The development of our microfluidic device is based on the ambition to offer research institutions a simple and efficient
in vitro testing of siRNA. Furthermore, our device is designed to be used for the production of RNAi - based therapeutics.
In order for our technology to be accessible to these institutions, it must first go through the process of market approval.
In the following text, the individual steps required for market approval in the European Union are explained in detail, drawing comparisons
between the US and EU requirements. The specific procedure for market approval in the US is then discussed in a separate chapter at the end
of this article. Concerning our project, it will be made clear how we have already implemented the corresponding requirements for our device
and how we will implement them in the future.
The process begins with the development and formulation of an innovative idea. This idea then should be concretized and future customers are included in the process to meet their needs and requirements for the product (Großklaus, 2014). In addition, the idea's technical feasibility and marketability must be evaluated. At the end of the idea process, there is the concrete idea of a product with its properties and areas of application and the verification that the product is marketable and can be technically implemented (Der lange Weg eines Medizinprodukts von der Idee über die Zulassung bis zum Patienten, 2016).
Using microfluidics in our project was first considered when we were looking for a suitable method to produce our siRNA therapeutic. Thanks to the so-called staggered herringbone micromixer technology, nanoparticles with a homogeneous size distribution can be produced using a microfluidic chip, which is essential for the efficacy and formulation of a therapeutic. Based on this consideration, we finally developed the concept of a microfluidic device that can be used for the production of RNAi-based therapeutics as well as for simple and standardized testing of siRNA. Unlike other devices on the market our innovative approach is fully automated. This minimizes the time required to operate the device and does not require any special personnel training.
After the idea was established, we conducted literature research and an interview with an employee of Merck KGaA, who is responsible for the marketing of microfluidic devices. Through these actions we figured out that there is a primary interest and need for our idea and the requirements that future users will have. During the research, we also discovered that replacing external components in smaller components, which are at best still integrated, and a more straightforward user interface would make microfluidic devices more accessible and affordable. The use of microfluidics eliminates the need to train personnel in alternative nanoparticle manufacturing processes. Once installed, there is no need for additional personnel to be trained to operate the device because of automation. In this way, our idea can support research institutions with less access to trained personnel, e.g., due to cost, and relieve other institutions of personnel and financial expenses.
Our proposal of a device in which the microfluidic chip can be exchanged is also viewed positively in the literature. This solves the common problem so far that only one chip can be inserted and used in a microfluidic device (Battat et al., 2022). Thus, the device can be used for the encapsulation of small molecules of various types, saving costs and resources.
Furthermore, we studied the microfluidics market's current and future development to better assess our idea's market viability. For the technical feasibility assessment, we presented our idea to the employee of Merck after our interview and asked for feedback on the design of our microfluidic chip. A technical drawing of a first prototype of our microfluidic chip was prepared. We were fortunate to get into contact with Dr. Sadaf Pashapour, who is the Head of Microfluidic Core Facility at the Institute for Molecular Systems Engineering in Stuttgart. Since we did not have access to the necessary facilities and machines, she kindly provided us with our manufactured prototype.
On the 23rd of April 2022, a StartUp Pitch took place on the Campus Im Neuenheimer Feld at Krehlklinik lecture hall and was organized by the AK Digital Medicine at the University of Heidelberg. In addition to our team members, young female founders from South America presented their startup idea from the medical-technical field. Investors have already funded these ideas for a future market launch. We were also able to pitch our project idea in front of an audience of over 100 other participants. Since the technical design of our microfluidic device was not very mature then, the other participants could not give us any constructive feedback. Nevertheless, the presentation gave us a first impression of how to pitch a product idea for a startup. At the same time, we got additional inspiration from the startups present on how to present our idea as successfully as possible to convince as many investors as possible.
A market analysis can be used to determine the chances of a successful market entry in advance of the approval process. At the same time, information from the market analysis can be used later in processes such as the further development of products or expansion into new markets (Marktanalyse-Methoden: Den eigenen Markt strukturiert durchleuchten, 2021). We have worked out some aspects of a market analysis for our project idea.
