MedTech Digital Week PMCF Clinical Investigations and Other Studies 04 Oct 2022 – Question and Answers
On 04. October 2022 ECLEVAR held a webinar at the MedTech Digital Week on PMCF Clinical Investigations and Other Studies.
This blog summarizes briefly the content of the webinar, and lists answers to the Questions from the Audience.
You can view the recording of the webinar on our web-site: LINK
Summary of the Presentation
With the MDR 2017/745 there is greater emphasis on clinical data and clinical evaluations, next to post-market surveillance, post-market performance and the health and safety of patients. For the re-certification of devices already on the market and initially CE-marked under the MDD and AIMDD, especially through the route of equivalence, the manufacturer has to prove availability of sufficient clinical data for safety and performance. Thus, post-market clinical follow-up studies, registers and Real World Evidence (RWE) are moving further into the focus of data collection routes to support re-certification.
The webinar covered:
- an overview on the Clinical Investigations Art. 62 through 82 MDR 2017/745, in connection with Annex I – Clinical Development Stages of the ISO 14155:2020 was provided.
- Differences and specifics of PMCF Clinical Investigation per Art. 74.1 MDR 2017/745
- Other Studies per Art. 82 MDR 2017/745 were highlighted for guidance, which applies to the different post-market data collections activities.
- Included was also a small excurse on the considerations for data protection per GDPR 2016/679.
Question and Answers
Q1: Which article would apply for postmarket clinical investigations within scope of its intended purpose but NO additional invasive or burdensome procedures?
A: It would fall under Art. 82 MDR 2017/745, and the national regulations of the countries in which the clinical investigation shall be conducted.
Q2: Is there a specific Reg covers Traditional Feasibility study and Registry Study?
A: In the EU there is no specific Regulation for early feasibility or registry studies. This is regulated by the MDR 2017/745, where the Traditional Feasibility Study would fall under MDR Art. 62, And the Registry Study under Art. 82 (other clinical investigations), respectively national law, see also MDCG 2021-6. MDR 2017/745 does not explicitly divide between the different pre-CE mark clinical investigations, but refers to ISO 14155, so more detailed description can be found in Annex I of ISO 14155:2020, which is also helpful for the now required Clinical Development Plan, and PMCF Plan.
Q3: Will it be sufficient as part of PMCF for a newly class IIa device – a clinical survey / user survey sufficient i.e to collect user experience? No equivalent device data, no literature available.
A: It would mainly depend what the results from the CER on data gaps are. And what methods you would like to use confirming the claims for performance, safety, and benefit/benefit-risk assessment in the conformity assessment and IFU for the device. This is clinical evidence data you need to collect.
You can plan for a high-quality survey (rank 4 MDCG 2020-6) covering all, or only a part of it. What would be economically and practically benefit you? As it is a new device, without equivalence data (does this include similar devices?), this is the route we would recommend at this stage, to get reliable data of good quality, you can build.
The quality of the data generated is reliant on how it is designed and conducted. For example, is it only about the feedback of users about device performance, ergonomics, satisfaction, or shall it cover more data, like subject’ gender, age, underlying disease, device details, date of treatment, any Adverse Events, concomitant medication (pain relief), comorbidities if necessary.
More information on what is required, and to be taken into account when planning PMCF activities can be found in MDR 2017/745 Annex XIV Part B # 6. Especially with the intention for general and specific methods to be used together at #6 a, b, and c.
Q4: Concerning GDPR, the EDPB released an opinion paper 03/2019 on the interplay between the CTR and the GDPR. In no. 20 the statement is: “However, it must be kept in mind that even though conditions for an informed consent under the CTR are gathered, a clear situation of imbalance of powers between the participant and the sponsor/investigator will imply that the consent is not “freely given” in the meaning of the GDPR.”. Do you expect a similar opinion for the MDR/ISO 14155 interplay with GDPR? Apologies for the tough question.
A: Yes. The opinion paper of the EDPB only refers to the Clinical Trials Regulation, GDPR refers to all Clinical Investigations whether CTR, MDR or IVDR, as well as the national Data Protection Laws would. Number 34 of the documents lists three alternatives:
“34. For all other processing activities, identified in this Opinion as processing operations purely related to research activities, the Q&A should be modified to reflect three alternative legal bases, depending on the whole circumstances attached to a specific clinical trial:
- a task carried out in the public interest under Article 6(1)(e) in conjunction with Article 9(2), (i) or (j) of the GDPR; or
- the legitimate interests of the controller under Article 6(1)(f) in conjunction with Article 9(2) (j) of the GDPR; or
- under specific circumstances, when all conditions are met, data subject’s explicit consent under Article 6(1)(a) and 9(2)(a) of the GDPR.”
