This information is covered under Food and Drug Administration guidance titled, “Food-Effect Bioavailability and Fed Bioequivalence Studies.”
Food effect bioavailability (BA) studies and fed bioequivalence (BE) studies are both used during the investigational phase of drug research. BA studies are typically conducted during the investigational new drug (IND) period in Phase 1 studies 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 typically conducted for abbreviated new drug applications (ANDAs) to demonstrate their bioequivalence to the reference listed drug (RLD) under fed conditions. However, fed BE studies may also be conducted for new drugs when definitive information regarding a possible food effect is required.
In this blog post you will learn:
1) A brief overview of Food Effect Studies
2) Study Considerations for Fed BA and BE Studies
3) Measuring Food Effects
Food Effect Studies
Food can change the rate and extent of absorption of drugs administered orally and the FDA requires the determination of a food effect for most drugs. One possible food effect is defined by changes in pharmacokinetic parameters where a reduced Cmax and delayed Tmax are observed under fed conditions relative to fasted. In this situation, engaging a pharmacokineticist during protocol development to devise a proper PK blood sampling schedule is important as consideration must be given to the possibility that food can alter the time course of plasma drug concentrations. A full PK profile must be generated based on an adequate sampling schedule or the study may fail to meet its objective of determining a food effect.
Possible outcomes of a food effect study include:
- No effect of food
- Delay in absorption (later Tmax) with a lower Cmax and no change in AUC
- Lower Cmax and lower AUC
- Higher exposure, with increase in Cmax and/or AUC
Immediate Release Drug Products
Food can alter the BA by various means, including:
- Delaying gastric emptying
- Stimulating bile flow
- Changing gastrointestinal (GI) pH
- Increasing splanchnic blood flow
- Changing luminal metabolism of a drug substance
- Physically or chemically interacting with a dosage form or a drug substance
For new drug applications (NDAs) and INDs, a food-effect BA study should be conducted for all new chemical entities. 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 can be used to design clinical safety and efficacy studies and to provide information for the product labels.
Among ANDAs for orally administered immediate-release drug products, BE studies under fasting and fed conditions are recommended with two caveats. Studies are usually not recommended when both the test product and the RLD are rapidly dissolving, have similar dissolution profiles and / or contain a drug substance with high solubility and high permeability (BCS Class I). They are also not recommended when the dosage and administration section of the RLD label states that the product should be taken only on an empty stomach or when the RLD label does not make any statements about the effect of food on absorption or administration.
Study Considerations for Fed BA and BE Studies
The guidance 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.
Both types of studies are usually conducted in healthy volunteers drawn from the general population. However, studies in a patient population are appropriate if safety concerns preclude the enrollment of healthy subjects. Usually a minimum of 12 subjects should complete the food-effect BA and fed BE studies but for BE studies sample size calculations should be made to insure a valid statistical outcome.
In general, the highest strength of a drug product intended to be marketed should be tested in food-effect BA and fed BE studies. The guidance recommends that studies use meal conditions 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. The test meal should derive approximately 150 calories from protein, 250 calories from carbohydrate and 500-600 calories from fat.
- Fasted Treatments: Following an overnight fast of at least 10 hours, subjects should be given the drug product with eight ounces of water. A further fast of four hours should occur post-dose.
- Fed Treatments: Following an overnight fast of at least 10 hours, subjects should start the recommended meal 30 minutes prior to being given the drug product. Subjects should eat this meal in 30 minutes or less, with the drug product given 30 minutes after the start of the meal. As with the fasted treatment, the drug product should be given with eight ounces of water, and subjects should fast for four hours post-dose.
Measuring Food Effects
Food-effect BA studies may be exploratory and descriptive, or a Sponsor may want to use a food effect BA study to make a label claim. The following exposure measures and pharmacokinetic parameters should be obtained from the resulting concentration-time curves for the test and reference products in food-effect BA and fed BE studies:
- Total exposure, or area under the concentration-time curve (AUC0-inf, AUC0-t)
- Peak exposure (Cmax)
- Time to peak exposure (Tmax)
- Lag-time (tlag) for modified-release products, if present
- Terminal elimination half-life
- Other relevant pharmacokinetic parameters
Individual subject measurements, as well as summary statistics (e.g., group averages, standard deviations, coefficients of variation) should be reported. An equivalence approach is recommended for food-effect BA (to make a claim of no food effects) and fed BE studies, analyzing data using an average criterion. Log-transformation of exposure measurements (AUC and Cmax) prior to analysis is recommended.
The 90 percent confidence interval for the ratio of population geometric means between test and reference products should be provided for AUC0-inf, AUC0-t, and Cmax. 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.