Keywords: Sample size planning, clinical study, clinical trial

Secondary keywords: Sample size, case number calculation

1 Introduction

Sample size planning plays a crucial role in the planning of a clinical trial. This determines how many participants need to be included to demonstrate a relevant effect – and thus ultimately the success or failure of the study. What considerations are involved in this process?

To demonstrate the efficacy of any clinical trial, such as PMCF or registration studies, hypotheses are tested against a primary endpoint. A hypothesis to be tested (called an alternative hypothesis) could be, for example, the superiority of a product over a standard therapy. Confirmation or rejection of a hypothesis is assessed based on collected data, and the results are then extrapolated to the entire population, i.e., the entire target group. For this to be meaningful, a sufficient number of observational data from the target group must be available. 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 ethically difficult to justify, ties up resources, and extends the study duration.

Sample size planning determines the minimum number of patients or study participants to be included in order to demonstrate an actual effect. A number of preliminary considerations are crucial for this.

2. Reasons for case number planning

The goal of every confirmatory clinical trial is to statistically prove a hypothesis. If the sample size is too small, a difference actually existing between two treatment groups cannot be demonstrated. This results in a non-significant statistical test, even though effects do indeed exist.

On the other hand, data collection is very time-consuming, ties up personnel resources, and incurs costs for each additional patient included. Furthermore, recruiting too many patients can lead to even small, medically irrelevant effects being detected.

A sample size plan for a clinical trial thus ensures that

1. An effect present in the target group is detected by 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 also no effect in the target group (population) with a sufficiently high degree of certainty.

The necessity of sample size planning during the planning phase of clinical trials is also legally mandated and reviewed by the ethics committee. Calculating the sample size is an essential part of both the clinical trial protocol and the statistical analysis plan.

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

Aspects of case number planning

Physicians, principal investigators, statisticians, and CROs work closely together on sample size planning. The starting point is always the primary endpoint and the hypothesis to be tested in the clinical trial.

3. Selection of statistical tests

The type of research question is crucial for selecting the appropriate statistical test. Different test procedures are required depending on whether the goal is to demonstrate the superiority or equivalence of a treatment. The scale level of the primary outcome variable also plays a decisive role. Different methods are used for nominal variables (yes/no, success/no success) than for ordinal variables (e.g., Likert scale) or continuous variables (e.g., visual analog scale (VAS), sum scores, etc.).

3.1 Effect size

The effect size indicates the relevant difference to be detected. Different measures are used depending on the test procedure employed. For continuous variables, the most well-known effect size is Cohen's d, which expresses the difference between two independent groups relative to their joint variance.

For categorical endpoints, the effect size W is used, which is calculated as the square root of the relative difference of the proportions.

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

Effect size ≈ 0.2: small effect

Effect size ≈ 0.5: medium effect

Effect size ≈ 0.8: large effect

Determining the effect size requires the most precise possible preliminary information from the literature or our own pilot studies. The medically and practically relevant difference that can be demonstrated is also taken into account. A mean blood pressure reduction of just 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 both patients and physicians.

3.2 Significance level of the statistical test

The significance level α must be defined in advance and documented in the study protocol and the statistical analysis plan (SAP). The significance level indicates the probability of obtaining a statistically significant test result if no effect is actually present in the target group. A further distinction is made between one-sided and two-sided tests. One-sided tests examine superiority hypotheses. Two-sided tests, which compare the effects of two therapies, are more common. A significance level of α = 5% has become established, while α = 2.5% is often used for one-sided tests.

3.3 Power or Might

During the planning phase, the study's power is also determined. This refers to the probability that a statistical test will detect the actual difference, i.e., yield a significant p-value. The power of a study should therefore be as high as possible. Values ​​between 80% and 90% are common. The higher the power of a study, the larger the resulting sample size.

