In order for a medical device to be placed on the market and put into service in Europe it must bear the CE mark. Clinical evaluation may either be a critical evaluation of the relevant scientific literature, a critical evaluation of the results of all clinical investigations made, or a combination thereof.
Clinical investigations are called for if the available data are not sufficient to demonstrate safety and performance of the device within the scope of its intended use, regardless of the class of the device.
For implantable devices and devices in class III, clinical investigations should be performed unless relying on existing data is justified. The clinical evaluation must be documented and integrated into the technical file or the design dossier, respectively, of the device.
As a consequence of amended legislation, the pressure on manufacturers to provide high-quality clinical data, increasingly from their own clinical investigations, has dramatically risen, a trend which will be further fostered when the revised standard EN ISO 14155 (2010) comes into force.
The general thrust of the involved regulatory bodies in Europe and North America is to increasingly approach a quality standard for clinical investigations of medical devices that is similar to the one used in pharmaceutical studies. Many manufacturers, especially those of medical devices in lower risk classes, are not accustomed to performing the thorough clinical investigations and have neither sufficient resources nor expertise.
For that reason, they seek the help of professional service providers and clinical contract research orgnaisations (CROs). The CROs involved in clinical research are, to a large extent, specialised in pharmaceutical drug development. It is thus important that the manufacturer ensures that a CRO contracted for medical device investigations understands this regulatory environment as well as the specifics of medical device investigations.
Regulatory environment for medical device investigations
As a rule, all clinical investigations need to be approved by Ethics Committees and notified to the competent authorities (CAs) of involved countries. Note that the responsible CA for a medical device investigation may not be the same as the CA for a pharmaceutical study. If a device is CE marked and used according to label claims, notification of the CA is usually waived. Other regulatory institutions may need to be involved in the regulatory process depending on national law.
An important difference to pharmaceutical studies is that, according to the Medical Device Directive 93/42/EEC, all serious adverse events in a medical device investigation need to be reported to the CAs of all countries in which a clinical investigation is being conducted. In contrast, in pharmaceutical studies generally only unexpected serious adverse events related to the medicinal product under investigation must be reported.
Good clinical practice
The applicable Good Clinical Practice (GCP) standard for medical device investigation is laid down in EN ISO 14155-1/2. However, these documents leave room for interpretation. Manufacturers therefore often resort to ICH-GCP, the standard for pharmaceutical development, which is not fully in accordance with the specifics of a medical device investigation.
Nevertheless, orientation to ICH-GCP, disregarding the medicine-specific aspects, may help to improve the quality of a medical device investigation. The specifics for medical device investigations are as follows.
- The objective of the clinical investigation is to demonstrate the safety and performance, in other words conformity with claims, of the medical device within the scope of the intended use. The language of the relevant US legislation (21 CFR 812) asks for the evaluation of safety and effectiveness which, in addition to conformity with label claims, includes an aspect of clinical benefit. In a pharmaceutical study the objective is to demonstrate the safety and efficacy, in other words biological activity, of the medicinal product. One consequence is that case numbers in a medical device investigation are usually lower than in pharmaceutical studies.
- Comparative studies have a different character for medical devices when compared to pharmaceuticals. In pharmaceutical studies the most robust comparator is a placebo control, which is often applied and generally required by authorities. In a medical device investigation, a placebo control is usually not feasible. For instance, it is ethically unjustifiable to run a cardiac pacemaker investigation with a control group that is only sham operated or that receives an inactive mock device. Studies comparing a medical device with standard therapy are conceivable in principle; however, there may be no standard therapy available which is similar enough to warrant comparison, especially for novel devices.
- The essential documents for a medical device investigation are similar to the ones required for a pharmaceutical study. However, the required contents may differ, such as for the clinical investigation plan, where a section on risk management is required. ICH-GCP for pharmaceutical studies has no similar requirement. The terminology may also be slightly different for similar documents.
- Adverse events, in particular adverse device effects, occurring during medical device investigations may not only concern the investigation subjects but also third parties, such as device operators. In contrast, adverse events in pharmaceutical studies are only monitored for the clinical study subjects.
