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CHECK THE PRESS RELEASES and follow RULES OF ENGAGEMENT BY THE FDA
Development of Monoclonal
Antibody Products Targeting SARSCoV-2, Including Addressing the
Impact of Emerging Variants,
During the COVID-19
Public Health Emergency
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research
INTRODUCTION
FDA plays a critical role in protecting the United States from threats such as emerging infectiousdiseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic.
FDA is issuing this guidance to provide recommendations to sponsors on the development of monoclonal antibody products targeting SARS-CoV-2, including addressing the impact of emerging variants, during the COVID-19 public health emergency.
This policy is intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Secretary of Health and Human Services (HHS) on January 31, 2020, effective January 27, 2020, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)).
DISCUSSION
A. Guiding Principles
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following guiding principles:
• Given the serious concerns raised by the emergence of SARS-CoV-2 variants, FDAintends to leverage its emergency authorities under section 564 of the FD&C Act, when appropriate, to foster the development and availability of therapeutics for use during the current public health emergency. When scientifically supported, FDA will streamline the
data necessary to support the development of monoclonal antibody products targeting SARS-CoV-2 and also expedite the review of these data.
• Given the dynamic public health situation created by changes in the prevalence of new variants over time, FDA’s streamlined approach will depend on its current assessment of benefit and risk for the intended use and population, the monoclonal antibody’s expected
coverage of important emerging variants, as well as FDA’s then-current understanding of SARS-CoV-2.
• 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 epitopes5 to minimize the risk of losing activity against emergent variants. FDA encourages collaborations between sponsors of individual monoclonal antibody products to address this unmet medical need.
Development Program Considerations to Support Use Under an EUA
Chemistry, Manufacturing, and Controls
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following chemistry, manufacturing, and controls recommendations:
• When feasible and scientifically supported, sponsors should attempt to leverageexperience obtained from other monoclonal antibody products in development and already licensed monoclonal antibody therapies. Specific examples include the following:
? The use of existing manufacturing platforms to establish a manufacturing process for investigational product development
? The selection of manufacturing facilities6 that have experience in manufacturing biotechnology products and have a history of recent inspection(s) (including using information shared by trusted foreign regulatory partners through mutual recognition agreements7)
? The potential to utilize already obtained modular data for viral clearance validation,and a purification process validation (e.g., impurity clearance)
? The selection of analytical methods that have already been qualified or validated.This may include adapting potency assay9 formats (including binding assays and/or neutralizing assays) with revised reagents that evaluate new variant protein(s) or pseudotyped virus/virus-like particles in the assay(s)
? The exploration of opportunities for less-experienced manufacturers to partner with those with more experience to leverage all available development tools
? The use of data that may be available from public consortia or partnerships that may contribute to understanding product performance
? The leveraging of related product quality data (e.g., formulation development) tosupport in-use stability and compatibility
? The use of prior development experience to anticipate the best dosage form, route of administration, and formulation (composition) selection
• FDA strongly recommends that sponsors discuss with FDA in advance (well before they occur) time-critical elements of the development program. Specific examples include the following:
? A plan that describes key aspects of the manufacturing development, including plans for scale-up
? Comparability protocols that include a detailed description of tests and acceptance criteria to evaluate the impact of manufacturing process changes on product quality
? A strategy for establishing a shelf life for the intended monoclonal antibody product targeting SARS-CoV-2. This may include opportunities to leverage related product data to justify the proposed shelf life
• Certain approaches may be appropriate for limited early phase development to enable rapid introduction of the product into clinical trials. Specific examples include the following:
? Use of a stable cell pool in lieu of a clonally derived cell bank to generate early clinical batches
? Consideration of interim results from limited safety testing results (e.g., for cell banks, unprocessed bulk harvest) to begin first-in-human (FIH) clinical trial(s) with full study reports to be available at time negotiated with FDA and submitted to the investigational new drug application (IND)
? Flexibility in the amount of stability study results provided in the IND submission to support the initiation of FIH clinical trials
? Use of two robust orthogonal virus clearance steps when modular/generic virus clearance data are not available.
? Manufacture of limited early clinical batches for FIH clinical trial(s) by mixing and diluting with sterile filtration employing aseptic technique10 rather than traditional
drug product manufacturing.
• FDA may not require completed process validation (excluding sterilization process validation) to support an EUA. However, sufficient process characterization is expected and should be consistent with the overall benefit-risk assessment of the product. If only limited process validation data are provided, the sponsor can propose additional elements for the control strategy. These elements can include additional controls in the manufacturing processes, taking into consideration the criticality assessment for individual process parameters, the ranges proposed for a given parameter, or the inclusion of additional in-process measurements or release specifications.
Pharmacology Toxicology
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following[/i]
pharmacology toxicology recommendations:
• The Agency intends to be flexible regarding selected nonclinical safety data submission expectations (e.g., timing of data submission to the IND) for monoclonal antibody products targeting SARS-CoV-2 to support clinical trial initiation. The degree of flexibility warranted will be influenced by the benefit-risk assessment for the intended
population (e.g., hospitalized, nonhospitalized, healthy trial subjects) and the potential coverage of important emerging variants. Thus, FDA strongly recommends that sponsors discuss the nonclinical requirements to support product administration in a specific clinical trial with the Agency through the pre-IND consultation process.