So, the legal basis for data processing is the informed consent pursuant to Art. 6 (1) a and Art. 9 (2) a of the EU General Data Protection Regulation (GDPR).
However, although study participation and data provision is voluntary, subjects need to be informed that they cannot participate in the Clinical Investigation without providing explicit consent to the processing of their data.
(Opinion 3/2019 concerning the Questions and Answers on the interplay between the Clinical Trials Regulation (CTR) and the General Data Protection regulation (GDPR) | European Data Protection Board (europa.eu))
Q5: Why are Standards Rank 12 per MDCG 2020-6 Appendix III, for IOL [Intra Ocular Lense] we need to follow 11 Standards incl. Clinical Investigation?
A: The 11 Standards are to be followed for IOL production, and ISO 14155:2020 for clinical investigations, and they are of high value for the product development, conformity, and post market stage.
Appendix III of the MDCG 2020-6 is about the hierarchi for clinical evidence of data; clinical data that shall clearly provide proof in the CER [Clinical Evaluation Report] that there is conformity of the device to the GSPRs. It does not refer to the importance of the Standards in general, or for development and production.
So, Rank 12 would be not using collected clinical data, but referencing the Standards, which are not specified for your device, but IOL in general. In addition, it would not provide real data for clinical evidence, performance and safety for your specific device, and patients who received treatment with your device. This does not mean that this is not possible, it only ranks the clinical evidence.
The CER shall cover clinical data for the device, and also for the SOTA [State-of-the-Art], especially at the time of re-certification of the device. So, referring to the Standards followed is of high value to underline the quality, but it does not provide real clinical data for your device. If you compare this to Rank 1 to 4, the difference is highly visible.
Q6: Can an official clinical measure that is a questionnaire (such as the IKDC in traumatology) be considered a client/clinic survey to obtain post-marketing data?
A: To answer this, it would raise a main question: How much would this questionnaire support confirming the claims for performance, safety, and benefit/benefit-risk assessment in the conformity assessment and IFU for the device, and does this questionnaire refer to your device?
The International Knee Documentation Committee subjective knee form (IKDC-SKF) would count as Patient Reported Outcome (PRO), so it would not be addressed to the clinic/surgeon.
The other aspect is: how significant for the clinical evidence would data from this questionnaire alone be? It might be wasted money to have this survey only based on the questionnaire, if with some additional questions to the surgeons (a user (surgeon) survey study), and a survey CIP (protocol), you might receive high quality data, that can be used for the CER ad PMCF Plan/Report update.
Information from this questionnaire are of course clinical data, but it does not provide further information, like subject demographics (gender, age), underlying disease, device details, date of treatment, any Adverse Events, concomitant medication (pain relief), comorbidities if necessary. It would be recommended to have a completed questionnaire at baseline, so changes can be measured.
It would also depend of the device class, if the clinical evidence is high (rank 4 of Appendix III MDCG 2020-6) or lower (rank 8), and what the results from the CER on data gaps are. If it is an implantable device Class III or IIb, other than the devices listed as WET, a clinical investigation should be considered for clinical evidence data, but a survey study can be done in addition.
Q7: To perform an anonymized clinical case or case series as part of PMCF, is it necessary to have a favorable CE [Ethics Committee – EC] or to report something to the CE [EC]?
A: It would depend on the type of study and if it is interventional according to Annex I of ISO 14155:2020 and MDR 2017/745.
If the Clinical Investigation (Case series here) is non-interventional and observational with a CE marked Product, the requirements for submission are regulated by each Member States national law. Many Countries would not request EC submission for observational studies with anonymized data, but some might. Thus, information about the Countries’ requirements and national law should be reviewed. It is also recommended to reach out to the relevant EC, in case of insecurity.
It is also needed to check, if notification to other Authorities need to be performed, even if no EC or CA submission is required, like the CNIL (Data Protection Agency) in France, or the Datatilsynet (Data Protection Agency) in Denmark.
Q8: Hi All what is the difference between First in Human clinical investigation and Early feasibility clinical investigation?
A: It might be, that there is no difference, if it is a clinical investigation at early stage of development of the device, without the device design being finalized, and also the first use in human at the same time.
It could be different, if the first early feasibility study was performed, so first in human took already place, and then it is the second early feasibility study with some changes to the device.
ISO 14155:2020 Annex I:
- “I.5.2 First in human clinical investigations: “A clinical investigation in which a medical device for a specific indication is evaluated for the first time in human subjects.”
