I have been an independent medical writer for the past 18 years. I’ve noticed that, though I have been able to make a comfortable living (touch wood), there are wide variations in my income both on a monthly and on a yearly basis. Specifically, if I look back over the past 12 months, the income in my best month was about 4 times that of my worst month. On a hearly basis, over the past 12 years, in my best year I earned around twice as much as my worst year. Of course the take home message from this is that you need to have cushion in the bank to fall back on during those low periods. However, I would be interested in knowing if other people in the field have similar experiences. Just to clarify I’m not talking about my first couple of years in the field before I was established.
A Whitepaper by Charles Hurwitz, PhD, and Nancy J Stark, PhD
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
It was people at the Cochrane Library, the US Agency for Healthcare Research and Quality (AHRQ), and the National Library of Congress who first worked with the problem of how to use the existing literature to evaluate safety, efficacy, or performance of products and procedures. The Global Harmonization Task Force Study Group 5 (now defunct) published a document titled “Clinical Evaluation” in May of 2007. (You may download a copy for free from CDG’s Vintage Guidances web page.) The Active Implantibles Medical Device Directive of 1990 discussed the essential requirement of clinical evaluations in Annex 7. The Medical Device Directive of 1993 discussed the essential requirement of clinical evaluations in Annex X. But neither directive gave much information about format. Both directives were updated in March 2010 with Directive 2007/47/EC, strengthening the requirement for clinical evaluations and their content, but without much regard to format, saying only that the clinical evaluation shall be documented as a report, regularly updated, and signed appropriately. [2. Directive 2007/47/EC]
Suggested Format from MEDDEV 2.7.1 r3 (2009)
In the year or two following the 2010 revision of the Medical Device Directive many of the Notified Bodies (NB) themselves didn’t know how a clinical evaluation report should be written or what their authority was in terms of reviewing them. Any CER that bore even a vague resemblance to what was described in the Directive was deemed to be acceptable. The variety of formats that have crossed our desks has been remarkable.
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
Think of the clinical evaluation report as a three-legged stool. One leg is the literature review, a second leg is the assessment of your risk management process, and the third leg is the assessment of any clinical investigations your firm has sponsored.
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
Provide a concise physical description of the device, cross referencing to relevant sections of the manufacturer’s technical information as appropriate. The description should cover information such as:
• materials, including whether the device incorporates a medicinal substance (already on the market or new), tissues, or blood products;
• the device components, including software and accessories;
• mechanical characteristics; and
• other characteristics, such as sterile vs. non-sterile, radioactive, and the like.
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 naïve 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 essence 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
Devices are physically applied on or in the body for a reason: to treat, mitigate, cure or diagnose. You must clearly state the medical conditions (indications) and discuss the medical background for each condition. Reviewers are not experts in all fields of medicine. Your goal as the medical writer is to remove all barriers to clarity, understanding, and full information.
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
Outline the developmental context for the device. The information should include whether the device is based on a new technology, a new clinical application of an existing technology, or the result of incremental change of an existing technology. The amount of information will differ according to the history of the technology. Where a completely new technology has been developed, this section would need to give an overview of the developmental process and the points in the development cycle at which clinical data have been generated. For example, a manufacturer developed an resorbable container in which a patient’s tissue was held in place until it could take hold and grow, as opposed to being held in place with a sling of sutures. The CER included data about both the resorbable container and preparation of the patient’s tissue.
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
Outline the considerations used to choose the clinical databases for the evaluation. Usually we see publication sources such as PubMed or MAUDE, but rarely do we see a discussion of why these databases were chosen. Provide an outline of the search and retrieval process for scientific literature, including the actual key words and search strings, and cross-reference these to your standard procedure for searching and reporting the literature (you have one, of course.)
5. Summary of the clinical data and appraisal
Provide a tabulation of the clinical data used in the evaluation, categorized according to whether the data address the performance or the safety of the device in question. (Note: many individual data sets will address both safety and performance.) Within each category, order the data according to the importance of their contribution to establishing the safety and performance of the device and in relation to any specific claims about performance or safety. Additionally, provide a brief outline of the data appraisal methods used in the evaluation, including any weighting criteria, and a summary of the key results.
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
Provide a description of the how the literature analysis, or analysis of sponsor-acquired clinical data, was used to assess performance.
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.)
Describe the total experience with the device, including numbers and characteristics of patients exposed to the device; and duration of follow-up of device recipients. You might include the number of patient-days of exposure, if some patients are exposed or followed longer than others. You should explain if patients were lost to follow-up.
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
State whether the manufacturer’s proposed product literature and Instructions for Use (IFU) are consistent with the clinical data. Does the literature cover all the hazards and other clinically relevant information that may impact on the use of the device? Implanted or home use devices require special consideration, describe how patients will be educated on the care and use of their device and how they can obtain help or additional information, especially outside of business hours.
7 Conclusions [to report]
Outline clearly the conclusions reached about the safety and performance of the device from the evaluation, with respect to the intended use of the device. State whether the risks identified in the risk management documentation have been addressed by the clinical data.
For each proposed clinical indication state whether: • the clinical evidence demonstrates conformity with relevant Essential Requirements; • the performance and safety of the device as claimed have been established; and • the risks associated with the use of the device are acceptable when weighed against the benefits to the patient
A word about risk assessments
The contents and process of assessing risk is poorly discussed in the MEDDEV 2.7.1 r3 guideline. Here we discuss the process as it is usually performed at CDG. We begin with examining the Instructions for Use (IFU) and the most current Risk Assessment Report (RAR) per ISO 14971. Do the clinical data reveal any new risks not already discussed? If yes, you may need to update the RAR and IFU. [5. ISO 14971 2012]
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.
