The US Food and Drug Administration (FDA) has issued draft guidance on the design of pivotal clinical studies to support pre-market approval (PMA) applications for Class III medical devices.

Class III products are the highest-risk category of medical device – those that support or sustain life, and whose failure would therefore be life-threatening. They are subject to the most stringent form of FDA device review.

Most Class I (non life-sustaining) medical devices are exempt from pre-market review in the US, while Class II devices (also non life-sustaining but more risky than Class I) generally have to go through the 510(k) procedure.

This involves a pre-market submission demonstrating that the device is substantially equivalent to a legally marketed product not subject to a PMA.

Design issues

The draft guidance put out by the FDA for a 90-day comment period outlines the agency’s expectations around clinical trial design issues for Class III devices, such as minimising data bias and variability, setting appropriate study objectives, selecting the right kind of study, and choosing trial sites /participants.

As the FDA notes in its introduction to the Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff - Design Considerations for Pivotal Clinical Investigations for Medical Devices, the agency has “articulated policies related to design of studies intended to support specific device types, and a general policy of tailoring the evidentiary burden to the regulatory requirement”.

Until now, though, it has not attempted to describe the different clinical study designs that may be appropriate to support a pre-market submission for a medical device, nor to define how a sponsor should decide which pivotal clinical study design should be used to support a submission for a particular device.

The draft guidance was among 25 items listed last January in a Plan of Action for Implementation of 510(k) and Science Recommendations announced by the FDA in an effort to improve the predictability and transparency of regulatory pathways for medical devices and to strengthen the 510(k) process.

Among the key actions were:

-     Streamlining the ‘de novo’ review process for certain innovative, lower-risk medical devices                  


-     Clarifying when clinical data should be filed as part of a pre-market submission for a medical device      


-     Establishing a new Center Science Council of senior FDA experts to assure timely and consistent science-based decision-making in the device review programme

Notification concerns

The FDA’s FDA’s Center for Devices and Radiological Health (CDRH) had set up two internal working groups in September 2009 to address concerns about the pre-market notification process for medical devices.

As the agency pointed out at the time, industry had argued that the 510(k) process was “unpredictable, inconsistent and opaque”, while consumers and healthcare professionals felt it was insufficiently robust.

The FDA’s new draft guidance has been developed primarily for clinical studies supporting PMA submissions, although the recommendations may also be used in designing trials for 510(k) filings, the agency noted. 

The draft guidance “can help manufacturers and researchers design a pivotal study that is a practical investment of time, effort, and resources and has a high likelihood of demonstrating safety and effectiveness”, the agency said.