Before market approval, we would like to consider patenting our device, as otherwise, mainly already successful market participants could copy our idea and profit from it. At the same time, we would hardly have a chance to establish ourselves on the market (Schutz für Gesundheit mit patentgeschützter Medizintechnik, n.d.). On the other hand, through research and the interview with a Merck employee, we have realized that new application areas are constantly being added in the field of microfluidics, which requires continuous development of this technology (see Part 1 and interview with Dr. Sebastiano Rupiani). By applying for a patent, we can provide incentives for these further developments, which allow both us and the end user to benefit from our patent (DPMA | Patentschutz, 2022). To understand precisely how a patent is structured, how the preparation of a patent must be carried out, which time it takes, and what the financial costs are, we conducted an interview with patent attorney Dr. Ayben Isilay Özdogan.
During the last months of the project we thought about the future of our compounds, methods and applications. That was the time when we decided to consult a patent examiner of ScienceValue Heidelberg (SVH), Dr. Ayben Işılay Özdoğan. She introduced us to the topic of intellectual property rights, meaning the rights which protect individual intellectual achievements, such as patent and utility model law.
In this context she told us about the process of claiming a patent. It is most important that the invention you want to protect is not already publicly available somewhere else. This is especially valid in the scientific community since new inventions are often published in papers. Due to the reason that the process may take a few years, one has to make sure that the patent application fulfils the given criteria: novelty, inventive step and industrial applicability. Inventive step is hereby a synonym for being not obvious to the skilled person. We also got insight into the structure of a patent. It comprises a description, claims, an abstract and figures if present. The description has to inform the reader about the details of the innovation and at the same time explain which problem it solves. Next, the claims have to define the subject matter for which the protection is requested. It is also necessary to select the patent type. In this regard, it is possible to choose between several options, for example national patents, European patents and patents of the patent cooperation treaty (PCT) which is an international patent valid in the member states of the treaty.
Dr. Özdoğan also explained the difference between a patent and an utility model. While a utility model is noticeably cheaper than a patent it is also more limited. A utility model is not able to protect processes and methods as well as it is limited on a national basis. A patent on the other side can be used worldwide. Additionally, the duration of a patent is 20 years whereas a utility model only persists 10 years
In the end, we learned a lot about the protection of our intellectual property. In our case, we for sure need to analyse and structure our invention and associated processes more in detail to claim our own patent. Nevertheless, we hope that our content can be used for future technologies and maybe helpful for solving problems which long for a solution.
In the first part of our project, we convinced ourselves through a market analysis that the product idea has a market position, is viable and financially feasible, and dealt with patent law issues. Finally, we began planning our way through market approval in the EU and the US.
In order to determine which regulations we need to fulfill for our device to be introduced to the market, we first needed to classify our device.
In general, our microfluidic device can be classified as a medical device, as it is intended to produce liposomes as carriers for therapeutics in addition to in vitro testing. Thus, it fulfills the definition from Article 2, paragraph 1 of the Medical Device Regulation (EU) 2017/745 (MDR). There, it is stated that medical devices by definition fulfill, among others, the purpose of "[...] treatment or alleviation of disease [...]" as well as the "[...]replacement or modification [...] of a [...] pathological process or state" (Article 2, paragraph 1, MDR).
Following this classification, we performed a medical device classification according to the risks of use under the Regulation (EU) 2017/745 on medical devices by applying the relevant classification rules from Annex VIII. Since the complete microfluidic device consists of the device itself as well as a replaceable MF chip, both components have to be classified separately following Chapter II, point 3.2.
According to Chapter I, paragraph 1 of Annex VIII, the duration of use for the chip is classified as "temporary" (Annex VIII, Chapter I, paragraph 1, MDR, 2017) since its use is completed within 60 min and the chip is intended for single use. The device into which the chip is inserted is classified as "long-term" (Annex VIII, Chapter I, paragraph 1, MDR, 2017), as this can be used indefinitely.
Since the non-invasive microfluidic chip aims to prepare a liposome solution to be tested in vitro on human cells, it is classified as Class III under Rule 3 of Chapter II of Annex VIII. The device itself complies with rule 1 of the same chapter and can therefore be assigned to class I (MDR, 2017).
Considering that the device is also non-invasive and must comply with certain sterility and hygiene requirements to be suitable for liposome production as carrier for therapeutics, it is additionally classified as IS (Class I sterile) (MDR, 2017). Therefore both components must be free of living bacteria or other microorganisms and their spores. This also means additional special sterility requirements and compliance with sterilization standards (such as MDSAP, MDR, IVDR, EN ISO 11135 and EN ISO 11137-1)(Zulassung Mikrobiologie und sterile Medizinprodukte, n.d.).