• Nonclinical safety assessment for monoclonal antibody products targeting SARS-CoV-2 should follow approaches outlined in the International Council for Harmonisation (ICH) guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Delivered
Pharmaceuticals (May 2012) and conduct the following:
? A tissue cross reactivity (TCR) study using a panel of human tissues.
When a monoclonal antibody binds to human tissues in the TCR study, FDA recommends evaluating monoclonal antibody binding to select tissues from nonclinical species to assist in species selection for repeat-dose toxicology testing. When binding of potential clinical concern is observed (e.g., cell membrane binding), FDA recommends discussing these data with the Agency because additional studies may be needed to help inform the potential clinical relevance of the findings.
? A short duration (i.e., 3 weeks of treatment) repeat-dose toxicology study in a single species, using the clinical formulation and route of administration(s) intended for clinical administration, that includes all standard toxicity endpoints including toxicokinetic analysis. FDA also recommends discussing specific study design considerations with the Agency.
• Toxicology studies with specific monoclonal antibody combinations are not needed for monoclonal antibody products targeting SARS-CoV-2 proteins, so monoclonal antibody products can be evaluated separately in toxicology studies. If a sponsor evaluates monoclonal antibody products in combination, FDA recommends using the same ratio intended for clinical administration.
• To support administration of monoclonal antibody products during pregnancy, FDA recommends conducting a TCR study using relevant human tissues or studies using alternative protein interaction technologies, with appropriate justification. If no specific concerns are identified in the repeat-dose toxicology and TCR studies, developmental and
reproductive toxicology studies are not needed.
Virology
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following
virology recommendations:
• A broad approach should initially be used to characterize the impact of amino acid changes, insertions, or deletions throughout the monoclonal antibody target protein to identify regions where changes specifically impact monoclonal antibody binding or activity, and subsequent analyses and surveillance can focus on these regions.
• Sponsors should monitor SARS-CoV-2 genomic databases continually for emerging SARS-CoV-2 variants and should evaluate phenotypically any specific variants that are prevalent or becoming prevalent that harbor substitutions in or near the target epitope.
The sponsor should conduct a more thorough analysis to include other substitutions at the same amino acid positions.
• Sponsors should characterize the epitopes to which monoclonal antibody products bind to enable identification of polymorphisms, which may affect binding, and to inform decisions regarding monoclonal antibody products planned for use in a combination therapy.
• Sponsors should characterize monoclonal antibody products with respect to epitope binding (affinity equilibrium dissociation constant (KD) and noncompetitive binding). The sponsor should characterize the mechanism of action for SARS-CoV-2 neutralization (e.g., blocking spike protein/receptor binding domain interaction with ACE2).
• The sponsor should determine the neutralizing activity (half maximal effective concentration (EC50) value) of investigational monoclonal antibody products, individually and if applicable in combination, against an array of circulating variants representing the diversity of the target protein and epitope to which the monoclonal antibody binds.
• The sponsor should evaluate the neutralizing activity of monoclonal antibodies,individually and if applicable in combination, against SARS-CoV-2 variants orpseudovirus harboring substitutions known to confer reduced susceptibility to other authorized or approved antibody products targeting SARS-CoV-2 infectivity.
• SARS-CoV-2 or pseudovirus should be serially passaged in cell culture in the presence of the monoclonal antibody product, individually and if applicable in combination, to select for resistant variants to understand the potential risk and nature of treatment-emergent
resistance. Sponsors should characterize genotypically and phenotypically the variants selected in this manner. Sponsors should determine the effect of resistance-associatedsubstitutions on approved and authorized monoclonal antibody products. These studies should be conducted under appropriate biocontainment.
• Clinical protocols should include detailed plans to (1) characterize the impact of SARSCoV-2 genetic variability on clinical and virologic outcomes (i.e., baseline resistance
analyses) and (2) identify SARS-CoV-2 genetic changes associated with treatment (i.e., treatment-emergent resistance analyses).
• Sponsors should also reference the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (February 2021) and the guidancefor industry Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency (June 2006).
Clinical
Sponsors of monoclonal antibody products targeting SARS-CoV-2 should consider the following clinical recommendations:
In general, sponsors should design monoclonal antibody product development programs evaluating the treatment or prevention of COVID-19 to assess the effect of investigational products on clinically meaningful aspects of the disease.
? An example of an acceptable endpoint to support an EUA for the treatment of outpatients with mild to moderate disease would be the proportion of patients with COVID-19 related hospitalizations or deaths from any cause through at least 28 days.
? Sponsors considering the use of a surrogate endpoint (e.g., viral pharmacodynamic endpoint) to support an EUA in situations where viral variants have affected the efficacy of currently authorized or approved treatment options should seek early input from the Agency on their proposals.
• Sponsors should scientifically justify the selection of doses and regimens for phase 3 trials and discuss with the Agency.
• Sponsors should enroll patients from populations disproportionately impacted by the COVID-19 pandemic (e.g., racial and ethnic minorities).
• The size and composition of the safety database needed to support an EUA will depend on factors such as the monoclonal antibody product’s proposed use (e.g., treatment versus prevention), the proposed patient population, and the extent and nature of the prior clinical experience with the product and with related products.
• Sponsors should also reference the guidance for industry COVID-19: Developing Drugs and Biological Products for Treatment or Prevention for additional recommendations on trial populations, trial design, efficacy endpoints, safety, and statistical considerations.
