Premarket approval (PMA) applications are some of the most demanding U.S regulatory submissions for Class III medical devices. It can take manufacturers two to three years to gather the data needed in support of a PMA medical device submission. The process includes designing a clinical study and collecting clinical data at different follow-up times. To eliminate some of the hurdles of a PMA submission—particularly regarding the gathering of clinical data—the U.S. Food and Drug Administration (FDA) introduced Section 216 of the Food and Drug Administration Modernization Act (FDAMA) in 1997. This section is commonly known as the six-year rule. This rule allows medical device manufacturers to leverage preclinical and clinical data of similar devices that have been granted premarket approval for at least six years. FDA’s guidance document also outlines that Section 216 of FDAMA can be used by manufacturers or the agency to determine whether a product development protocol has been completed under Section 515 for another device, establishing a performance standard or special control under this Act, or classifying or reclassifying another device under Section 513 or subsection (l)(2).¹

The six-year rule establishes any information in a PMA filed with the Secretary pursuant to Section 515(c) shall be available six years after the application has been approved by the Secretary. The information in the application may include data from clinical or preclinical tests or studies that demonstrate the safety and effectiveness of a device but excludes descriptions of methods of manufacture, product composition, and other trade secrets.

FDA’s guidance document outlines several criteria regarding the applicability of the six-year rule, including submission type, timing of the rule’s implementation, timing of the original application approval, type of data being leveraged, and source of data being leveraged. The six-year rule can only be applied to data in which a PMA application was filed and granted after Nov. 28, 1990, and approved for at least six years. The type of data being leveraged includes preclinical data (e.g., side-by-side bench testing comparisons), clinical data from published articles, and any information from the publicly available Summary of the Safety and Effectiveness Data (SSED) that supports a subject device’s safety and effectiveness. The FDA will not accept any data from devices approved before Nov. 28, 1990, as part of the PMA submission incorporating the six-year rule.

Although this section of the FDAMA is not commonly used in PMAs submitted to the FDA, there have been several notable PMAs utilizing this rule. Some devices granted PMA approval include bone growth stimulators in orthopedic therapy. Orthofix Inc. and Theragen Inc. are manufacturers that leveraged the six-year rule and gained approval for their bone growth stimulators. Orthofix’s AccelStim product is used to non-invasively treat established non-unions and accelerate the healing of tibial fractures. According to Orthofix, more than one million people have been treated with its pulsed electromagnetic field (PEMF) devices.² Theragen’s ActaStim-S Spine Fusion Stimulator is a noninvasive bone growth stimulator indicated as an adjunct electrical treatment to primary lumbar spinal fusion surgery for one or two levels, available to U.S. patients to support their spinal surgery.

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Avanos is another manufacturer to have succeeded in FDA’s PMA process using the six-year rule. The Apharetta, Ga.-based firm obtained approval for TriVisc, a three-injection hyaluronic acid treatment for knee osteoarthritis pain. Roughly 35 million doses of the TriVisc treatment have been distributed worldwide to patients suffering from painful knee osteoarthritis, according to Avanos’ website.

Furthermore, there have also been several premarket approvals in the neurology space, primarily neurological electrical stimulators. Abbott Laboratories and Boston Scientific Corp. have successfully marketed neurological electrical stimulators using the six-year rule. These devices are intended to treat patients with movement disorders such as Parkinson’s disease and essential tremor through deep brain stimulation (DBS) therapy. DBS systems are implanted devices similar to pacemakers that deliver mild electrical pulses to modulate specific targets in the brain through thin wires called leads. Data shows that more than 150,000 patients have benefited from DBS therapy.³

For manufacturers seeking to obtain a PMA by applying the six-year rule to their FDA submission, it is important to clearly outline the applicability of Section 216 to their application. The submission must thoroughly compare the subject device to the product of interest in relationship with the intended use and population, design features, the results of non-clinical testing, and the pertinency of the published clinical data of the device of interest in lieu of providing a clinical data set. The purpose of the technological comparison is to establish sufficient similarity between the two products. The sponsor must prove that the risks associated with the subject device can be reasonably justified as not posing more significant risk than the device of interest. Overall, this program alleviates some of the hurdles of the PMA process for proposed Class III devices by allowing manufacturers to utilize clinical data of highly similar Class III products that exist in the medical device market. 

References

1. bit.ly/4feU80J
2. bit.ly/3YhkZDm
3. bit.ly/3LXSByR

Eleni Golloshi is a Regulatory Affairs associate at MCRA, supporting and advising clients in the completion of various U.S regulatory submissions, specifically for orthopedic and spine implants. Golloshi has supported projects including Breakthrough Device Designation requests, 510(k)s, Pre-Submissions, Premarket Approvals (PMAs), Compassionate Use Requests, etc. Golloshi attended the University of Tennessee and earned a bachelor’s degree in biomedical engineering.