The US Food and Drug Administration (FDA) on Monday published two new draft guidance documents providing recommendations to sponsors planning to conduct food-effect (FE) studies for orally administered drug products and for sponsors submitting bioavailability (BA) information.
Both draft guidances deal with how the body absorbs drugs and whether certain foods could have an impact on drug efficacy.
“There are many factors at play to properly formulate a drug so that it’s released into the body in the most effective and efficient way to achieve clinical effect. In addition to the makeup of the drug itself, the way it’s absorbed in the body may change based on our own physiology, whether or not we take a drug with food, and even what types of food we eat throughout the day. All of this can impact the drug’s efficacy and safety,” said FDA Commissioner Scott Gottlieb.
The 27-page draft guidance includes recommendations on how companies can meet the BA requirements set forth in the regulations, in addition to providing recommendations on conducting relative BA studies during the investigational new drug (IND) application period for a drug intended to be submitted in a new drug application.
BA relates to the rate and extent of active ingredient absorption by the body and availability at the site of action, data on which can inform the overall safety and efficacy.
The draft is divided into separate categories covering study design considerations, assessing BA for various dosage forms, additional information on in vitro
approaches, special topics and three appendices.
Specific dosage forms and the ways to assess BA are also outlined, including for solutions and other solubilized dosage forms, capsules, tablets (including conventional, buccal, chewable, orally disintegrating and sublingual dosage forms), suspensions and modified release products.
Among the special topics are sections covering discussions of enantiomers versus racemates, drug products with complex mixtures as the active ingredients, drugs with long half-lives, orally administered drugs intended for local action, combination and coadministered drugs, endogenous substances, narrow therapeutic index drugs and characterizing the effects of alcoholic beverages on modified release drugs.
The 14-page draft guidance on food-effect (FE) studies features recommendations for such studies, when they should occur and considerations for designing studies, data analyses and labeling, among other considerations.
According to the draft, pharmacokinetic studies to assess the effect of food on the systemic exposure of the drug can help determine: “(1) if, and to what extent, food impacts the systemic exposure of the drug; (2) whether food increases or decreases 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.”
If FE studies indicate that food does not have a clinically significant impact on the pharmacokinetics (PK) of a drug, the draft says that sponsors can conduct pivotal trials without regard to food, and the labeling can state that the drug can be taken with or without food.
However, in other cases, clinical pharmacology characteristics of the drug may suggest that a drug be administered only under fasted conditions, or in other cases, drugs have undesired side effects that can be alleviated when taken with a meal, or in others, the evaluation of the effect of additional meal types on the PK of the drug may be helpful, FDA says.
Regardless, the agency calls for early studies to help identify absorption challenges earlier in the development process.
“The sponsor should conduct 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,” the draft says.
Bioavailability Studies Submitted in NDAs or INDs — General Considerations Draft Guidance for Industry
Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical Pharmacology Considerations Draft Guidance for Industry