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?

You can get a free initial consultation here: free initial consultation

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

Keywords: sample size planning, clinical study, clinical trial

Secondary keywords: sample size, sample size calculation

1 Introduction

When planning a clinical trial, sample size planning plays an important role. This determines how many test subjects must be included in order to demonstrate a relevant effect - and thus ultimately the success or failure of a study. What considerations play a role here?

To demonstrate the effectiveness of any clinical trial, e.g. B. PMCF or in registration studies, hypotheses are tested based on a primary endpoint. A hypothesis to be proven (called alternative hypothesis) can e.g. B. the superiority of a product over a standard therapy. The confirmation or rejection of a hypothesis is assessed based on collected data and the results are then transferred to the population, i.e. to the entire target group. For this to be meaningful, there must be enough data from observations from the target group. If there are too few observations, actual treatment effects cannot be demonstrated and the study fails. On the other hand, a large sample size leads to high costs, is difficult to justify ethically, ties up resources and extends the duration of the study.

The sample size planning is used to determine the minimum number of patients or test subjects to be included in order to prove an actual effect. A number of preliminary considerations are crucial for this.

2. Reasons for case number planning

The aim of every confirmatory clinical trial is to statistically prove a hypothesis. If the sample size is too small, an actual difference between two treatment groups cannot be demonstrated. The result is a non-significant statistical test, even though effects actually exist.

On the other hand, data collection requires a lot of time, human resources are tied up and costs arise for each additional patient included. If too many patients are recruited, this also leads to even small, medically irrelevant effects being detected.

Sample number planning for a clinical trial ensures that:

1. An effect present in the target group is detected with the statistical test, i.e. the test delivers a significant result
2. If the statistical test does not show a significant result, a sufficient sample size ensures that there is no effect in the target group (population) with a sufficiently high degree of certainty.

The need for sample size planning in the planning phase of clinical trials is also required by law and is reviewed by the ethics committee. Calculating the sample size is an essential part of the clinical trial plan and the statistical analysis plan.

For prospective study designs, sample size planning before the start of the study is essential, but in pilot studies or retrospective studies it should also be considered in advance how high the minimum sample size must be.

Aspects of caseload planning

Doctors, investigators, statisticians and CRO work closely together when planning the number of cases. The starting point is always the primary endpoint and the hypothesis of the clinical study to be tested.

3. Selection of statistical test

On the one hand, the type of question is essential for selecting the appropriate statistical test. Depending on whether superiority or equivalence of a treatment is to be demonstrated, different testing procedures are required. The scale level of the primary target variable also plays a crucial role. Different methods are used for nominal characteristics (yes/no, success/no success) than for ordinal (e.g. Likert scale) or continuous characteristics (e.g. visual analogue scale (VAS), sum scores, etc.).

3.1 Effect size

The effect size indicates the relevant difference to be detected. Depending on the test method used, different measurements are used. The best-known effect size for continuous variables is Cohen's d, which indicates the difference between two independent groups in relation to the common variance.

For categorical endpoints, the effect size W is used, which is the root of the squared relative difference in proportions.

According to Cohen (1988), the following general rules of thumb apply:

Effect size ≈ 0.2: small effect

Effect size ≈ 0.5: medium effect

Effect size ≈ 0.8: large effect

To determine the effect size, preliminary information that is as precise as possible from the literature or our own pilot studies is required. The medically and practically relevant difference that can be proven is also taken into account. A mean blood pressure reduction of a few mmHg, i.e. a very small effect size, can be statistically proven with a sufficiently large sample size, but is practically irrelevant for patients and doctors.

3.2 Significance level of the statistical test

The significance level a must be determined in advance and written down in the study protocol and the statistical analysis plan (SAP). The significance level indicates the probability of obtaining a statistically significant test result if there is actually no effect in the target group. A further distinction is made as to whether the test is carried out on one or two sides. One-sided tests test superiority hypotheses. Two-sided questions that compare the difference between two therapies are common. The value a = 5% has been established as the significance level; if the question is one-sided, a = 2.5% is often used.

3.3 Power or might

The power of the study is also determined in the planning phase. This refers to the probability that a statistical test will prove the actual difference, i.e. deliver a significant p-value. The power of a study should therefore be as high as possible. Values ​​between 80% and 90% are common here. The higher the power of a study, the higher the resulting number of cases.