According to the definition of the USC, our device and microfluidics chip is a medical device because it is "intended for use [...] in the cure, [...] [and] treatment [...] of disease [...]" under 21 USC §321(h). (21 USC, §321(h)(2)).
The classification of our medical device for approval in the US. is described in part 860 of Title 21 of the Code of Federal Regulations (CFR). It requires, i.e., the classification based on the Classification Panels in parts 862-892 of the 21 CFR. However, since we did not find a classification for our device in the panels, we have to apply for classification into classes I or II through a DeNovo procedure (Hastenteufel & Renaud, 2019). As a result, we cannot yet describe a specific approval pathway in the US for our two functional components. Therefore, we will only compare the corresponding requirements from the USA with the individual steps for approval in the EU. In Part 5 of this article, we will explain in more detail how the DeNovo Classification for our medical device will proceed.
The device has to meet the general safety and performance requirements described in Annex I of the MDR. As a basic requirement for the device Chapter 1 of the Annex I states that it "[... ]shall achieve the performance intended by its manufacturer and shall be designed and manufactured in such a way that, during normal conditions of use, they are suitable for their intended purpose.[...]" (Annex I, Chapter 1, paragraph 1, MDR, 2017).
Therefore, the next step is to develop a prototype for the microfluidic device as well and to further develop both prototypes. Moreover, the instructions for use of both the device and the chip must be completed to fulfill the requirements of Annex I and to carry out a sufficient risk assessment of the medical device later on (Der lange Weg eines Medizinprodukts von der Idee über die Zulassung bis zum Patienten, 2016).
The preliminary using instructions have been prepared following the requirements of EN IEC/IEEE 82079-1-2019 (Preparation of Information for Use)(INSTRKTIV B.V., n.d.). This preliminary information for the use of our microfluidic device and chip can be found in English at the following link. However, as we intend to introduce our product to the market in the USA and European Union, the final information for use will be available in all official languages of the EU, including English.
Both EU law (Annex I of the MDR, 2017) and US law (21 CFR part 820, 2018) require the establishment of a risk management system for medical devices (Höss, 2018).
The risk management system (RMS) consists of the following steps that must be continuously established, documented, and maintained throughout a product cycle:
The exact procedures within the individual steps are described in the standard DIN EN ISO 14971 (Höss, 2018). This procedure according to the ISO standard is also accepted by the FDA in the approval process (Hastenteufel & Renaud, 2019).
We can implement the RMS for our project by already applying the steps described above to our considerations for the technical composition of our MF device. This will be shown using a case study:
If the liquid containers are not inserted correctly into the device, this can lead to uncontrolled liquid leaking from the containers. This can endanger people and the environment. The risk can be classified as "As Low As Reasonably Practicable" (Höss, 2018).
One possible action to eliminate or control the risk is integrating a snapping-in mechanism that signals the user that the container has been correctly inserted. In addition, the software for the device can be programmed so that the device cannot be started if containers are not inserted correctly. At the same time, a message on the device display indicates to the user that the containers are not inserted correctly. Furthermore, warnings for immoderate pressure and solvent level will be shown on the display.
As a result, the extent of the risk remains the same, but the probability is significantly reduced. During the product cycle, it must now be monitored whether and how this risk continues to occur.
Clinical evaluation is essential for all medical devices. As part of the technical documentation, it is required for the EU conformity assessment, which is necessary for a medical device to be approved in the EU (Johner Institut GmbH, n.d.-b). The procedure for preparing the Clinical Evaluation is precisely defined in Article 61, paragraph 1 of the MDR:
"The manufacturer shall specify and justify the level of clinical evidence necessary to demonstrate conformity with the relevant general safety and performance requirements.[...] To that end, manufacturers shall plan, conduct and document a clinical evaluation in accordance with this Article and Part A of Annex XIV." (Article 61, paragraph 1, sentence 2 and 4, MDR, 2017). For our Class III microfluidics chip, we can consult a panel of experts in advance, who "review[ ] the manufacturer's intended clinical development strategy and proposals for clinical investigation" (Article 61, paragraph 2, sentence 1, MDR, 2017). For our microfluidics Chip, this means that compliance with Annex I requirements must be confirmed by a clinical evaluation and available clinical data, in addition to the risk management and information materials such as the instructions for use or labeling (MDR, 2017).
