Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Dr. Dakshina Chilukuri, a clinical pharmacology reviewer in CDER’s Office of Clinical Pharmacology. Dr. Chilukuri will be sharing some thoughts with us on the newly published final guidance titled, “Bioavailability Studies Submitted in NDAs or INDs – General Considerations.” Welcome, Dr. Chilukuri! Thank you for speaking with us today.
Dr. Chilukuri, for listeners who may not be familiar with this topic, what is bioavailability, and how does it inform the regulatory review process?
Bioavailability (also called BA) is the rate and extent an active ingredient from a drug is absorbed in the body and becomes available at the site of action to produce a pharmacological effect. BA data generally provide information about the amount of active drug ingredient systemically absorbed in the body, the change in this concentration over time, and whether increasing the dose of the drug also proportionally increases the amount of systemically-absorbed active drug ingredient.
Relative or comparative BA for an orally administered drug product can be measured by comparing the plasma exposure profile of the orally administered drug to that of a suitable reference product. Absolute BA is measured using an intravenous reference product, and relative BA is measured using an oral reference product.
BA studies are important in the regulatory review process because BA data help determine the appropriate dose for a medication that is both safe and effective. Comparative BA assessments also help determine whether dose adjustments are required for different formulations and/or conditions of administration.
Can you give us a brief overview of the evolution of this guidance? Are there specific changes that you want to highlight?
Sure, FDA published the first version of this guidance in 2002, and it covered the broad subject of BA studies and bioequivalence (also called BE) studies in new drug applications (which are called NDAs) and abbreviated new drug applications (which are called ANDAs). Overtime, we have realized the need for guidance providing recommendations consistent with the evolving science and drug development best practices for new drugs and generic drug products separately. In 2014, FDA issued a draft version that provided recommendations for BA and BE studies in the NDA pathway alone and removed the recommendations for the ANDA pathway to be published in a separate guidance. Then in 2019, FDA published a revised draft version that focused solely on BA studies. We are now publishing this final version of this guidance, and it contains a few technical changes from the 2019 version made to address the public comments received and changes to improve the clarity of the document.
Can you provide a general overview of the guidance and potentially delve into how it provides recommendations for different dosage forms?
Yes, this guidance provides recommendations for demonstrating BA using both in vitro and in vivo approaches. The in vitro approaches discussed include dissolution studies and the in vivo approaches discussed include pharmacokinetic studies, in vitro-in vivo correlation evaluations, pharmacodynamic studies, and comparative clinical studies.
The general principles for conducting BA studies included in this guidance are for studying simple dosage forms intended for oral administration, such as oral solutions, tablets, and capsules, but can also be applied to non-orally administered drugs that rely on systemic exposure measures to determine BA, such as transdermal delivery systems. For complex formulations, this guidance provides detailed recommendations regarding the conduct of BA studies supporting the approval of modified release products, and we encourage sponsors to contact the appropriate review division for specific questions about demonstrating BA for complex formulations not discussed in this guidance.
How should sponsors design bioavailability studies, and when should they 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. 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. 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.
Depending on the context, a BA assessment may be needed at various stages of the drug development process. When a specific BA study should be performed depends on the what information sponsors are seeking from the 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.
For our final question, can you provide a couple of key items that you especially want listeners to remember?
Sure. First, I hope listeners remember that BA assessment is a critical element to help determine the safety and efficacy in new drug development as well as drug product lifecycle
Second, it is important to know that different dosage forms of a drug can require different BA approaches, and for orally administered drug products, consumption of food can affect BA measurements, which is something we hadn’t yet discussed on this episode. This guidance provides detailed recommendations for BA approaches for multiple dosage forms and provides specific recommendations for when to conduct BA studies with food, and under what scenarios. There is a separate guidance that describes the expectations and methods for conducting food-effect studies.
Lastly, I want listeners to remember that if sponsors make changes to the drug product, dosing, route of administration, etc. during their drug development program, BA studies may need to be conducted to ensure their drug products are adequately evaluated and characterized.
Dr. Chilukuri, thank you for speaking with us today about the final guidance on bioavailability studies submitted in NDAs or INDs. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this final guidance.
To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.