From Device Licensure and Beyond

Although FDA involvement during device development is important prior to the approval of a device, only device marketing clearance and post-market requirements will be discussed. 

Classification

The foundation of FDA regulation of medical devices is the risk based classification of devices.  The classification dictates the level of regulatory oversight for the product type, with devices being assigned to one of three classes.  Class III devices are subject to the highest level of oversight, with all classes being subject to some basic controls, such as the need to follow appropriate design controls, with the higher classes incorporating additional specific requirements, such as premarket approval.

510(k)

Class II devices require marketing clearance through the submission of a premarket notification application.  A premarket notification application is referred to as a 510(k), so named for the regulation describing these types of submissions.  In a 510(k), the sponsor demonstrates that the device is substantially equivalent to a legally marketed device.  This involves comparing aspects of the predicate device and the new device, such as, the intended use, device features, and performance, as needed for the type of device. 

Four to five thousand 510(k)s are cleared in the Center for Devices and Radiological Health (CDRH) each year.  These files are anywhere from several pages to several feet thick and are often reviewed by individuals, but may involve team review.  These files have a 90 day review cycle and involve sign-off at the review division level.  General postmarket requirements apply to devices cleared under the 510(k) process, such as the need to report adverse device effects to the FDA; however, additional postmarket requirements are rarely imposed.  The 510(k) clearance process is less difficult than the process for Class III approvals.

PMA

Class III devices require FDA approval prior to marketing.  The most common mechanism for obtaining approval is through submission of a premarket approval (PMA) application.  The sponsor of a PMA needs to demonstrate that the device is reasonably safe and effective for the intended use(s), through submission of details on the device description and manufacture, results of pre-clinical and usually clinical studies, the biocompatibility, sterilization, packaging and shelf-life of the device, as well as other information as described in the PMA regulation. 

Thirty to fifty original PMAs are approved by the CDRH each year.  The size of these files tends to be measured in feet and always involve a team review.  A PMA may be submitted in a modular format, where non-clinical information is submitted for review prior to the clinical section.  When the clinical section is submitted, whether or not the other sections had been previously submitted, the PMA has a 180 day review cycle.

Review of a PMA involves most of the offices within the CDRH.  The Office of Device Evaluation or the Office of In Vitro Diagnostic Device Evaluation and Safety has the lead responsibility for the PMA.  This involves review responsibilities and communicating with the sponsor of the submission, and coordinating the reviews from the other offices.  The Office of Health and Industry Programs is responsible for commenting on the patient labeling.  The statisticical reviewers are located in the Office of Surveillance and Biometrics.  Consulting reviewers, such as engineers and physiologists, are in the new Office of Science and Engineering Laboratories.  Last, but not least, the Office of Compliance includes the Divisions of Enforcement who review the manufacturing section of the PMA and the Division of Bioresearch Monitoring who audits the clinical data to determine the extent to which the appropriate regulations and the clinical protocol have been followed.  This office also has responsibility for incorporating the findings of the FDA field staff who conduct inspections of clinical sites and manufacturers.

After the in-house review of a PMA, an FDA advisory panel review may be required.  These independent panels of experts are comprised of representatives from clinical practice and academia, with both an industry and a consumer representative.  The panel provides recommendations regarding the approvability of the device, conditions of approval and labeling. 

When a decision has been made as to whether the device should be approved, the closeout process begins for the PMA.  This involves putting together the necessary documentation, such as the lead reviewer memo and the consulting review memos and the necessary clearances from the Office of Compliance.  In addition, the final review of the labeling and summary of safety and effectiveness data is done at this time, and the approval order completed.  The labeling and summary are the tools FDA has to communicate information to device users and patients.  The approval order is the letter of approval to market the device and includes conditions that must be met to be in compliance with FDA requirements.

Finally, a “one pager” is written for the FDA internet and depending on the potential public health significance or public interest regarding the device approved, it may also be necessary to complete a press release for the approval.  Sign-off for a PMA application is at the office level, including sign-off by the PMA staff and possibly the Office Director, in addition to the review division.

Postmarket

For many implantable devices one of the conditions of approval is the conduct of a postapproval study.  These studies may be intended to provide longer term safety and effectiveness data, to include the collection of additional information that may be used to modify the labeling, to study learning curve or training issues, or to address some other potential issue specific to the device that was approved. 

All medical devices are subject to postmarket surveillance requirements.  The most common and ubiquitous surveillance requirement is the Medical Device Reporting (MDR) System.  Clinical facilities are to report deaths and serious injuries to manufacturers and device related deaths to FDA.  Manufacturers are to report device related deaths, serious injuries and certain malfunctions to FDA.  In addition, there are voluntary reports from clinical professionals and consumers submitted to FDA.  This reporting system is intended to provide an early warning mechanism regarding rare events and long term failure modes, and is not a comprehensive repository of adverse event data. 

Other Regulatory Responsibilities

Additional regulatory requirements include those associated with the conduct of clinical studies in the US.  Studies of significant risk devices in the US require an approved Investigational Device Exemptions (IDE) application.  Both the sponsor of the study and the clinical investigators have specific responsibilities that are spelled out in the IDE regulations, such as not conducting the study until both FDA and institutional review board (IRB) approval are obtained and conducting the study in accordance with the investigational plan and applicable FDA regulations.

Endovascular Graft Example

There have been two endovascular grafts for treatment of abdominal aortic aneurysms (AAA) that recently went through the PMA approval process.  From these relatively recent approvals, it is apparent that fractures and aneurysm rupture are not “fatal flaws” from a regulatory standpoint, as these problems were discussed during the review of the devices and they were still granted approval.  Although randomization is not needed in clinical studies used to support approval, propensity scoring is a useful tool to look at the differences between the study and control groups.  There is a heightened sensitivity regarding follow-up compliance and the need for complete datasets.  As issues such as rupture and fractures and the appropriate study design have been discussed by the advisory panel, no panel review will be required for a new endovascular graft intended for the treatment of AAA, if no new issues are identified.

From the information continuing to be collected for the Medtronic AneuRx system, it is clear that continued, close, active long-term follow-up is needed for these devices.  In order to ensure that the longer-term data that are obtained during postapproval studies are communicated to physician users, yearly clinical updates are now required for all marketed endovascular grafts. 

The loss of the Guidant Ancure system, in combination with recent investigations of individuals by the Office of Criminal Investigations and the Department of Justice, has made it clear that it is imperative to be aware of and to follow clinical protocol, reporting and all regulatory requirements when conducting clinical studies and marketing medical devices.  Although the FDA did not withdraw the PMA approval for the Ancure, this device is no longer marketed.  In addition, the manufacturer has paid a settlement of over 90 million dollars so far.  These actions were a result of not submitting MDR reports for incidents observed by Guidant personnel while providing case support and were not related to any change in the safety and effectiveness profile of the device.    Lessons learned from this and other cases are as follows: 1) MDR applies to information gained from any source; 2) breaking the rules in itself can lead to actions by FDA and/or DOJ, irrespective of device performance; 3) it is not too late to get into trouble for mistakes made years ago (e.g., during the early days of endovascular grafting); and 4) it is a good idea to conduct an internal audit to determine whether there is a need to address even old offenses.

Additional information on the regulation of medical devices can be found in the following:

http://www.fda.gov/cdrh