Medical Device Link.

REGULATION AND STANDARDS COLUMN

Beyond device risks

The European medical device Directives place significant importance on the need to identify risks related to the use of medical devices and to reduce those risks as much as possible. The Directives require that any risks that may be associated with the use of medical devices are acceptable when weighed against the benefits to the patient and compatible with a high level of protection of health and safety.

The need to evaluate risks related to the use of the devices is well understood by the sponsors of medical device clinical studies. However, risk management concepts and principles extend far beyond device-related risks. They can be applied to managing the risks associated with conducting clinical studies (Table I), which can negatively affect the outcome of those clinical studies even if the devices are shown to be safe and perform as intended by the manufacturer. A systematic and comprehensive approach to management of risks for clinical studies should cover a broad range of risks. However, this article will discuss primarily those related to European requirements.

European clinical study requirements

Table 1: Some risks associated with European clinical studies. (click image to enlarge)

Clinical studies of non-CE marked devices and studies of new uses of a CE-marked device conducted in Europe must be notified to the Competent Authority (CA) in the country where the study is to take place. The information submitted to the CA usually includes the clinical study protocol, investigator’s brochure, device risk analysis and other information depending on the requirements of the CA.

If the information supplied to the CA is inadequate or incomplete, the CA can raise questions that the sponsor may not be able to address adequately and this can lead to a delay in the start of the study. Understanding the regulatory expectations of the CA, which unfortunately differ across Europe, can reduce this risk. In addition, when questions are raised, the manner in which they are answered can have a profound effect on the success or failure of the points to be made.

A CA may question the usability of clinical study data to support CE-marking of the product studied because of a high rate of protocol deviations or other Good Clinical Practice (GCP) issues. This risk can be significantly reduced by ensuring that clinical investigators understand the importance of adhering to the clinical protocol. The requirement to follow the protocol or to seek agreement from the sponsor before deviating from the protocol should be addressed in written contracts between the sponsor and the investigator and investigation site. Investigators, even those who have active clinical research programmes, should be trained and informed of the regulatory requirements and sponsors’ expectations in this regard. This risk can be reduced further by ensuring that competent clinical monitors are used for ensuring that the study is being conducted in accordance with the study protocol and according to established GCP principles. These are described in ISO 14155, Clinical Investigation of Medical Devices for Human Subjects, Parts 1 and 2, which are the European harmonised standards for medical devices.

If Ethics Committees determine that the clinical study design is inadequate, or that there is insufficient preclinical data or poor device risk analysis, they will usually deny approval of the clinical study. Sponsors can reduce this risk by understanding and following ISO 14155 and the requirements and expectations of the specific Ethics Committee involved in the review and approval of the clinical study.

Data and the CE-marking process

Notified Bodies are responsible for conducting specific activities related to the conformity assessment procedures stated in the Directives for medical devices in the higher risk categories. These activities include the evaluation of clinical data, including clinical studies, if they have been conducted to support the CE-marking process. After completion of a clinical study, the Notified Body can raise questions regarding clinical study design, the number of patients studied, study conclusions, and other information related to clinical study data. In more serious cases, this can lead to denial of the certifications required for CE-marking. Consulting with the Notified Body before the study has been initiated to obtain concurrence on the strategy and design of the clinical study can reduce this risk.

If major changes are made in the design of the device during the clinical study, the Notified Body can raise questions regarding the applicability of study data obtained with the previous device design. Sponsors can reduce the risks associated with device design changes by understanding the possible impact these changes can have on study conclusions, understanding the regulations applied to device changes, reviewing applicable guidance documents, and developing procedures for managing these types of changes.

Sponsor-related risks

Sponsors are sometimes a source of risks associated with the conduct of clinical studies. For example, some sponsors have a poor understanding of local requirements for notification of the clinical study to the CA, or submission of study documents to the Ethics Committee and the order in which this should be done in a specific country. This lack of knowledge can lead to the submission of incomplete or inadequate information to the CA or Ethics Committees and therefore to delays in study approval and/or its start. Sponsors should ensure that they understand all applicable local requirements. This is especially important in Europe where there are differences among Member States regarding notification requirements and whether or not it is necessary to obtain approval from an Ethics Committee before notifying the study to the CA.

The failure of sponsors to adequately clarify the responsibilities and duties of investigators and other contractors such as clinical research organisations, clinical monitors or data management organisations in written agreements can lead to problems during the conduct of the study and doubts concerning the validity of the clinical study data. These agreements should be developed or reviewed by persons with the requisite knowledge and expertise to ensure that sponsors’ interests are addressed; where applicable, legal expertise should be obtained.

