FDA makes exception for antibody drug conjugates in mass balance studies final guidance

The US Food and Drug Administration (FDA) has finalized a guidance that lays out clinical pharmacology information that sponsors of investigational drugs conducting human radiolabeled mass balance studies should include in their premarket applications. While the agency made some changes based on industry feedback, the final guidance is mostly unchanged from the draft version.
 
On 18 July, FDA finalized the guidance, which was initially published in draft form in May 2022. It lays out when sponsors should consider conducting radiolabeled mass balance studies, how they should be designed, and how to report the results. (RELATED: FDA sheds light on conducting human radiolabeled mass balance studies, Regulatory Focus 10 May 2022)
 
Since the draft was published, industry stakeholders have asked FDA for additional leeway in the requirements outlined by regulators, such as requiring fewer subjects in the studies and encouraging a preference for male trial subjects, with exceptions for females of non-child-bearing age. One area where the agency has given more leeway is allowing exceptions for antibody drug conjugates (ADC).
 
Janssen asked FDA to allow circumstances when ADCs could be excluded from mass balance studies, including instances where the drug’s absorption, distribution, metabolism and excretion (ADME) data could be gleaned from medical literature or when there is low exposure to the ADC. AbbVie asked the agency to exclude ADCs altogether, arguing the studies may not be feasible. (RELATED: Drugmakers request changes to FDA’s mass balance studies guidance, Regulatory Focus 9 August 2022)
 
The draft guidance originally excluded monoclonal antibodies, endogenous substances, and analogs such as peptides, hormones, oligonucleotides, or products with known metabolism and elimination pathways from mass balance studies. In the final guidance, FDA added that there may be situations where mass balance studies for ADCs may not be feasible, and sponsors should look at other ways to get the information.
 
“When a human radiolabeled mass balance study is not feasible (e.g., antibody drug conjugates, safety concerns because of the potential for radiolabeled moieties distributing extensively to critical organs), the sponsor should use alternative approaches, such as animal mass balance studies, non-radiolabeled clinical sample analysis via nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS), or in vitro assessments to characterize the ADME of the investigational drug,” said the agency. “Sponsors considering alternative approaches should consult with the appropriate FDA review division.”
 
In their draft guidance comments companies, including Pfizer, Novartis, and AstraZeneca, noted that mass balance studies are typically conducted using between four and six evaluable subjects, and FDA should provide a rationale for why it chose to set the threshold at the higher end. They also argued that enrolling up to six health subjects in studies, especially cancer drug trials, is often challenging, and requiring four subjects should be a reasonable threshold.
 
However, FDA has stuck to its recommendation that sponsors enroll at least six study participants.
 
“In general, a mass balance study should include at least six evaluable volunteers who have completed the study procedures as detailed by the protocol,” said the agency. “Having fewer evaluable subjects may limit the interpretability of the study results.”
 
Similarly, Takeda had asked the FDA to specify a preference for male trial subjects in mass balance studies and suggested that while they can typically be conducted in men, women of nonchild-bearing potential may also be considered when the drug is being developed for a predominantly female population. However, the agency has not updated the final guidance and maintained that the studies should be conducted on healthy adult volunteers unless there are safety concerns, in which case they can be conducted in the patient population of interest.
 
Final guidance