This year's blog series continues during Advent with our three-part "Advent Special." In this series, we aim to provide you with comprehensive information on the important interfaces between the various types of clinical trials and their technical documentation, as well as the relevant documents.

What's special about our campaign is that the content is spread over the first three weeks of Advent. Each week, we'll take a detailed look at one type of clinical trial and its respective interfaces. In January, we'll continue with the topic of risk management in clinical trials. 

The first part of our blog special dealt with the interfaces in the "registration study" (clinical trials according to Article 62 of the MDR). Part 2 now examines PMCF studies (Article 74 of the MDR, MPDG, ISO 14155). This third and final part now explains the interfaces in DiGA studies.

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 2: Interfaces to technical documentation in PMCF studies and connection to the MDR

1 Introduction

The correct term for a clinical trial involving medical devices is “clinical trial”.

A distinction is made between the following types of clinical trials:

• Basic research: other clinical trials (MDR Article 82)
• Pilot study/approval study: clinical trials to demonstrate the conformity of products (MDR Article 62)
• PMCF study: clinical trials related to products bearing the CE marking (MDR Article 74)

In addition, there is now the so-called DiGA study, especially in Germany:

• Study with a digital health application (DiGA) to demonstrate positive care effects in order to obtain reimbursement status.
• d. R. with CE marked medical device: PMCF study
• If planned into the approval process, an approval study is also possible

(Sources: DiGAV, DVG, DiGA guidelines)

Fig. 1: Types of clinical trials

These different types differ in terms of the respective regulatory requirements and thus in terms of the different interfaces to the technical documentation of the medical device to be examined.

A DiGA study is a PMCF study. Therefore, the same special features apply:

A DiGA and thus PMCF study, which takes place with a CE-marked medical device within the scope of its intended purpose and without burdensome examinations, constitutes an exception to Article 74 of the MDR:

Figure 4: Article 74 of the MDR (Source: Presentation slides, BfArM event, https://www.bfarm.de/DE/Service/Veranstaltungen/Dialogveranstaltungen/2021/210505-klinische_Pruefungen_von_MP.html )

However, regardless of this, the documents in Annex XV Chapter II and Articles 80ff of the MDR are still binding.

2. Documents to be submitted for DiGA studies

The additional phase in a DiGA study includes creating the evaluation concept based on a systematic literature search, data collection with the DiGA itself on the user, and the systematic evaluation of this data.

The clinical evaluation – and in this case, preferably the most recently completed one – serves as essential input for this purpose. It lists the various claims for the medical device, and the appropriate ones for the DiGA concept must be identified from these claims. Furthermore, the claims required for the clinical evaluation regarding clinical performance, safety, and clinical benefit were already defined in the clinical evaluation plan and subsequently substantiated with data in the clinical evaluation report.

Note: This is precisely where the use of the interface to the DiGA topic "medical benefit" or patient-relevant structural and procedural improvements is recommended, because this data can then be used in the update of the clinical assessment after the DiGA study.

 

We have already reported on this in detail in our blog post about the evaluation concept this year.

Following the development of the evaluation concept and the identification of suitable endpoints for the DiGA study, the next step is the creation of the study documents. As with the PMCF study, the following documents must also be prepared for DiGA studies. Depending on whether Article 74 of the MDR applies, the application is submitted to the Ethics Committee for a vote and to the Federal Institute for Drugs and Medical Devices (BfArM). If Article 74 does not apply, only professional consultation with the relevant ethics committee is required, in accordance with Section 15 of the Professional Code of Conduct for Physicians (BO). Regardless of the application procedure, the following documents must be prepared, and these relate to the technical documentation:

• Test plan - attachments according to appendix XV chapter. II 3 MDR.
• Clinical Investigator's Handbook - Annexes according to Annex XV Chapter II 2 MDR.