The requirements for insurance coverage of clinical studies for medical devices vary throughout Europe. If a sponsor fails to identify local insurance needs when planning a clinical study, critical financial problems could arise because of a failure to include insurance costs in the clinical study budget. This could lead to a delay in the start of the study. The importance of addressing this issue has been discussed in a previous article.¹

One of the most important risks associated with the conduct of a device clinical study concerns the management of adverse events occurring during the study. Unfortunately, sponsors sometimes incorrectly assume that investigators, particularly those who are well known or who have active clinical study programmes, understand regulatory reporting requirements. This is often not the case. Therefore, if investigators fail to understand adverse event reporting requirements, this could lead to the failure to properly report, evaluate or document adverse event reports. If poorly managed adverse events come to the attention of Ethics Committees or CAs, or later to Notified Bodies during an examination of clinical study records, questions could be raised on device safety. In some cases, these types of questions have led to studies being terminated. This risk can be reduced by ensuring that all involved parties, including sponsors, investigators, investigational site staff and monitors are properly trained to understand European reporting requirements.

Investigator risks

The capability of the clinical investigator to fulfil his or her duties when conducting a clinical study is a major factor in the success of the study. Significant risks are associated with this role. These include the failure of investigators to recruit enough patients at an acceptable recruitment rate, failure to follow the clinical protocol, and failure to comply with adverse event reporting requirements, as discussed previously. An investigator may not use the device in accordance with the device instructions for use, which can result in new patient risks and increased sponsor liability. An investigator may not properly complete case report forms or ensure that required clinical source documents such as specified laboratory test results are made available for monitoring visits. Some investigators have been known to initiate clinical studies before all necessary approvals have been obtained. Some investigators may have conflicts of interest with regard to the device itself or the management and monitoring of the clinical study. In rare cases, fraudulent activities can occur.

Sponsors generally conduct training of investigators on device technology and the clinical aspects of the study. However, investigators should also be trained on regulatory requirements and sponsor expectations regarding these requirements.

The agreements between the investigator and investigation site should clearly specify investigator duties and responsibilities and include criteria relating to the termination of the contract and disqualification of the site. Any conflicts of interest should be identified and properly addressed, by requiring documented disclosure or eliminating the conflict of interest so that this will not be interpreted as a factor that could invalidate the objectivity of the clinical study conduct and results.

Clinical study monitoring

Maria E. Donawa Donawa Consulting, Piazza Albania 10, I-00153 Rome, Italy, tel. +39 06 578 2665, e-mail: medonawa@donawa.com www.donawa.com

Clinical study monitors help ensure the rights and safety of human subjects involved in clinical investigations and the quality and integrity of clinical study data by conducting regular visits to investigation sites and examining clinical study records and documents. The sponsor may assume these duties or delegate them to external monitors or contract research organisations.

Important risks are associated with clinical monitoring of medical device studies. If monitors are not sufficiently experienced or knowledgeable with regard to medical device clinical studies or if they have not been adequately trained to understand these requirements, incorrect assumptions could be made concerning the information and data that they examine during monitoring visits.

If sponsors have not adequately trained monitors on the requirements of the clinical study as specified in the study protocol, monitors may not conduct acceptable reviews of the case report forms and associated source documentation. In addition, they may not recognise important problems in the conduct of the study such as the occurrence of adverse events, which have not been managed or recorded correctly.

Data management

The success of a clinical study depends on many factors, as discussed above. However, if all these factors are satisfactorily addressed, but clinical study data are not appropriately managed, sponsors incur unacceptable risks not only related to the clinical study, but also to the device project for which the study was conducted. A previous article discussed the importance of data management and a guideline developed to provide information on accepted data management practices.² Some sponsors manage clinical data within their own organisations and others contract outside organisations for data management. This critical activity should be conducted in accordance with documented procedures and established controls.

Regulatory oversight and enforcement

Adoption of the medical device European Directives introduced harmonised requirements for the regulation of medical device clinical studies conducted in Europe. However, the level of enforcement programmes for evaluating the correct conduct of clinical studies varies tremendously from country to country.

There are risks associated with the lack of uniform enforcement programmes in Europe. This is because enforcement that is properly developed and implemented can identify regulatory compliance problems related to the conduct of clinical studies and ensures that the requirements are met. For example, the United States Food and Drug Administration (FDA) maintains an active programme for inspecting Institutional Review Boards (Ethics Committees), sponsors, contract research organisations, monitors and clinical investigators. Inspection guidance documents that apply to these groups have been developed and can be obtained from FDA’s website.³ These documents not only help FDA investigators conduct inspections appropriately, but also provide useful information on compliance and FDA expectations to the parties subject to these inspections.

Similar guidance documents and an approach to enforcement of conducting device clinical studies have not been developed in Europe. The general nature of the requirements, the lack of certain guidance documents and variability of enforcement programmes in Europe necessarily entails certain risks. To reduce these risks, sponsors should take measures to ensure that they and all the parties involved in the conduct of their clinical studies understand the requirements, but also address any doubts regarding the requirements, where possible, well ahead of the start of a study.

Dr Maria E. Donawa physician, pathologist and pharmacist with 25 years’ regulatory experience, worked with the US FDA before becoming President of Donawa Consulting, an international consultancy firm, which provides clinical research, quality management system, regulatory affairs, and European Authorised Representative services to medical technology companies.