What makes a trial pivotal

Examples of devices approved through priority review include a transcatheter artificial heart valve for patients deemed inoperable for open aortic valve replacement, an ablation system that non-invasively erodes metastatic cancer, and technology that delivers radiofrequency energy to the lungs of patients whose severe persistent asthma is not well controlled with other treatments.

To obtain a priority review designation—which was formerly referred to as expedited review—a device must treat a serious, unmet medical need, such as a life-threatening illness for which inadequate therapy exists [ 12 ]. FDA has proposed applying the same criteria that it currently uses to make priority review designations for its new EAP pathway to accelerate the delivery of novel devices to patients.

We limited our research to devices granted premarket approval PMA , an FDA review designation for the highest risk devices. We did not include products cleared through demonstrating substantial equivalence since these products are, by definition, similar to other devices and therefore less likely to represent significant innovations. We focused our research on devices with priority review status because the criteria for this designation are the same as FDA outlines in its new policy.

We could only obtain data on approved products, as information on unapproved devices is not publicly available. FDA was able to provide basic aggregated information on products that were rejected by the agency or withdrawn from review during our study timeframe. The applicable aggregate data from FDA is included in this paper as it was received from the agency.

We further restricted our analysis to device reviews completed from January through August because data prior to that time were often incomplete. We examined clinical studies considered pivotal to FDA review. Each device application typically has one study that gathers the final data on safety and effectiveness needed for FDA review [ 13 ].

One device had two pivotal trials; for the purposes of this study, we combined the data from these two trials. We sought to understand the length of the pivotal trial, the length of time between the end of data collection and the FDA receipt date of the application, the FDA review time and the total time from the start of the trial to FDA approval.

Additionally, we sought information on the number of enrollees in pivotal trials and the length of the primary endpoints. Finally, we examined the availability of the product abroad at the time the application was submitted to FDA. In some cases, the SSED lacked complete data.

To ensure the accuracy of data entry, each of us extracted information on half the devices; then, the other would confirm data on each entry. We jointly resolved discrepancies. We calculated the mean and median of the following: length of the pivotal trial as defined from the start date of a study to the date of database lock or primary endpoint completion if we did not have the lock date ; length of FDA review from the date of submission to approval which includes time when the agency is not evaluating the application and is awaiting additional information from the sponsor ; time from the initiation of pivotal trials to FDA approval; and length of primary outcome measures.

For dates with only the month and year listed, we used the first of the month. We converted days to months, using 30 days as equal to one month for our calculations. The calculation of the length of FDA review includes time when FDA is not evaluating the application as the agency awaits additional information from the product sponsor. We could not calculate only the time when FDA is reviewing the application because that information is not publicly available for each application; the only available information is the aggregate length of FDA review including the time that manufacturers prepare responses to agency questions.

In calculating the primary measure evaluation time, we omitted devices that did not require patient follow-up. We sought to understand how often FDA receives an application before the end of a trial, which can occur, for example, if the device sponsor submits an application before locking the database and then updates the data during FDA review. The data used in this study did not indicate, for each device, why device sponsors submitted applications before the end of the database lock.

Due to this phenomenon, we did not calculate the mean and median for these data. Last, we calculated the mean and median trial enrollment, including patients that dropped out or were lost to follow up.

In some cases, the enrollment figure represents the number of procedures. This occurred, for example, with data on a hip implant where the number of hips replaced—not number of patients—represent the primary data point in the trial. Table 1 illustrates some of the clinical trial and FDA review characteristics of each product.

The dark blue bar represents the length of the pivotal clinical trial and the grey section corresponds to the FDA review time. The light blue or checkered sections represent the time between the end of the trial and submission to FDA.

Where this light blue box is checkered, this represents the time when the pivotal trial had not been completed but the application was already submitted to FDA. We identified 27 approved device applications designated for priority review from January through August We excluded two products from some of our calculations due to a lack of complete information. These products were a pediatric glucose sensor and implantable miniature telescope because we lacked complete trial start and end times, and therefore could not calculate the length of the trial, time from the start of the trial until approval, or whether the application was submitted to FDA before the end of the trial see Table 1.

The mean duration of pivotal trials was 3 years and 5 months, with a 3 year median. The briefest trial was only 3 months, for a continuous glucose monitor for diabetic patients. The longest pivotal trial lasted approximately 7 years, for a non-cemented ankle replacement that can simultaneously move in more than one direction see Table 1.

The mean length of FDA review time was 1 year and 9 months, and the median time was 1 year and 3 months. This calculation, as previously mentioned, includes time when FDA is not reviewing the application as the agency awaits additional information from the product sponsor. The time from the initiation of the pivotal trial to FDA approval was a mean of 5 years and 1 month, with a median of 4 years and 8 months.

The longest time period was more than 9 years, for a metal-on-metal hip resurfacing system. Of the 25 approved applications for which we have an end date for the pivotal study, 12 applications were submitted to FDA for review before the final extract date see Table 1.

The mean and median duration of primary measure evaluation follow-up was 12 months, ranging from 6 days to nearly 3 years. We did not include five devices in this calculation that lacked patient follow-up; these included a computerized sedation system and several diagnostics, such as a device for detecting melanoma in atypical skin lesions see Table 1.

Mean enrollment in pivotal trials was , with a median of All rights reserved. New findings comparing 3 decades of newly approved indications show the proportion of new approvals being supported by just 1 pivotal trial has quadrupled. More recent US Food and Drug Administration FDA approvals of new therapies have been supported by fewer pivotal trials—and those trials have mostly featured less rigorous, longer trial durations.

New findings from a cross-sectional analysis of drugs and biologics approved by the FDA in the last 3 decades show a shifting priority in pivotal efficacy trial makeup and federal standard for marketing approval. Investigators, led by Audrey D. Zhang, AB, and Joseph S. Head Lessor hereby delivers and subleasesleases to the Head Lessee, and the Head Lessee hereby accepts and subleasesleases from the Head Lessor, under the Head Lease as herein supplemented, the Facility described in Exhibit A hereto.

Sample 1. Sample 2. Sample 3.