The following documents from the technical documentation are required for this purpose:

• Clinical evaluation - in accordance with Article 61 of the MDR.
• Instructions for use
• Biological safety test results
• MP Functionality/Information about MP (How MP Works)
• How it works and further information about the medical device.
• Risk analysis and assessment including residual risks
• List basic security and performance requirements
• If necessary, suitable processing or sterilization processes
• Proof of CE marking (Required if the test product bears a CE marking.)

2.1 Interfaces to technical documentation

The following table lists the above-mentioned documents to be submitted as well as the elements contained therein and the respective correspondence in the technical documentation:

document	Regulatory requirement	elements	Technical Documentation
Test plan	Appendix XV Ch. II 3 MDR	Labeling and description of the product, including the intended purpose, manufacturer, traceability, target group, materials in contact with the human body, medical and surgical procedures associated with its use and the training and experience required for its use, triage the reference literature, the current state of the art in clinical care in the relevant area	Product description, intended purpose, product specification, preclinical evaluation as a preliminary stage of the final clinical evaluation with state of the art chapter, instructions for use with description of the application
Test plan	Appendix XV Ch. II 3 MDR	Risks and clinical benefits of the product under test	Risk analysis, risk management report, preclinical assessment with risk-benefit assessment
Test plan	Appendix XV Ch. II 3 MDR	Information about the test product, any comparators and other products	Product description, instructions for use
Test plan	Appendix XV Ch. II 3 MDR	technical and functional characteristics of the product	Product description, instructions for use, product specification
Clinical Investigator Handbook	Appendix XV Ch. II 2 MDR	Labeling and description of the device, including information on the intended purpose, risk classification and applicable classification rule in accordance with Annex VIII, design and manufacture of the device and reference to previous and similar generations of the device.	Product description, intended purpose, product specification, preclinical evaluation as a preliminary stage of the final clinical evaluation with state of the art chapter, instructions for use with description of the application Classification
Clinical Investigator Handbook	Appendix XV Ch. II 2 MDR	Manufacturer's information on installation, maintenance, compliance with hygiene standards and use, including storage and handling requirements, and, where this information is available, the information to be included on the label and the instructions for use to be provided with the product when it is placed on the market.	--
Clinical Investigator Manual/Preclinical Assessment	Appendix XV Ch. II 2.3 MDR	Preclinical assessment based on data from relevant preclinical tests and experiments, in particular from design calculations, in vitro tests, ex vivo tests, animal experiments, mechanical or electrical tests, reliability tests, sterilization validations, software verifications and validations, performance tests, evaluations biocompatibility and biosafety, where applicable.	Preclinical assessment as a preliminary stage of the final clinical assessment
Clinical Investigator Manual/Preclinical Assessment	Appendix XV Ch. II 2.3 MDR	Existing clinical data, in particular — from the relevant available scientific literature on safety, performance, clinical benefit to patients, design features and intended purpose of the device and/or similar or similar products, — other relevant available clinical data on safety, performance, clinical benefit for the patients, design characteristics and intended purpose of similar or similar devices from the same manufacturer, including the length of time the device has been on the market, as well as the data from a review of performance and safety aspects and clinical utility and any corrective actions taken.	Preclinical assessment as a preliminary stage of the final clinical assessment
Clinical Investigator Manual/Preclinical Assessment	Appendix XV Ch. II 2.3 MDR	Summary of the benefit-risk analysis and risk management, including information on known or foreseeable risks, any undesirable side effects, contraindications and warnings.	Instructions for use, preclinical evaluation as a preliminary stage of the final clinical evaluation
Clinical Investigator Handbook	Appendix XV Ch. II 2 MDR	For products containing a medicinal product, including a derivative of human blood or plasma, or for products manufactured using non-viable tissues or cells of human or animal origin or their derivatives.	Only in this case: Information about the medicinal product or the tissues, the cells or their derivatives and the fulfillment of the relevant essential safety and performance requirements and the specific risk management relating to the medicinal product or the tissues or cells or their derivatives and evidence of the incorporation of these components the clinical benefit and/or safety of the product
Clinical Investigator Handbook	Appendix XV Ch. II 2 MDR	A list detailing compliance with the relevant essential safety and performance requirements set out in Annex I, including the standards and specifications applied, in whole or in part, and a description of the solutions chosen to meet the relevant essential safety and performance requirements, where applicable these standards and specifications are only partially or not at all fulfilled or are completely missing.	Checklist of basic performance and security requirements List of standards
Instructions for use	Appendix XV Ch. II 2.2 MDR	--	Instructions for use
Insurance basic safety and performance requirements	Annex XV Chapter II 4.1 MDR	Assurance that basic safety and performance requirements are met.	Checklist of basic performance and security requirements
Biological safety test results	Appendix XV Ch. II 2.3 MDR	Data from relevant preclinical tests and trials, in particular biocompatibility and biosafety assessments, where applicable.	Test reports, biosafety report
How the MP works/information about the MP	--	How it works and further information about the medical device	Product description, instructions for use, product specification
Risk analysis and assessment including residual risks	Appendix XV Ch. II 2.5 or 4.6 MDR	Summary of the benefit-risk analysis and risk management, including information on known or foreseeable risks, any undesirable side effects, contraindications and warnings. Full details of the available technical documentation, for example detailed risk analysis/management documents or specific test reports, will be provided upon request to the competent authority reviewing an application.	Risk management documentation according to ISO 14971
List basic security and performance requirements	Appendix XV Ch. II 2.7 MDR	--	Checklist of basic performance and security requirements
If necessary, suitable processing or sterilization processes	--	Sterilization process, validation	Documentation of the sterilization process

