Swami emphasized that PolyNovo is working in close collaboration with both the FDA and BARDA on the burns trial and that there is a shared desire to speed up the process.
He said that there were 3 options.
The first was to simply continue to move forward until all 120 patients are enrolled. If this is how it plays out, enrolment will probably complete sometime around May.
A second potential option hinged on interim analysis of trial data. Whether this is a viable option will be decided by the FDA working with biostatisticians.
Interim analysis for efficacy can lead to a clinical trial being stopped early for benefit, as explained below
The process involves a statistical hypothesis test on primary and potentially key secondary outcome(s) at some interim point in the trial, and if there is a large enough signal early in the study suggesting efficacy of one intervention arm over another, then it may be ethically imperative and most efficient to stop the study early. Stopping early and reporting on findings will allow for the investigational product to progress faster in the development process to reach the target clinical population sooner…
Interim analyses for early efficacy involve formal statistical hypothesis tests that mirror those prespecified in the primary analysis plan at the end of the study, and the methodology in this arena provides statistically justified guidelines to help researchers evaluate whether the resultant test statistic is “significant enough” such that it provides strong enough evidence to merit stopping for early efficacy. *
While stopping a trial early for benefit isn’t common, my research indicates that it has happened in over 150 clinical trials. However, stopping trials early for this reason has its critics and there are numerous studies that suggest that the majority of trials truncated due to early, strong signals of efficacy are ultimately shown to have overstated efficacy.
Swami stated that the group looking at this option (I think he said based on the first 60 patients) would make their call “shortly”.
The third option mentioned by Swami involves the potential inclusion of Real World Evidence (RWE) in PolyNovo’s PMA submission to support “added claims”.
The following, from its website, explains the FDA’s thinking about the use of Real World Data in regulatory decision-making on medical devices.
To protect and promote public health, FDA needs to understand and evaluate the available evidence related to regulated products. For medical devices, common sources of available evidence include non-clinical and clinical studies provided to FDA by a device manufacturer or sponsor of a device premarket or postmarket submission. FDA recognizes that a wealth of clinical data in the form of RWD are routinely collected in the course of clinical practice during the treatment and management of patients. Although these data typically have different quality controls compared to data collected within a traditional clinical study, under certain circumstances RWD may be used to generate RWE to help inform or augment FDA’s understanding of the benefit-risk profile of devices at various points in their life cycle. Per 21 CFR 860.7(c)(1), “[a]lthough [a] manufacturer may submit any form of evidence to the Food and Drug Administration in an attempt to substantiate the safety and effectiveness of a device, the agency relies upon only valid scientific evidence to determine whether there is reasonable assurance that the device is safe and effective.” RWE derived from relevant and reliable RWD may constitute valid scientific evidence…
RWD that includes patient experience datamay provide new insights into the performance of a device. In addition, RWD may foster inclusion of target populations that are otherwise underrepresented in clinical studies. Similarly, leveraging RWD may allow for studies of a longer period of time than would be practical in a traditional clinical study and so may allow for data to be gathered on longer term outcomes. Clinical evidence generated from fit-for-purpose RWD informs device benefit-risk profiles assessment from a real-world environment, allows evaluation of outcomes which may not be feasible in traditional clinical studies, and better aligns with device innovation cycles to inform future device modifications and new technology 101 development. Finally, RWD may include information from broader clinical experiences than is usually represented in traditional clinical studies. RWE is an important factor for understanding and regulating medical devices, and therefore, FDA encourages the medical community to learn more from routine clinical care to help support safety and effectiveness of medical devices. Use of relevant and reliable RWD to generate RWE can benefit stakeholders throughout the ecosystem, including but not limited to, patients, health care providers, manufacturers, and FDA.
Additionally, in some cases, a traditional clinical study may be impractical or excessively challenging to conduct. Ethical issues regarding treatment assignment, and other similar challenges, may present themselves when developing and attempting to execute such a study. Analyses of RWD, using appropriate methods, may in some cases provide similar information with comparable or even superior characteristics to information collected and analyzed through a traditional clinical study. Under the right conditions, RWE may be suitable to support the marketing authorization of a new device or the expansion of the indications for use of devices that are already on the market.
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