Bioanalysis related Postmarketing Requirements for ERTs:FDA

In this post, the FDA approvals (publicly available) from enzyme replacement therapy in the year 2017 is reviewed. To date, the FDA has approved two enzyme replacement therapy for marketing in the United States. The two approved enzymes are Cerliponase Alpha (BioMarin) and Vestronidase alfa-vjbk (Ultragenyx) for CLN2 and MPSVII respectively. Both products were reviewed under breakthrough designation and granted approval as an orphan drug.

Bioanalysis has an integral part of the drug development process. Bioanalysis is the measurement of any quantifiable metabolites or proteins to provide evidence for clinical decision making. Bioanalysis includes the measurement of drug concentration in various biological matrix ( pharmacokinetics), measurement of the metabolites that inform drug efficacy (pharmacodynamic markers) or quantifying surrogate biomarker as clinical endpoints. In addition, bioanalysis of anti-drug antibodies and its correlation with hypersensitivity/adverse outcomes assist to determine associated safety risk with the administration of these drugs/enzymes.

FDA provides oversight, experts opinions, critical reviews throughout the drug development processes. The review of postmarketing commitment related to bioanalysis provides a current trend and requirement on bioanalytical assays, pharmacokinetic studies, and immunogenicity studies. This can help identify gaps, if any, during bioanalysis for clinical and non-clinical studies. Few common bioanalysis related commitments are :

Evaluation of patient genotype and residual enzyme activity and diagnosis:
Recently, the FDA and researchers have focused on evaluating the genotype of individual patients and correlate the genotype with the severity of the disease. In rare metabolic diseases, the diagnosis is usually performed based on the residual enzyme activity and the clinical presentation. These enzymatic and clinical characteristics are also utilized to classify the severity of the disease. In some diseases, residual enzymes are also detected using immunological methods and named as cross-reactive immunological materials (CRIM). These CRIM status have shown to correlate with the immune response against therapeutic enzymes.

With the advent of next-generation sequencing technology, the genotyping of individual patients has become more accessible and inexpensive. There are several advantages of genotyping such as genotyping is a non-invasive procedure that requires a small number of samples. In contrast, the residual enzyme activity measurement requires the fibroblast samples or biopsy of affected tissues. In addition, genotyping can be performed well before the onset of disease and if the causal relationship of common pathogenic mutation with residual enzyme activity and clinical presentation can be established, the disease can be diagnosed early and prophylactic treatment can be given before the irreversible stage of the diseases.

Evaluate patient genotyping, residual enzyme activity, and correlate with safety and efficacy:
Based on the genotype, the protein function prediction may be performed. The missense mutation at non-crucial sites may partially decrease the enzyme activity, and similar mutations in the active sites may completely abolish the enzyme activity. The premature stop codon and nonsense mutation may truncate and inactivate the proteins, but CRIM positive status. In other mutations, the nonsense mutation may destabilize the mRNA resulting in degradation and negative CRIM status. Identifying these pathogenic mutations, and correlating with safety such as anti-drug antibodies (binding and neutralizing antibodies), hypersensitivity/adverse events; and efficacy may help understand the interplay of disease-specific genetic, immunologic factors and disease presentation for improving clinical outcomes.

Evaluate the bioanalytical method (validations) and incurred sample repeats:
The sensitivity, specificity, and robustness/stability/reproducibility of bioanalytical methods directly impacts the integrity of data generated from the methods. Both the FDA and sponsors recognize the importance of bioanalytical studies such as method validations, incurred sample repeats (ISRs). In the approval letter, the FDA has highlighted the sensitivity issue of the neutralizing antibody detection assay and requested to re-develop a neutralizing antibody assay that has suitable sensitivity and retest the samples from clinical trials. FDA is also concerned that the in-vitro detection assays may not reflect the enzyme activity and requested to develop an enzyme activity based neutralizing assay that mimics the cellular environment. The FDA expects the sponsor to develop a robust and fit-for-purpose anti-drug antibody assay with sufficient sensitivity. In another approval letter, the FDA has requested to conduct the ISR studies for pharmacodynamic marker assay. This point highlights the requirement of characterization/validation of the bioanalytical assay including assay reproducibility and stability of analyte with study samples.

In conclusion, the characterization of genotype and residual enzyme activity with disease progression and post-treatment safety and efficacy should be an integral part of ongoing and future clinical studies. The bioanalytical method validations and ISR studies should be conducted and the sensitivity/stability and suitability should be discussed with the regulatory agencies.

Of note, in the future, the parallel observational/natural history studies should be incorporated in the clinical trials that allow appropriate selection of clinical endpoints and biomarker qualifications. The appropriate clinical endpoint and surrogate biomarker will accelerate the drug development process. The well designed natural history studies may serve as the control arm for clinical trials in a rare disease where the patient population is low. The FDA has emphasized its intent and importance by allocating grants studying the natural history of six different rare diseases.

Disclaimer: This post is a personal opinion and may differ from FDA requirements
Approval letter 1
Approval Letter 2


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