4. Example from our NOVUSSTAT consulting practice

As part of a clinical trial, the improvement in quality of life, as measured by the score on the "Physical Functioning" scale of the SF-36 questionnaire, will be demonstrated after a 3-month therapy. The scale ranges from 0 to 100 points. The measurement instrument is well-documented and validated, and numerous publications exist using this instrument. The norm table from the German National Health Survey ^[1] shows that healthy individuals aged 40-70 years have a mean score of 80-90 with a standard deviation of approximately 20 points. For the study population, this physical functioning level at baseline (before therapy) is expected to be 50 points (standard deviation 25 points), as results from a pilot study have shown. After three months of therapy, the aim is to achieve an improvement in physical functioning of 30 points, so that the mean functional level after therapy corresponds to that of healthy individuals of the same age. A low correlation of 0.2 is expected (and confirmed by the data from the pilot study) between the first measurement before therapy and the second measurement after 3 months of therapy, due to the time interval.

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

Fig. 1 Calculation of the effect size

Based on the given information and prior data, an effect size of 0.949, or approximately 1, is obtained. This information is now needed to calculate the minimum required sample size to detect an effect of d = 0.949.

For a normally distributed variable, a two-sided paired t-test can be used to confirm the finding. With a 5% significance level and a power of 90%, at least 14 observations are required (see Figure 2).

Fig. 2 Calculation of sample size for a two-sided paired t-test.

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

In a subsequent sensitivity analysis, we examine how sensitive the sample size is to deviations from the assumptions. This can be achieved by varying the effect size within reasonable limits, or by using a non-parametric alternative to determine the sample size. Reducing the power reduces the required sample size.

A graphical sensitivity analysis can be seen in Figure 3.

Fig. 3 Sensitivity analysis: Sample size depending on effect size and study power

5. Sources/Literature

• Sample size 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 the sample size 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 a crucial part of the preparation. Calculating the sample size ensures that the actual effect can be demonstrated. Professional sample size planning ensures that the sample size remains as small as possible. Sample size planning is tailored to the specific trial, taking into account the study design, the primary outcome variable, the hypothesis to be tested, and the required level of certainty. 

Therefore, our study planning always includes sample size planning as a first step. The entire study concept is based on this. Subsequent planning (e.g., how many study centers are needed? How long will recruitment take? etc.) can then build upon this foundation.

We would like to take this opportunity to thank our partner Novustat for the guest contribution, as we believe that this topic is often underestimated.

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

Statistics consultancy Novustat

8. Outlook

In one of the next blog posts, we will revisit the topic of "study types" 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/dokumente/thieme/final/de/dokumente/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 

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. The third part focused on the application process for other clinical trials. We will now conclude the Christmas special today with the topic of safety reporting in clinical trials , which is also explicitly regulated in the MDCG document 2020-10/1.

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 4: Safety reporting in clinical trials - Article 82 MDR

1. Definitions

During clinical trials, undesirable or even serious adverse events can occur at any time, the latter of which must be reported to the authorities. The MDR defines an adverse event as  

... an adverse medical event, unanticipated illness or injury, or adverse clinical symptoms, including abnormal laboratory findings, in subjects, users, or other persons in a clinical trial, even if unrelated to the investigational device. 

A serious adverse event is defined as follows:

“Serious adverse event” means an adverse event that resulted in any of the following:

a) death,

b) serious deterioration in the subject's health, which in turn resulted in any of the following consequences:

1. life-threatening illness or injury,
2. permanent physical damage or permanent impairment of a bodily function,
3. inpatient treatment or extension of the patient's inpatient treatment,
4. medical or surgical intervention to prevent a life-threatening illness or injury or permanent physical damage or permanent impairment of a bodily function,
5. chronic disease,

c) Fetal endangerment, fetal death or congenital physical or mental impairment or birth defect. 

In clinical trials, further “events” are now defined:

“Product defect” means an inadequacy in the identification, quality, durability, reliability, safety or performance of a test product, including malfunction, application error or inadequacy of information provided by the manufacturer.

The MDCG document also defines these three events in Chapter 3.

Adverse events are abbreviated “UE”. In English these are “Averse events”, the abbreviation for this is “AE”.

