In this newsletter, we want to share basic information and terms about clinical trials regarding medical devices that became a hot topic along with MDR 2017/745.
First of all, as medical device manufacturers, we ought to understand why this critical and cumbersome work is required:
Whether the potential risks of a medical device are acceptable is determined by comparing such risks with the benefits provided by the use of the device as intended. In order to make this benefit-risk analysis, clinical data of the product must be collected and evaluated in order to demonstrate the efficacy and safety of the device under evaluation.
These data are then analysed, evaluated and submitted to the notified body as a part of the technical file as evidence to show compliance to GSPR (General Safety and Performance Requirements) if it can be scientifically proven that the product provides more benefit than the risk when used as intended.
Clinical data, the importance of which increased with the MDR (2017/745 Medical Device Regulation), can be collected through:
- Published clinical studies employing an equivalent product of the medical device under evaluation in case equivalency can be proven under MDR (2017/745).
- If the medical device is a product used in the market, feedback from patients, doctors and distributors of the product itself or adverse event reports / recalls of equivalent products
- Clinical studies designed and managed under ISO 14155 and MDR of the product before market access (pre-market) or after market access(post-market)
Until now, clinical evidence in order to show the safety and performance of medical devices has mostly been collected using equivalent device(s) clinical data gathered from publicly available scientific sources.
However, since the proof of “equivalency” became more difficult with MDR (2017/745), the requirement of post-market clinical follow up has become more inevitable. The necessity for generating clinical data pertaining to the device under evaluation has increased due to the increased clinical evidence requirement for the clinical evaluation of medical devices in order to show compliance with GSPR in terms of safety and performance of the device.
Figure 1 Data used for Clinical Evidence
Clinical Research
According to “ISO 14155 – Clinical Investigation of medical devices for human subjects”, clinical research is scientific studies that measure the safety and performance of the device in question on the specified intended use and target population.
Sponsor of Clinical Research
The person, institution or organization responsible for the initiation, conduct and funding of clinical trials is referred to as the sponsor. If a clinical trial is conducted by the sponsor, it is called a “Sponsor Initiated Clinical Trial”. On the other hand, clinical studies initiated and conducted by academicians working at university for their scientific research are classified as “Investigator Initiated Clinical Trial”.
Ethical Committee and competent authority application procedures and rules are different for investigator initiated and sponsor initiated clinical trials. Even if the investigator conducting the research is an academician, if the investigator and the study are sponsored by the company that owns the investigational device, the clinical research will be considered as sponsor initiated clinical research. In such cases, the auditing of the research by an independent committee may be required to obtain consent in order to maintain the independence of the research.
Who is the manager of Clinical Research?
A clinical trial may be conducted by the sponsor's employees if they have the right team and experience. If such a team or experience does not exist, the sponsor may delegate all or some of its duties and authorities related to the clinical trial to the "Contract Research Organization", shortly referred to as the "CRO", with a written agreement. These organizations can provide services at all stages, from design and document preparation to study closure, or they can only perform certain parts of clinical research steps.
Design of Clinical Research
Clinical research involves a great responsibility as they are performed on human subjects. At all stages of a clinical study, the risk-benefit ratio should be considered. A risk-based approach is also required by MDR as well as the latest version of ISO 14155. The sponsor of the trial has a legal responsibility towards the laws and regulations of the country where the study will be performed.
Apart from these, it should be designed very well since it requires a long period, considering the use of serious human resource, examinations and materials, reaching the number of patients and the follow-up period of the researched subject. Improperly designed clinical trials will not provide sufficient and useful clinical evidence; therefore, the effort, time and financial investment spent on clinical research are wasted. Hence, your research should be carefully designed from the start.
Synopsis and Protocol of Clinical Research
There are different types of clinical research. The type of clinical trial is determined according to a number of parameters such as the previous collection of clinical data pertaining to the patients, the status of the device (in the design phase or on the market), the purpose of use, the hypothesis to be proven by the study and the targeted clinical data.
The Clinical Research Protocol (Clinical Study Plan) is a significant document that contains all the details of the study to be conducted, the purpose of the study, how it will be conducted, which methods will be used, under which conditions and according to what the patients will be included, ways to eliminate possible risks, endpoints, follow-up period and how to analyse the data collected statistically.
On the other hand, a synopsis can be considered as the summary of the protocol and does not contain much detail other than general information.
