Should I cancel IIT 2

Clinical trials of medical devices most manufacturers try to avoid it at all costs. No wonder: a clinical trial is time-consuming and costly, and the regulatory requirements for it are extensive and complex.

This article describes when clinical trials are necessary, how they are carried out and which regulatory requirements must be observed. He also names the seven biggest challenges that manufacturers have to overcome.

1. Clinical studies and clinical trials of medical devices

a) definition

Definition:

"Systematic investigation that involves one or more human subjects and that is carried out to assess the safety or performance of a product"

Source: MDR, Article 2, Paragraph 45

The Medical Devices Implementation Act MPDG defines the term "other clinical trials":

Definition:
"[...] a clinical trial that
  1. is not part of a systematic and planned process for product development or product monitoring of a current or future manufacturer,
  2. is not carried out with the aim of proving the conformity of a product with the requirements of Regulation (EU) 2017/745,
  3. serves to answer scientific or other questions and
  4. takes place outside of a clinical development plan according to Annex XIV Part A Number 1 Letter a of Regulation (EU) 2017/745 "

b) Objectives of the clinical trials

Medical device manufacturers must demonstrate in clinical trials that their products are safe and deliver the promised clinical performance and benefits - benefits that outweigh the risks. You are obliged to provide this evidence based on clinical data. If these clinical data are not available in sufficient quantity or quality (e.g. in the scientific literature), the manufacturers must collect this data as part of clinical trials.

Note that the objectives stated here refer to the "clinical trials", not the "other clinical trials".

c) Delimitation of clinical trials and clinical studies

EN ISO 14155: 2011 states in the notes on the definition of the term clinical trial that this is synonymous with clinical trials. In practice, however, this equation leads to misunderstandings and regulatory problems.

If one speaks of “clinical study” for medicinal products, the term “clinical trial” is used for medical products. The MPG and the MDD have already done this.

However, neither the MPG nor the MDD knew the term “other clinical trials”. This is why the term “clinical studies” was used in experimental tests and in basic research.

In the meantime, the EU Medical Device Regulation (MDR) has introduced the term “other clinical trials” and also includes basic research and feasibility studies; she speaks of "answering scientific or other questions". Therefore, the term “clinical study” should no longer be used in the context of medical devices.

Rather, manufacturers should differentiate between “clinical trials” and “other clinical trials” and within which the respective objectives.

Please note: The same regulatory requirements do not apply to clinical trials and other clinical trials of medical devices. However, in both cases it must be checked whether the BfArM should be involved. In both cases, the requirements of the MDR had to be observed and an ethics committee had to be asked for approval.

example

The following example illustrates the demarcation:

Table 1: Example to illustrate the delimitation of “clinical trials"And" other clinical trials ".

Particularly in the case of medical products that are based on new processes, manufacturers find it difficult to make a distinction: Does the clinical trial serve to try out or develop the process? Or does it serve to collect the clinical data for the approval of the medical device? Or both? Manufacturers should clearly state this.

d) Classification of "clinical trials" in the context of medical devices

Further types of “clinical trials” are the post-market clinical follow-up studies (PMCF studies) and the observational studies.

Application observations are characterized by the fact that there are no measures, i.e. no interventions in the process of diagnosis or therapy.

All clinical "studies" with medical devices are clinical trials. There are different types:

Table 2: Clinical trials differ based on their goals and timingthe implementation.

Examples of "measures":

  • Additional ultrasound examination
  • Additional blood draw
  • Advanced physical exam
  • Allocation (also randomized) of the patient to a control group that is examined or treated differently than another group

If, on the other hand, one were to only observe medical staff at their work or question patients, one would not speak of an intervention or a measure. There is no clinical trial. In this case, one speaks of a non-interventional clinical trial (e.g. application observation).

