The topic of "real-world data" and "real-world evidence" is gaining momentum, particularly with digital health applications (DiGA), and is now also becoming relevant for medical devices. What exactly are these concepts? And to what extent can they be applied to data collection for medical devices? When does it make sense?
Underlying regulations
Digital Healthcare Act (DVG)
Digital Health Applications Ordinance (DiGAV)
DiGA Guidelines
EU Regulation 2017/745 (MDR)
ISO 14155
1. What are Real World Data (RWD) and Real World Evidence (RWE)?
“ Real-world data refers to data on the use, potential benefits, or risks of a drug that comes from sources other than traditional clinical trials .” This definition comes from Jacqueline Corrigan-Curay, JD, MD, Director of the FDA’s Office of Medical Policy-Center. It shows that this topic has already entered the pharmaceutical industry and is already being used, particularly in the United States.
What exactly is "real-world data"? This term refers to data collected from actual, routine clinical practice. The evidence provided by this data from routine clinical practice is called "real-world evidence.".
2. Real World Data – Collection and Use
2.1 Real World Data in Pharmaceuticals
Real-world data is typically collected through observational studies. These are regulated for pharmaceuticals. For example, the German Federal Institute for Drugs and Medical Devices (BfArM) issued the following guidelines in December 2019
"Joint recommendations of the Federal Institute for Drugs and Medical Devices and the Paul Ehrlich Institute on post-marketing surveillance studies pursuant to Section 67 Paragraph 6 of the German Medicines Act and on the notification of non-interventional safety studies pursuant to Section 63f of the German Medicines Act"
published.
Such regulations do not yet exist for medical devices.
2.2 Data from routine clinical practice with medical devices
For digital health applications (DiGAs), an evaluation concept is required before the DiGA study or the application for inclusion in the DiGA directory. This concept should include "a systematic data analysis, in addition to a systematic literature search and evaluation, also the inclusion of systematically evaluated data obtained in the application of the DiGA ."
Therefore, these are data from the routine clinical use of DiGA.
Roche Diabetes also comments on this topic:
„Evaluating the Benefits of Digital Health Applications Using Real-World Data: When evaluating the benefits of digital health applications, it should be considered that, in the field of pharmacological approval procedures, the perspective is increasingly gaining ground that randomized controlled trials (RCTs) provide an incomplete picture of real-world healthcare. While RCTs are suitable for establishing valid causal relationships between an intervention and its effect, real-world data (RWD) are seen as potential sources for gaining insights into how certified medical devices and approved drugs influence patient outcomes in real-world healthcare. The European Medicines Agency (EMA) is therefore intensively discussing how RWD can be integrated into addressing complex issues in the future...“
(Source: Roche Diabetes Policy Portal , accessed on 30.03.2021)
The increasing digitalization of healthcare and the resulting rise in the availability of digital datasets form the basis for a more intensive future use of RWD and RWE. These developments open up potential opportunities for new players in the system: Platforms for data exchange between healthcare providers and institutions will be necessary to generate and process RWE data (Meinert et al., 2018).
But it's not only the Digital Healthcare Act (DVG) that requires such data; the Medical Device Regulation (MDR) also mandates post-market clinical follow-up (PMCF). PMCF aims to continuously collect clinical data on medical devices, primarily to assess the effectiveness of their use in routine or standard care for specific patients or users. This data must therefore accurately reflect everyday clinical practice and routine care.
Annex IXV of the MDR states in paragraph 1 of Part B:
“ Post-market clinical follow-up shall be understood as an ongoing process for updating the clinical evaluation in accordance with Article 61 and Part A of this Annex and shall be addressed in the manufacturer’s post-market surveillance plan. In post-market clinical follow-up, the manufacturer shall proactively collect and evaluate clinical data arising from the use in or on the human body of a CE-marked product that has been placed on the market or put into service within the scope of its intended purpose in accordance with the relevant conformity assessment procedure, in order to confirm the safety and performance during the expected lifetime of the product, to ensure the continuing acceptability of the identified risks and to identify emerging risks on the basis of relevant evidence .”
Since the conditions in routine clinical practice are usually different from those of a randomized controlled clinical trial, which takes place within a defined framework, randomized controlled clinical trials (RCTs) are only partially suitable as PMCF studies. Their results can only be extrapolated to actual routine use to a limited extent. Furthermore, they may not necessarily identify new risks and benefits, or off-label use.