Since the purpose of a clinical trial, the criteria to be measured, the medical methods to be used, the place of use and indication of the device and the patient profile will differ for each clinical trial, a separate protocol is prepared for each and approval is obtained for each trial from the authorized institutions.
Clinical Research Steps
The basic steps of clinical research, which consists of many stages, are as follows;
- Preparation of Clinical Research Protocol
- Preparation of clinical trial documents (Case Report Form, Informed Consent Form, Monitoring Plan, Investigator's Brochure, Ethical Committee Application Form, Competent Authority Application Form, Safety Plan, etc.)
- Site selection and preparation of related clinical trial agreements with the centre and the investigator(s)
- Application to the Ethical Committee and Competent Authority of the country where the trial will be performed,
- After receiving required approvals for the clinical trial, the study team is formed in each center, and the study is started with an initiation visit where necessary information and training is given.
- Initiation of recruitment of patients for the clinical trial and completing recruitment by reaching the number and criteria specified in the protocol
- Conducting the clinical trial according to the protocol
- Monitoring and auditing of clinical trial
- Closing out the clinical trial by paying a close-out visit to the center and locking the data collected
- Preparation of the final report by analysing the data obtained from the clinical trial according to statistical methods planned within the statistical plan
- Preparation of the contents of clinical trial results for publication in scientific journals and to be used in technical file documentation such as the clinical evaluation report etc.
The center selection where the trial will be carried out is one of the important issues. Choosing centers with a large targeted patient population and experienced investigators for the treatment for which the device is used will ensure that the research is carried out more effectively, the targeted number of patients is reached within the planned timeframe and the device success data are collected accurately.
Another important issue, which actually can be considered as the most important one, is the selection of the principal investigator and investigators who are responsible for running the clinical trial. It is of outmost importance to select appropriately trained and experienced physicians having extensive knowhow about the related treatment and devices used in the treatment in order to be able to measure the performance of the device accurately. It should not be forgotten that the investigator and the clinical research team must have received "Good Clinical Practices" (GCP) training, and if they have not, they should be reminded to do so.
In order to facilitate the selection of centers and investigators to take part in clinical research, DeSia provides support by making a preliminary agreement with hospitals and scanning the possible investigators for the field.
Change in Clinical Trial
Upon approval from the ethical committee and competent authority, no changes can be made to the principles stated in the clinical trial protocol. In order to make any changes to the clinical trial protocol, the modified protocol should be submitted by notifying the authorities and reapproved if necessary. For this reason, the design phase and protocol preparation should be carried out meticulously.
Patient Relations during the Clinical Research Process
The selection of patients takes place according to the inclusion/exclusion criteria determined in the protocol, and every patient who accepts to be included in the trial should sign an "Informed Consent Form" prior to their inclusion in the trial which is extremely important in terms of regulations. Patients can only be included in the study after this form is signed. It should be noted that they have the right to withdraw their consent at any time and leave the study.
Informed Consent Forms should contain specific information prepared specifically for the study related to the protocol considering the local regulations in the local language. Therefore, the permissions received for general statements such as "I consent to the use of patient data and examinations in clinical trials" is not considered as “informed consent” for the trial. The “Informed Consent Form” should include all the necessary information from the protocol about the device to be used in the study, the study itself and the risks and benefits of the treatment etc.
When findings related to negative or undesirable effects on patients are encountered during the trial, information on these adverse events (AE) is collected and an "Adverse Event Report" is prepared. This report is submitted to the Ethics Committee and the Competent Authority at certain intervals depending on the level of seriousness and local regulations. If several unexpected serious adverse events are encountered and initial risk-benefit expectation has dramatically changed, the clinical trial can also be terminated in order not to compromise patients’ safety. Hence, it is crucial to follow the adverse events and analyse them during the course of the trial.
Clinical Trial Cost
Clinical trials are studies that can have high expenses because of the requirements of the implementation of ISO 14155, GCP, MDR and other local regulations. In addition, the costs of having experienced team members and investigators as well as required devices, interventions, tests, examinations and equipment, and the costs of different institutions such as CROs, certification bodies, and insurance companies add up very quickly.
In some cases (pre-market studies, interventional clinical trials, etc.), it may be stipulated that patients are covered by private health insurance. In such cases, we provide services from our existing business partners to create clinical trial insurance.
Completion of the Clinical Trial
The collected data are compiled and analysed within the framework of statistical models defined in the statistical plan. Based on this analysis, the Final Clinical Research Report is prepared.
