Navigating facilitated regulatory pathways during a disease X pandemic

Abstract

In 2018, the Bill and Melinda Gates Foundation convened over thirty subject matter experts in clinical development, manufacturing, and regulatory assessment to determine how the development and approval of medical countermeasures could be accelerated in the event of Disease X. Disease X is the result of a presently unknown pathogen with epidemic or pandemic potential. A key opportunity to accelerate the scientific assessment and regulatory approval of medical countermeasures exists within efficient navigation of facilitated regulatory pathways. It was identified that not all stakeholders will be able to skillfully navigate the facilitated pathways offered by the various regulatory agencies during a public health emergency. To democratize this knowledge, we have written an overview of the facilitated approaches which have been developed and refined by Stringent Regulatory Authorities and the World Health Organization for the primary assessment of medical products. We discuss the conditions necessary for use of these approaches, scenarios in which certain pathways may be applicable, and the pros and cons of these approaches. We also address opportunities available to developers in, or developers who wish to access, low-income countries that may have nascent regulatory frameworks.

Keywords: DNA vaccines; Drug regulation; Drug safety; Gene therapy; Recombinant vaccine.

Fig. 1. Navigating facilitated regulatory pathways during an epidemic or pandemic.

Top. In the routine assessment and authorization pathway, market authorization is granted following the completion of successful phased clinical trials, analysis of comprehensive data sets from adequate and well-controlled trials, and a standard regulatory assessment timeline. Middle. Rapid assessment and authorization based on less comprehensive data derived earlier in product development shorten the overall timeline for serious indications of unmet clinical need. Rolling reviews, increased institutional support, and frequent scientific advice may accelerate the development and assessment processes. In some jurisdictions, an authorization with conditions to be met post-authorization may be granted–bridging the gap between when definitive clinical trials are conducted and market authorization. In some cases, intermediate endpoints or unvalidated surrogates may be sufficient for an initial conditional or accelerated authorization to meet unmet clinical needs for serious and life-threatening diseases. Further confirmatory studies are required post-authorization to either validate the clinical benefit assumptions or not. If not validated, the product is removed. These pathways run the risk of possibly depleting clinical trial material potentially delaying larger-scale trials. Another risk relates to not having adequate capacity to supply need if investments in manufacturing capacity are not made earlier enough in product development. Bottom. In declared public health emergencies, temporary authorization may be given based on promising pre-clinical data and early human clinical (if possible) and safety data. Such authorizations are usually valid for the duration of the declared emergency. These approaches require significant at-risk investment, ensuring large scale manufacturing early on, in order to meet the need of the emergency. The animal rule is an option in both routine and emergency situations. It allows authorization based on animal efficacy and human safety data, when it is not ethical or possible to conduct human efficacy trials.