2. Categorization of clinical trials

a) Categorization options

Clinical trials can be categorized according to various aspects:

  1. According to purpose (e.g. approval, research, etc. see above)
  2. According to phase (at the beginning of development, before approval, after approval, etc. The division into phases 0 to IV can be found primarily in drug studies and is not the subject of consideration here.
  3. According to study design (see below)

b) Categorization according to study design

This categorization is based on the attributes of the study design, for example:

  1. Number of patients (<100,> 1000 (= cohort))
  2. Number of study centers (e.g. multi-center)
  3. Timing of planning: retrospective versus prospective
  4. Blinding: unblinded ("open label"), simply blinded ("single blinded"), double blinded ("double blinded")
  5. Randomized / non-randomized: allocation of the patients into study arms according to the random principle
  6. With or without the use of placebos ("placebo-controlled")
  7. Time period: Longitudinal studies follow patients over a longer period of time, sometimes over their entire life.
  8. Interventional, non-interventional

Different study designs are defined depending on these attributes. The following table gives examples.

Table 3: The study design determines the scientific significance of a clinical trial.

The MDR requires manufacturers to determine the level of evidence. The higher the level of evidence, the higher the scientific validity must be.

The goal of the clinical trial and the primary endpoint matched to it determine the design. The evidence and the scientific validity result from this.

A randomized clinical trial is not always possible. You can also conduct a case series prospectively and in a controlled manner and thereby reach level 3. However, this level alone does not determine the scientific significance.

3. Clinical trials in practice

a) Phases and Activities

The clinical tests of medical devices usually take place in phases, which ideally are carried out sequentially, sometimes also iteratively in practice.

  1. set goals
    In the first phase, the manufacturers, as sponsors of the clinical trial, determine the regulatory requirements, decide whether a clinical trial is necessary and roughly define its goals.
  2. Schedule a clinical trial
    Then the manufacturers - mostly with the help of biostatisticians - formulate the hypotheses and goals more precisely and define the study design. You plan the course of the study, select people and provide budgets.
  3. Prepare for clinical trial
    The manufacturers select the test centers and clinical investigators and obtain the opinion of ethics committees and authorities. You prepare the processes (including documentation) and tools (e.g. electronic data acquisition) and train those involved.
  4. Conduct a clinical trial
    The investigators and the medical staff involved collect the data. The clinical monitors continuously check the data for plausibility and completeness and the implementation at the test center as part of on-site visits. The data managers evaluate the data in order to inform the authorities in the event of problems or to adjust or cancel the clinical trial.
  5. Evaluate data, assess the safety and performance of the product
    The manufacturers or their service providers evaluate the data. They evaluate whether the hypotheses could be verified and thus the safety and performance of the product could be proven. They prepare reports and the clinical evaluation.

b) The seven biggest mistakes in clinical trials

The Johner Institute regularly encounters the following sources of error with manufacturers who carry out clinical trials as sponsors:

  1. Unclear whether a clinical trial is necessary
    The manufacturers do not know whether a clinical trial is even necessary. In particular, it is unclear whether the data so far are sufficient to prove the safety and performance. An unnecessary test is a waste of time and money. If, on the other hand, a clinical trial is prescribed but not carried out, this jeopardizes legally compliant marketing.
  2. Imprecise or wrong goals
    The manufacturers have to define exactly which so-called “endpoints” the study has to substantiate with clinical data. Otherwise, you run the risk that the study will prove a hypothesis, but that this evidence will not be suitable to demonstrate safety, performance and clinical benefit.
  3. Wrong study design
    The importance of planning can hardly be stressed enough: the wrong population size, an inappropriate form of clinical trial, or an unrealistic project plan can all contribute to the failure of a clinical trial. Even an agile, iterative incremental approach is not a target-oriented recipe in the context of clinical trials.
  4. Inadequate monitoring and data management
    Errors and gaps in the data and a recording that does not correspond to the clinical trial plan destroy the informative value of a clinical trial. Close monitoring and well-founded data management are therefore essential for clinical trials.
  5. Lack of equivalence
    Some manufacturers use the findings from clinical trials to further improve the product. You then have to prove the equivalence of the products that will be used in the clinical trial and the products that are to be approved.
  6. Insufficient number of participants
    Many manufacturers find it difficult to recruit enough study participants to obtain the necessary evidence. This is especially true in these cases:
    • Rare disease
    • The advantage (= superiority) of the product compared to alternatives is small or even questionable.
    • The product appears strange or "risky" to the patient.
    • There are not enough investigators interested in the study.
  7. Unclear regulatory requirements
    The MDR and v. a. the MPDG have now clearly defined and stipulated the requirements for “other clinical trials”. This also applies to PMCF studies. Manufacturers should be aware of this. You should also not assume that “studies” with products that have already been approved do not require approval.

