By Michael Kanis, National Sales Engineering Manager, Proven Process Medical Devices, and Jodi Hutchins, RAC, CQA
All Those in Favor of Using Real World Evidence, Say Aye!
Medical Devices are used in the real world every day, so shouldn't they be tested in the real world? You would think so. But the FDA hasn’t necessarily been of that mindset -- until now.
Per FDA regulations, testing has to be conducted under supervised clinical trials, which have pre-designed protocols.1 When most think of clinical studies, they think of the structured, randomized clinical studies conducted for drug products; however clinical studies are also required for some high risk medical device applications. When determining if real-world evidence is relevant, one should consider that medical devices work physically, while drugs work chemically or biologically. Therefore, medical devices are tested by the end users or clinical professionals that will use them during the medical device validation process. Some devices are low risk and easy to use, while others are quite complex/high risk medical devices that require professional knowledge and/or detailed instructions for use. It is these high risk devices that require clinical type testing for FDA approval.
Another factor calling for real-world data is that medical devices are invented, so human factors/user error type testing should be conducted during design of the prototype to ensure the devices are not in need of further improvements prior to full scale medical device manufacturing and production. Medical device manufacturers can appreciate that devices may go through various iterations during the medical device development process, and if proper procedures are being followed, then continuous testing is being conducted and documented in the Design History File (DHF) to ensure the product is safe and effective for use. It stands to reason, then, there could be even more to learn once a medical device enters the post market/post production stage, or in layman’s terms, real-world use.
The FDA is starting to recognize the value of Real-World Evidence (RWE) as an important contributing factor for understanding and regulating medical devices by issuing the draft guidance, Use of Real-World Evidence to Support Regulatory Decision Making for Medical Devices, in July of 2016.2 The draft guidance also states, “the FDA has issued plans for and has begun implementation of a national evaluation system that leverages Real World Data (RWD) to more quickly identify safety problems, to better understand the benefit-risk profile of devices used in clinical care, and to reduce the time and cost of evidence generation to inform FDA premarket approval and clearance.”3
Real-World Data (RWD) is data collected from sources outside of traditional clinical trials. These sources may include large simple trials, or pragmatic clinical trials, prospective observational or registry studies, retrospective database studies, case reports, administrative and healthcare claims, electronic health records, data obtained as part of a public health investigation or routine public health surveillance, and registries (e.g., device, procedural, or disease registries). The data is typically derived from electronic systems used in healthcare delivery, data contained within medical devices, and/or in tracking patient experience during care, including in-home-use settings.
Definition direct from the guidance:4 Real-World Evidence (RWE) is the evidence derived from aggregation and analysis of RWD elements.
Definition direct from the guidance:5 In summary of the above, real-world evidence would be derived from real-world data sources. However, real-world evidence need not be generated solely through retrospective analysis of pre-existing real-world data. “Increasingly, clinical trials are being conducted in real-world, every day settings to improve the generalizability of results and to reduce inefficiencies related to separate research infrastructures.”6 FDA stresses that the released “guidance should not be interpreted to convey that FDA is changing the evidentiary standards used in regulatory decision-making”, but with the shift to more “real-world” clinical studies and the aforementioned plans for implementation of a national evaluation system, the FDA is slowly starting to come on board with the value of using real-world evidence in regulatory decision making.7
Real World Effects on Device Development
Because in some cases a traditional clinical trial may be impractical given the realities and complexities of medical device innovation and the entire device development life cycle8, the FDA is coming around to the idea of using real-world data. In fact, real-world data may in some cases provide similar information, possibly even superior characteristics to information collected through traditional clinical trials. However, since not all RWD are necessarily collected and maintained in a way that provides sufficient reliability, the use of RWE for specific regulatory purposes will only be considered based on the quality of the data needed based on level of regulatory action requested. Per their usual focus of public safety and erring on the side of caution, the bottom line advice from the FDA is, if a sponsor is considering the use of RWE to meet data requirements to support a regulatory decision by the FDA, the sponsor should contact the FDA through the pre-submission process to ascertain if it will even be allowed within the constraints of current regulatory standards.9
Application and Examples of RWE
The FDA guidance cites where RWE may potentially be applied to enhance understanding of medical device performance at different points in the total product life cycle, including, but not limited to:10
- generation of hypotheses to be tested in a prospective clinical study
- as a historical control, a prior in a Bayesian trial, or as one source of data in a hierarchical model or a hybrid data synthesis
- in a setting where a registry or some other systematic data collection mechanism exists, RWD can potentially be used as a concurrent control group or as a mechanism for collecting data related to a clinical study to support device approval or clearance
- in some circumstances where real-world use of a device is in a broader patient population or wider set of circumstances than described in the device labeling, it may be possible to use existing systematically collected RWD to expand the labeling to include additional indications for use or to update the labeling to include the new information on safety and effectiveness
- for public health surveillance efforts, RWD is used to understand the evolution of the benefits and risks of medical devices after they have been approved or cleared in the United States
- to conduct post-approval studies that are imposed at the time of device approval or post-market surveillance studies ordered under Section 522 of the FD&C Act
The FDA also offered “generalized” examples in the guidance where RWE was already used in regulatory decision making, paving the way for others to do the same:11
- expanded indications for use
