The topic of “real world data” and “real world evidence” is now also gaining momentum for medical devices thanks to digital health applications (DiGA). What is this about? And to what extent can this topic be transferred to data collection for medical devices? When does it make sense?
Underlying regulations
Digital Care Act (DVG)
Digital Health Applications Ordinance (DiGAV)
DiGA Guide
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 about the use or potential benefits or risks of a drug obtained from sources other than traditional clinical trials .” This definition comes from Jacqueline Corrigan-Curay, JD, MD, director of the Office of Medical FDA Policy Centers. It shows that this topic has already found its way into the pharmaceutical industry and is already being used, particularly in the USA.
So what is “real world data”? This refers to data collection that relates to actual clinical routine. The evidence provided by this data from routine clinical practice is referred to as “real world evidence”.
2. Real World Data – Collection and Use
2.1 Real World Data for Pharmaceuticals
Real world data is usually collected as part of observational studies. These are regulated for pharmaceuticals. For example, BfArM published the following in December 2019
“Joint recommendations of the Federal Institute for Drugs and Medical Devices and the Paul Ehrlich Institute on application observations in accordance with Section 67 Paragraph 6 of the Medicines Act and on the notification of non-interventional safety tests in accordance with Section 63f of the Medicines Act”
published.
There are currently no such regulations for medical devices.
2.2 Data from routine clinical practice for medical devices
For DiGAs, an evaluation concept is required before the DiGA study or the application for inclusion in the DiGA directory. This should include a “ systematic data evaluation in addition to a systematic literature search and evaluation as well as the inclusion of our own systematically evaluated data that were obtained using the DiGA .”
Therefore, these are data from 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 taken into account that in the area of pharmacological approval procedures the perspective is increasingly gaining ground that randomized, controlled studies represent an incomplete reflection of the reality of care. Randomized, controlled studies are suitable for establishing valid causality between an intervention and its effect. Real-world data (RWD) is seen as a potential source to gain insight into how certified medical devices and approved medications impact patient outcomes in real-world care. The European Medicines Agency (EMA) is therefore intensively discussing how RWD can be integrated in the future to solve complex issues ...“
(Source: Roche Diabetes Policy Portal , accessed on March 30, 2021)
The advancing digitalization of the healthcare system and the resulting increasing availability of digital data sets form the basis for more intensive use of RWD and RWE in the future. These developments open up potential opportunities for new players in the system: platforms for data exchange between service providers and institutions are necessary in order to generate and process RWE data (Meinert et al., 2018).
But it's not just the DVG that requires such data, the MDR also requires clinical follow-up (Post-Market Clinical Follow-up, PMCF). This is intended to continuously collect clinical data on the medical device, with the primary aim of checking whether its use in normal or routine care is effective for a specific patient or user. This data must therefore well reflect routine everyday life and routine care.
In Annex IXV of the MDR, the first sentence of Part B states:
“ Post-market clinical follow-up shall be understood as an ongoing process to update the clinical assessment in accordance with Article 61 and Part A of this Annex and shall be reflected in the manufacturer's surveillance plan before being placed on the market. During post-market clinical follow-up, the manufacturer proactively collects and assesses clinical data resulting from the use in or on humans of a CE-marked product placed on the market or put into service in accordance with the relevant conformity assessment procedure for its intended purpose Body to confirm the safety and performance over the expected life of the product, to ensure the continued 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 in a randomized, controlled clinical trial, which takes place within a defined framework, randomized, controlled clinical trials (randomized controlled trials, RCTs) are only partially suitable as PMCF studies. Their results can only be applied to actual routine applications to a limited extent. In addition, new risks and opportunities as well as off-label use cannot necessarily be identified.
2.3 Regulation of medical devices?
But how can such studies be classified from a regulatory perspective in relation to medical devices? Here we should first make an excursion into evidence-based medicine.
Figure 1: Evidence hierarchy according to evidence-based medicine (EbM), source: DiGA Vademecum)
First, a distinction is made between interventional and non-interventional studies, so-called observational studies. In interventional studies, if the use of the medical device is planned and carried out in a specific population and all the conditions for this are specified, it is referred to as an interventional study. Results here can always be traced back to the intervention. Interventional studies are therefore often comparative and always prospective. The intervention studies include the much-cited, much-demanded and probably much-feared randomized controlled trial (RCT), the “gold standard” in evidence-based medicine.
In observational studies, no planned intervention is carried out, which is why they are also called non-interventional studies. Here the application and the further course of the patient are observed and appropriate conclusions are drawn.
In observational studies, no intervention is carried out in accordance with a clinical test plan; treatment is carried out exclusively according to therapeutic practice. Observational studies can also be conducted both comparatively and non-comparatively; They can also be based on retrospective data. The most well-known non-interventional types with a control group include the cohort study and the case-control study. But registries also collect data from routine clinical practice and are then evaluated retrospectively.
Since the results of observational studies can be influenced by a number of biases and confounding factors, their internal validity is lower than that of intervention studies. In any case, when it comes to answering the question of the clinical effect of a specific intervention, its evidence is generally lower than that of an intervention study, since this is precisely the one that assesses internal validity. (Anvil, 2020)
Correlations can be determined through observation; However, a causal connection cannot be proven. However, compared to intervention studies, observational studies can usually be carried out more quickly and cost-effectively and have higher external validity than intervention studies. Without a defined framework for the application to be evaluated, the observational study has lower internal validity (and therefore lower significance with regard to effectiveness), but can therefore provide a better insight into the effectiveness in the context of the actual circumstances of everyday clinical practice .
The data collected in this way is “real world data” (RWD). The evidence obtained from it is referred to as “real world evidence” (RWE).
From a regulatory perspective, the medical device can only be used in routine clinical practice if it has a CE mark. The observational study is not based on a clinical test plan, but rather an observation plan. Therefore, Article 74 of the MDR does not apply (§ 74 is the basis for post-marketing clinical trials, for which the documents required in Annex XV Chapter II must still be drawn up, e.g. the trial plan).
Until now, observational studies were regulated via Section 23b MPG (exceptions to clinical trials) and professional advice under Section 15 of the Professional Code for Doctors (BO). This paragraph is now no longer applicable with the MDR. In §82 (2) the MDR refers to the option of member states to regulate other clinical trials at local level. The German Medical Devices EU Adaptation Act – MPEUAnpG does this by defining “other clinical trials that already bear the CE mark” in Section 47. It is also clearly stated there that neither a report to the federal authority nor an approval vote from the ethics committee is necessary if the observation study meets the following two criteria:
- The participants are not exposed to any additional stress/therapies (to routine therapeutic treatment).
- the medical device is used within the scope of its intended purpose.
What remains is professional advice in accordance with Section 15 BO from the doctor who is carrying out the observation 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 as of May 26, 2021 and does not fall under the umbrella of the MDR, it offers another option for data collection in order to in turn support the P(ost) M(arket) C(linical) F( ollow-up) requirements of the MDR.
We not only support manufacturers in finding the right survey method, but can also assist with 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
Anvil (2020) Medical Research Study Types. URL: https://www.amboss.com/de/wissen/ Medical research study types (accessed on March 30, 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