The US Food and Drug Administration (FDA) Expanded Access (EA) Program, which allows for compassionate uses of unapproved therapeutics and diagnostics outside of clinical trials, has gained significant traction during the Coronavirus 2019 (COVID-19) pandemic. While development of vaccines has been the major focus, uncertainties around new vaccine safety and effectiveness have spawned interest in other pharmacological options. Experimental drugs can also be approved under the FDA Emergency Use Authorization (EUA) program, designed to combat infectious disease and other threats. Here, we review the US experience in 2020 with pharmacological EA and EUA approvals during the pandemic. We also provide a description of, and clinical rationale for, each of the EA-or EUA-approved drugs (e.g. remdesivir, convalescent plasma, propofol 2%, hydroxychloroquine, ruxolitinib, bamlanivimab) during the pandemic and concluding reflections on the EA program and its potential future uses. Teaser: Several drugs have been authorized by the US FDA through the Expanded Access and/or the Emergency Use Authorization programs during the COVID-19 pandemic. How well did these programs function and what have we learned?Reviews POST SCREEN

Basing on the example of two cases, the clinical and morphological variability of mitochondrial encephalomyopathies is demonstrated. Both patients were of short build, and the clinical signs and symptoms were dementia, ataxia, epilepsy and hardness of hearing, whereas signs of myopathy were very mild or absent. Computed tomography showed infratentorial pronounced atrophy of the brain and basal ganglia calcifications, in one case additionally ischemic infarctions, as can be seen in "mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome" (MELAS). A CT follow-up over 8 years with a progression of the abnormalities parallel to the progressive clinical course is demonstrated. Besides typical "ragged red fibres-myopathy" different abnormalities of mitochondria were seen by the electron microscope. One of the patients died; he had exceptional pathological-anatomical findings with mitochondrial cardiomyopathy, angioma and necrotising encephalopathy of Leigh's type. The two case reports show that in patients with such multisystemic neurological signs and CT-findings mitochondrial encephalomyopathy should be considered and a muscle biopsy should be performed.

The clinical trial agreement (CTA) is a key but often underappreciated document governing the relationship between a study site and a sponsor. Previous anecdotal materials have suggested that investigators may not often be involved in the review or negotiation of the CTA and may attach little importance to it. To provide more systematic current information, survey methods were used to explore the level of engagement, knowledge, and perceptions of investigators in the United States. The survey was distributed to more than 700 investigators-university affiliated and nonaffiliated-and/or related study staff, of whom 167 responded. Most respondents identified that they did not manage the clinical trial agreement process but were actively engaged in its review. Most were encouraged by their institutions to participate. However, some respondents expressed concerns with regard to their satisfaction with the content of the CTA, particularly with respect to issues such as financial negotiations and payments, indemnification, and subject injury language. The majority of investigators either strongly agreed or agreed that it was important for the investigator to be actively involved in the CTA process. Data from this survey provide the first systematic look at the current practices of US investigators, possible issues, and areas for improvement from the investigator's point of view.

The accuracy of the "Histomat", an apparatus for automated histophotometric determination of malignant or benign tissues, was used on samples from 235 breast tumours (94 malignant and 141 benign tumours). Analysis of the measured data, using the schema developed by the manufacturer (Hytec), showed that in tumours of the breast this type of histophotometric analysis cannot distinguish between benign and malignant tissue changes. Its diagnostic use is therefore not justified.