Serious adverse events are abbreviated “SAE”. In English we speak of “serious adverse events”, which are abbreviated as “SAE”.

2. What events need to be reported?

2.1 Clinical trials according to Article 62 of the MDR

First of all, all events in clinical trials must be documented. These include:

• all adverse events
• any serious adverse events
• any product defects that could have resulted in serious adverse events
• as well as any new information about the product in relation to the event that occurred 

Which events must now be reported can be seen from Article 80 of the MDR and the MDCG document:

The sponsor shall immediately report, via the electronic system referred to in Article 73, to all Member States in which the clinical trial is being conducted:

a) any serious adverse event that has a causal relationship with the investigational device, the comparator or the test method or for which a causal relationship appears to be entirely possible,

b) any product defect that could have resulted in serious adverse events in the absence of appropriate measures or intervention or under less favorable circumstances,

c) any new information relating to an event referred to in points (a) and (b). 

Reportable events must be reported by the sponsor of the clinical trial, which may be the manufacturer, the legal representative or another person6 or entity.

Reportable events must be reported at the same time to all authorities where the clinical trial was initiated. For this purpose, a list must be made in the table specified in the MDCG document.

The deadlines for reporting are defined in particular in MDCG-2020/1 in Chapter 8. The sponsor reports every reportable event to the authorities in whose jurisdiction the clinical trial is being carried out (including in other EU countries and in third countries),

• any reportable event that indicates an imminent threat of death, serious injury or serious illness and requires immediate remedial action for other patients/subjects, users or other persons or new knowledge thereof: immediately, but not later than 2 calendar days after the sponsor has become aware of a new reportable event or of new information in connection with an already reported event . This includes significant and unexpected events that may pose a potential threat to public health. Also included is the possibility of multiple deaths occurring at short intervals.
• Any other reportable event or a new finding/update thereto: immediately, but no later than 7 calendar days after the date on which the sponsor became aware of the new reportable event or of new information relating to an already reported event .

In order for the sponsor to be able to comply with the deadlines, the sponsor must ensure that the reportable events can be reported by the investigator to the sponsor immediately, but not later than 3 calendar days after the testing staff of the testing center became aware of the event. An appropriate system must be set up for this purpose.

2.2 Clinical trials according to Article 74 of the MDR

In accordance with Article 80 Section 5 of the MDR, the vigilance provisions of Articles 87 to 90 and the legal acts adopted pursuant to Article 91 apply to post-marketing clinical trials (PMCF studies).

A distinction is made here between the following “events”:

According to the MDR, an “incident” means

... a malfunction or deterioration in the characteristics or performance of a product already made available on the market, including errors in use due to ergonomic features, as well as an inadequacy of the information provided by the manufacturer or an undesirable side effect.

A

… “serious incident” means an event that has had, could have had or might have had, directly or indirectly, any of the following consequences: a) the death of a patient, user or other person, b) the temporary or permanent serious deterioration of the health status of a person patient, user or other persons, c) a serious threat to public health.

According to Article 87 Section 1 of the MDR

… any serious incident related to devices made available on the Union market, other than expected adverse reactions, which are clearly documented in the product information, quantified in the technical documentation and subject to trend reporting in accordance with Article 88 of the MDR,

Report to.

However, for those serious adverse events where a causal link has been established between the serious adverse event and the previous investigational procedure, the reporting procedures for clinical trials in accordance with Article 80 of the MDR apply.

The MDCG document therefore defines reportable events in clinical trials under the PMCF as those serious adverse events for which a causal relationship has been established between the serious adverse event and the previous investigational procedure.

According to Article 87 of the MDR

… the time limit within which the notification referred to in paragraph 1 of Article 87 must be made depends on the seriousness of the serious incident.

Section 3 of Article 87 states:

Manufacturers shall report any serious incident referred to in point (a) of paragraph 1 immediately after establishing a causal relationship or a reasonable possibility of a causal relationship between the incident and their product, but no later than 15 days after becoming aware of the incident.