In our clinical evaluation, we must later show that we have taken existing alternative treatment options into account, such as the production of liposomes by other, already established methods. In particular, we have to demonstrate the benefits and the safety of our chip and thus, our liposome manufacturing process compared to these other processes and the medical devices used.
Clinical data are also part of the clinical evaluation. For the clinical data, relevant information can be searched in already available results of clinical examination or publications, or further clinical investigations have to be collected or produced by clinical studies. Later it is checked if the available data demonstrates compliance with the MDR or has to be subsidized by further information. These clinical data must be continuously updated and supplemented by post-market clinical follow-up plans and PMS (Medical Device Coordination Group, 2019).
Another essential point of the clinical evaluation is to show that the benefits outweigh the risks. This is justified by clinical data and also continuously re-evaluated in the course of PMS.
The possibility of performing clinical evaluations according to the equivalence principle was severely restricted after Revision 4 of the current MEDDEV 2.7/1, and the MDR became effective. Thus, equivalence is limited to products of the same manufacturer and product family (Die Klinische Bewertung - MEDDEV, MDD, AIMDD, MDR | Orangeglobal, n.d.). At the same time, it must now be demonstrated for comparable products that equivalence exists in technical as well as biological and clinical terms (Röthler, 2019). Nevertheless, we should consider this option because a successful clinical evaluation based on the equivalence principle saves costs and the need for trained personnel for the specific clinical testing and evaluation that would otherwise be required (Medizinprodukte: Klinische Bewertung | TÜV NORD, n.d.). This will require us to conduct intensive future research on the microfluidic market to possibly locate suitable products for clinical evaluation according to the equivalence principle.
According to Article 61, paragraph 10 of the MDR, it can be established in duly justified cases that compliance with the general safety and performance requirements can be adequately demonstrated even without clinical evaluations. This proof can be provided, among others, by "[...]performance evaluation, bench testing and pre-clinical evaluation [...]" (Article 61, paragraph 10, sentence 2, MDR, 2017). This article can be applied to our device without the microfluidics chip, as it is not intended for use on patients and therefore does not support the clinical evaluation described above.
For the approval process in the US., when submitting our clinical data, we must also comply with a rule introduced by the FDA in 2019 for data from clinical investigations performed outside the US. Its purpose is to ensure the quality and integrity of data from these investigations and protect human subjects. Under this rule, clinical data from outside the US must not only meet the general requirements of parts 50, 56 and 812 of 21 CFR. They must also include a statement that each investigation was conducted following the GCP described in section 21 CFR 812.28 (a)(1). This includes obtaining and documenting a review and approval by an independent ethics committee (IEC) (Center for Devices and Radiological Health & Center for Biologics Evaluation and Research, 2018).
The establishment of a quality management system (QMS) is mandatory (Article 10, paragraph 9, MDR, 2017) and usually set up by the manufacturers prior to or in parallel to the steps of Part 3.2.2 and 3.2.3. This obligation arises because the successful establishment will ensure compliance with requirements from the MDR, among other things, due to planned internal audits (Medical Device Coordination Group, 2019). ISO 9001 is the internationally recognized standard for quality management systems. ISO 13485 extends the requirements for QMS since patient safety also plays a role in medical devices and must therefore be included in the process (Qualitätsmanagement Für Medizinprodukte Nach MDR Und ISO 13485, n.d.).
Article 10, paragraph 9 of the MDR contains the aspects that the QMS should at least include (MDR, 2017). Basically, successful quality management consists of defining quality objectives and achieving them in a reproducible manner. At the same time, continuous consideration must be given to how quality improvement can be achieved and how all stakeholder requirements can be met. The stakeholders for our device are shown graphically in Figure 1:
To achieve this goal, the manufacturer must continuously monitor the processes internally and implement improvement measures.
The establishment of a QMS for our device is described using the so-called PDCA cycle (Plan-Do-Check-Act) (Qualitätsmanagement Für Medizinprodukte Nach MDR Und ISO 13485, n.d.):
This analysis results in the addition of the final test procedure so that the defect is detected before shipment to the customer and intensive follow-up training of the responsible employee (Hastenteufel & Renaud, 2019).
