The European Medicines Agency has established initiatives for the provision of accelerated development support and evaluation procedures for COVID-19 treatments and vaccines. These initiatives generally follow the EMA Emergent Health Threats Plan published at the end of 2018 . Similar to FDA’s CTAP, EMA’s COVID-19 Pandemic Emergency Task Force aims to coordinate and enable fast regulatory action during the development, authorization, and safety monitoring of products or procedures intended for the treatment and prevention of COVID-19 . Collectively, this task force and its accessory committees are empowered to rapidly address emergency use requests . Although perhaps not as dramatic as the aspirational time reductions established by the FDA’s CTAP, the EMA’s refocusing of resources and shorter response times to accelerate the development and approval of emergency use products are nevertheless laudable. In the United Kingdom, the MHRA6 has also revised customary regulatory procedures to conform with COVID-19 emergency requirements by creating flexible regulations spanning early consultation, accelerated clinical development and review, and alternatives to facility inspection.During a public health emergency, one can envision the preferential utilization of existing indoor manufacturing capacity, at least in the near term. Processes making use of indoor cultivation and conventional purification can be scrutinized more quickly by regulatory agencies due to their familiarity, resulting in shorter time-to-clinic and time-to-deployment periods. Although many, perhaps most, process operations will be familiar to regulators, there are some peculiarities of plant-based systems that differentiate them from conventional processes and, hence, require the satisfaction of additional criteria. Meeting these criteria is in no way insurmountable,grow trays 4×4 as evidenced by the rapid planning and implementation of PMP programs for SARS-CoV-2/COVID-19 by PMP companies such as Medicago, iBio, and Kentucky Bioprocessing.
During emergency situations when speed is critical, transient expression systems are more likely to be used than stable transgenic hosts, unless GM lines were developed in advance and can be activated on the basis of demand . The vectors used for transient expression in plants are non-pathogenic in mammalian hosts and environmentally containable if applied indoors, and by now they are well known to the regulatory agencies. Accordingly, transient expression systems have been deployed rapidly for the development of COVID-19 interventions. The vaccine space has shown great innovation and the World Health Organization has maintained a database of COVID-19 vaccines in development,including current efforts involving PMPs. For example, Medicago announced the development of its VLP-based vaccine against COVID-19 in March 2020, within 20 days of receiving the virus genome sequence, and initiated a Phase I safety and immunogenicity study in July.If successful, the company expects to commence Phase II/III pivotal trials by late 2020. Medicago is also developing therapeutic antibodies for patients infected with SARS-CoV-2, and this program is currently in preclinical development. Furthermore, iBio has announced the preclinical development of two SARS-CoV-2 vaccine candidates, one VLP and one subunit vaccine.Kentucky Bioprocessing has announced the production and preclinical evaluation of a conjugate TMV-based vaccine and has requested regulatory authorization for a first in-human clinical study.These efforts required only a few months to reach these stages of development and are a testament to the rapid expression, prototyping, and production advantages offered by transient expression.The PMP vaccine candidates described above are all being developed by companies in North America. The rapid translation of PMPs from bench to clinic reflects the conformance of chemistry, manufacturing, and control procedures on one hand, and environmental safety and containment practices on the other, with existing regulatory statutes.
This legislative system has distinct advantages over the European model, by offering a more flexible platform for discovery, optimization, and manufacturing. New products are not evaluated for compliance with GM legislation as they are in the EU and the United States but are judged on their own merits. In contrast, development programs in the EU face additional hurdles even when using 8 WHO 2020. DRAFT landscape of COVID-19 candidate vaccines. Process validation in manufacturing is a necessary but resource intensive measure required for marketing authorization. Following the publication of the Guidance for Industry “Process Validation: General Principles and Practices,” and the EU’s revision of Annex 15 to Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use, validation became a life-cycle process with three principal stages: process design, process qualification, and continuous process verification . During emergency situations, the regulatory agencies have authorized the concurrent validation of manufacturing processes, including design qualification , installation qualification , operational qualification , and performance qualification . Although new facility construction or repurposing/ re-qualification may not immediately help with the current pandemic, given that only existing and qualified facilities will be used in the near term, it will position the industry for the rapid scale-up of countermeasures that may be applied over the next several years. An example is the April 2020 announcement by the Bill & Melinda Gates Foundation of its intention to fund “at-risk” development of vaccine manufacturing facilities to accommodate pandemic-relevant volumes of vaccines, before knowing which vaccines will succeed in clinical trials. Manufacturing at-risk with existing facilities is also being implemented on a global scale.