2.3 Regulation of medical devices?
But how can such studies be classified from a regulatory perspective with regard to medical devices? First, a brief overview of evidence-based medicine is necessary.
Figure 1: Hierarchy of evidence according to evidence-based medicine (EBM), Source: DiGA Vademecum)
A distinction is first made between interventional and non-interventional studies, also known as observational studies. Interventional studies involve the planned and implementation of the medical device's application in a specific population, and all necessary conditions are defined. The results are always attributable to the intervention. Interventional studies are therefore often comparative and always prospective. Among the interventional studies is the much-cited, much-demanded, and perhaps much-feared randomized controlled trial (RCT), the "gold standard" in evidence-based medicine.
Observational studies do not involve a planned intervention; they are therefore also called non-interventional studies. Here, the application and subsequent course of the treatment in the patient are observed, and appropriate conclusions are drawn.
In observational studies, no intervention is performed according to a clinical trial protocol; treatment is carried out exclusively according to standard therapeutic practice. Observational studies can be conducted as comparative or non-comparative studies and can also be based on retrospective data. Among the best-known non-interventional types with a control group are cohort studies and case-control studies. Registries also collect data from routine clinical practice and are subsequently analyzed retrospectively.
Because the results of observational studies can be influenced by a number of biases and confounders, their internal validity is lower than that of interventional studies. In any case, their evidence is generally lower with regard to answering the question of the clinical effect of a specific intervention than that of an interventional study, since the latter specifically assesses internal validity. (Amboss, 2020)
Observation allows for the identification of correlations; however, it does not establish a causal relationship. Compared to interventional studies, observational studies are generally faster and less expensive to conduct and have higher external validity. While observational studies lack a defined framework for the application being evaluated, resulting in lower internal validity (and therefore less predictive power regarding efficacy), they can provide a better understanding of efficacy within the context of real-world clinical practice.
The data collected in this way is referred to as "real-world data" (RWD). The evidence derived from it is accordingly called "real-world evidence" (RWE).
From a regulatory perspective, the medical device can only be used in routine clinical practice if it bears a CE mark. The observational study is not based on a clinical trial protocol, but rather on an observational plan. Therefore, Article 74 of the MDR does not apply (Section 74 is the basis for post-market clinical investigations, for which the documents required in Annex XV Chapter II must nevertheless be prepared, e.g., the study protocol).
Previously, observational studies were regulated under Section 23b of the German Medical Devices Act (MPG) (exceptions to clinical trials) and the professional consultation required by Section 15 of the Professional Code of Conduct for Physicians (BO). This section is now repealed with the MDR. Section 82(2) of the MDR refers to the option for Member States to regulate other clinical trials at the local level. The German Medical Devices EU Adaptation Act (MPEUAnpG) does this by defining "other clinical trials that already bear the CE marking" in Section 47. It is also clearly stated there that neither notification to the Federal Authority nor an approval from the ethics committee is required if the observational study meets the following two criteria:
- The participants will not be exposed to any additional burdens/therapies (beyond routine therapeutic treatment)
- The medical device is used within the scope of its intended purpose.
What remains, therefore, is professional legal advice pursuant to Section 15 of the Professional Code of Conduct for the physician who is conducting the observational study with the CE-marked product in accordance with the observation plan.
3. What we can do for you
Since such data collection by RWD is no longer regulated from 26 May 2021 and does not fall under the umbrella of the MDR, it offers another possibility for data collection in order to meet the P(ost) M(arket) C(linical) F(ollow-up) requirements of the MDR.
We not only support manufacturers in finding the right data collection method, but can also assist them in all aspects of conducting an RWD observational study.
4. How we can help you
At medXteam we clarify whether and if so which clinical trial needs to be carried out under what conditions and according to what requirements during the pre-study phase: In 3 steps we determine the correct and cost-effective strategy in relation to the clinical trial required in your case Data collection.
Do you already have some initial questions?
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Literature sources
Amboss (2020) Study types in medical research. URL: https://www.amboss.com/de/wissen/ Study types in medical research (accessed on 30.03.2021)
Meinert E, Alturkistani A, Brindley D, Knight P, Wells G, Pennington N. The technological imperative for value-based health care. British Journal of Hospital Medicine. 2018;79(6):328-32