Drugmakers request changes to FDA’s mass balance studies guidance

Regulatory NewsRegulatory News | 09 August 2022 | By

The pharmaceutical industry is calling for changes to the US Food and Drug Administration’s (FDA) draft guidance on radiolabeled mass balance studies, suggesting the guidance be revised to require fewer subjects, and mention a male preference for these studies, with exceptions for females of non-child-bearing age. One manufacturer recommended that antibody drug conjugates (ADCs) be excluded from these studies.
 
The comments were submitted in response to FDA’s draft guidance, which was released for comment in May. (RELATED: FDA sheds light on conducting human radiolabeled mass balance studies, Regulatory Focus 10 May 2022)
 
In the guidance, FDA recommends mass balance studies for all new molecular entities to obtain information on the drug’s absorption, distribution, metabolism and excretion (ADME).
 
Janssen: Exclude ADCs from mass balance studies
 
Drugmaker Janssen broadly expressed its support for the guidance. The company “commends FDA for its commitment to advance guidance on clinical pharmacology considerations for human radiolabeled mass balance studies. We find the Guidance to be well written and believe that it provides sponsors with much needed guidance when conducting mass balance studies.”
 
However, the firm requested that FDA clarify circumstances for excluding ADCs from mass balance studies, such as situations where there is already available ADME data available in the literature for these products, or there is low exposure of the conjugate.
 
The guidance excludes monoclonal antibodies; endogenous substances; and analogs such as peptides, hormones, and oligonucleotides; or products with known metabolism and elimination pathways from mass balance studies but does not mention ADCs.
 
Yet AbbVie wants an outright exclusion for ADCs, asserting that, “Like monoclonal antibodies, a mass balance study might not be feasible” for these products.
 
Include fewer patients
 
Several companies, including Pfizer, Novartis, and AstraZeneca, want the number of participants for these studies pared down. The guidance specifies that, “In general, a mass balance study should include at least six evaluable subjects who have completed the study procedures as detailed by the protocol.”
 
Pfizer writes that “it is standard practice for mass balance studies to include four to six evaluable subjects. We suggest clarifying the rationale for using six as a baseline.”
 
Novartis similarly urged that a “small homogenous group of 4-6 healthy volunteers should be sufficient with subsequent extension/bridging to actual patients and investigation of variables such as age, gender ethnicity, and health on the metabolic profile as needed.”
 
AstraZeneca said conducting studies in six patients “might be challenging when the study is conducted in oncology patients and in several cases, 4 subjects have provided reasonable estimate.”
 
Guidance should mention male preference  
 
Takeda said the guidance should specify a male preference for mass balance studies. The guidance states that “mass balance studies can be conducted in healthy adult subjects. If safety concerns preclude the enrollment of healthy subjects, mass balance studies can be conducted in the patient population of interest.”
 
Instead, the company suggests that the guidance should be reworded to state these studies “can typically be conducted in male subjects. The study may be conducted in females of nonchildren-bearing potential when the treatment population is predominately females.”
 
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