- Defining source data – the essential data set to be monitored and verified in a medical device investigation – can be a challenge. Medical devices often create large amounts of data that are transmitted, processed and stored via specific software interfaces. The clinical investigation monitor in charge of verifying source data is usually not sufficiently technically competent to control these data, and if they were it would not be cost-effective to do so. Thus, for such data sets, specific monitoring rules have to be established focusing on supervising data processing rather than individual data points.
- It is not unusual for technical personnel from the sponsor to be present during device application and operation, especially when technically complex devices are involved. This situation, where sponsor representatives are in direct contact with study subjects, is unheard of and against the rules in pharmaceutical studies. The technical staff involved need to be made aware of the requirements for individual data protection and investigation subject confidentiality.
- Medical device accountability during a clinical investigation does not only involve monitoring stored and dispensed devices, but most importantly the return of all used devices to the investigative site and possibly the sponsor. This may be a challenge in the case of long-term implanted devices. Complete return is essential for the manufacturer to investigate the device, notably in the case of adverse events.
In summary, the design, conduct, monitoring and evaluation of a medical device investigation will be considerably different from a pharmaceutical study.
Evaluating, selecting and monitoring a CRO
Given the striking differences between medical device investigations and pharmaceutical studies, not just any CRO will do. When selecting a CRO for conducting a medical device investigation, it is essential to ascertain that the organisation and assigned staff have the required knowledge, expertise and experience.
Expertise in the specific medical device technology or indication may be hard to come by, but at least a general knowledge and expertise of medical device regulation and investigative principles are musts.
The above discussion of the specifics of medical device investigations may be used for querying potential candidates about their knowledge. In addition to expertise, other factors should be considered.
At this stage, a preliminary quote should be requested based on a synopsis of the investigation and a detailed list of the tasks to be covered by the CRO. It is recommended to develop a questionnaire in order to evaluate a number of longlisted CRO candidates. Price is an important factor; however, the most economic provider is not necessarily the most desirable one.
The price tag must be evaluated in view of the services and the expertise offered. Most likely there will be no ideal candidate and one can resort to pre-defined priorities to reach a decision. Such priorities can be elaborated by answering questions, such as:
- Is overall experience more relevant than specific expertise?
- Is geographic location more important than expertise?
- Is cultural literacy more important than knowledge?
- Is the qualification of the assigned staff more important than the corporate expertise?
Two or three of the evaluated candidates should be put on a shortlist and further evaluated by on-site visits and even audits.
The staff of the selected CRO must be carefully trained in the indication, the clinical investigation plan and the device characteristics. A monitoring plan including communication, reporting, quality control and source data verification procedures should be requested from the CRO and mutually agreed upon. Based on the monitoring plan the activities of the CRO will be supervised and controlled.
Clinical investigations of medical devices are distinctly different from clinical studies for pharmaceuticals. It is essential that as a manufacturer and potential investigation sponsor one is aware of these differences and the respective legal and regulatory requirements.
When outsourcing clinical investigations, a CRO in medical device development is the best possible option. If no such CRO is available, in-depth training in medical device rules and regulations, and specific instruction in the medical device in question and its use, are essential for success.
European legislation on clinical evaluation
The relevant EU legislation addressing the clinical evaluation of medical devices is the Medical Device Directive 93/42/EEC, as amended (March 2010; MDD) and the Active Implantable Medical Device Directive 90/385/EEC, as amended (March 2010; AIMD). This legislation was transposed into national law in all concerned countries.
As both directives are New Approach Directives, they depend on supporting external standards. The applicable standard for clinical investigation is EN ISO 14155-1/2 (2003). This standard is currently being updated to EN ISO 14155 (2010), but has not yet been put into force. European and US legislation explicitly require adherence to the Declaration of Helsinki, which defines the ethical principles to be respected when performing investigations on human subjects.
Further guidance on clinical evaluation of medical devices is given by the EU guidance document MEDDEV 2.7.1 Rev. 3. In addition, other legislation may be applicable to medical device investigations; for example the Low Voltage Directive 73/23/EEC for active medical devices.