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Formatting Clinical Evaluation Reports
©2015 Clinical Device Group Inc, all rights reserved.
A number of clients have commented to me this year that Notified Bodies are rejecting their Clinical Evaluation Reports for nonconformance to the formatting rules of MEDDEV 2.7.1 r3. Some companies are undertaking complete rewrites of their existing clinical evaluations, so concerned are they that the reports will be rejected at the next review cycle. The EU intends to change the formatting rules, however my European colleagues inform me the 2009 version of the guideline is still firmly in effect and that changes are likely to come slowly. In this whitepaper we'll review the format suggested by MEDDEV 2.7.1 r3 and look at some common formatting errors. [1. MEDDEV 2.7.1 rev 3]
A Muddled History
Suggested Format from MEDDEV 2.7.1 r3 (2009)
However as time has passed the NBs have better understood their role in the evaluation process. They have formed their own professional society, the Notified Body Operations Group (NBOG), and have issued best practice guides for their members. With the issuance of a checklist for an audit of a Notified Body's review process, NBs are being held accountable for their decisions and are refusing to accept reports that do not correspond strictly to the MEDDEV 2.7.1 r3 guideline. [3. NBOG CL 2010-1]
Appendix E of the MEDDEV guideline is "a possible" format for a clinical evaluation report. This is the format you are expected to follow for compliance. Reviewers work with a checklist at the back of the guideline when reviewing a CER and if a section or item is missing you may get a nonconformity, costing extra weeks of review time and lost sales opportunities. What follows is a review of the recommended format for a CER. [4. MEDDEV 2.7.1 r3 p32]
1. General Details—A Three-Legged Stool
The three "legs" are brought together as attachments to a finalized report, the "seat" of the stool. In the opening paragraphs of the seat you must take care to identify exactly what device(s) are covered by the report; identifying the devices by proprietary name, any code names assigned during device development (one company used the code name "Kermit" because they intended to leap over the competition,) and the manufacturer(s) of the device.
Your firm should assign (or outsource) a medical writer who will act as project manager for preparing the report, have authority to obtain and inspect all necessary records and reports, and have authority to work with external services as needed. In our experience as consultants, it takes about 140 hours of labor over a three month duration to write a clinical evaluation.
2. Description of the device and its intended application in or on the body
• materials, including whether the device incorporates a medicinal substance (already on the market or new), tissues, or blood products;
You should think like the sales department of a successful department store: "there shall be no barriers to customer buying." In a CER case, there should be no barriers to the Notified Body quickly understanding your technology. Anticipate the questions a naive reviewer will have and address the questions in the seat of the report. It's useful to include diagrams, drawings, photographs, comparative tables, lists of animal safety testing, text boxes, and the like. These tools help the reviewer to grasp the essense of your technology without doing a lot of independent research.
Don't forget to state the intended application of the device – single use or reusable; invasive or non invasive; implantable or not; duration of use or contact with the body; organs, tissues or body fluids contacted by the device; is the device used in the home – and describe how the device achieves its intended purposes.
Sometimes clients forget about the processing aids or biological substances used during the manufacturing process. Metal parts are routinely washed with solvents to remove oily residues, biological products may have their origin from unidentified sources of tissue (fish from the sea.) Sometimes the final processing takes place in the physician's office or lab. You should be able to demonstrate the absence of any inadvertent residue, or that any such residue does not interfere with safety or performance.
3. Intended therapeutic and/or diagnostic indications and claims
You then identify the target treatment groups and diseases for the medical conditions. Who are the patient groups that will be exposed to the device? Let's say the medical condition is pregnancy. The likely patient group is young, healthy women with no concomitant illnesses or genetic variants.
What are the diseases or disease subgroups for the medical conditions? Again, suppose the medical condition is pregnancy. You may be targeting pregnant women with diabetes, preeclampsia, or other issues. Finally, list the specific safety or performance claims (intended uses) you will make for the device and defend them.
You will have some strategic issues to deal with along the way. For example, do you want to mix device indications and, say, cosmetic indications in the same clinical evaluation? Or is it a smarter to submit an evaluation for medical use today and amend it for cosmetic use in the future?
4. Context of the evaluation
For a long standing technology, a shorter description of the history of the technology (with appropriate references) could be used. For example, the CER for a new wound dressing would not need to trace the history of wound dressings all the way back to the Romans.
Clearly state if the clinical data used in the evaluation are for an equivalent device. Identify the equivalent device(s) and provide a justification of the equivalency, cross-referenced to the relevant non-clinical documentation that supports the claim. Not to be confused with substantial equivalence, MEDDEV 2.7.1 r3 equivalence (page 42) means, "1) Clinically: used for the same clinical condition or purpose, at the same site in the body, in similar population (including age, anatomy, physiology); have similar relevant critical performance according to expected clinical effect for specific intended use, 2) Technically: used under similar conditions of use; have similar specifications and properties e.g. tensile strength, viscosity, surface characteristics; be of similar design; use similar deployment methods (if relevant); have similar principles of operation, 3) Biologically: use same materials in contact with the same human tissues or body fluids."
State the Essential Requirements relevant to the device in question. In particular, describe any special design features that pose performance or safety concerns, e.g. the presence of medicinal, human or animal components. These features should be identified in the device risk management documentation as requiring assessment from a clinical perspective.
Sources of data
5. Summary of the clinical data and appraisal
Include full citations for literature-based data and the titles and investigation codes (if relevant) of any clinical investigation reports. At CDG, we begin an independent Excel spreadsheet as soon as we start reviewing abstracts. The spreadsheet lists the complete title and citation for the abstract, and a justification if the full article is not reviewed further. The spreadsheet is provided as an attachment to the CER.
Cross-reference the entry for each item of data to its location in the manufacturer’s technical documentation.
6. Data analysis
Identify the datasets that are considered to be the most important in contributing to the demonstration of the overall performance of the device and, where useful, particular performance characteristics. Outline why they are considered to be “pivotal” datasets and how they demonstrate the performance of the device collectively (e.g. consistency of results, statistical significance, clinically significance of effects.)
Provide a summary of device-related adverse effects, paying particular attention to serious adverse device effects.
Provide specific comment on whether the safety characteristics and intended purpose of the device require training of the end-user.
6.3 Product literature and instructions for use
For each proposed clinical indication state whether:
A word about risk assessments
Preparing a spreadsheet listing the clinical benefits and risks is a good strategy for grasping their scope. Describe the nature of each benefit and risk in a column and the anticipated outcome in the next column. Indicate the anticipated frequency of occurrence of each benefit and risk in column three. In column four, identify type of adverse effect likely to occur. Next, indicate if the risk would result in a mild, moderate, or severe adverse effect; for example, a headache rarely meets the criteria of serious, yet it could be severe. Sometimes we indicate if the risk is associated with the procedure or the device itself. Finally, indicate how the risks have been mitigated. We are trying to gather together as much information as possible to understand the overall risk of the device.
Subjectively, we then compare the benefits and risks to determine if one outweighs the other. A number of factors may come into consideration. For example, let's say that two patients suffer from spondylolisthesis, a defect in the spine which causes vertebra to slip to one side of the body. Let's also assume that one patient is in her thirties and the other in her seventies. Knowing that it takes a year to recover from corrective surgery, spinal fusion may make sense for the younger patient for whom pain management over fifty years of remaining life is unreasonable. Spinal fusion may not make sense in the older patient, whose life expectancy is ten more years, and who does not want to spend 10% of their remaining lifetime recovering from surgery.
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