Characteristics of Clinical Studies Used for US Food and Drug Administration Supplemental Indication Approvals of Drugs and Biologics, 2017 to 2019.

Importance: After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. Objective: To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. Design, Setting, and Participants: This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Main Outcomes and Measures: Number and design of pivotal trials supporting both supplemental and original indication approvals. Results: From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. Conclusions and Relevance: These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

[The medicinal treatment of COVID-19: a brief update]. / Medicamenteuze behandeling van COVID-19.

Much has changed in the medical treatment of COVID-19 after the first patient with an infection with SARS-CoV-2 in the Netherlands was diagnosed in February 2020. On the basis of limited data, at first only off-label use of (hydroxy)chloroquine seemed to be a treatment option. However, now based on the findings of several randomized studies, other medicines have been included in the Dutch guidelines about the treatment of COVID-19. In this article, we will briefly discuss the current state of affairs with regard to the drugs (hydroxy) chloroquine, remdesivir and corticosteroids. Again, it appears that only well-executed randomized clinical trials can determine the status of various supposedly effective drugs.

Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents.

BACKGROUND: Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE: To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS: This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS: Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION: For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.

[Biosimilars antibodies: positioning compared to originators - the experience in rheumatology and the biosimilars of trastuzumab in oncology]. / Anticorps biosimilaires versus princeps - L'expérience en rhumatologie et les biosimilaires du trastuzumab en oncologie.

Biosimilars have demonstrated their equivalence with biologic originators, according to rigorous specifications imposed by the regulatory agencies, the FDA and the EMA. Their development is justified by the very high cost of biopharmaceuticals, and strong incentives for their prescription lead us to hope substantial savings, allowing to finance other innovative molecules. Trastuzumab marked history of the treatment of breast cancer. Four biosimilars of trastuzumab are available for routine use and we will detail the key points of their development.

TITLE: Anticorps biosimilaires versus princeps - L'expérience en rhumatologie et les biosimilaires du trastuzumab en oncologie. ABSTRACT: Les biosimilaires sont des produits ayant montré leur équivalence avec le traitement biologique de référence, selon un cahier des charges strict imposé par les agences d'enregistrement, la FDA et l'EMA. Leur développement et leur utilisation sont justifiés par le coût très élevé des biomédicaments, et de fortes incitations à leur prescription font espérer des économies substantielles, permettant le financement d'autres molécules innovantes. Le trastuzumab a marqué l'histoire des traitements du cancer du sein, quatre biosimilaires étant désormais disponibles pour une utilisation en routine. Nous détaillerons ici les points clés de leur développement.