In this Q&A, Iain Shaw, Senior Director, 14C Enabled Drug Development, shares his perspective on how human ADME study design is changing in practice, from earlier planning and added complexity to the broader impact of the FDA’s 2024 mass balance guidance (2). He also discusses why these studies are becoming a more strategic part of the clinical pharmacology package.
What were key highlights of the 2024 FDA guidance on mass balance?
In 2024, the FDA’s guidance confirmed for the first time the agency's expectations for conducting human ADME programs, consolidating feedback about the design and conduct of these studies over many years. Key points focused on:
- Increasing the number of evaluable subjects required
- Considering the target % radioactivity recovered from the radiolabeled dose
- Best practices for pooling and profiling methodology across study designs
What differences have you noticed in how these studies are conducted, now that the guideline has been in effect for a couple of years?
There seem to be more molecules where the human ADME program is under discussion earlier in development than in the past.
The general rule used to be that ADME data needed to be in hand by end of Phase 2, therefore ADME discussions needed to begin shortly after positive proof of concept data was generated. Now, it’s not uncommon that we are discussing human ADME requirements as first-in-human programs are completing.
The fact that there is an actual guidance that can be referenced has likely raised the profile of human ADME studies, alongside the earlier influence of the MIST guidance (3) and growing recognition of the value of understanding drug disposition earlier. Conducting earlier ADME studies will increase the number of candidates available but add complexity as there will be less prior human safety and pharmacokinetic data available to help inform the details of study designs.
What has changed as far as the number of volunteers required in an ADME study?
There is a clear requirement in the guidance to generate data in six evaluable subjects. That has inevitably resulted in most designs allowing for seven or eight subjects to be dosed to mitigate for potential drop-out of participants. More volunteers dosed helps avoid an incomplete dataset, however, it does result in an increase in budgets for clinical conduct, sample analysis, and data analysis, for example.
What has changed as far ADME study conduct?
We have noticed an impact on study residency. The guidance document makes two statements with respect to recovery of radioactivity.
- Section G on recovery states: “the total recovery of radioactivity in the urine and feces should exceed 90 percent of the administered dose.”
- In the following section, it continues: “sample collection should continue until the cumulative radioactivity exceeds 90 percent of the administered dose in the urine and feces; and the total radioactivity recovered in the urine and feces is less than 1 percent of the administered dose over a 24-hour period on 2 consecutive sample collection days.”
From a practical perspective, we see that clients prefer to adhere to the latter wording in our synopses and protocols. As a result, 7-day studies are extending slightly to ensure collections meet all required criteria and data sets are complete.
There are times when we can challenge this target, but most decision makers in this situation take a conservative approach—and for good reasons. As a clinical unit, we want to avoid any risk of an incomplete tag on the data. Similarly, no client wants to be the one that presents such data to the regulator.
What other trends are you seeing in how ADME studies are considered?
The addition of absolute bioavailability assessment via an intravenous microtracer period to the human ADME study design has been a growing trend, even prior to the final guidance issued. A combined study adds intravenous pharmacokinetics and absolute bioavailability to the study objectives and where the analysis is extended, it can also allow for an assessment of fraction absorbed and fraction surviving gut metabolism.
Additionally, these assessments are frequently now combined with microADME, where the oral radiolabeled dose is limited to 1-3uCi and where accelerator mass spectrometry is the main method of sample analysis.
These comprehensive studies not only generate a considerable amount of data to enable a good understanding of drug disposition but are often a significant study in the “human first, human only” approach now taken by several prominent companies in relation to human metabolism investigations.
While “human first, human only” may be the overall trajectory from a drug development perspective, we also see many clients adopting the IVMT/microADME and still generating nonclinical metabolism data to accompany the data generated in human participants. This is a common part of our Synthesis-to Clinic™ programs, which integrate human ADME studies as part of a holistic program of work that includes drug substance synthesis, drug product manufacturing and clinical testing.
The ADME study used to be the straightforward part of the overall Synthesis-to- Clinic™ program, the complexity was often elsewhere in the building blocks needed to make dosing in the clinic possible. What we have seen over the last couple of years is the introduction of drugs earlier in development for human radiolabelled study investigation and the demand to generate more data from that single study to help inform future development and registration.
The ADME study is no longer a tick box exercise, but an increasingly important part of the clinical pharmacology package.
For more information on how we conduct human ADME studies, contact us today.
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