The Serum Institute of India, the world’s largest vaccine manufacturer, is producing at-risk hundreds of millions of doses of the Oxford University COVID-19 vaccine, while the product is still undergoing clinical studies.Operation Warp Speed 13 in the United States is also an at-risk multi-agency program that aims to expand resources to deliver 300 million doses of safe and effective but “yet-to be-identified” vaccines for COVID-19 by January 2021, as part of a broader strategy to accelerate the development, manufacturing, and distribution of COVID-19 countermeasures, including vaccines, therapeutics, and diagnostics. The program had access to US$10 billion initially and can be readily expanded. As of August 2020, OWS had invested more than US$8 billion in various companies to accelerate manufacturing, clinical evaluation, and enhanced distribution channels for critical products.For example, over a period of approximately 6 months, OWS helped to accelerate development, clinical evaluation , and at-risk manufacturing of two mRNA based COVID-19 vaccines, with at least three more vaccines heading into advanced clinical development and large-scale manufacturing by September/October 2020.Once manufactured, PMP products must pass quality criteria meeting a defined specification before they reach the clinic. These criteria apply to properties such as identity, uniformity, batch-to-batch consistency, potency, purity, stability , residual DNA, absence of vector, low levels of plant metabolites such as pyridine alkaloids, and other criteria as specified in guidance documents . Host and process-related impurities in PMPs, such as residual HCP, residual vector, pyridine alkaloids from solanaceous hosts , phenolics, heavy metals , and other impurities that could introduce a health risk to consumers, have been successfully managed by upstream process controls and/or state-of-the-art purification methods and have not impeded the development of PMP products . The theoretical risk posed by non-mammalian glycans, once seen as the Achilles heel of PMPs, has not materialized in practice. Plant-derived vaccine antigens carrying plant-type glycans have not induced adverse events in clinical studies, where immune responses were directed primarily to the polypeptide portion of glycoproteins . One solution for products intended for systemic administration, where glycan differences could introduce a pharmacokinetic and/or safety risk , is the engineering of plant hosts to express glycoproteins with mammalian-compatible glycan structures . For example, ZMapp was manufactured using the transgenic N. benthamiana line ΔXT/FT, expressing RNA interference constructs to knock down the expression of the enzymes XylT and FucT responsible for plant-specific glycans,horticulture products as a chassis for transient expression of the mAbs . In addition to meeting molecular identity and physicochemical quality attributes, PMP products must also be safe for use at the doses intended and efficacious in model systems in vitro, in vivo, and ex vivo, following the guidance documents listed above. Once proven efficacious and safe in clinical studies, successful biologic candidates can be approved via a BLA in the United States and a new marketing authorization in the EU.In emergency situations, diagnostic reagents, vaccine antigens, and prophylactic and therapeutic proteins may be deployed prior to normal marketing authorization via fast-track procedures such as the FDA’s emergency use authorization .This applies to products approved for marketing in other indications that may be effective in a new emergency indication , and new products that may have preclinical data but little or no clinical safety and efficacy data. Such pathways enable controlled emergency administration of a novel product to patients simultaneously with traditional regulatory procedures required for subsequent marketing approval.
In the United States, the FDA has granted EUAs for several diagnostic devices, personal protective devices, and certain other medical devices, and continuously monitors EUAs for drugs. For example, the EUA for chloroquine and hydroxychloroquine to treat COVID-19 patients was short-lived, whereas remdesivir remains under EUA evaluation for severe COVID-19 cases. The mRNA-based SARS-CoV-2 vaccines currently undergoing Phase III clinical evaluation by Pfizer/BioNTech and Moderna/ NIAID, and other vaccines reaching advanced stages of development, are prime candidates for rapid deployment via the EUA process. No PMPs have yet been granted EUA, but plant-made antibodies and other prophylactic and therapeutic APIs may be evaluated and deployed via this route. One example of such a PMP candidate is griffithsin, a broad-spectrum antiviral lectin that could be administered as a prophylactic and/or therapeutic for viral infections, as discussed later. The FDA’s EUA is a temporary authorization subject to constant review and can be rescinded or extended at any time based on empirical results and the overall emergency environment. Similarly, the EU has granted conditional marketing authorisation to rapidly deploy drugs such as remdesivir for COVID-19 in parallel with the standard marketing approval process for the new indication.The regulations commonly known as the animal rule 17 allow for the approval of drugs and licensure of biologic products when human efficacy studies are not ethical and field trials to study the effectiveness of drugs or biologic products are not feasible. The animal rule is intended for drugs and biologics developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances. Under the animal rule, efficacy is established based on adequate and well-controlled studies in animal models of the human disease or condition of interest, and safety is evaluated under the pre-existing requirements for drugs and biologic products.As an example, the plant-derived mAb cocktail ZMapp for Ebola virus disease, manufactured by Kentucky Bioprocessing for Mapp Biopharmaceutical 18 and other partners, and deployed during the Ebola outbreak in West Africa in 2014, was evaluated only in primates infected with the Congolese variant of the virus , with no randomized controlled clinical trial before administration to infected patients under a compassionate use protocol . Although the fast-track and streamlined review and authorization procedures described above can reduce time-to-deployment and time-to-approval for new or repurposed products, current clinical studies to demonstrate safety and efficacy generally follow traditional sequential designs. Products are licensed or approved for marketing based on statistically significant performance differences compared to controls, including placebo or standards of care, typically generated in large Phase III pivotal trials. One controversial proposal, described in a draft WHO report , is to accelerate the assessment of safety and efficacy for emergency vaccines by administering the medical intervention with deliberate exposure of subjects to the threat agent in a challenge study. Although the focus of the WHO draft report was on vaccines, the concept could conceivably be extended to non-vaccine prophylactics and therapeutics. Results could be generated quickly as the proportion of treated and control subjects would be known, as would the times of infection and challenge. Challenge studies in humans, also known as controlled human infection models or controlled human infection studies , are fraught with ethical challenges but have already been used to assess vaccines for cholera, malaria, and typhoid . The dilemma for a pathogen like SARS-CoV-2 is that there is no rescue medication yet available for those who might contract the disease during the challenge, as there was for the other diseases, putting either study participants or emergency staff at risk .In the EU, the current regulatory environment is a substantial barrier to the rapid expansion of PMP resources to accelerate the approval and deployment of products and reagents at relevant scales in emergency situations.