4. Example from our NOVUSTAT consulting practice

As part of a clinical trial, the improvement in quality of life, measured by the score of the “Physical Functioning” scale of the SF-36 questionnaire, should be demonstrated after 3 months of therapy. The scale ranges from 0 to 100 points. The measuring instrument is well documented, validated and there are numerous publications with this measuring instrument. From the standard value table of the Federal Health Survey ^[1] it can be seen that healthy people in the age range 40-70 years have a mean score of 80-90 with a standard deviation of around 20 score points. For the study population, this physical function at inclusion (before therapy) will be 50 score points (standard deviation 25 score points), as results of a pilot study have shown. After three months of therapy, the goal is to achieve an improvement in physical functioning by 30 score points, so that the average functional ability after therapy corresponds to that of healthy people of the same age. A low value of 0.2 is expected for the correlation between the first measurement before therapy and the second measurement after 3 months of therapy (and confirmed with the data from the pilot study) due to the time interval.

If you enter these values ​​into G*Power, a software for calculating the sample size, you get the following result:

Fig. 1 Calculating the effect size

Based on the information and prior information, you get an effect size of 0.949, i.e. around 1. This information is now needed to calculate the minimum sample size required to detect an effect of d = 0.949.

For a normally distributed characteristic, a two-tailed t-test for paired samples can be used to demonstrate this. With a 5% significance level and a power of 90%, at least 14 observations are required for detection (see Figure 2).

Fig. 2 Sample size calculation for a two-tailed t-test with paired samples.

Taking into account a drop-out rate of 10%, at least 1.1*14 = 15.4, i.e. 16 patients, must be recruited.

As part of a sensitivity analysis, we check how sensitively the number of cases reacts to deviations from the assumptions. On the one hand, the effect size can be varied within reasonable limits, and on the other hand, the sample size can also be carried out using a non-parametric alternative. Reducing the power results in a reduction in the number of cases required.

A graphical sensitivity analysis can be seen in Figure 3.

Fig. 3 Sensitivity analysis: number of cases depending on the effect size and power of the study

5. Sources/literature

• Case number planning in clinical trials
• Chow S, Shao J, Wang H. 2008. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman & Hall/CRC Biostatistics Series.
• Bock J., Determining sample sizes for biological experiments and controlled clinical trials. Oldenbourg 1998

6. What we can do for you

Before the start of a clinical trial, sample size planning is an important part of the preparation. The sample number calculation ensures that the actual effect can be proven. Professional sample size planning ensures that the sample size remains as small as possible. The sample size planning is tailored to the respective test, taking into account the study design, the primary target variable, the hypothesis to be proven and the required security.  

That's why our study planning basically and always includes case number planning as a first step. The entire study concept is based on this. And thus further planning (e.g. How many test centers are needed? How long do I need to recruit? etc.) can build on this.

At this point we would like to thank our partner Novustat for the guest article, as we think that this topic in particular is often underestimated.

About the author: "Dr. Robert Grünwald has been self-employed with the statistical consultancy Novustat for 6 years and and his team primarily advises customers from the pharmaceutical, medical technology and industrial sectors on all questions relating to statistical evaluations."

Statistics consultancy Novustat

8. Outlook

In one of the next blog posts we will take up the topic of “study types” again and take a closer look at the approval study according to MDR Article 62.

9. 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?

You can get a free initial consultation here: free initial consultation 

[1] https://www.thieme.de/statics/documents/thieme/final/de/documents/zw_das-gesundheitswesen/gesu-suppl_klein.pdf

The medXteam GmbH blog series continues in the new year and takes up the topic of DiGA studies with the first article in 2021.

Underlying regulations

Digital Healthcare Act (DVG)
Digital Health Applications Ordinance (DiGAV)
DiGA Guide

1. What is a DiGA?

In Chapter 2.1, the guide provides a definition of “digital helpers in the hands of patients”. Accordingly, digital health applications (DiGAs) are “ medical devices of risk class I or IIa (according to the MDR or, as part of the transitional regulations or until the MDR comes into force on May 26, 2021, according to the MDD). This is based

• the main function of DiGA on digital technologies.
• DiGA is not a digital application that is only used to read or control a device; the medical purpose must be achieved essentially through the main digital function.
• The DiGA supports the detection, monitoring, treatment or alleviation of diseases or the detection, treatment, alleviation or compensation of injuries or disabilities.
• The DiGA is not used for primary prevention (see also chapter 2.1.4 DiGA in prevention).
• The DiGA is used jointly by the patient or by the service provider and the patient, i.e. applications that are only used by the doctor to treat the patient (“practice equipment”) are not DiGA.”