Table 1: Clinical trial documents and technical documentation

Since this is a CE-marked product, all these documents are already included in the technical documentation and are incorporated in particular into the study plan and the clinical investigator's manual.

The CE-marked medical device is therefore the investigational product tested in the PMCF study, for which the clinical data are collected. This means that the documents and results must refer to precisely this product and not to a previous version!

Technical Documentation:

• Product description
• Intended use
• product specification
• final clinical evaluation with state of the art chapter and literature review and risk-benefit analysis
• Risk management documentation according to ISO 14971: PHA, risk analysis, risk management report
• Instructions for use
• Classification
• Checklist of basic performance and security requirements
• List of standards
• Verification test reports
• Biosafety report (if applicable)
• Sterilization process documentation (if applicable)

2.2 Synergies

Looking at the list above, it is noticeable that this already constitutes almost the entire technical documentation.

A good example of leveraging synergies in document creation is the study protocol. Many sections contain the same content as other technical documentation documents. The intended purpose, product description, etc., are just a few examples. Furthermore, the final clinical evaluation includes state-of-the-art clinical data that can also be used for the study protocol and the investigator's manual.

And here the digitalization of clinical trials plays a role again:

The close integration of clinical trials not only with the literature search process and thus with clinical evaluation, as reported in the penultimate blog post, but also with technical documentation, necessitates the digitization of essential clinical trial documents such as...

• Clinical trial plan (Appendix XV, Chapter II, Section 3 of the MDR)
• Clinical Investigator's Manual (Appendix XV, Chapter II, Section 2 of the MDR)
• clinical evaluation

possible.

The advantages of digitalization are obvious:

• more efficient work
• Target-oriented use of capacities
• Elimination of inefficiencies in the creation, maintenance and modification of technical documentation content, clinical evaluation and literature searches
• long-term reduction in care costs

The "Polarion" software application allows interfaces such as intended purpose, risk management, usability, clinical evaluation, and clinical trials to be assigned to projects and reused as needed. This significantly simplifies and accelerates the creation and maintenance of documents. Furthermore, redundancies and inconsistencies are avoided.

3. Outlook

Our " Advent Special " has now come to an end. We wish all our readers a peaceful and relaxing Christmas and plenty of time to do something other than deal with medical products.

In the new year, we will resume with the topic of "Risk management in clinical trials".

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