This is because many of the DSP techniques are product-dependent and, therefore, similar regardless of the platform, including most of the DSP equipment, with which regulatory agencies are already familiar. Of course, the APIs themselves must be fully characterized and shown to meet designated criteria in their specification, but this applies to all products regardless of source.During a health emergency, such as the COVID-19 pandemic, regulatory agencies worldwide have re-assessed guidelines and restructured their requirements to enable the accelerated review of clinical study proposals, to facilitate clinical studies of safety and efficacy, and to expedite the manufacturing and deployment of re-purposed approved drugs as well as novel products . These revised regulatory procedures could be implemented again in future emergency situations. It is also possible that some of the streamlined procedures that can expedite product development and regulatory review and approval will remain in place even in the absence of a health emergency, permanently eliminating certain redundancies and bureaucratic requirements. Changes in the United States and European regulatory processes are highlighted, large plastic pots with a cautionary note that these modified procedures are subject to constant review and revision to reflect an evolving public health situation.In the spring of 2020, the FDA established a special emergency program for candidate diagnostics, vaccines, and therapies for SARS-CoV-2 and COVID-19.
The Coronavirus Treatment Acceleration Program 5 aims to utilize every available method to move new treatments to patients in need as quickly as possible, while simultaneously assessing the safety and efficacy of new modes of intervention. As of September 2020, CTAP was overseeing more than 300 active clinical trials for new treatments and was reviewing nearly 600 preclinical-stage programs for new medical interventions. Responding to pressure for procedural streamlining and rapid response, the FDA refocused staff priorities, modified its guidelines to fit emergency situations, and achieved a remarkable set of benchmarks . In comparison to the review and response timelines described in the previous section, the FDA’s emergency response structure within CTAP is exemplary and, as noted, these changes have successfully enabled the rapid evaluation of hundreds of new diagnostics and candidate vaccine and therapeutic products.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, 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 Bio-processing.7During 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,8 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.9 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 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 , large pots plastic 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.12 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-tobe-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.14 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, 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.