The efforts to end the COVID-19 pandemic have been multifaceted: epidemiological data for understanding, vaccines and non-pharmaceutical interventions for prevention, and new or repurposed drugs for treatment. In this blog post, Monia Tumminello, Manager, Cortellis Regulatory Intelligence™, and Jaime Polychrones, Medical Writer, Cortellis Regulatory Intelligence, discuss the regulatory response to therapeutic development, from issuing new guidance to fast track and conditional approvals.
COVID-19 vaccine development and administration have progressed quickly, facilitated by fast track regulatory approvals and coordinated investment in manufacturing and distribution. As healthcare professionals care for their patients with COVID-19, the speed at which treatments have been investigated (both formally and informally) has also been unprecedented.
To facilitate the development of these medicines, many of the support measures offered by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for vaccine development are also available, including the free scientific advice, accelerated assessment and fast-track authorizations. In this post, we describe these measures and how developments have evolved into treatment guidelines.
New regulatory guidance
As early as May 2020, the FDA had published new guidance for researchers to help to make the process for submitting applications to initiate studies for new drugs and biological products more efficient. It also outlined recommendations for clinical trial design to evaluate the safety and effectiveness of new products. The COVID-19 Public Health Emergency: General Considerations for Pre-IND (Investigational New Drug application) Meeting Requests for COVID-19 Related Drugs and Biological Products guidance outlines a more efficient process to receive agency feedback on supporting data, to be able to start clinical trials faster. The COVID-19: Developing Drugs and Biological Products for Treatment or Prevention guidance provides the current recommendations for the review of the safety and effectiveness of investigational products in later-stage trials.
In a joint statement endorsed by the EMA, international medicines regulators described the key characteristics of clinical trials that are most likely to generate the conclusive evidence needed to enable the accelerated approval of potential treatments against COVID-19. The EMA also contributed to an internationally generated report regarding the acceptable primary endpoints in clinical trials conducted for the development of COVID-19 treatments, with the aim of facilitating rapid and consistent implementation of future clinical trials for COVID-19 medicines worldwide.
Collaboration is key
Global collaborations are also in place. In addition to vaccines, the National Institutes of Health Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership supports therapeutic development. Similarly, the Access to COVID-19 Tools (ACT) Accelerator is a global collaboration to accelerate the development, production and equitable access to COVID-19 tests, treatments and vaccines.
The ACT Accelerator brings together governments, scientists, businesses, civil society, philanthropists and global health organizations.
Launched at the end of April 2020, the ACT Accelerator brings together governments, scientists, businesses, civil society, philanthropists and global health organizations. It includes the Bill & Melinda Gates Foundation, Coalition for Epidemic Preparedness Innovations (CEPI), FIND, Gavi, The Global Fund, Unitaid, Wellcome, the World Health Organization, the World Bank and Global Financing Facility.
EMA’s Human Medicines Committee (CHMP) published a statement urging the E.U. research community to prioritize large randomized controlled studies because they are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential treatments of COVID-19. The statement promotes a harmonized approach to data collection and a robust methodology for COVID-19 clinical trials across the E.U. to make best use of the available supply of investigational agents. It emphasizes the need to include all E.U. countries in these trials.
The FDA also created a special emergency program for possible COVID-19 therapies called the Coronavirus Treatment Acceleration Program (CTAP) to expedite the development of treatments and streamline efforts across federal partners, developers and researchers. According to the website, as of January 5, 2021, there are more than 590 drug development programs in planning stages, more than 390 trials that have been reviewed by the FDA, 8 COVID-19 treatments that have been authorized for emergency use and one treatment currently approved by the FDA for use in COVID-19.
As of January 5, 2021, there are more than 590 drug development programs in planning stages, more than 390 trials that have been reviewed by the FDA, 8 COVID-19 treatments that have been authorized for emergency use and one treatment currently approved by the FDA for use in COVID-19.
Rapid review and approval
Emergency use authorizations (EUAs) have been granted by the FDA for:
- remdesivir, which was later approved for use in a subset of the population covered by the EUA;
- Fresenius Kabi Propoven for maintaining sedation via continuous infusion;
- REGIOCIT replacement solution for adult patients treated with continuous renal replacement therapy (CRRT);
- convalescent plasma;
- combination baricitinib and remdesivir; and
- combination casirivimab and imdevimab.
As of January 4, 2021, 71 therapies had received advice from the EMA
As of January 4, 2021, 71 therapies had received advice from the EMA, in preparation for eventual applications for marketing authorization. The EMA has granted conditional marketing authorization for remdesivir and has approved dexamethasone to treat adults with COVID-19 requiring respiratory support.
Given the accelerated timelines for therapeutic development, observational studies of real-world data have been suggested by both the EMA and FDA. This approach could increase the effectiveness and efficiency of regulatory processes and decision-making in the development, authorization and monitoring of medicines to treat COVID-19. It could also address knowledge gaps that cannot be addressed by clinical trials.
In addition, the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) and EMA strongly encourage all researchers to register their pharmacoepidemiological studies related to the COVID-19 pandemic in the E.U. post-authorization study (PAS) register. Researchers are also encouraged to upload and make public the study protocol, with a description of the data collected or planned to be collected, to support the design of observational studies by others.
Treatment recommendations and guidance
As the European Commission (EC) stated early in the pandemic, “…the evolution of the COVID-19 pandemic is affecting countries with different levels of severity at varying times. The practical experience on how to manage patients, in particular severe cases, is scarce and scattered in Europe. While the experience and the number of cases treated by some hospitals is important, others are only starting to deal with complex patients.”
To foster communication about learnings regarding treatment of COVID-19 patients, the EC quickly launched the COVID-19 Clinical Management Support System (CMSS) to help create rapid connections among healthcare professionals in hospitals dealing with COVID-19 cases in the E.U., United Kingdom and European Economic Area (EEA) countries. This cooperation aims to speed up the adoption of specific treatment options, improve communication and training and help reduce some of the uncertainties around the virus. In addition, the EC adopted guidelines for cross-border healthcare cooperation.
In the United States, the NIH published treatment guidelines for healthcare providers, from a panel of physicians, statisticians and other experts. These were based on published and preliminary data and the clinical expertise of the panelists, with the intent of updating them as new information was published.
The regulatory agencies also continue to monitor and encourage the reporting of side effects of all medications, regardless of their purpose and both on-label and off-label, in patients with confirmed or suspected COVID-19. As a result, ithey found that co-administration of remdesivir and chloroquine phosphate or hydroxychloroquine sulfate could reduce the antiviral activity of remdesivir.
Based on publications questioning whether angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) or whether non-steroidal anti-inflammatory medicines (NSAIDs) such as ibuprofen might worsen coronavirus disease, the EMA closely monitored the situation and determined that neither ACE inhibitors/ARBs nor NSAIDs appear to affect the risk of COVID-19 infection or the outcome for patients with COVID-19 disease. The FDA issued guidelines on its use, both under the EUA and as an investigational product based on potential effectiveness of convalescent plasma in COVID-19 treatment,.
With effective treatments, we’ve observed a decrease in the COVID-19 mortality rate, even as case numbers increase again. Efforts to decrease the spread of infection, epidemiological data from testing and contact tracing are crucial. In the next post in this series, we will discuss how regulators are addressing this need to track how and where infections are occurring.
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