c) Tasks and selection of Clinical Research Organizations (CROs)

Clinical Research Organizations (CROs) help with all of the above. Most CROs specialize in drug research.

Do you need assistance?

The Johner Institute supports you in all activities. First of all, we clarify whether a clinical test (as part of the clinical evaluation) is even necessary. In this way you can avoid unnecessary efforts.

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4. Regulatory requirements for clinical trials

a) Medical Device Directives (MDD, AIMD)

Both the medical device directive MDD and the directive for active implantable medical devices form the legal framework for clinical trials until May 2020. This includes the following obligations:

  • The manufacturers must prove - as far as this is possible at the time - that the products the basic requirements that are not examined in the course of the clinical trial, d. H. the products must be safe.
  • Manufacturers need to Inform the authorities and usually wait for their approval.
  • To do this, they have to Vote by an ethics committee catch up.
  • Products for clinical trials must be manufactured by the manufacturer as such mark.
  • Manufacturers are also obliged to provide a documentation to create, e.g. a test plan, a manual, information and consent forms, contact details of manufacturers and test doctors, test information, monitoring plan and a precise description of the product.
  • In addition, a Insurance coverage for the test subjects.
  • Manufacturers must report serious incidents.

The guidelines oblige manufacturers to adhere to the ethical principles set out in the Helsinki Declaration.

b) Medical Device Ordinance MDR

The requirements of the Medical Device Regulation (MDR) go well beyond those of the MDD. They are more extensive and specific. In the case of special groups of people such as children, pregnant women and breastfeeding women, there are specific requirements for information and examinations.

The MDR specifies when and how the data is to be stored in EUDAMED (in the future), how to proceed in the event of changes to the study design and what the requirements for clinical trials with products that already have a CE mark are.

Annex XV of the MDR sets further requirements for the implementation, documentation and sponsors (manufacturers) of clinical trials.

In addition, the MDR reserves the right to add further requirements via common specifications (CS).

c) Medical Devices Act MPG

The fourth section of the MPG describes the implementation of the EU directives in national (German) law. This section is entitled "Clinical evaluation, performance evaluation, clinical test, performance evaluation test" and consists of the following chapters:

  • 19 Clinical evaluation, performance evaluation
  • 20 General requirements for clinical trials
  • 21 Special requirements for clinical trials
  • 22 Ethics Committee Procedure
  • 22a Approval procedure at the higher federal authority
  • 22b Withdrawal, revocation and suspension of the approval or the approving evaluation
  • 22c Changes after approval of clinical trials
  • 23 Conducting the clinical trial
  • 23a Reports of the termination or discontinuation of clinical trials
  • 23b Exceptions to clinical trials
  • 24 Performance evaluation test

The PMCF studies after admission fall under §23b MPG.

d) Ordinance on clinical testing of medical devices MPKPV

Until mid-May 2020, the implementation provisions of the "Ordinance on Clinical Testing of Medical Devices" (MPKPV) regulate the approval process, among other things.

The scope of the regulation deserves special attention:

The regulation applies to clinical trials [...] according to §§ 20 to 24 of the Medical Devices Act, the results of which are to be used for:

  1. the implementation of a conformity assessment procedure in accordance with the Medical Devices Ordinance,
  2. the implementation of a conformity assessment procedure with a medical device that is allowed to carry the CE marking in order to achieve a new purpose that goes beyond the purpose on which the CE marking is based, or
  3. the acquisition and evaluation of the manufacturer's experience with regard to the clinical safety and performance of a medical device that is allowed to carry the CE mark, provided that invasive or other stressful examinations are also carried out

This means: The MPKPV applies if the manufacturer wants to prove the safety and performance of a product that he wants to put on the market for the first time (possibly after a change) or if he wants to carry out invasive examinations with a product that is already CE-marked. The latter only applies when it comes to assessing the safety and performance of a medical device.