DiGA are therefore approved medical products that carry a CE mark and have therefore met the basic safety and performance requirements in accordance with Appendix I of the MDR. However, only Class I and Class IIa medical devices. Also those that are upgraded from class I to class IIa by the MDR. However, all medical devices in classes IIb and III and those that fall under class IIa under Directive 93/42/EEC (MDD) and are classified in class IIb and higher with the MDR do not belong to the group of DiGAs. These cannot be included in the directory.

2 How does DiGA get into the reimbursement register?

The DiGA process is generally only possible with a CE-marked product. The manufacturer can now decide whether he would like to be included in the directory directly and permanently or whether this should initially be done provisionally.

The procedure is designed as a so-called “fast-track procedure”.

Image1-DiGA: Process of the fast track procedure. Source: DiGA guidelines from BfArM

Image2-DiGA: Application for final inclusion in the DiGA directory. Source: DiGA guidelines from BfArM

In order to be included as a DiGA in the reimbursement directory (DiGA directory), various requirements must be met and the review process at the BfArM must be successfully completed. This includes, among other things, an evaluation concept and a clinical study based on it. What does this mean for the medical devices in question? How can the requirements be met and what is the best way to handle the process?

2.1 What is a DiGA study?

In addition to the general requirements

• Safety and functionality
• data protection
• Information security
• Interoperability

and other quality requirements such as:

• robustness
• Consumer protection
• Ease of use
• Support for service providers
• Quality of medical content
• Patient safety

The manufacturer of a DiGA must prove which positive supply effect is achieved. The DiGA guidelines define the positive supply effect as follows:

“As already laid out in the definition of the DiGA in accordance with Section 33a SGB V, the particular focus is on patient-centeredness of the effects to be proven. Both medical benefits and patient-relevant structure and process improvements relate directly to patients and must be proven using appropriate endpoints.”

A medical benefit (mN) is therefore:

• an improvement in the state of health (e.g. reduction of pain, improvement of symptoms, ...),
• a shortening of the duration of the illness (e.g. shortened duration of sick leave, shortened duration of therapy, ...),
• an extension of survival or
• an improvement in the quality of life.

Patient-relevant structure and process improvements (pSVV) are:

1. coordination of treatment processes,
2. Alignment of treatment with guidelines and recognized standards,
3. adherence,
4. Facilitating access to care,
5. patient safety,
6. health literacy,
7. patient sovereignty,
8. Coping with illness-related difficulties in everyday life

or

9. Reduction of therapy-related expenses and burdens on patients and their relatives.

2.2 Requirements for a DiGA study

The legislature places special and clearly defined requirements on a DiGA study. These are described in the DiGA guide :

• In principle, a clinical study must be carried out; publications alone are not enough.
• In this study, the manufacturer must demonstrate at least one positive care effect, which comes either from the area of ​​medical benefit or from the area of ​​patient-relevant structure and process improvements.
• First, the patient group and thus the indications for DiGA for which inclusion in the DiGA directory is requested must be determined. Reimbursement will only be made for these indications. According to the guidelines, the definition and limitation of this patient group must be “based on one or more indications according to ICD-10, whereby only three- and four-digit entries are permitted.”
• The study must be a superiority study because it must show that using DiGA is better than not using it. This is why it is a controlled clinical study: the selection of the comparison or control group must be based on the reality of care. When comparing with treatment without the use of a DiGA, e.g. B. a comparison with standard treatment (the standard of care) is also possible. Or the comparison versus non-treatment is useful if, for example, a DiGA offers care for patients who would otherwise mostly remain untreated and perhaps wait for a place to be treated.
• The study must be a quantitative comparative study and the chosen methodology must be adequate to the chosen subject of investigation. The following designs are possible:
  • observational/analytical study: e.g. B. Case/control studies, cohort studies
  • experimental intervention study: e.g. B. nonrandomized/randomized controlled trials
  • Meta-analyses in the evaluation of our own primary data

