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The Use of Animals in Research
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
In cases where human efficacy trials may not be feasible or ethical, a new drug or biologic designed to reduce or prevent life-threatening consequences induced by biological, chemical, or radiological agents may bypass the human clinical trial phase following successful preclinical trials in animals. Known as the Animal Efficacy Rule or simply the “Animal Rule”, this law was authorized by the FDA in the United States in 2002 following the September 11th terrorist attacks and designed to counter potential acts of bioterrorism (United States Food & Drug Administration 2019a). Under the Animal Rule, the FDA may approve a new product following animal studies without human clinical trials if the mechanism by which the product works is established and well-understood, and preclinical studies demonstrate a response predictive for humans in multiple animal species. Only a handful of products have been approved by the FDA using the Animal Rule, but include treatments for plague (caused by infection with the bacterium Yersinia pestis) and the Ebola virus.
An overview of tecovirimat for smallpox treatment and expanded anti-orthopoxvirus applications
Published in Expert Review of Anti-infective Therapy, 2021
Andrew T. Russo, Douglas W. Grosenbach, Jarasvech Chinsangaram, Kady M. Honeychurch, Paul G Long, Candace Lovejoy, Biswajit Maiti, Ingrid Meara, Dennis E. Hruby
Smallpox is a strictly human disease [56] and no longer circulates in the population. Since cases of smallpox no longer occur it is not possible to evaluate efficacy of antiviral drugs in humans. Therefore, development of tecovirimat was conducted according to recommendations in the USFDA Animal Efficacy Rule (Animal Rule) [57]. In 2002 the USFDA established the ‘Animal Efficacy Rule’ to provide a pathway for development of drug (21 CFR 314.600 through 314.650) and biological (and 21 CFR 601.90 through 601.95) products, ‘when human efficacy studies are not ethical or feasible.’ [57,58].
Broad-spectrum coronavirus antiviral drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Allison L. Totura, Sina Bavari
While SARS-CoV and MERS-CoV were rapidly identified following clinical reports of novel atypical pneumonia, progress in developing effective antivirals for SARS-CoV and MERS-CoV has been impeded by several factors. A key finding from our review of the literature is that current animal models for highly pathogenic coronaviruses SARS-CoV and MERS-CoV are not adequate to support advanced development of antiviral therapeutics. MERS-CoV continues to circulate on the Arabian Peninsula, providing the opportunity to investigate some treatments of MERS in clinical trials. However, future emerging coronaviruses may require use of the FDA Animal Efficacy Rule for Investigational New Drugs (INDs). INDs must fulfill the Animal Efficacy Rule criteria of i) reasonable safety for initial use in humans, ii) pharmacological data that support reasonably well-understood mechanism of activity against the pathogen, and iii) efficacy in animal models with disease signs representative of clinical illness in humans (including one non-rodent model). While the vigorous pursuit of small animal models has been successful in generating rodent models that recapitulate severe SARS and MERS disease signs (including morbidity and mortality), progress in generating additional animal models has lagged, particularly in primate models of SARS-CoV or MERS-CoV infection. Past strategies for experimental treatment regimens primarily relied on combination therapies with approved drugs known to have acceptable safety profiles and broad-spectrum antiviral activity including IFNs, ribavirin, and corticosteroids. However, analyses of data returned from these treatments indicated that most regimens were not effective in treating SARS and MERS patients. With sufficient investment in the development of drug discovery pipeline model systems, pan-coronavirus targets based on supportive in vitro and in vivo evidence for effective treatments during the current MERS outbreaks and future outbreaks of emergent CoVs (Figure 3).
Small animal models of filovirus disease: recent advances and future directions
Published in Expert Opinion on Drug Discovery, 2018
Robert W. Cross, Karla A. Fenton, Thomas W. Geisbert
Understanding the biology of filovirus infections has progressed over the last 50 years, yet there are still no approved vaccines or antiviral therapeutics for the prevention or treatment for any of the known filoviruses. The rarity of human exposure to these agents coupled to the remote locations of outbreaks has made study of human disease exceedingly difficult. The development and validation of countermeasures against high consequence infections such as those caused by filoviruses has been hampered by ethical issues. Some of these issues include the use of high CFR pathogens in humans where placebo use leads to unmanageable risk for participants chosen to take them. Further, there are no approved alternative treatments available should they be necessary as a failsafe treatment option in clinical trials [26]. Regardless of these challenges, evaluation of potential MCMs remains a major priority for the international health community and thus demands a solution to mitigate these risks and allow approval of successful MCM candidates. In 2002, the United States Food and Drug Administration (US FDA) offered a ruling known as the ‘Animal Efficacy Rule’ (21 CFR 314,600) to address the requirement where-in data taken from adequately controlled pre-clinical animal efficacy studies could be considered for approval applications where human clinical trials were otherwise unreasonable [27]. Briefly, this ‘Animal Rule’ outlines expectations that test articles would provide similar protection for humans as it does animals after exposure to the lethal agent. Importantly, the supporting data must fulfill all the efficacy concerns of human clinical trials while simultaneously providing a more thorough description on comparative pathogenic disease mechanisms followed by the precise means by which the test article will interrupt the course of disease to increase survival. Within this guidance, are recommendations that at least one or more animal model will accurately recapitulate the human pathophysiology of the agent in question [26].