- post-market surveillance studies
- post-approval device surveillance as a condition of approval
- control group
- supplementary data
- objective performance criteria and performance goals
Obstacles to Using RWD/RWE
Akin to other new and novel approaches when it comes to regulatory, there are going to be obstacles to overcome before RWD/RWE is sanctioned for general use. The FDA has to take all aspects into account, while always prioritizing public and patient safety. This is why they take their time and release guidance for public discussion requesting feedback from the industry and stakeholders. A few noteworthy obstacles being discussed currently:
Reliability and Relevance of RWD... The FDA is well aware of these topics and they are discussed in depth within the draft guidance itself. As far as relevance of RWD as an obstacle, one can logically deduce most of the existing data elements that are being proposed for use as RWD were primarily input into respective systems for non-regulatory purposes (e.g., quality assurance (QA) and quality improvement (QI) in the case of clinical care registries). Therefore, the FDA has to assess whether the individual data elements contained within existing RWD sources are sufficient and relevant to fulfill a regulatory purpose, not only for the individual device(s) being reviewed, but also as part of a larger scale purpose of RWE.12 Similarly, the FDA will assess the reliability of the data and the data sources, which currently “are not systematically characterized, aggregated, and analyzed in a way such that it can be relied upon to inform regulatory decision-making.”13 The primary factors the FDA considers for assessing the reliability of RWD include; how the data were collected (data accrual), whether the data as collected are complete, accuracy and adequacy, and whether the people and processes in place during data collection and analysis provide adequate assurance that bias is minimized and data quality and integrity are sufficient (data assurance).14
Technology... The current landscape of differing software, different guidelines, etc., of respective data sources, most certainly have areas where improvements could be made in the “development of real-world evidence and the infrastructure necessary for efficient and scalable generation”, and it is always advantageous to look to the experts in the industry for feedback. We need to think “bigger picture” on how to implement, validate and maintain the captured data, if we ever want to see sanctioned use of RWE in our future. Those with vested interest in the stakeholder community should unite for “the development of a robust evidence generation system that provides the necessary infrastructure and evidence to meet these needs” in order to satisfy the FDA's demands for reliable and relevant data.15
Patient Privacy...16 With clinical studies, patient privacy is controlled within the confines of the study. As we move to possible ubiquity of real world data on a larger scale, there might be more risk to patient privacy being exposed. This is obviously a consideration that needs to be investigated thoroughly.
Legal and Regulatory challenges... As all of us in this field know, changes in regulatory don’t happen overnight. There will be many meetings held discussing the obstacles above, and then some, before the draft becomes final guidance. As one resource surmised, “In addition to technical barriers related to data capture and integration, a number of legal and regulatory challenges must be addressed prior to routine integration of these real-world data sources with more traditional structured clinical datasets.”17
Are Your Medical Devices Ready for the “Real World”?
The latest technology in medical devices has brought real-time data to the fingertips of patients and healthcare professionals. Wearable, implantable, and home health monitoring devices that are equipped with internet connectivity are commonplace now. “Some medical device product companies offer a cloud-based platform that enables wireless transfer, storage, and display of clinical data. This platform is generating an enormous amount of clinical data” which is part of the Real-World Data that could ...help the healthcare industry in many ways.”18
Proven Process Medical Devices (PPMD) has 24 years of experience in developing and manufacturing complex medical devices. Most PPMD customers today require that their new medical devices be equipped with internet connectivity to managed databases that collect operating efficiency, patient data and diagnostic reports. Here are a few of the devices PPMD had built that could offer benefits to RWD/RWE in the future:
- Active implantable drug delivery devices: These medical devices have bi-directional connectivity to collect drug dosing and implant performance. Big data can be collected regarding dosing levels and related patient pain mitigation.
- A diagnostic home-use device that measures diabetic foot neuropathy: This medical device uses a real-time proprietary wireless data collection system that collates data in order to prevent foot ulcers.
- A clinical device for combat veterans with lower leg amputations: This device features real-time connectivity that measures the gait of a patient fitted with a prosthetic. The measurements allow for better fit and corresponding physical therapy routine, which can reduce co-morbidity issues that could develop from an improperly fitted prosthetic.
The complex medical devices mentioned above are just a few examples of what Proven Process Medical Devices can deliver in terms of cutting-edge, forward thinking devices. In general, PPMD has integrated software and robust electronics into many of their client’s devices, so that Real-World Data can be collected for long-term benefit.
Looking Towards the Future
Although the FDA’s request for feedback has closed for this guidance, we still need to do our part to think towards the future, especially towards more stream-lined data collection, and how it can affect us individually and collectively. By adhering to changes in the regulatory landscape (example, UDI) and implementing small scale steps towards more systematic data will get us one step closer to large scale use. These changes can prove to be beneficial for patients and the public overall. Ultimately, the evidence necessary to make regulatory decisions overlaps with evidence to guide clinical decisions in individual patients. It makes sense to make the data more systematic for the greater good. If you have ideas on developing a new source for RWD or how it can be used in your device application, consultation with the FDA is recommended to ensure that relevance and reliability are addressed during the initial stages of development.19
Michael Kanis is the National Sales Engineering Manager for Proven Process Medical Devices. He holds a B.S. in Marketing and Entrepreneurial Studies from Babson College. Mike is responsible for all marketing and sales for the firm. Jodi Hutchins, RAC, CQA, is an expert on regulatory matters and holds a B.A. in Chemistry from the University of South Florida in Tampa.