Investigators, due to their academic careers, and sponsors, due to both CE certification requirements and the increasing importance of evidence-based data, generally request presentations on the research topic and results in order to increase awareness of their products by taking place in congresses and scientific literature. As in all steps, DeSia also provides services in preparing the result and writing scientific publications.
Terms
Clinical trials can be divided into 2 groups according to the time of patient recruitment:
- Retrospective Studies: These studies are based on retrospective data collection. In order to carry out such a study, the data pertaining to patients who have already been treated with the investigational device in question prior to the study initiation in the centers should be available in accordance with the intended study.
- Prospective Studies: Patient data are collected prospectively. Patients are included in the study and treated with the device in question after all approvals and consents are received.
Prospective studies can be divided into two main groups as "Observational" and "Interventional".
- a) Observational: In observational clinical studies, researchers follow human subjects within an investigation plan/protocol.
Patients can receive interventional therapy that includes a medical device as routine therapy, but researchers cannot use any specific interventional therapy and/or examination other than those included in routine procedure. The study should be based on the approved indication of the product.
The product should be used routinely.
- b) Interventional: In interventional clinical studies, researchers follow patients within an investigation plan/protocol.
While the patients are undergoing an interventional treatment in which the medical device will be used, the investigator may perform non-routine testing, imaging and surgery to answer specific questions (e.g. particular patient population: children, the elderly, diabetics, etc.)
An existing device can be compared with a new device, two different treatment methods can be compared, and specific questions can be answered with different interventions/imaging.
Randomized: When the clinical trial is designed as randomized, patients recruited for the study are randomly distributed to different groups (2 or more) for comparison. Such studies are highly scientific and carry very little bias, especially if randomization and the study are appropriately designed. Randomized controlled trials are considered the “gold standard” in clinical research.
While post-market studies can be designed both prospectively and retrospectively, since medical devices that have not yet received CE certificates are pre-market, their clinical studies cannot be retrospective. Pre-market studies can only be designed as interventional prospective studies. For this reason, the Ethical Committee and Competent Authority approvals of pre-market products may take more time than in post-market studies as they would be investigated by the authorities more closely and in a more detailed manner in order to make sure the device or the treatment does not create more risks than benefits to the patients.
Prospective Post-Market: Trial approval is rather easier to obtain than pre-market studies (to verify the approved purpose of use and safety from the manufacturer). Particularly for non-interventional observational studies, the approval process is much simpler and, in many countries, the reimbursement of treatment is done as in routine use.
Principal Investigator: S/he is the lead investigator of the study responsible for managing the clinical trial (at all centers where the study is conducted). If the clinical trial is conducted in more than one center, there are investigators at each center other than the principal investigator. The investigator(s) in each center is responsible for their own center and conducts the study in coordination with the principal investigator.
Each hospital where the clinical research is carried out is called a clinical trial site or center.
Patients included in the study are called subjects according to ISO 14155, and before being included in the study, they must sign an "Informed Consent Form" (ICF) indicating that they agree to participate in the study and they are fully aware of all the procedures, requirements, risk and benefits of the treatment and the device. In cases where the number of patients to be included according to the clinical trial protocol is high, more than one center can be selected as a trial site in order to include patients in the trial within a reasonable time frame. This should be planned and stated in the clinical trial protocol.
Endpoints: These are the performance and/or safety criteria that are intended to measure /evaluate the device in question with the clinical trial. They must be specified and defined in the clinical trial protocol. They are determined according to the intended use of the device and the expected benefit-risk as well as the expected performance measurement of the device related to its clinical claims. Accurate determination of endpoints is important for the relevance of clinical data collected at the end of the clinical study for the device.
Statistical Studies / Statistical Plan: These are studies that ensure the determination of the number of patients to be included in the clinical trial in order to be able to collect and reach statistically meaningful results, the formation of statistical hypotheses about the desired result, the methods and models through which the obtained data will be interpreted, and the scientific evaluation of the results. All this information about patient number calculation as well as the plan regarding how to analyse the collected data is given in the statistical plan of the trial.
Good Clinical Practices: It is an ethical and scientific quality standard for designing, conducting, collecting and reporting of clinical trials on humans’ subjects. It provides reassurance to the patients that their rights, health and privacy are protected and that the data obtained from the research is reliable.
ISO 14155: 2020 Clinical investigation of medical devices for human subjects: It is the ISO standard to be followed when designing and conducting a clinical trial with medical devices.
