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FDA's COVID therapeutics, mAbs guidance accounts for variants

Posted 23 February 2021 | By Kari Oakes 

FDA's COVID therapeutics, mAbs guidance accounts for variants

Janet Woodcock, MD

As the world rolls into year 2 of the COVID-19 pandemic, regulators and drug developers are grappling with how to address variant strains of SARS-CoV-2 as they bud and expand globally.
The inevitable path for RNA viruses is to mutate, a fact acknowledged by Janet Woodcock, MD, acting commissioner US Food and Drug Administration, in a Monday press conference announcing the availability of new and updated guidance for developers of therapeutics, vaccines, and tests for COVID-19.
Collectively, the guidances outline FDA’s vision of a forward-thinking, collaborative and flexible approach to tackle the evolving nature of the pandemic. (RELATED: FDA unveils plans to tackle COVID variants, Regulatory Focus 22 February 2021)
“So as long as there is a larger amount of infection going around the world, the probability is that additional virus variants will emerge,” said Woodcock. “We’re going to use every tool in our toolbox to fight the pandemic, including modifications and pivoting as the virus adapts. We want to get ahead of it and we remain committed to getting a product out there even in the face of virus changes.”
The new suite of two updated and two new guidance documents provide a roadmap for how developers of vaccines, tests, and therapeutics, including monoclonal antibody (mAb) products.
New guidance for monoclonal antibody sponsors
A new guidance document for developers of mAbs to treat COVID-19 addresses some concerns specific to those development programs. “The FDA is aware that some of the monoclonal antibodies that have been authorized are less active against some of the SARS-CoV-2 variants that have emerged,” wrote the agency in announcing the new guidances.
A second, broader guidance document issued in May 2020 and updated Monday addresses concerns for drugs and biological products, including Phase 2 and 3 clinical trial considerations. That guidance’s updates address how to account for effectiveness against variants in clinical trial design, and also how the increasing availability of COVID-19 vaccines affects trials of therapeutics against the novel coronavirus.
In both documents, FDA urges developers “to continuously monitor genomic databases for emerging SARS-CoV-2 variants and evaluate phenotypically any specific variants in the product target that are becoming prevalent or could potentially impact its activity.”
For mAb developers, FDA first lays out several guiding principles. First, the agency makes clear that it will expedite and streamline the submission and review process for emergency use authorization (EUA) of mAbs, where possible. In taking this approach, FDA will use a benefit-risk approach to balance the need for speed with potential risks to intended populations.
Next, mAb developers should include a plan to address variant strains in their development plans: “FDA strongly recommends that individual monoclonal antibody products be developed with the expectation that they will be combined with one or more monoclonal antibody products that bind to different epitopes to minimize the risk of losing activity against emergent variants,” according to the guidance document.
Sponsors should consider collaborating to address this problem, wrote the agency. “Sharing of information regarding SARS-CoV-2 variants among sponsors, consortia, or other partnerships may help expedite the development of therapeutics to address these variants.”
The guidance also outlines pharmacology toxicology recommendations, including a recommendation for tissue cross-reactivity studies using a panel of human tissues as well as short-duration, repeat-dose, single-species toxicology studies.
Virology studies should use “a broad approach” initially, to look for how amino acid changes, insertions or deletions in the virus’ target protein(s) affect activity of the mAb. Epitope binding and mechanism of action of neutralization for each mAb should be included in the EUA submission. The guidance also details how to determine neutralizing activity of mAbs against variants.
Clinical considerations for mAb sponsors include a focus on enrolling patients impacted disproportionately by COVID-19 during the pandemic; the document also provides guidance on considerations for endpoints and the size and composition of safety databases.
The mAb guidance document outlines specific chemistry, manufacturing and controls considerations to capitalize on existing resources, share resources and use publicly available data “that may contribute to understanding product performance.” Sponsors should look ahead and communicate early with FDA for time-critical aspects of development.
Updated considerations for clinical trials of COVID-19 therapeutics
In updating the May 2020 guidance in this area, FDA indicated that protocols should account for how emerging variants might affect assay performance. Also, developers should include viral isolates representing the most common variants circulating globally when characterizing antiviral activity of drugs in development. Cell culture phenotype assays can be used to characterize how specific amino acid shifts in the drug target affect drug activity, though pseudo virus or other surrogates can be considered. (RELATED: FDA issues two guidances to accelerate COVID-19 treatments, Regulatory Focus 12 May 2020)
Now that vaccines are in wide clinical use, “[s]ponsors should address the possibility of drug and COVID-19 vaccine interactions for drugs that may interfere with vaccine effectiveness,” such as mAbs that target the vaccine antigen, according to the guidance. FDA advises early consultation when such interactions seem likely.
“We need to make sure that the health care providers have the best available diagnostics therapeutics and vaccines to fight the virus, and these need to be may need to be modified over time to remain maximally effective,” said Woodcock.
Monoclonal antibody guidance
Therapeutic trial guidance


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