• The DiGA study can have a prospective or retrospective approach. The latter, for example, if the medical device has been on the market for a long time and the appropriate data in the required form (comparative) has already been collected with the DiGA and documented accordingly).
• The DiGA study must be carried out in Germany: either as a PMCF study if the medical device is already approved (Article 74 of the MDR or until May 2021: § 23b MPG) or as an approval study to prove the conformity of the medical device with the basic performance - and safety requirements (Article 62 of the MDR or until May 2021: §§ 20 – 23a MPG).
• The DiGA study must still be entered into a study register and the results must be published in full
• The following regulations for clinical trials with medical devices must be applied to the DiGA study:
  • DIN EN ISO 14155 “Clinical testing of medical devices on humans – Good Clinical Practice” and the FDA guideline “Design Considerations for Pivotal Clinical Investigations for Medical Devices”
  • When medical involvement occurs, the ethical principles of the Declaration of Helsinki apply.
  • At least one professional legal consultation must be carried out with an ethics committee (see PMCF study - § 23b MPG!) or under the MDR at least an opinion from the ethics committee must be obtained (Article 74 of the MDR).

This shows the interface to the medical device regulations and the possible use of the clinical data collected in this way for the PMCF (or for the approval of the medical device. It is therefore urgently recommended to comply with ISO 14155 and the MPG/MDR requirements.

3. What we can do for you

A DiGA study is a national specialty, simply because it can only be carried out in Germany. It is also a study requirement for medical devices for which, as part of meeting the basic safety and performance requirements for medical devices, clinical data can normally be waived when demonstrated in the clinical evaluation. Instead, performance data is used.

Basically, we meet DiGA manufacturers where they are and we try to combine regulatory medical device and DiGA requirements with regard to clinical studies as far as possible, since such an effort can certainly be used for both areas. This means you can kill two birds (MDR and DVG) with one stone. That starts e.g. B. when formulating the correct intended purpose of the medical device in order to be able to score points later in negotiations with the health insurance company. It continues with the assessment of the right timing of the DiGA study, with the evaluation concept and study planning and ends with proof of the positive care effect.

That's why we're first working with the DiGA manufacturers to develop a strategy on how they can optimally demonstrate the positive supply effect on their supply path. Depending on your initial situation and your goals.

4. Outlook

In the next blog post we will look in detail at an essential part of the planning phase of a clinical trial, statistical sample size planning. 

5. 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?

You can get a free initial consultation here: free initial consultation 

The clinical trial types blog series will be interrupted by our “Christmas Special” in December. We would like to inform you comprehensively about the important changes to clinical trials due to the MDR this year so that you are prepared for 2021.

The special thing about our campaign is that the contribution grows until Christmas. New sections are added every week. The topic of DiGA studies will continue in January.

The first part of our December special gave you a guide to the application process for clinical trials as part of the conformity assessment procedure with the higher federal authority and the ethics committees. The second part dealt with the application process for clinical trials with CE-marked products. Today's third part is about the application process for other clinical trials.

Abbreviations.

BOB (higher federal authority)

EK (Ethics Commission)

KP (clinical examination)

MDR (medical device regulation; Regulation 2017/745)

MPEUAnpG (the Medical Devices EU Adaptation Act was passed as law by the Bundestag on May 25, 2020. This MPAnpG-EU describes the Medical Devices Implementation Act (MPDG) in Article 1)

MPDG (the MPDG will gradually replace the Medical Devices Act (MPG) from May 26, 2021 and will be legally binding for all manufacturers and operators of medical devices in Germany).

Part 3: Application procedure - approval process for other clinical trials - Article 82 MDR

1 Introduction

Currently and until the MDR comes into effect on May 21, 2021, the topic of “other clinical trials” is not regulated. And this despite the fact that basic research has not only existed since EU Regulation 2017/745 (Medical Device Regulation, MDR) in 2017. But clinical trials in the context of basic human research that are not carried out to assess clinical performance, safety and benefit often led to uncertainty among the respective ethics committees and to some projects that could not be implemented.

All of this is changing with the MDR: 

The MDR now regulates this in Article 82 with the so-called “other clinical investigations”, whose implementation at the national level in Germany via the MPEUAnpG (Medical Devices EU Adaptation Act) in Chapter 4, Subsection 2 , § 47 to § 61 is detailed. This also includes the application and approval procedures for this type of clinical trial, which can be carried out with a product in development, with a prototype or with CE-marked products. This depends on when the scientific or other question needs to be answered.