- 5.3 Early feasibility investigations: “A limited clinical investigation of a device early in development, typically before the device design has been finalised, for a specific indication (e.g. innovative device for a new or established intended use, marketed device for a novel clinical application). It can be used to evaluate the device design concept concerning initial clinical safety, and device clinical performance or effectiveness (if appropriate) as per intended use in a small number of subjects when this information cannot practically be provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable. Information obtained from an early feasibility clinical investigation can guide device modifications. An early feasibility clinical investigation does not necessarily involve the first clinical use of a device.
- NOTE Early feasibility clinical investigation can also be called proof of concept clinical investigation.”
Q9: Survey – User Survey versus Patient survey, if a patient is the user, would this then be also a user survey, and is “User” and “End-User” then the same??
A1: User Survey or patient survey are not defined anywhere, so this would be specified on your device’s intended use and intended user. Thus, during survey planning and in Survey Protocol, it shall clearly state to whom this survey addressed (physician, other health care professionals, patients) and on which level (patient level, health professional level, etc.).
Patient-level does not imply that only the patients are required to complete the surveys, it might also be health professionals providing patient data.
For this consideration it can be taken into account for example, MDR 2017/745 Art. 2 (57), Adverse event: “in subjects, users or other persons”. The subjects are the patients, the users would be healthcare professional, but this does not link to the differentiation of patient and user with respect to surveys and “intended user”.
End User is also not defined in the MDR, although mentioned in the definition for “recall” (MDR 2017/745 Art. 2 (62), so this is the real end user, which might also be the patient, or healthcare professional.
End User might be the patient, if it is a device for lay persons, or a healthcare professional. If you are planning end user surveys to patients includes some difficulties that need to be considered:
- The language needs to be in a simple and understandable way, also translated to all national languages for the areas, the survey study will be carried out.
- Pseudonymization versus anonymization requires different submission strategies (EC, GDPR, ICF) and the considerations, if the survey can be answered by the patients, of if a survey to the user (Physician, health care professional) would provide more reliable data, with less bias.
- Is it possible to guarantee anonymization (Survey via ePRO, via paper and shipped back to Sponsor directly or via or Site)
- If an Investigator is not involved, it might not be possible to have an EC involved (I.e., Germany’s EC are only involved, if an investigator is involved).
Q10: What impact would pseudonymized vs. anonymized data have?
A3: Slide 44 includes the difference between pseudonymization and anonymization:
- 2) pseudonymized (encrypted) personal data, in which all information that allows direct conclusions to be drawn about a person’s identity is replaced by a code (e.g. a number) or (e.g. in the case of image recordings) made unrecognizable. The effect of this is that the data can no longer be assigned to a person without the addition of additional information and without disproportionate effort (Subject Identification Log, SISD).
- This means, EC submission, ICF process, subject ID log
- 3) anonymized data that can no longer be traced back to a person
- For many Countries this means no EC submission, no SID log, no ICF process, but information to the subject of the use of their anonymized data might be considered. This might also be discussed with the Site’s (hospital/institution) Data Protection Officer.
- But note: anonymized is not traceable, so no SDV can be performed, no correction can be requested.
- GDPR Clause 26: with regards to anonymized data
“The principles of data protection should therefore not apply to anonymous information, namely information which does not relate to an identified or identifiable natural person or to personal data rendered anonymous in such a manner that the data subject is not or no longer identifiable. This Regulation does not therefore concern the processing of such anonymous information, including for statistical or research purposes.”
- Article 13 Information to be provided where personal data are collected from the data subject
“1. Where personal data relating to a data subject are collected from the data subject, the controller shall, at the time when personal data are obtained, provide the data subject with all of the following information: … “(ICF)
- Article 14 Information to be provided where personal data have not been obtained from the data subject
“1. Where personal data have not been obtained from the data subject, the controller shall provide the data subject with the following information:…”
Q11: Can you explain the difference between a clinical investigation as per Art. 62 MDR with a non-CE marked device and per Art. 82 MDR with a non-CE marked device? Isn’t a clinical investigation with non-CE marked device always an Art. 62 clinical investigation?
A4: To answer this question, I would like to link you to several slides of the presentation, where you can find the details:
CE-marked devices, or non-CE-marked devices – country specific
- Clinical investigations, not performed pursuant to any of the purposes listed in Article 62(1), which are:
- “to establish and verify that, under normal conditions of use, a device is designed, manufactured and packaged in such a way that it is suitable for one or more of the specific purposes listed in point (1) of Article 2, and achieves the performance intended as specified by its manufacturer;
- to establish and verify the clinical benefits of a device as specified by its manufacturer;
- to establish and verify the clinical safety of the device and to determine any undesirable side-effects, under normal conditions of use of the device, and assess whether they constitute acceptable risks when weighed against the benefits to be achieved by the device.”
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