Our entire quality management is recorded in the so-called QM manual. It contains the documentation of the process implementations, activity descriptions, and work instructions. This documentation is supplemented by the corresponding evidence that activities have also been carried out following the specification documents.
The documentation of the conformity of our devices with the requirements of the MDR can be found in the medical device file (Qualitätsmanagement Für Medizinprodukte Nach MDR Und ISO 13485, n.d.).
Due to the classifications of the components of our medical device, our QMS must be certified by a notified body. This process is described in more detail in part 2.2.7 EU declaration of conformity.
The establishment of a QMS is also required in the USA, regulated in 21 CFR part 820 (21 CFR, 2018). According to this paragraph, the following documents must be submitted for quality management:
The similarities in content to ISO 13485 derive from the fact that in 2016, the FDA collaborated on aligning ISO 13485 and 21 CFR 820. Since 2018, there has even been a discussion within the FDA to recognize ISO 13485 in the US approval process.
In contrast to the European Union, our QMS does not have to be certified in the US, but is checked as part of the premarket approval. Nevertheless, as in the EU, there is a regular review of the QMS by the FDA. Among other things, Management Controls, Corrective and Preventive Actions (CAPA) and Production and Process Control are reviewed (Hastenteufel & Renaud, 2019).
The technical documentation covers all documents that a medical device manufacturer must provide to obtain an EU conformity assessment and, thus, a CE marking (Medical Device Coordination Group, 2019). After obtaining the EU declaration of conformity, the technical documentation must be accessible to competent authorities (CAs) for ten years (Article 10, paragraph 8, MDR, 2017).
Annexes II and III of the MDR define which documents and information must be included in the technical documentation (MDR, 2017). With the inclusion of our project, the essential points are summarized below.
If requested by the CA, the manufacturer must provide the technical documentation in the requested language of the European Union (Medical Device Coordination Group, 2019).
For product documentation in the US, three files must be submitted to the FDA.
The design history file (DHF) is described in 21 CFR part 820.30. It depicts the entire process of developing the design of a medical device. This includes the development of a design (design output) based on factors and requirements that the medical device must later meet (design input). This design is then tested to verify that it meets the requirements (design verification). At the end of the process comes the design validation, which contains the final concept of the design. Throughout the process, it is also necessary to document how changes to the design have been incorporated (Salvatore, 2021).
The 21 CFR part 820.181 describes the so-called Device Master Record (DMR) (Salvatore, 2022). It contains information on how the device is to be produced. Important information here is, for example, how the device will be assembled, tested and packaged during production.
Finally, the Device History Record (DHR) provides evidence that all the requirements mentioned in the Device Master Record are fulfilled. This is done, for example, by results of product testing (Salvatore, 2021). This record is described in 21 CFR part 820.184.
Since some content requirements of the documentation of our product overlap according to Title 21 of the Code of Federal Regulations and the MDR, we can adopt this data from the EU approval process. However, some documents that are not part of the technical documentation are also required by the FDA. For example, for the DMR, we have to add information concerning measurement and monitoring, installation, maintenance and servicing [21]. At the same time, some terms are defined differently by the FDA and the EU, which means that documents required by both bodies must be modified accordingly. An example of this is the term "label." The FDA defines the term as the "display of written, printed, or graphic matter upon the immediate container of any article [...]" (21 CFR part 201(k), 2018). This definition includes directions for use as well as circulars and labels. The MDR does not directly define the term "label". However, it can be inferred from the context that this primarily refers to labels directly on the device, since all separate information such as the instructions for use are mentioned separately (Seib, 2022).
Since our microfluidics chip belongs to class III and our device to class Is, we have to apply to a notified body (NB) to obtain a Declaration of Conformity for both components. The exact procedure of conformity assessment and the tasks of the NBs are described in Part 3.2.7 EU Declaration of Conformity.
Before the application, we must find a suitable Notified Body for our device. A list of NBs is available in the NANDO database.
From this list, we need to find an NB accredited for the code MDS 1005: "Devices in sterile condition ."In the next step, we have to request the evaluation of our QMS and our technical documentation from this NB. The contents that the application must contain are listed in chapter 1, paragraph 2 of Annex IX (Medical Device Coordination Group, 2019).
