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. Vikram Arya, the Associate Director for Therapeutic Review in the Division of Infectious Disease Pharmacology and Dr. Brian Booth, the Director of the Division of Cancer Pharmacology I. Both are in CDER’s Office of Clinical Pharmacology. Dr. Arya and Dr. Booth will be sharing some thoughts with us on the newly published final guidance titled, “Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations.” Welcome, Dr. Arya and Dr. Booth. Thank you for speaking with us today.
Let’s begin with Dr. Arya. Can you explain to the audience why assessing the effects of food on drugs is important and provide some of the reasons that FDA issued this document?
Yes, I’d be happy to. Orally administered drugs enter the body through the gastrointestinal tract of our digestive system. Assessing the effect of food on drugs is important because food can affect the physiology of the gastrointestinal tract and thereby alter the ability of our body to absorb certain drugs. Some types of food can cause the absorption of a specific drug to increase or decrease, and other types of food may not show any effect on the absorption of the same drug. It is important to assess the effect of food on a drug because food can have a significant impact on the safety and effectiveness of the drug. If the absorption of the drug is increased by food, it can cause an increase in the number of adverse events and side effects. Conversely, if food decreases the absorption of the drug, it has the potential to make the drug less effective.
The FDA issued this document to provide best practices for conducting food effects studies. From a drug development and regulatory review standpoint, we are interested in three broad considerations. First, we want to assess if the absorption of a drug is affected by the consumption of food. Second, if food does have an effect on a drug’s absorption, we next want to understand what type of food affects the drug’s absorption and also identify the specific effect of each food type. Lastly, we want to comprehensively review the study results and develop practical food intake instructions in the prescribing information that explain when to take the drug relative to eating food that affects the drug’s absorption.
The next two questions are for Dr. Booth. When should food effects studies be conducted during drug development?
The FDA recommends conducting food effect studies early in development. Generally speaking, a preliminary food assessment (called the pilot food effect assessment) should be conducted as part of the first-in-human single dose trial. In this preliminary assessment, a cohort of subjects are administered the drug in the presence and absence of food. This initial study is not a definitive food effect study, rather a preliminary assessment that helps inform dosing strategies for subsequent phases of drug development until a to-be-marketed formulation is identified. When a to-be-marketed formulation is identified, we recommend conducting a pivotal food effect trial to assess the effect of food on the to-be-marketed formulation before conducting the pivotal safety and efficacy trials to ensure that the dosing instructions in relation to food intake can be described in the prescribing information.
What types of foods should be included in a food effects study?
We recommend that for all orally administered drugs under development, a food effect study should be conducted with a high-fat meal because high-fat meals generally have the biggest effect on drug absorption. If a drug shows a significant increase or decrease in absorption with a high fat meal, then evaluating the effect of additional meal types on the pharmacokinetics of the drug could be important because other types of meals may have a lesser effect, and this information can provide practical dosing instructions regarding concomitant food intake that could potentially improve patient compliance.
Dr. Arya, the next two questions are for you. What are some general considerations for designing food effects studies?
Generally, a standalone food effect trial follows a randomized, single-dose, crossover design with an adequate washout period. Subjects receive a single dose of the drug with the meal conditions being evaluated such as a high fat meal and perhaps a low fat meal or after fasting overnight for at least 10 hours. Plasma samples are collected from the subjects during the study at predesignated time points to assess the pharmacokinetic parameters, and these parameters are then compared to assess the effect of food on the pharmacokinetics of the drug.
Ultimately, we are trying to develop a practical set of dosing instructions so that the safe and effective dose of the drug can be conveniently administered . For example, there may be cases where fasting for 8-10 hours between doses may not be practical or even possible because the drug is given multiple times a day. However, if food significantly increases or decreases the exposure of the drug, fasting conditions may be necessary. In these cases, we have to determine a fasting timeframe that is practical for the patient while also determining that the fasting timeframe will ensure the administration of the drug will be safe and effective.
To be able to develop suitable dosing instructions, the guidance recommends conducting a food effects study with appropriate and practical separation times after considering the frequency of dosing, patient demographics, disease condition, and any other relevant factors in order to determine how much time should be staggered between food consumption and the drug administration to avoid the food effect.
Can you give us a brief overview of the evolution of this guidance?