Section 4:

Notwithstanding paragraph 3, in the event of a serious threat to public health, the notification referred to in paragraph 1 shall be made without delay, but no later than two days after the manufacturer becomes aware of that threat.

Section 5:

Notwithstanding paragraph 3, in the event of death or an unforeseen serious deterioration in the health of a person, the notification shall be made immediately after the manufacturer has established a causal link between the product and the serious incident or as soon as it suspects such a link, but no later than ten days after he became aware of the serious incident.

3. Causality

The relationship between the use of the medical device (including the medical-surgical procedure) and the occurrence of each adverse event must be assessed and categorized.
The assessment of causality is based on the investigator's clinical judgment.
The relevant documents, such as: For example, the Investigator's Brochure (IB), the clinical trial plan or the risk analysis and risk management report should be consulted. All foreseeable serious adverse events and potential risks are listed there and have been assessed accordingly. The presence of disruptive factors such as B. Concomitant medication/treatment, the natural history of the underlying disease, other concurrent medical conditions or risk factors should also be considered. The above considerations also apply to the serious adverse events occurring in the control group.
Each serious adverse event is classified according to four different levels of causality:

1. No connection
2. Possible connection
3. Probable connection
4. Causal connection

The following definitions apply to assess the relationship of the serious adverse event to the investigational product, control product or investigational procedure:

a. No context:

A connection with the product, the control product or the test procedure can be excluded if:

• the event has no temporal connection with the use of the investigational product or the procedures associated with the use of the investigational product, the investigational product is related,
• the serious adverse event does not follow a known reaction pattern to the medical device (if the reaction pattern was previously known) and is biologically implausible,
• Stopping use of the medical device or reducing the level of activation/exposure - if clinically feasible -
  and reintroducing use (or increasing the level of activation/exposure) do not affect the serious adverse event,
• the event relates to a part of the body or an organ that cannot be influenced by the product or procedure,
• the serious adverse event can be attributed to another cause (e.g. an underlying or concurrent disease/clinical condition, an effect of another product, drug, treatment or other risk factors),
• the event does not depend - if applicable - on an incorrect result of the test product used for diagnosis.

Determining non-relationship may not require all of the criteria listed above to be met simultaneously, depending on the type of device/procedure and the serious adverse event.

b. Possible connection:

The connection with the use of the test product or the control product or the connection with the procedures is weak, but cannot
be completely excluded. Alternative causes are also possible (e.g., an underlying or concurrent disease/clinical condition and/or an effect of another product, drug or treatment). Cases in which the connection cannot be assessed or no information is available should also be considered possible.

c. Likely connection:

The connection with the use of the investigational product or the control product or the connection with procedures appears relevant and/or the event cannot be reasonably explained by another cause.

d. Causal relationship:

The serious adverse event is clearly related to the investigational product, control product or procedures if:

• the event is a known adverse reaction to the product category of the investigational device or similar products and procedures,
• the event is temporally related to the use/application of the investigational product or the procedures,
• the event affects a part of the body or an organ,

          o on which the test product or the procedures are used

          o on which the test product or the procedures have/have an effect

• the serious adverse event follows a known reaction pattern to the medical device (if the reaction pattern is already known),
• interrupting the use of the medical device (or reducing the level of activation/exposure) and reintroducing its use
  (or increasing the level of activation/exposure) has an impact on the serious adverse event (if clinically possible),
• other possible causes (e.g. an underlying or concurrent disease/clinical condition and/or an effect of another product, drug or treatment) have been reasonably excluded,
• the damage to the study participant is due to an application error,
• the event depends on an incorrect result of the test product used for diagnosis.

To establish the association, all of the criteria listed above may not need to be met at the same time, depending on the type of device/procedure and the serious adverse event.

4. Outlook

That was part 4 of our “ Christmas Special ” and at the same time the conclusion of the divided blog post on changes caused by the MDR. 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.

If you have any questions about this, please feel free to get in touch. As always, our free initial consultation available. Now medXteam says goodbye to the Christmas break and wishes all readers a peaceful, contemplative Christmas. Have a healthy new year!

DiGA studies will continue in January.

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