A crucial difference between the European Union and the US is that in the US, the FDA has sole responsibility for approval and surveillance (Hastenteufel & Renaud, 2019). The FDA center for Devices and Radiological Health (CDRH) is responsible for medical devices. The CDRH is, in turn, divided into offices, each of which assumes different tasks in the regulation and supervision of the medical device industry. Relevant for us are the Office for Compliance, which performs regular audits, and the office of device evaluation for submitting and approving our two functional components. The respective authorities automatically take over these processes and do not have to be applied for by the manufacturer (Information About FDA & Notified Bodies for Medical Device Companies, n.d.).
The last step before applying for CE certification for our device and chip is to obtain the EU Declaration of Conformity. Figure 2 shows how the conformity assessment procedures will be carried out for the device and the microfluidics chip:
It can be seen at Figure 2 that for the declaration of conformity both functional components must comply with Article 10 as well as Annexes I, II, III, and XIV. In addition, the QMS and the technical documentation for the device and the chip must be checked and certified by an NB following Annex IX. Furthermore, according to Annex XI, Part A, the QMS for production must be certified by an NB for both components of our medical device. The inspection of the device focuses on the manufacturing processes involved in securing and maintaining sterile conditions. For the microfluidics chip, the entire production QMS is assessed. While the class Is device already receives a declaration of conformity at this point, a type examination must be carried out for the class III microfluidics chip in accordance with annex X. During this examination, a notified body checks whether the technical documentation, the processes during the product cycle and the chip itself meet the requirements of the MDR. Part B of Annex XI additionally specifies that for Class III devices, the conformity of the manufacturing process and the manufactured product must also comply with the type examination (Hastenteufel & Renaud, 2019). In addition, since the chip is also to be used to manufacture therapeutics, point 5.2 of Annex IX must be observed. This states that the NB must additionally verify the substance's quality, safety and usefulness in accordance with the methods laid down in Annex I to Directive 2001/83/EC. In addition, a scientific opinion from the EMA on the quality and safety of the substance, including the benefit or risk of the use of the substance, is requested. If this opinion is positive, the NB issues a declaration of compliance. The included information is listed in Annex IV of the MDR (MDR, 2017).
After receiving the declaration of conformity for our two functional components, the chip and the device as well as all packaging and the instructions for use must be provided with the CE label. The label must be affixed in a visible and legible manner and, according to Annex V of the MDR, must not deviate from the certain proportions, even when reduced in size.
Since the declarations of conformity for our medical device have been issued by a notified body, the corresponding CE labels contain the four-digit identification number of the relevant NB.
No marks that could lead to confusion with the CE mark may be used on our product or the instructions for use and packaging (Medical Device Coordination Group, 2019).
The registration of our device and chip with Eudamed was done online at the following link: https://webgate.ec.europa.eu/eudamed/landing-page#/.
First, we have to register as the manufacturer of our medical device. For this purpose, Eudamed requires the following data:
After the competent authority has verified our data and validated it in Eudamed, we receive a Single Registration Number (SRN) from the electronic system. This SRN is essential for applying for a conformity assessment with an NB and registering our product in Eudamed in compliance with Article 29. This registration includes the following:
Authorized representatives also need a SRN to access Eudamed and provide data.
Suppose the manufacturer has its product designed or manufactured by another legal or natural person. In that case, the information on that person's identity is part of the information that must be provided to Eudamed before the product is registered (Medical Device Coordination Group, 2019).
In the US, we are also required to register as a manufacturer in compliance with Title 21 CFR 807. The FDA charges an annual fee for the establishment registration (Center for Devices and Radiological Health, 2017), which is currently $6,493. Afterward, we have to register and list the two components of our microfluidic device that are manufactured at our registered establishment (Center for Devices and Radiological Health, 2022).
After our payment is received, we will obtain a Payment Identification Number (PIN) and a Payment Confirmation Number (PCN). We then can proceed to initial registration and listing of our device. This must be done within 30 days before marketing (see §807.22(a)). In the following years, we must again submit registration information between October 1 and December 31. If anything changes in the registration and listing information during the year, such as introducing another device for commercial distribution, it must be updated immediately (Center for Devices and Radiological Health, 2017).