This guidance finalizes the draft version issued in February 2019, and revisesand replaces the 2002 FDA guidance titled Food-Effect Bioavailability and Fed Bioequivalence Studies. Information on fed bioequivalence studies to be submitted in abbreviated new drug applications (ANDAs) is now found in the FDA guidance for industry titled Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. Specific recommendations concerning fed comparability trials are now described in the FDA guidance for industry titled Bioavailability Studies Submitted in NDAs or INDs — General Considerations. A key goal for revising this guidance from the previous version issued in 2002 was to focus the guidance on the clinical pharmacology considerations for the design and conduct of food effect trials. In line with this goal, we have made several key revisions that we hope listeners will find helpful. Namely, we dedicated a section on pilot food effect assessments, defined the composition of a low fat meal to facilitate development of practical dosing instructions, added a recommendation to assess the food effects at the clinically recommended dose (and not the highest strength), acknowledged the evolving role of Model Informed Drug Development based approaches for food effect assessment and expanded the labeling recommendations section to reflect current labeling practices.
The last question is for Dr. Booth. What are a couple of key items that you especially want listeners to remember?
That’s a great question. I’d like listeners to remember that food can increase or decrease blood levels of various drugs, which can lead to higher or lower rates of adverse reactions or efficacy. In some cases, food can be used to improve tolerability of a drug that causes GI discomfort. Well-conducted FE studies can inform how, when, and why drugs should or should not be administered with food. Drug developers should assess the effect of food on the pharmacokinetics of a new drug early in its development to guide the overall drug development program and inform final product labeling. This final guidance has been issued to provide recommendations on the conduct of food effect studies for orally administered drug products.
Dr. Arya and Dr. Booth, thank you for speaking with us today about the final guidance on the clinical pharmacology considerations for assessing the effects of food on drugs in INDs and NDAs. 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.
Vikram Arya, Ph.D.
Vikram Arya is Associate Director for Therapeutic Review in the Division of Infectious Disease Pharmacology (DIDP) in the Office of Clinical Pharmacology (OCP), CDER, FDA and Co-Chair of the Food Effect Guidance Revision Working Group. He is primarily responsible for providing technical and strategic leadership in the areas of regulatory science, policy implementation, and drug regulation to a multi-disciplinary group of scientific professionals. Prior to his current role, he was a master reviewer and team leader in OCP and extensively contributed to the review of clinical pharmacology aspects of regulatory submissions and benefit/risk assessment of antiviral drugs. He is the recipient of the FDA Outstanding Service Award, FDA Leveraging and Collaboration Award, FDA Group Recognition Award, CDER Leadership Excellence Award and several CDER Regulatory Science Excellence and Team Excellence Awards to recognize his contributions to a variety of regulatory science and policy setting initiatives. He is a fellow of the Excellence in Government (EIG) Fellows Program. He currently serves as the Immediate Past President of the American College of Clinical Pharmacology (ACCP), is a fellow of ACCP, and an Editorial Board member of the Journal of Clinical Pharmacology (JCP).
Brian Booth, Ph.D.
Brian Booth, Ph.D. is the Director of the Division of Cancer Pharmacology I, in the Office of Clinical Pharmacology at the U.S. Food and Drug Administration. Dr. Booth obtained a Bachelor of Science in Physiology at McGill University in 1988, and subsequently pursued a Doctorate in Pharmacology and Toxicology at Queen’s University (1993) in Canada. Following a Post-Doctoral Fellowship in the Department of Pharmaceutics at the State University of New York at Buffalo, where he studied the interaction between nitric oxide donors and the neuropeptide calcitonin gene-related peptide. Dr. Booth joined the Office of Clinical Pharmacology and Biopharmaceutics, FDA, in 1998. In 2004, he became the Acting Team Leader in the Division of Oncology Drug Products, after serving as a reviewer/pharmacometrician in this division. In November 2006, Dr. Booth was appointed as Deputy Director of the Division of Clinical Pharmacology V. At the FDA, Dr. Booth has been involved with the clinical pharmacology development of several hundred new oncology drugs, ranging from phase 1 to phase 4. In addition to IND and NDA/BLA reviews, Dr. Booth has been involved with teaching and development of new clinical pharmacology reviewers and medical officers, development of the analytical method validation, food effects, ARA drug-drug interactions, ADC- drugs, liposome drug product, PD-1/PD-L1 and studies in hepatic impairment Guidances for Industry, and clinical pharmacology modeling and simulation projects. He has authored 81 peer reviewed articles and book chapters.