2. Approval process for other clinical trials with medical devices (Article 82 MDR and MPEUAnpG § 47-53)

2.1 Definition: Section 3 Sentence 4 of the MPEUAnpG

An “other clinical trial” of a product is a clinical trial that

a) is not part of a systematic and planned product development process or product observation of a current or future manufacturer,

b) is not carried out with the aim of demonstrating the conformity of a product with the requirements of Regulation (EU) 2017/745,

c) serves to answer scientific or other questions and

d) takes place outside of a clinical development plan in accordance with Annex XIV Part A Number 1 Letter a of Regulation (EU) 2017/745.

“Other clinical trials” are therefore NOT used to demonstrate performance, safety and benefits in accordance with Article 62 Section 1 MDR. They are therefore not to be equated with clinical trials as part of the conformity assessment procedure (Article 62 Para. 1 of the MDR) or with clinical trials in relation to products that bear the CE marking (Article 74 of the MDR) and thus PMCF studies!

In principle, however, it also applies to “other clinical trials” that the test product must meet the basic safety and performance requirements and be safe (Section 62 Paragraph 4, Letter l).

The “other KP” must comply with Section 62 MDR paragraphs 2, 3 and 4 letters b, c, d, f, h and l and paragraph 6.

Who will check this now?

2.2 Which applications must be submitted?

In order to check whether products/prototypes with which the other clinical trial is to be carried out are safe and meet the above requirements, the following must be observed:

• The requirements for other KP are regulated in Sections 47ff MPEUAnpG and described in the corresponding blog post from November (Other clinical trials with medical devices).
• Here too, an approving EC statement is required (= EC vote).
• According to Section 53 of the MPEUAnpG, a report to BfArM is now also required:

“According to Section 47 Paragraph 2 Number 2, any other clinical trial must be reported by the sponsor to the responsible higher federal authority via the German Medical Device Information and Database System in accordance with Section 86.”

• Changes must also be reported (Section 54 MPEUAnpG).

The deadlines for the EC statement are the same as for clinical trials according to Article 62 Para. 1 of the MDR (Part 1 of the Christmas special).

Informed regarding the report to BfArM

the Federal Institute for Drugs and Medical Devices [...] via an automated process, the authority responsible for the sponsor's registered office or the registered office of its legal representative and the authorities responsible for the testing centers via a notification.

So there is only information, but no assessment/approval etc. takes place.

Subsection 2 - Title 1 - Section 47 Paragraph 3 of the MPEUAnpG defines the procedure for other clinical trials with products that already bear the CE marking in accordance with Article 20 Paragraph 1 of Regulation (EU) 2017/745, insofar as the other clinical trial is carried out within the scope of the intended purpose covered by the CE marking and the test subjects are not subjected to any additional invasive or stressful procedures beyond the normal conditions of use of the product.

• In this case, no opinion from the ethics committee is required.
• A report to the higher federal authority does not have to be made either.

2.3 What does this mean?

For other clinical trials with prototypes, medical devices in development (without the CE mark) or with their components, a statement from the EC is required as with an approval study (see part 1 of the Christmas special). This means that once the MDR is valid, an EC vote is definitely required for other clinical trials. (Article 62 paragraph 4 sentence b) This other clinical trial must be reported to BfArM (Section 47 MPEUAnpG).

For CE-marked products, neither an EC vote nor a notification to BfArM is required for other clinical tests to answer scientific or other questions.

But be careful : If additional invasive or stressful procedures are used as part of the other clinical trial or if the medical device is used outside of its intended purpose, the sponsor must report the other clinical trial to BfArM and obtain a statement from the EC.

2.4 What effects does this have?

The EC vote required for other clinical trials with non-CE-marked medical devices means a full examination of the qualifications of the main investigator and examiner: The MDR itself says nothing about this; these requirements arise from the national regulations in Section 30 of the MPEUAnpG:

those who can demonstrate at least two years of experience in the clinical testing of medical devices can be appointed as head of a clinical trial or other clinical trial .

(5) Proof of the required qualifications must be provided through a current CV and other meaningful documents.

This means that two years of experience with medical device studies is also required as a qualification requirement for other clinical trials that require an EC vote. This therefore also represents a major hurdle for these clinical trials from May 2021.

3. Outlook

That was part 3 of our “ Christmas Special ” and this week there will be another article on safety reporting in clinical trials, which is regulated in detail in the guidance document MDCG 2020-10/1. We will once again provide you with comprehensive information about the important changes to clinical trials brought about by the MDR this year so that you are prepared for 2021.

The special thing about this campaign is that the contribution will continue to grow with part 4 this week until Christmas.

DiGA studies will continue in January.

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?

You can get a free initial consultation here: free initial consultation