FDA bioavailability guidance takes industry feedback into consideration

Posted 14 April 2022 | By Ferdous Al-Faruque 

FDA bioavailability guidance takes industry feedback into consideration

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The US Food and Drug Administration (FDA) has published a final guidance on the bioavailability (BA) data drug sponsors should include in their premarket applications. The guidance has been several years in the making after garnering significant feedback from industry, which the agency says it has addressed in the latest version.
FDA published the Bioavailability Studies in NDAs or INDs–General Considerations guidance on 14 April, which outlines the agency’s current thinking on bioavailability data that sponsors should include in investigational new drug (IND) applications, new drug applications (NDA) and NDA supplements. The guidance is finalized from the 2019 draft guidance issued by the Center for Drug Evaluation and Research (CDER), which itself was an update from an earlier 2014 draft guidance. (RELATED: FDA Drafts 2 New Guidances on Effects of Food on Drugs, Bioavailability Studies, Regulatory Focus 25 February 2019)
BA is defined by FDA as the rate or extent to which the active ingredient of a drug is absorbed at the site of action by patients. It helps inform the right dosage levels depending on various factors such as the patient’s physical characteristics and whether they have eaten any food alongside the drug.
“This guidance contains recommendations on how to meet the BA requirements … as they apply to dosage forms intended for oral administration,” FDA states. “These dosage forms include tablets, capsules, solutions, suspensions, conventional (e.g., immediate-release (IR) drug products) and modified-release (MR) (e.g., extended-release (ER), delayed-release (DR)) drug products.”
The agency notes the guidance can also be applied to some non-orally administered drugs when appropriate such as those taken through the skin, vaginally and rectally.
“The guidance provides recommendations on conducting BA studies during the investigational period for a drug intended to be submitted for approval in an NDA and bioequivalence (BE) studies during the postapproval period for certain changes to drug products with an approved NDA,” FDA added.
In an FDA Guidance Recap Podcast, Dakshina Chilukuri, a clinical pharmacology reviewer in CDER’s Office of Clinical Pharmacology summarized the agency’s expectations for BA studies and how they should be performed during drug development.
“Generally, BA studies should be conducted in healthy volunteers under fasted conditions using the highest strength of the drug with an adequate washout period between treatments,” he said. “It is important that sponsors include adequate samples and sampling time points in the study design to achieve sufficient power for the analyses.
“BA studies are typically conducted using a crossover design,” he added. “However, if a crossover study design is problematic, for example when studying a drug with a long half-life, a parallel design can be used.”
Chilukuri also noted BA assessments may be needed at various stages of the drug development process depending on what information sponsors are looking for from their analysis.
“For example, absolute BA studies are usually conducted early in drug development when oral and IV formulations become available, whereas BA studies establishing in vivo similarity between a clinical trial formulation and a to-be marketed formulation are typically conducted later in drug development, often close to the NDA submission,” he said.
FDA also said it tried to accommodate stakeholder feedback before finalizing the guidance by making certain changes from the 2019 draft version including specifying that individual pharmacokinetic profiles will be considered for products with complex release characteristics; clarifying that if the drug labeling specifies the drug to be taken with food but does not elaborate on the fed conditions, the sponsor should use a high-fat meal as the fed condition; adding statistical approaches for dissolution; clarifying that enzymes can be added to the dissolution medium to better understand the effect of over-encapsulation on drug release; and removing the 10 percent alcohol level for dose-dumping studies.
Despite the changes, there are a number of stakeholder concerns the agency seems to have passed on. (RELATED: Drugmakers Call for Changes to FDA Bioavailability Guidance, Regulatory Focus 24 June 2019)
For instance, Pfizer and PhRMA had questioned why FDA removed bioequivalence from the title of the guidance, when bioequivalence studies are still referenced.
“This guidance focuses on BA studies, whereas the guidance it will replace covered both BA and BE studies,” Pfizer wrote in its comments on the draft guidance. “It is not clear if there will be another guidance to address BE studies.”
AstraZeneca similarly requested that FDA replace mentions of BE with BA. “If demonstration of BE is not a requirement, we suggest replacing ‘BE studies’ with ‘BA studies’ in this guidance,” the drugmaker said in its comments.
Instead of taking out references to BE, FDA notes that it has only included BE studies to evaluate changes to drugs that have received an NDA in the postmarket setting.
The agency also notes the guidance does not address BE for abbreviated new drug applications (ANDAs) and ANDA supplements. Rather, regulators published a separate draft guidance on the topic titled, Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA in August 2021.


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