Guidance Recap Podcast | Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies
Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Suresh Doddapaneni, Deputy Director of the Division of Inflammation and Immune Pharmacology, Dr. Zhixia (Grace) Yan Danielsen, Deputy Director of the Division of Infectious Disease Pharmacology, and Dr. Anuradha Ramamoorthy, Master Scientist, all from the Office of Clinical Pharmacology within the Office of Translational Sciences in the Center for Drug Evaluation and Research. They will share some thoughts with us on the newly published final guidance titled, “Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies.” Welcome Dr. Doddapaneni, Danielsen, and Ramamoorthy. Thank you for speaking with us today.
Let’s start with Dr. Doddapaneni. For those less familiar with this topic, could you explain what is a human radiolabeled mass balance study?
Thank you for having us to discuss this guidance. To answer your questions, a human radiolabeled mass balance study administers a carbon 14 or tritium radiolabeled investigational drug compound. Following the administration, the radiolabeled drug and its metabolites are measured in blood, urine, and feces using specific radiolabeled analytical techniques in addition to non-radiolabeled techniques. Generally, these studies are a direct way to obtain quantitative, comprehensive, and essential information on absorption, distribution, metabolism, and excretion (also called ADME) of the drug in the body.
Dr. Danielsen, can you explain ADME in simple terms?
Certainly, it starts with absorption, where the drug moves from where it was administered—like an ointment on the skin or a pill that’s swallowed—into the bloodstream. Next is distribution, which is all about the drug moving from the bloodstream to different organs and tissues throughout the body. Then we have metabolism, where the drug is broken down by enzymes into what we call metabolites, which may still be active or not. Finally, there’s excretion, the stage where the drug and any metabolites are eliminated from the body, mostly through urine and feces.
Dr. Ramamoorthy, now that we have that background information, could you explain why FDA is publishing this guidance?
Though mass balance studies are routinely conducted studies, the FDA saw a specific need for a dedicated guidance on mass balance studies to set expectations and recommend best practices for these studies. This will help ensure that the data provided in new drug applications are consistent and of high quality. By publishing this guidance, the Agency wants to underscore the importance of using mass balance studies to inform the subsequent drug development program.
Dr. Doddapaneni, How do the results of these studies impact the drug development process?
A mass balance study offers crucial insights into the overall metabolism and excretion pathways of a drug and its metabolites. It helps identify which metabolites appear in plasma and their quantities relative to the administered drug. As we advance the development of an investigational drug, it is important to consider several clinical pharmacology studies, such as hepatic impairment, renal impairment, and potential drug-to-drug interaction studies. The findings from mass balance studies are instrumental in determining whether studies for hepatic or renal impairments are necessary, and the design of drug interaction studies.
Additionally, these studies provide input on which metabolites need to be structurally characterized and which should be tested for safety in nonclinical studies. Lastly, we see instances of mass balance studies are combined with an absolute bioavailability study, this can shed light on absolute bioavailability which is how much of the drug dose is absorbed into the bloodstream.
Dr. Danielsen, are there situations where a human radiolabeled mass balance study might not be necessary?
Human radiolabeled mass balance studies are generally needed for all new molecular entities because they provide essential data that guides subsequent drug development program. However, there are some exceptions to this recommendation. For instance, if the findings from mass balance studies are already available from acceptable literature sources or included in FDA-approved product labeling, then conducting another study might be redundant.
In addition, specific types of drugs might not require these studies. For example, monoclonal antibodies, oligonucleotide therapeutics, and endogenous substances such as peptides and hormones typically do not need these studies if their metabolism and excretion pathways are well-understood based on basic pharmacology and nonclinical ADME data, unless structural modifications are expected to alter their ADME properties.
Additionally, drugs which exhibit minimal metabolism, where the majority of the dose—90 percent or more—is recovered in the urine as the unchanged parent drug, may also bypass this requirement. Lastly, drugs resulting in no or negligible systemic exposure often do not need mass balance studies.
Dr. Ramamoorthy, what does the guidance suggest about the timing of these studies?
The guidance generally recommends mass balance studies be conducted early in drug development, at the latest before initiating any late-phase clinical trials. As the information from mass balance studies is leveraged to inform the overall drug development program, it is a good practice to conduct mass balance studies early in the drug development program such that there is sufficient information to justify the eligibility criteria in the safety and efficacy trials and determine if additional safety testing for metabolites may be needed.
Delaying the conduct of the mass balance study until later stages of drug development (such as after confirmatory trials are initiated or completed) can lead to significant delays in the approval of the drugs if there are residual uncertainties related to safety. It could also limit the usage of the drug in certain patient populations if there is residual uncertainty related to the drug's metabolism or excretion pathways.
Dr. Doddapaneni, what are some considerations for designing these studies?
When we talk about designing a mass balance study, we are really looking at a few key aspects to make sure the data we get will be informative. First, the number of participants: at least six evaluable subjects are needed. This is crucial because having fewer can really limit the interpretation of study results. The final number of subjects to be enrolled will depend on the drug's pharmacokinetic characteristics and the specific goals of the study.
Now, about the radioactivity dose, the guidelines don't specify exactly how much radioactivity to use. Instead, sponsors should follow established guidelines like those from the International Commission on Radiological Protection (ICRP) and Association of Clinical Research Professionals (ACRP. This ensures safety and compliance across the board.
Moving on to the dosage of the investigational drug, we recommend using the final intended dose of the investigational drug. If that dose isn't set yet, a dose within the pharmacokinetic linearity range is the way to go. This approach allows us to extrapolate the mass balance results from the study dose to whatever the final dose ends up being.
