Revisiting the Term "Compassionate Use" and Leadership of the World Health Organization in Resolving Confusion in the Age of COVID-19 and Beyond.

We discuss the term "compassionate use" (CU) as an example of terminology having a huge impact on drug regulation. CU is used in many confusing situations, and its meaning varies significantly. We ethically affirm the necessity of CU. We insist that CU should be properly placed in exceptional status. The regulation of CUs is much more lenient than that of clinical trials because of the difference in the purpose. Whether consciously or unconsciously, abuse results in confusion and is never acceptable. The World Health Organization (WHO) proposed not to use the previous term CU but to replace it with another one. WHO also proposed the term MEURI (monitored emergency use of unregistered and experimental interventions). However, this was extremely incomplete, and WHO used the term CU subsequently. The main purpose of the proposal needs to be thoroughly implemented. In the context of the COVID-19 pandemic and beyond, expectations regarding WHO's role and leadership in global health issues are rising. We hope that WHO will play a major role in promoting research ethics preparedness while discontinuing the use of confusing terms such as CU and will develop alternative terms and their content. We discuss the evaluation of MEURI, the Japanese version of CU, and appropriate and inappropriate terminology related to the therapeutic use of unapproved drugs. We also discuss the expected appearance of CU including its name. It is appropriate to target group/cohort patients and unapproved drugs in the late stage of development. It is also important to solve the problem of incentives for CUs of pharmaceutical companies that are rushing to obtain marketing approval. The UK's Early Access to Medicine Scheme has provided many suggestions. We believe that our opinion can contribute to WHO's efforts to resolve the confusion and promote research ethics preparedness in health emergencies.

Adapting an Expanded Access program to enable investigational treatments for COVID-19.

Retrospective case studies of initiatives supported by the National Institutes of Health's Clinical and Translational Science Award (CTSA) hubs can be used to identify facilitators and barriers of translational science. This case study investigates how a CTSA Expanded Access program adapted to changing FDA guidance issued in 2020 to support clinicians' treatment of COVID-19 patients in Michigan. We studied how this program changed throughout the pandemic to support physicians' requests for remdesivir, convalescent plasma, and other uses of unapproved drugs and novel medical devices. A protocol for retrospective translational science case studies of health interventions developed by CTSA evaluators was used for this case study. Data collection methods included seven interviews and a review of institutional data, peer-reviewed publications, news stories, and other public records. The barriers identified include evolving guidance, misalignment of organizational operations, and the complexity of the research infrastructure. The facilitators of translation include collaboration between research and care teams, increasing engagement with a broad network of supporters, and ongoing professional development for research staff. The findings of this case study can be used to inform future investigations of the principles underlying the translational process.

Proof-of-concept trial of an amniotic fluid-derived extracellular vesicle biologic for treating high risk patients with mild-to-moderate acute COVID-19 infection.

A pandemic brought on by COVID-19 has created a scalable health crisis. The search to help alleviate COVID-19-related complications through therapeutics has become a necessity. Zofin is an investigational, acellular biologic derived from full-term perinatal amniotic fluid that contains extracellular vesicles. Extracellular nanoparticles as such have been studied for their immunomodulatory benefits via cellular therapeutics and, if applied to COVID-19-related inflammation, could benefit patient outcome. Subjects (n = 8) experiencing mild-to-moderate COVID-19 symptoms were treated with the experimental intervention. Complete blood count, complete metabolic panel, inflammatory biomarkers, and absolute lymphocyte counts were recorded prior to and on days 4, 8, 14, 21, and 30 as markers of disease progression. Additionally, chest x-rays were taken of the patients prior to and on days 8 and 30. Patients experienced no serious adverse events. All COVID-19-associated symptoms resolved or became stable with no indication of disease worsening as found by patient and chest x-ray reports. Inflammatory biomarkers (CRP, IL-6, TNF- α ) and absolute lymphocyte counts improved throughout the study period. Findings from a proof-of-concept, expanded access trial for COVID-19 patients prove the acellular biologic is safe and potentially effective to prevent disease progression in a high-risk COVID-19 population with mild-to-moderate symptoms.