A research study (“other clinical testing”) to try out new MRT sequences would not fall within the scope of the MPKPV.

e) Medical Devices Implementation Act MPDG

The Medical Devices Implementation Act MPDG and the new national regulations will replace the MPG and MPKPV. It now has almost the same requirements for “research studies” (“other clinical trials”) and for “clinical trials”. The MPDG also insists on "other clinical trials":

  • Minimization of risks and burdens and their compatibility with the expected benefits
  • Qualifications of investigators
  • Insurance coverage
  • Consent of the test persons (there are special regulations)
  • Positive vote of the ethics committee (exceptions may be possible for CE-marked products)
  • Notification to the competent higher federal authority (exceptions may be possible for CE-marked products)

In the case of "other clinical trials", the MPDG requires that "the other clinical trial has been reported to the competent higher federal authority in accordance with Section 53 (1)." For the "clinical trials", it is necessary that "the competent higher federal authority has granted approval for this".

PMCF studies according to Article 74 MDR are not explicitly described and defined in the MPDG. Therefore, the requirements of the MDR are decisive.

f) NB-MED and MEDDEV documents

The EU Commission and the notified bodies have published further documents. This includes the following guidance documents from MEDDEV and NB-MED:

  • NB-MED / 2.7 / Rec1: Clinical investigations, clinical evaluation
  • MEDDEV 2.7 / 2 rev. 2: "Guidelines for Competent Authorities for making a validation / assessment of a clinical investigation application under directives 90/385 / EEC and 93/42 / EC"
  • MEDDEV 2.7 / 3 rev. 3: "Clinical investigations: serious adverse reporting under directives 90/385 / EEC and 93/42 / EC"
  • MEDDEV 2.7 / 4: "Guidelines on Clinical investigations: a guide for manufacturers and notified bodies"
  • MEDDEV 2.12 / 2: "Post Market Clinical Follow-up Studies"

The list reveals that there are currently no documents specifically designed to achieve compliance with the MDR.

g) ISO 14155

ISO 14155 gives the most precise specifications for the implementation of clinical trials. This standard bears the title "Clinical Testing of Medical Devices on Humans - Good Clinical Practice". For example, it pretends

  • how test plans are to be created,
  • how to deal with changes,
  • which documents and forms with which content are required and
  • who bears what responsibility.

h) Further regulatory requirements in the context of medical devices

Manufacturers should follow these regulations and best practices:

  • Medical Device Safety Plan Ordinance MPSV
  • Ordinance on the database-supported information system on medical devices of the German Institute for Medical Documentation and Information (DIMDIV)
  • FDA Guidances for "Good Clinical Practice"

i) Regulatory requirements for clinical trials in the context of research

If the clinical trial does not serve to prove the safety and performance in the context of the approval of a product, it counts to the "other clinical trials", which is why the requirements of the MDR apply.

The rules of “Good Clinical Practice” must also be observed, for example in clinical research. The Declaration of Helsinki must be observed in any case. In most cases, a vote must be obtained from the ethics committee.

5. Conclusion and recommendation

It is very understandable that many manufacturers shy away from subjecting their medical devices to clinical tests. The effort involved and the regulatory requirements involved are immense. It is all too easy to make mistakes here that destroy the value of the clinical trial or even have criminal consequences.

On the one hand, the MDR increases the requirements for clinical trials and, on the other hand, the number of cases in which such a clinical trial becomes necessary. This is also due to the fact that the MDR and many notified bodies only accept clinical data (e.g. from the literature) that were collected with equivalent products.

The Johner Institute therefore recommends either planning the clinical strategy early on in the development process, particularly for innovative products and implantable products and those of class III, or, in the case of own CE-marked products, to collect the missing clinical data as part of PMCF studies in order to avoid deviations and in the worst case to avoid certificate revocation.