The Changing Landscape of European Medical Device Regulations
Patrick D. Mize, Ph.D.
Contact Dr. Mize http://goo.gl/PV31NZ
Advisor: Product Development / Regulatory Services
The Clinical Evaluation Report [CER]
The CER, which is included in your Technical File or Design Dossier, is required when bringing a medical device to market and helps demonstrate that the device achieves the intended purposes while minimizing any anticipated risks and foreseeable adverse events and conforms to the relevant Essential Requirements of the Medical Directives. The CER summarizes design characteristics, risk evaluation and mitigation, performance and pre-clinical testing of the device, literature reviews / references, clinical trial results, internal CAPA information and post-launch surveillance data. This compilation provides objective evidence that the device conforms to the relevant Medical Device Directive both at launch and during post-market clinical follow up.
Clinical evaluation is the assessment and analysis of pre-clinical and clinical data needed to verify the clinical safety and performance of a medical device. A Clinical Evaluation Report (CER) outlines the scope and context of the clinical evaluation of your device and includes these parts:
- Overview, scope, plan, essential design characteristics
- Risk assessment and mitigation
- Literature review and report
- Pre-clinical and performance studies
- Clinical data
- Appraisal and analysis stages of the evaluation
- Post-marketing surveillance and CAPA reviews
- Conclusions about device safety and performance
Clinical evaluation is an ongoing process that is first conducted during the conformity assessment process leading to initial EC labeling and marketing and is repeated periodically during the life cycle of the device. Post Market Surveillance [PMS] continues throughout the time the device is marketed and beyond for implantable devices. These surveillance programs monitor ongoing performance and safety. PMS can include adverse event reports, results from published literature on the device, clinical investigations, and formal post-marketing surveillance, including Post-Market Clinical Follow-Up Studies. This continued evaluation is essential for identifying further risks that occur with use of the device and, if necessary, may result in design or labeling changes.
Plan and Essential Design Characteristics
In my experience, the overall plan, design of the device, and determination of the essential design characteristics or “critical attributes” are crucial for the successful development of the device. Clearly defining the design characteristics and critical attributes related to the intended use and users allows the team to focus on the risks of the design and performance necessary for the desired clinical efficacy. Development and validation needs can then be assessed and a pathway (plan) for development can be finalized. A full knowledge of the regulatory hurdles necessary for approval is essential at this step. Many of the Essential Requirements have ISO standards or standards from other organizations which both dictate and guide the manufacturer in the necessary design and testing of the medical device.
Risk assessment and mitigation
ISO 14971 is the risk management standard for medical devices. Its purpose is to help manufacturers establish a medical device risk management process they can use to identify hazards, to estimate and evaluate risks, and to develop, implement, and monitor the effectiveness of risk control measures.
The CER should reference or contain the Risk Management Report. Risk management is the systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating and controlling risk. Risk evaluation and mitigation differentiates most critical product features related to safety or harm, quantifies and determines the acceptability of risk, and provides focus and priority for product development and life cycle activities.
Risk management is required in the development process and should continue during the full life cycle for marketed medical devices in the EU.
The risk management process defines:
- a hazard as a potential source of harm
- harm as physical injury or damage to the health of people, or damage to property or the environment
- a risk as a combination of the probability of occurrence of harm and the severity of that harm
- severity as a measure of the possible consequences of a hazard
Risk mitigation occurs through modification of the design and procedures for use of the medical device in the intended population. Any residual risk, risk remaining after risk control measures have been taken must be acceptable when weighed against the clinical benefit in the intended use population. Identified risks should be evaluated and quantified during pre-clinical, validation and clinical studies to determine if the identified hazard has been mitigated through design and procedural modifications.
Literature Review and Report
A literature review should include investigations published on other similar devices and characteristics of the intended use population. The literature review for established devices investigates, in a systematic and thorough manner, the clinical literature and includes clinical outcomes and adverse event data. The CER may serve as the primary source of clinical evidence to support commercialization and may justify no new clinical investigations.
The literature review should not only cover your device and comparable devices but also alternative treatments for the intended use. For example, the literature review for a new device to treat atrial fibrillation would include any published pre-clinical or clinical studies of the new device, published clinical studies of similar devices used for the same intended use, and medical / drug treatments for atrial fibrillation. The true safety and effectiveness of the new treatment can then be compared to all alternatives.
The literature review is composed of the following parts:
The Review Plan:
- Identifies the purpose and scope of the review;
- Includes the intended use of the medical device and its classification;
- Defines a search strategy [terms to include, other comparator medical devices, and the approach to captures the safety and efficacy of current clinical treatment];
- Defines search restriction and limitations; years included and excluded, number of articles, type of article (pre-clinical studies, clinical trials, meta-analysis of trials, reviews, etc.), and a rationale for each;
- Identifies the sources to use to identify useful citations [e.g., Medline, EMBASE, Google, Cochrane Clinical Reviews, etc.12].
Although Medline includes over 19 million citations, there are about 2000 global medical journals that aren’t included. EMBASE gives access to MedLine citations and to the other 2000 journals that Medline doesn’t abstract. EMBASE is required for a literature review compliant with the Directives.
- Gather and list articles selected from initial literature search
- Read the articles, excluded articles about the same study, state the reason for exclusion in the table
- Read the remaining articles again and exclude the articles that are redundant or irrelevant or unusable for other reasons, state the reason for exclusion in the table
- Weight each article according to relevant criteria
- Same or similar device: Actual device, Similar Device, Other device
- Indication: Same indication, Minor difference, Major difference
- Subject population: Same population, Similar population, Different population
- Compile the data with regard to the study design, number of patients, success or failure of device, adverse events, etc.
- Recommend that safety and performance data be put into tables for ease of comparison
- Data Analysis
- Conclusions based on purpose and scope of the literature review and intended use of the reviewed medical device
- Although Medline includes over 19 million citations, there are about 2000 global medical journals that aren’t included. EMBASE gives access to MedLine citations and to the other 2000 journals that Medline doesn’t abstract. EMBASE is required for a literature review compliant with the Directives.