In terms of study design, a single dose mass balance study is the typical study design used to get the data we need. However, multiple dose studies may be considered if the drug or its active metabolites have time-dependent pharmacokinetics, or if a single dose study isn't feasible—for instance, if the study has to be conducted in patients.
Lastly, for administration, we generally suggest sponsors use the final intended route—how the drug will be given in real-world medical use. But sometimes, practical issues mean we have to adjust that plan. For example, for inhalation products, we might administer the radiolabeled dose orally instead. When alternative routes are proposed to be used in the study than what is intended for the investigational drug administration, it is important to touch base with the appropriate review division and provide justification for the change.
All of this ensures that the mass balance study design is robust and provides reliable, applicable data for moving forward with drug development.
Dr. Danielsen, can you provide some additional considerations for tracking radioactivity in recovery studies?
For tracking radioactivity, the total recovery of radioactivity in urine and feces should ideally exceed 90% of the administered dose. This high level of recovery is crucial because it allows for a reliable understanding of how the drug is eliminated from the body. If there is lower recovery, it is essential to investigate the potential reasons for this. Whether it is variability in ADME or other factors, identifying these causes is a key step in ensuring the reliability of the study results.
In addition to recovery, metabolite profiling should be carried out in plasma, urine, and feces samples. Ideally, over 80% of the radioactivity found in the excreta should be identified. This helps us to understand the metabolic pathways of the parent drug and the information gathered is fundamental to designing drug-drug interaction studies and determining if further non-clinical safety studies are necessary.
Dr. Ramamoorthy, can you provide some additional considerations for conducting sample collections?
Sure, in radiolabeled mass balance studies, samples such as plasma, urine, and feces are typically collected to analyze the total radioactivity, the parent drug, and its metabolites. Depending on the drug, it may also be necessary to collect other types of samples.
Typically, there are two main considerations for sample collection: (1) collection should continue until the cumulative radioactivity exceeds 90 percent of the administered dose in urine and feces and (2) the total radioactivity recovered in these samples is less than 1 percent of the administered dose over a 24-hour period on two consecutive days of collection.
However, this may be challenging for drugs or metabolites that have a long half-life. In such cases, achieving over 90 percent recovery might be difficult without extended stay in the clinic. In such scenarios, alternative sampling strategies can be considered, and we recommend consulting with the relevant FDA division.
Post-collection, proper storage and handling of samples is crucial to ensure their integrity before bioanalysis. Inadequate storing and handling practices can adversely affect the stability of the drug or metabolites, which could compromise the study results.
Regarding the pooling of samples for bioanalysis, while generally it is not recommended for quantitative analysis of total radioactivity or quantitative analysis of the parent drug and metabolites of interest, pooling may be appropriate for metabolite profiling. This may involve combining samples across different time points within a single subject or across multiple subjects for each timepoint. To ensure clarity, the rationale and strategy behind such pooling should be documented in the study report submitted to the FDA.
Dr. Doddapaneni, what are some additional considerations in conducting bioanalytical measurements?
The objective of the mass balance study determines what bioanalytical quantification technique can be used. Typically, both radiolabeled and non-radiolabeled analytical techniques are used. and this is based on the goal of the study – whether it is performing quantitative analysis of total radioactivity or if it is to perform quantitative analysis of parent drug and metabolites of interest or to perform metabolite profiling. The goal of the study also determines the need for method validation.
Dr. Danielsen, what are the guidance recommendations for reporting the results of these studies to FDA?
It is important to report the plasma concentration profiles for both total radioactivity as well as the parent drug and any metabolites of interest. This step helps us see not just the path of the total drug-related entities in the systemic circulation but also how it compares with that of the parent drug.
It is crucial to present descriptive statistics of pharmacokinetic parameters of total radioactivity, the parent drug, and any metabolites of interest in plasma. These parameters, like the area under the concentration time curve (AUC), maximum concentration (C max), time to maximum concentration (T max), and terminal half-life, provide detailed insights into the overall exposure to the drug, how quickly it reaches its peak in the body, and how long it stays there.
Another critical aspect is tracking the cumulative percentages of the administered radioactivity dose recovered in urine, feces, and total excreta over time. This measurement helps understand how much of the drug is excreted and through which bodily processes.
Finally, it’s vital to obtain quantitative information on the radioactivity linked to the parent drug and each identified metabolite in the collected matrices, such as plasma, urine, and feces. Typically, a biotransformation scheme, which includes the structures or descriptions of the metabolites, is also part of the New Drug Application submission. The results from human mass balance studies are usually included in Section 12.3 Pharmacokinetics of the approved drug labeling.
Reporting these study results gives us a comprehensive view of how a drug is processed within the body, providing crucial information for its safe and effective use.
Dr. Ramamoorthy, for our final question, what are a couple of key items from the guidance that you especially want listeners to remember?
A human mass balance study is the single most direct method to obtain quantitative and comprehensive information on the ADME of an investigational drug in the human body. A well-designed mass balance study is essential to a inform the design and conduct of other clinical studies in the drug development program. So, appropriate attention should be given to deciding whether and when to conduct the study. We recommend that sponsors considering alternative approaches from what is recommended in the guidance consult with the appropriate FDA review division to ensure their development plans meet all regulatory requirements.
Dr. Doddapaneni, Danielsen, and Ramamoorthy, thank you for taking the time to share your thoughts on the final guidance on clinical pharmacology considerations for human radiolabeled mass balance studies. We have learned so much from your insights on this 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 look at the snapshot and to read the guidance.