Problems With Drug Absorption Studies Still ‘Relatively Common’ In EU
Inadequacies Have Drawn Major Objections During Initial EMA Review
Executive Summary
A retrospective analysis of new drugs evaluated by the European Medicines Agency since 2010 shows that a lack of, or major deficiencies in, human mass balance studies is still a concern in regulatory submissions.
Despite the availability of clear guidance on performing human mass balance studies, which are essential to help understand how drugs are absorbed, metabolized and excreted after dosing, deficiencies on this front are still “relatively common” in new drug applications in the EU.
This could have an impact on the benefit-risk assessment of the proposed medicinal product and lead to unnecessary precautions being added to the product’s labeling, senior regulators warn in a recent article published in Pharmacometrics & Systems Pharmacology, a journal of the American Society for Clinical Pharmacology and Therapeutics.
The article, authored by senior regulators at the European Medicines Agency and national medicines agencies in the UK and Sweden, highlights a number of common issues in relation to mass balance studies following a retrospective analysis of new drug applications evaluated by the EMA since 2010.
It also makes several “best practice” recommendations that drug companies may consider before initiating mass balance studies to ensure they are well designed and conclusive, which in turn could help prevent the need for further postmarket studies and possible delays in the marketing authorization.
The article explains that a mass balance study “is one of the most frequent areas of regulatory concern” in the clinical pharmacology field during the review of a marketing authorization application (MAA), because it provides information on the exposure of the parent compound and metabolites and the elimination pathway. During the evaluation of an MAA, regulators often consider it essential to resolve these issues before an authorization is granted.
Despite clear guidance on plasma metabolite identification and the availability of extensive literature reviews, the regulators found that “shortcomings in the understanding of circulating metabolites are still apparent in recent regulatory submissions” as these were identified in a number of MAAs during the past 10 years.
For example, the regulators found that concerns were raised by the EMA following the initial assessment of five drugs because no mass balance study was performed: Reagila (cariprazine), Mavenclad (cladribine), Fexinidazole Winthrop (fexinidazole), masitinib, and Rubraca (rucaparib). In all these cases, the lack of data was highlighted as a concern and triggered questions that had to be answered by the applicant during the assessment process, the regulators explained.
However, a new study was not needed for all these drugs. Available knowledge of the substance and its metabolites, combined with consideration of the indication and the difficulties in performing the study, meant that eventually three drugs were licensed without the study (cladribine, cariprazine and fexinidazole).
Regarding the use of human mass balance studies to explain drug elimination pathways, the article highlights instances of incomplete or missing the identification and quantification of the excretion pathways, as well as of the enzymes or transporters involved in the elimination process, as part of the scientific evaluation of MAA dossiers.
For example, no such study was conducted initially in relation to six MAAs concerning Rubraca, Intuniv (guanfacine), Qizenday (biotin), masitinib, Vabomere (meropenem/vaborbactam) and fexinidazole. This was considered a “significant deficiency in the dossier” as it was difficult to understand the clearance pathways without these data. In each of these cases, the company was asked to agree to conduct a human mass balance study during the regulatory assessment process or to adequately justify the lack of these data, the article states.
The authors say that lack of knowledge and uncertainty in relation to drug-drug interactions can lead to unnecessary cautionary wording and contraindications in the summary of product characteristics.