AKAO 2017 Annual Report

32 notifications are cleared without clinical data, in some cases, the FDA requires significant clinical data to support substantial equivalence. In reviewing a pre-market notification, the FDA may request additional information, including clinical data, which may significantly prolong the review process. After a device receives 510(k) clearance, any subsequent modification of the device that could significantly affect its safety or effectiveness, or that would constitute a major change in its intended use, will require a new 510(k) clearance or could require pre-market approval. The FDA requires each manufacturer to make this determination initially, but the FDA may review any such decision and may disagree with a manufacturer’s determination. If the FDA disagrees with a manufacturer’s determination, the FDA may require the manufacturer to cease marketing and/or recall the modified device until 510(k) clearance or a PMA is obtained. PMA applications must be supported by valid scientific evidence, which typically requires extensive data, including technical, preclinical, clinical and manufacturing data, to demonstrate to the FDA’s satisfaction the safety and effectiveness of the device. For diagnostic tests, a PMA application typically includes data regarding analytical and clinical validation studies. As part of its review of the PMA, the FDA will conduct a pre-approval inspection of the manufacturing facility or facilities to ensure compliance with the Quality System Regulation, which requires manufacturers to follow design, testing, control, documentation and other quality assurance procedures. We and our partner Microgenics Corporation (a part of Thermo Fisher Scientific, Inc.) (“Thermo Fisher”) are developing an in vitro assay for plazomicin and have worked together to generate the data required for submission of a 510(k) premarket notification. Thermo Fisher submitted the 510(k) in January 2018, and it was accepted for substantive review on February 7, 2018. We anticipate coordination between the Center for Drug Evaluation and Research and Center for Devices and Radiological Health on the review of the plazomicin in vitro assay submission. Though Thermo Fisher and Achaogen have mutually agreed to submit via the 510(k) regulatory pathway, the FDA may conclude that an alternate approval pathway or new 510(k) submission is required. The assay may also be classified as a PMA if the FDA determines that the device is high risk. The assay may also be classified by the FDA as a companion diagnostic for plazomicin in association with plazomicin’s possible indication for BSI. On August 6, 2014, the FDA issued a final guidance document addressing the development and clearance or approval process for “ In vitro Companion Diagnostic Devices.” According to the guidance, the companion diagnostic device should be developed and approved or cleared contemporaneously with the therapeutic. In the event our in vitro assay for plazomicin becomes classified as a companion diagnostic, we believe our development program is consistent with the guidance. In the European Economic Area (“EEA”), in vitro medical devices are required to conform with the essential requirements of the EU Directive on In Vitro Diagnostic Medical Devices (Directive No 98/79/EC, as amended). To demonstrate compliance with the essential requirements, the manufacturer must undergo a conformity assessment procedure. The conformity assessment varies according to the type of medical device and its classification. For low- risk devices, the conformity assessment can be carried out internally, but for higher risk devices it requires the intervention of an accredited EEA Notified Body. If successful, the conformity assessment concludes with the drawing up by the manufacturer of an EC Declaration of Conformity entitling the manufacturer to affix the CE mark to its products and to sell them throughout the EEA. The data generated for the U.S. registration will be sufficient to satisfy the regulatory requirements for the EU and other countries. On April 5, 2017, the European Parliament passed the Medical Devices Regulation (Regulation 2017/745), which repeals and replaces the EU Medical Devices Directive and the Active Implantable Medical Devices Directive, as well the In Vitro Diagnostic Medical Devices Regulation (Regulation 2017/746), which repeals and replaces the EU Directive on In Vitro Diagnostic Medical Devices. Unlike directives, which must be implemented into the national laws of the EEA member States, regulations are directly applicable, i.e., without the need for adoption of EEA member State laws implementing them, in all EEA member States and are intended to eliminate current differences in the regulation of medical devices among EEA member States. The Medical Devices Regulation and the In Vitro Diagnostic Medical Devices Regulation, among other things, are intended to establish a uniform, transparent, predictable and sustainable regulatory framework across the EEA for medical devices and ensure a high level of safety and health while supporting innovation.