Helpful Lessons and Cautionary Tales: How Should COVID-19 Drug Development and Access Inform Approaches to Non-Pandemic Diseases?

After witnessing extraordinary scientific and regulatory efforts to speed development of and access to new COVID-19 interventions, patients facing other serious diseases have begun to ask "where's our Operation Warp Speed?" and "why isn't Emergency Use Authorization an option for our health crises?" Although this pandemic bears a number of unique features, the response to COVID-19 offers translatable lessons, in both its successes and failures, for non-pandemic diseases. These include the importance of collaborating across sectors, supporting the highest-priority research efforts, adopting rigorous and innovative trial designs, and sharing reliable information quickly. In addition, the regulatory response to the pandemic demonstrates that lowering standards for marketing authorization can result in increased safety concerns, missed opportunities for research and treatment, and delays in determining what works. Accordingly, policymakers and patient advocates seeking to build on the COVID-19 experience for non-pandemic diseases with unmet treatment needs should focus their efforts on promoting robust and efficient research designs, improving access to clinical trials, and facilitating use of the Food and Drug Administration's existing Expanded Access pathway.

The use of remdesivir outside of clinical trials during the COVID-19 pandemic.

With a scientific background from filoviruses, paramyxoviruses, SARS-CoV, and MERS-CoV, remdesivir entered into the COVID-19 battle to become one of the favorable therapeutic candidates with potential antiviral activity in the treatment of this disease. Globally, remdesivir was accessed and investigated through clinical research (clinical trials) and clinical practice (compassionate use, expanded access, early access scheme, and emergency use). Currently, remdesivir approval status differs between states. This paper aims to review and analyze regulatory approaches for accessing and investigating remdesivir, by communicating regulatory variability between countries in terms of terminology, modalities, and protocols.

Update to Drugs, Devices, and the FDA: How Recent Legislative Changes Have Impacted Approval of New Therapies.

Two major legislative actions since 2015, the 21st Century Cures Act of 2016 and the U.S. Food and Drug Administration (FDA) Reauthorization Act of 2017, contain significant provisions that potentially streamline drug development times, and by extension, may reduce costs. Evidence suggests, however, that development times have already been significantly affected by previous legislation and FDA programs, through accelerated approval pathways and adoption of more flexible definitions of clinical evidence of efficacy. The COVID-19 pandemic is pushing researchers and commercial entities to further test the limits of drug and vaccine development times and approvals, at an as yet unknown level of risk to patients. COVID-19 drug and vaccine trials are even now making use of accelerated drug approval programs, blended trials, and adaptive trial design to accelerate approval of therapeutics in the pandemic.

COVID-19: Regulatory Landscape of Medicinal and Medical Device Products for Human Use.

Against the backdrop of the COVID pandemic, the scientific and medical communities are working with all deliberate speed with state-of-the-art technologies to develop diagnostic and therapeutic products that can identify, treat, and prevent infection with SARS-CoV-2. These activities may only be legally conducted with the necessary statutes and regulations in place to facilitate the timely development, manufacturing, evaluation, and distribution of products that meet quality standards. The present regulatory landscape for medicinal and medical products for human use has been shaped by nearly 12 decades of statutory history that followed in reaction to disasters and tragedies. Five distinct, closely woven threads of statutory history have led to the regulatory infrastructure we have in place: (1) standardized processes for routine development of medicinal and medical device products for human use; (2) processes for expedited development to shorten time frames and expand patient populations; (3) mechanisms of Expanded Access to make medicinal products available to patients prior to approval of the US Food and Drug Administration; (4) Emergency Use Authorization during public health emergencies; and (5) the development of pathways for bringing generic drugs and biosimilar biologics to market. These mechanisms are being brought to bear to facilitate the defeat of infection with SARS-CoV-2.