The Use of Published Literature in FDA Medical Device Submissions
By Miriam Sharif-Murray, M.S., Nerac Analyst
Originally Published November 2, 2021
When one thinks of published literature used to support a device submission, the European Union, Medical Device Regulations (MDR), and Clinical Literature Evaluations come to mind. But many do not know that, in some cases, published literature can be used in addition to and instead of an original clinical investigation to support a device submission in the United States as well. In their guidance for industry, titled Supplements to Approved Applications for Class III Medical Devices: Use of Published Literature, Use of Previously Submitted Materials, and Priority Review, the FDA explains the circumstances in which published literature can be used to support supplements to Premarket Approvals (PMAs), product development protocols (PDPs), and Humanitarian Device Exemptions (HDEs).
When a manufacturer desires to make a change to a Class III device that has been approved via a PMA or PDP that affects the device’s safety and effectiveness (new indication for use, a change to the labeling, new manufacturing site, etc.) or a change to an HDE that affects its safety and probable benefit, a supplement application is required. The US Federal Food Drug and Cosmetic Act (called “the act”) requires that applicants submitting a medical device application provide “reasonable assurance” that the device is safe and effective when used under the same conditions and by the same patient population that is described in the device labeling (instructions for use, packaging, marketing material, etc.).
According to the FDA regulation 21 CFR 860.7, the safety and effectiveness of a device should be established based on valid scientific evidence “from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use.” Though original clinical investigations are the means by which most Class III medical device submissions are supported, reports in the medical device literature may be used to demonstrate that valid scientific evidence exist. If the literature is “sufficient, detailed, objective, and directly applicable” to the subject device, it may be used as the sole basis for approval of the PMA, PDP, and HDE supplements.
FDA gives 3 examples in which the use of published reports is appropriate to support determinations of safety and effectiveness in supplements:
- Reports of Prior United States Marketing Experience –
- Class III devices that were on the market before May 28, 1976 (pre-amendment devices) for which the applicant must submit safety and effectiveness information under 515(b) of the act.
- Already marketed devices that have been studied by individuals other than the applicant for new or different uses. The guidance mentions that applicants who submit supplements for these types of devices have access to “a body of published literature that reports experience with the applicant’s specific device or experience with a device of similar technology and performance” that could apply to the safety and effectiveness review of the supplement.
- Reports of Foreign Marketing Experience – When a device has been used for a clinical trial outside of the United States, reported in published literature, and the applicant is able to gain access to the underlying data, study conduct, and results, the agency will evaluate the report for sufficiency to support the approval of a PMA supplement.
- Reports of Foreign Marketing Experience Combined with Applicant Sponsored Studies – When the applicant has sponsored studies that, alone, are deemed by the agency insufficient to demonstrate the safety and effectiveness of the device, published literature describing foreign device trials using the applicant’s product may be used in addition to their own studies.
In each example above, the applicant’s access to the underlying data and additional details not available in the published literature increases the chance that the report will be accepted to support a supplement. Briefly, this additional data includes: the study protocol, prospective statistical analysis plan, randomization codes, full accounting of study subjects, records for each study subject, and information on subjects who died during the study, and those who discontinued the study.
Furthermore, the quality of the published report can affect the likelihood that it is sufficient to support supplement approval. According to the guidance, the presence of the following factors increases the likelihood that the report by itself will be adequate:
- The reports reflect multiple studies conducted by different investigators, each of the studies has an adequate design, all published studies are reported, and the findings across studies are consistent.
- The reports reflect high level of detail, including clear and adequate descriptions of statistical plans, analytic methods (prospectively determined), study endpoints, and a full accounting of all enrolled patients.
- The reports identify relevant endpoints that can be objectively assessed and that are not dependent on investigator judgment (e.g., radiographically documented endpoints, restoration of function, or overall mortality). Such endpoints are more reliable than more subjective endpoints, such as relief of pain or symptoms reported by the study subject.
- The reports identify results of a priori statistical analysis plans that provide consistent conclusions of safety and effectiveness rather than unplanned statistical analyses (sometimes referred to as “data dredging”).
- The reports describe studies conducted by investigators of recognized competence who have a demonstrated history of compliance with the laws and regulations governing the study of human subjects.
The first step to identifying reports that meet the requirements set forth by the FDA is to plan and execute a focused literature search and review process. Search terms and inclusion/exclusion criteria must be clearly defined with the objective of selecting literature that demonstrates safety, effectiveness, and/or probable benefit.
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