The FDA issued its final guidance on the clinical pharmacology considerations for human radiolabeled mass balance studies (ADME, or hADME) in July 2024.
The draft guidance, published in May 2022, had an immediate impact on the expectations of the study design and conduct of ADME studies, such as the expected number of evaluable subjects, while other parts, such as expectations around the criteria for mass balance recovery and the recognition of the different approaches to metabolite characterization by AMS-enable investigations, were still being evaluated.
With the finalization of this guidance, drug developers, clinical research organizations (CRO’s), and other outsourcing partners are establishing new compliance strategies for conducting ADME programs in 2024 and beyond. In this article, Dr. Adam Robinson-Miller, Senior Manager, 14C Enabled Drug Development, shares thoughts on the newly approved guidelines' impact for the industry.
What are human ADME studies?
Conventional ADME and AMS-enabled mass balance (also called microADME) studies are usually straightforward in their design. In these programs, single-dose studies are typically conducted in a small cohort of healthy volunteers to help drug companies generate data to support drug development and registration.
The goals of an ADME study are to understand of the recovery of the radioactivity administered as the parent drug, identify the routes and rates of elimination, and generate samples of plasma, urine, and feces to allow for metabolite profiling and identification.
At Quotient Sciences, our ADME studies utilize 14C radiolabeled drug substances.
When is an ADME study typically conducted?
A human mass balance/ADME study is a requirement prior to submitting a New Drug Application (NDA). These studies are typically performed before the end of Phase II, although they may be done sooner depending on the indication or in cases where there is fast track or orphan drug designation which may shorten the overall development timeline.
What is the FDA guidance on mass balance?
The FDA’s guidance has described for the first time the agency's expectations for conducting these studies. Many of the expectations reflect the design and conduct of these studies over many years. There are some differences between the traditional approach to conventional and microADME studies that have been significant and have been translated into the final guidance document.
Key topics of interest include:
- An increase in the number of evaluable subjects
- Consideration around the target % radioactivity recovered from the radiolabeled dose
- Best practice with respect to pooling and profiling methodology across different study designs
- Guidance around the design of AMS enabled studies
Quotient Sciences have described our approach to address potential changes, from the draft guidance in a poster presented at ISSX Boston 2023 and video.
What is Quotient Sciences’ approach to ADME studies?
Quotient Sciences have evaluated the new guidance to ensure that our ADME programs can remain compliant with the new requirements, including:
- Recommendation to dosing increase to n=8. This allows us to de-risk the likelihood of completing an ADME with an incomplete data set. There will be situations when we must consider restricting dosing. For example, when administering a higher dose than 1mSv or administering an oncology molecule in healthy volunteers, which may make recruitment challenging. In those scenarios, we would discuss the suitability of dosing n=6 subjects only and strategies to maximize the resultant dataset.
- Discharge criteria greater than 90% and less than 1% on 2 consecutive days. Challenges may be faced when recovery does not reach 90% but remains greater than 1% each day; we might be obligated to continue collecting until 90% is achieved. This could result in extended residency periods for drugs with very long terminal half-life. This risk is mitigated by ensuring appropriate wording to allow flexibility and investigator discretion, with robust discussions with our partners.
- Greater than 80% radioactivity in excreta to be identified. This ensures compliance in our metabolite profiling and identification scope.
How will ADME studies be conducted in the future?
We know that ADME studies are critical to adequately describe the metabolism of their study drug and, therefore, to their program’s success in meeting its milestones to reach the market. These changes underscore the FDA’s commitment to rigorous scientific evaluation, a value that is also core to our mission as a company.
As the technology is now firmly established, there is also an increased demand for AMS-enabled microADME studies. Both approaches allow the generation of critical data to support new drug registration. Quotient Sciences can adopt either methodology as reflected by the specific needs of the molecule.
Quotient Sciences can support conducting human mass balance studies that meet the highest regulatory standards. Contact us to discuss your next ADME program.
