis plan for the study should be considered during the preparation of the study protocol.
Efficient Design and Performance of Food Effect Studies
BioPharma Services, Inc. has extensive expertise in conducting all early-phase clinical trials, including food effect studies. We have designed and successfully performed more than 2,000 early-phase clinical trials, including over 20 food effect studies. Under the leadership of our chief scientific officer (CSO), Dr. John Oldenhof, BioPharma’s excellence has been recognized with over 20 awards and distinctions.
Dr. John Oldenhof
Chief Scientific Officer & Executive VP of Scientific Affairs
Dr. Oldenhof has over 18 years of senior management experience in Phase 1 clinical pharmacology, product development, biostatistics, data management, and regulatory and scientific affairs.
Dr. Janice Faulknor
Medical Director & Principal Investigator
Dr. Janice Faulknor has over 15 years of experience as a PI or sub-investigator of over 100 clinical trials in various therapeutic areas.
BioPharma employees include over 250 multidisciplinary experts, among which there are at least 8 Ph.D. graduates. Our multidisciplinary team that designs and conducts food effect studies includes pharmacokinetic scientists, pharmacologists, physicians, pharmacists, bioanalytical laboratory scientists, biostatisticians, medical writers, and volunteer recruitment and screening specialists.
High-Quality Full-Service Solution for Food Effect Studies
Our team has extensive experience designing and conducting all aspects of food effect studies, from program/trial design to the generation of a clinical study report (CSR).
Comprehensive design of food effect studies and generation of a study protocol
Our pharmacokinetic team competently designs food effect studies based on the available information from preclinical data, product information, or, in cases of a 505 (b)(2) new formulation of an existing compound, the literature. The key elements of the study design including the product information, required sample size to maintain the statistical power, proper blood samplings based on known or predicted pharmacokinetic profile, study population, safety measurements etc. Moreover, the scientific rationale/design for the food effect study is clearly defined in the study protocol.
Generally, food effect studies are designed as crossover, two-period studies where the subjects in one of the study arms receives the study drug under fed conditions and the subjects in the other arm are dosed under fasting conditions. A proper pharmacokinetic blood sampling schedule is designed by our pharmacokinetic scientists to clearly determine the pharmacokinetic profile of the evaluated NCE or IMP. Next, our experienced medical writing team generates the study protocol based on the study design.
Efficient subject recruitment and screening
Food effect bioavailability and fed bioequivalence studies are generally performed on normal healthy volunteers (NHVs). Under certain conditions, when safety concerns arise, the studies may also be conducted on patient populations. BioPharma Services has developed a database including more than 18,000 NHVs and individuals from special populations. We have also established a comprehensive screening procedure with patient safety as our highest priority. Thus, we are able to efficiently recruit participants for all early-phase clinical trials, including food effect studies.
Under their guidance, the clinical team conducts food effect studies as per protocol dosing and obtains plasma samples at predefined periods. Our clinical team conducts all early-phase clinical studies, including food effect studies, in our state-of-the-art Phase 1 center in Toronto, Canada. Our center is equipped for extensive safety monitoring, including dedicated Phase 1 intensive monitoring units.
In-house bioanalytical capabilities
BioPharma’s bioanalytical team, led by Dr. Nicki Hughes, analyzes the plasma samples obtained during the course of food effect studies using well-validated methods. The bioanalysis is performed in our in-house bioanalytical laboratory, whose good laboratory practice (GLP) has been certified by the Standards Council of Canada (SCC). Our bioanalytical team can perform in-house liquid chromatography with tandem mass spectrometry (LC/MS/MS) analysis that enables the confirmation and quantification of low-abundance analytes.
Expert statistical support
Our team of experienced statisticians can support all statistical aspects of the study, including developing a statistical analysis plan, performance of a power analysis, safety data management, and statistical analysis of the findings using Statistical Analysis Software (SAS).
Preparation of the CSR
Finally, the pharmacokinetics team reviews the study results and prepares the pharmacokinetic and statistical sections to be incorporated in CSR, and the medical writing team finalizes the CSR with all necessary tables following ICH template as per specific regulatory submission purpose.
Implications of Food Effect Studies for the Clinical Drug Development Process
Food effect studies play a critical role in understanding how food affects the bioavailability of oral drug candidates and, if indicated, should be completed before the submission of an NDA or an ANDA. The obtained bioavailability information can be used in the design of further clinical safety and efficacy studies. Eventually, it may also have implications for the instructions on product labels on whether drug administration should be related to food intake.
BioPharma’s multidisciplinary team of experts assists study sponsors with interpreting the findings from food effect studies and with the decisions regarding their implementation in the next stages of clinical drug development.
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Food Effect FAQ
What is Food-Effect Bioavailability Study?
Food-effect Bioavailability studies are studies to evaluate the potential impact of food on the rate and extent of absorption of the investigational product. Food can alter Bioavailability 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
What is Fed Bioequivalence Study?
Fed Bioequivalence studies are studies to evaluate the bioequivalence between the test and reference product under fed conditions.
What is the Difference Between Food-Effect Bioavailability and Fed Bioequivalence Studies?
Food effect Bioavailability studies are usually conducted for new drugs and drug products during the IND period to assess the effects of food on the Bioavailability of a drug when the drug product is administered shortly after a meal (fed conditions), as compared to administration under fasting conditions.
Fed Bioequivalence studies, on the other hand, are conducted for ANDAs to demonstrate their bioequivalence to the reference listed drug (RLD) under fed conditions.
When Are Food-Effect Bioavailability or Fed Bioequivalence Studies Required?
It’s recommended to perform a food-effect Bioavailability study for all new chemical entities during the IND period. They are often done early in the drug development process to guide and select formulations for further development.
Single-dose Bioequivalence studies under fed conditions are generally required for most FDA ANDA submissions for both immediate-release (IR) and extended-release (ER) formulations. For EMA and TPD, Bioequivalence studies under fed conditions might be waived for IR formulations.
Why Are Food-Effect Bioavailability Studies Necessary?
Administration of a drug product with food may change the Bioequivalence by affecting either the drug substance or the drug product (i.e., formulation). This impact is difficult to determine the exact mechanism without performing specific mechanistic studies. Food-effect Bioavailability studies evaluate the impact of food on the Bioavailability of the product, which is critical for drug administration direction in the label.
Likewise, understanding your drug substance and formulation allows the sponsor to predict the potential interaction and mechanism, while the actual studies confirmed the effect on Pharmacokinetic profiles. Some important features should be considered before planning for food-effect Bioavailability or Fed Bioequivalence studies, including but not limited to:
- General Design
- Sample Size and Study Population
- Dosage Strength
- Test Meal and Drug Administration
- Sample Collection