The Registration takes place online and can be done through this link.
21 CFR part 807.25 states that we must provide the following information at the time of registration:
Since our device will be initially manufactured in the EU and imported into the US, we must also provide the following data:
In the next step, our two functional components must first go through the process of DeNovo classification, as already described in Part 3.1. After assigning the device and chip to one of the risk classes is it certain which requirements must be met by each of the two components. Depending on the classification, the required premarket submission is then submitted to obtain an FDA premarket submission number.
The DeNovo application is a risk-based classification process that can be used to assign a product to Class I or Class II when there are no
lawfully marketed predicate products. The product for which a DeNovo application is approved can then be placed on the market and used as a
predicate for future marketing authorization applications.
A DeNovo application must contain at least the following elements to be accepted by the FDA:
The required information and documentation are submitted online through the CDRH Customer Collaboration Portal (CDRH Portal)
(Center for Devices and Radiological Health, 2022a).
Link: https://fda-cdrh.okta.com/signin/register
The DeNovo application requires an additional fee of $28,114 (Center for Devices and Radiological Health, 2022c)
in addition to the Annual Establishment Registration Fee of $6,493 (see Part 4).
After submitting the DeNovo designation application, the FDA will verify that all necessary information has been provided during an Acceptance Review. Subsequently, the applicant will be notified electronically within 15 calendar days whether or not the de novo application has been accepted for substantive review. In the latter case, the required RTA information must be completed within 180 days.
During the substantive review, the first step is to check whether a legally marketed product of the same type exists and, thus, whether our medical device is eligible for a de novo classification. Subsequently, the submitted data are reviewed. Some deficiencies can be addressed through an interactive review, while others require a formal request for additional information. In this case, the de novo request is placed on hold and we have 180 calendar days to submit a complete response. If this has not occurred after the deadline, our request will be withdrawn and we will be required to submit a new request.
In general, the FDA will deny our De Novo application if we cannot adequately demonstrate that our proposed controls provide sufficient evidence of the safety and effectiveness of our medical device and the risk-benefit balance is not favorable. In this case, our device will be classified as Class III and the applicant will not be allowed to market the device legally. However, suppose these basic requirements can be sufficiently demonstrated. In that case, the FDA will grant the De Novo Requests for our two device components and establish a new classification rule for our device type (Center for Devices and Radiological Health, 2022a).
According to Article 83 of MDR, our medical device manufacturers, authorized representatives, distributors, and importers are collectively responsible for establishing and keeping a post-market surveillance system (PMS) (BSI Group Deutschland GmbH, 2020). This is to ensure that the device's conformity with the MDR's safety and performance requirements continues to be guaranteed after market launch (Kramer, 2013). As already indicated in Part 3.2.4, the PMS is defined as part of the quality management system and describes the process for monitoring and reacting to the performance of our medical device after market introduction. It consists of a Vigilance System and a Post-Market Clinical Follow-Up.
The goal of the Vigilance System is collecting information in case of complaints, adverse events or even serious incidents, which must always be followed by an adequate response (The Vigilance Process in Post-Market Surveillance, 2022).
The Post-Market Clinical Follow-up (PMCF) is particularly interesting for our class III microfluidics chip. This term describes the proactive collection and analysis of clinical data after market introduction of our medical device. It is also intended to ensure that the clinical evaluation of our device is always up to date (PMCF-Studien Und Artikel 74 Der MDR, 2021). In this context, it must be considered that only clinical data, as defined in Annex II, paragraph 48, or data from literature sources are allowed for clinical evaluation.
The collection and analysis of data in the course of the vigilance system, as well as the resulting measures, can be presented as a PDCA cycle, as in the QMS (BSI Group Deutschland GmbH, 2020):
According to Annex III of the MDR, these actions are recorded in a PMS plan. In addition, according to Article 85, the summarized results of the PMS must be recorded in a report and made available to the CA (MDR, 2017).
In contrast to the European Union, in the US, we do not automatically have to submit PMS data to the FDA for our device components. However, the FDA can order the transmission at any time, e.g., if an adverse effect becomes known. In this case, we have 30 calendar days to submit a post-market surveillance plan for approval. The PMS plan must fulfill the regulation's requirements (Donawa, 2005).