BUSINESS OVERVIEW 6 moderate-risk devices classified in Class I I I by operation of law, 45 days to determine whether it is sufficiently complete to permit the FD&C Act allows the FDA to classify a low- to moderate-risk a substantive review. If the PMA application is complete, the FDA device not previously classified into Class I or I I, a process known will file the PMA application. If the FDA accepts the application as the de novo process. A company may apply directly to the FDA for filing, the agency will begin an in-depth substantive review of for classification of its device as de novo or may submit a de novo the application. By statute, the FDA has 180 days to review the petitionwithin 30 days of receiving a not substantially equivalent application although, generally, review of the application often determination. takes between one to three years, and may take significantly Modifications to a 510(k)-cleared device may require the longer. If the FDA has questions, it will likely issue a first major submission of a traditional 510(k), but modifications meeting deficiency letter within 150 days of filing. It may also refer the PMA application to an FDA advisory panel for additional review, certain conditions may be candidates for FDA review under a and will conduct a preapproval inspection of the manufacturing Special 510(k). A new 510(k) is required when the modification facility to ensure compliance with the Medical Device Quality constitutes a major change in the device’s intended use or would System Regulation, or QSR, either of which could extend the 180- significantly affect the safety or effectiveness of the device. A day response target. In addition, the FDA may request additional Special 510(k) al lows a manufacturer to declare conformance information or request the performance of additional clinical trials to design controls without providing new data. When the in which case the PMA application approval may be delayed while modification involves a change in material, the nature of the “new” the trials are conducted and the data acquired are submitted in an material will determine whether a traditional or Special 510(k) is amendment to the PMA. Even with additional trials, the FDA may necessary. not approve the PMA application. A modification to a 510(k)-cleared product that would constitute If the FDA’s evaluations of both the PMA application and the a major change in its intended use or any change that would manufacturing facilities are favorable, the FDA will either issue significantly affect the safety or effectiveness of the device may, an approval letter authorizing commercial marketing or an in some circumstances, even cause the product to be a new, approvable letter that usually contains a number of conditions Class I I I device. In that case, the significant changes would requirethat must be met in order to secure final approval. If the FDA’s the submission of a PMA application, if the change raises complex evaluations are not favorable, the FDA wil l deny approval of or novel scientific issues or the product has a new intended use. A the PMA application or issue a not approvable letter. The PMA manufacturer may be required to submit extensive preclinical and application process, including the gathering of clinical and non- clinical data depending on the nature of the changes. clinical data and the submission to and review by the FDA, can take The FDA requires every manufacturer to make the determination several years, and the process can be expensive and uncertain. regarding the need for a new 510(k) submission in the first Moreover, even if the FDA approves a PMA application, the FDA instance, but the FDA may review any manufacturer’s decision. may approve the device with an indication that is narrower or If the FDA disagrees with the manufacturer’s determination more limited than originally sought. The FDA can impose post- and requires a new 510(k) clearance, or even PMA application approval conditions that it believes necessary to ensure the approval, for modifications to previously cleared products for safety and effectiveness of the device, including, among other which the manufacturer concluded that new a clearance or things, restrictions on labeling, promotion, sale and distribution. approval is unnecessary, the manufacturer may be required to After approval of a PMA application, a new PMA application or cease marketing or distribution of the products or to recall the PMA application supplement may be required for a modification modified product until it obtains clearance or approval, and the to the device, its labeling, or its manufacturing process. PMA manufacturer may be subject to significant regulatory fines or application supplements often require submission of the same penalties. In addition, the FDA may make substantial changes to type of information as an initial PMA application, except that industry requirements regarding the 510(k) process. the supplement is limited to information needed to support any changes from the device covered by the approved PMA Premarket Approval Application application and may or may not require as extensive technical or The PMA application process for approval to market a medical clinical data or the convening of an advisory panel. The time for device is more complex, costly and time-consuming than the 510(k) review of a PMA application supplement may vary depending on clearance procedure. A PMA application must be supported the type of change, but it can be lengthy. In addition, in some cases by extensive data, including technical information regarding the FDA might require additional clinical data. device design and development, preclinical studies, clinical trials, manufacturing and controls information and labeling information Investigational Device Exemption that demonstrate the safety and effectiveness of the device for its A clinical trial is typical ly required for a PMA application and, intended use. After a PMA application is submitted, the FDA has in a smal l percentage of cases, the FDA may require a clinical GENSIGHT BIOLOGICS – 2017 Registration Document– 95