Notified Body Check List
After you’ve written the report you should check your work using the Notified Body checklist on page 35 of the MEDDEV guidance. Here you will find a thorough and detailed itemization of the points you should include in the report. If you meet all of the criteria in the checklist, a Notified Body will have little power to reject your evaluation based on format alone. [6 MEDDEV 2.7.1 r3, p 35.]
 MEDDEV 2.7.1 r3, Clinical Evaluation: A guide for manufacturers and Notified Bodies, 2009.
 Directive 2007/4/EC, Official Journal of the European Union, L 247/21.
 NBOG CL 2010-1 Checklist for audit of Notified Body’s review of Clinical Data/Clinical Evaluation.
 MEDDEV 2.7.1 r3, p32.
 ISO 14971 Application of Risk Management to Medical Devices, 2012.
 MEDDEV 2.7.1 r3, p 35.
According to MEDDEV 2.7.1 2009 any company wishing to market their medical device in Europe must submit (among other things) a Clinical Evaluation Review (CER). There is a useful guidance document available for downloading (http://ec.europa.eu/health/medical-devices/files/meddev/2_7_1rev_3_en.pdf) but the question remains is there one single correct way to write a CER with equal emphasis on all the sections mentioned in the guidance. In other words should a CER for an infusion pump that has been on the market for 10 years and has been sold in the tens of thousands of units look like a CER for a new dental implant that has not yet been marketed?
To answer this question we should look at what is going through the reviewer’s head when she is reading the CER. Besides checking off the checkboxes on the form provided to make sure that all relevant sections are included in the document, the reviewer is asking one main question: do the potential benefits provided by the device to the patient outweigh the risks?
How can the medical device manufacturer prove to the reviewer that their device is both safe and effective? This is where the main difference in approach for the two devices mentioned above enters. If I am writing a CER about a device that has an extensive history of clinical use I will emphasize that as my strong suit. I will present post-marketing data about number of complaints and adverse events per unit sold (hopefully low). In addition, in many cases there may be articles published in peer reviewed journals that deal with the device in question. In accordance with this strategy I will de-emphasize bench testing, comparison with similar devices, animal studies or cadaver studies, as ten years of data about actual real world clinical use is of much higher value. For a new dental implant, because I have no clinical data, I will emphasize bench testing and the similarity of my implant to other implants already in the market. I will then show through the literature search how safe and effective these similar devices are.
The new MEDEV directive detailing the required contents of Clinical Evaluations has been out for several years now but there still seems to be some confusion about how to implement it.
As a freelance medical writer/regulatory consultant I have written more than 50 Clinical Evaluations over the past 5 years. In addition I have revised Clinical Evaluations that clients have written themselves, submitted to a notified body and received non-conformities. I’d like to share with you the 4 top reasons that I have seen for these non-conformities:
1) Failure to describe article search procedure – You must include your search strings, where you searched and how many hits you got for each search.
2) Unqualified person wrote the document – I have seen Clinical Evaluations where the director of marketing wrote the document. I’m sure that he/she is a very good director of marketing but in most cases that does not make them qualified to provide an analysis of the scientific literature and other required content.
3) Failure to grade the articles evaluated – You must explain your grading system and use it to justify inclusion/exclusion of articles.
4) Including only a literature review – A Clinical Evaluation is much more than just a literature review. Depending on where you device is in its life cycle, you may also need to include information such as post-marketing data, bench tests, unpublished clinical studies and comparisons with similar devices.
Some of you reading the above may be thinking: “we submitted a Clinical Evaluation with some or all of these defects and no non-conformities were generated”. This can definitely be the case because there is still a certain amount of inconsistencies between notified bodies and within the notified bodies themselves as to how Clinical Evaluations are to be reviewed. However, I can definitely say that over the past several years notified bodies have become much more strict in their reviews of Clinical Evaluations.
I have worked as project manager for three different outsourcing companies and have worked a s freelancer both directly with clients and through outsourcing companies.
The first company (Let’s call it Company X) that I worked for as project manager had an interesting business model whereby they worked only with freelancers so that the only people receiving a salary were the CEO and the office manager. The company had a marketing guy (also freelance) who would generate leads and pass them on to me. I would contact the lead, make my pitch and send a proposal. If the proposal was accepted I was given 70% of the amount and Company X kept 30%. I could then either do the project myself or find a freelance writer to do the project. In any case I was responsible for the quality of the output.
If I took an experienced writer to do the project I generally would give them 60% and keep 10% for myself. If the writer was new and need more input from me it would be closer to 50% and 20%. My policy was to always tell the writers what percentage of the project they were getting and how much I was getting. I also offered to show them the proposal sent to the client so that they wouldn’t have any doubts. Interestingly no one asked to see the proposal and no one asked for a bigger percentage. In my experience one of the drawbacks to working through an outsourcing company is the feeling that you are being exploited. By being upfront with the writers we avoided this problem.
For my 10% I would review all material before it was sent to the client and resolve any problems.
Company X paid both the writer and me within 30 days of billing, regardless of if they had been paid by the client or not (as long as the client was satisfied with the work).
During the 10+ years I worked as project manager and my subsequent work as a freelance writer I gained a number of insights which I will share with you in my next entry.
I have been active in the technical writing field for more than 20 years and I have met more than a few writers who feel blocked in their career path both in terms of interest and money. One alternative that uses many of the same skill sets used in technical communication is the regulatory field.
My personal story is a good illustration of this. I was working a freelance technical writer for a start-up company that was developing a new type of imaging device to be used in the operating room. The device was quite large and complicated and required (to my delight) a several hundred page manual. In addition, for the company to survive it needed to receive regulatory approval from the FDA to market its device. Due to the novel approach of this device the approval was far from automatic. Because it was kind of difficult to get clear explanations about the system from many of the engineers (sound familiar?) I began asking the VP of regulatory affairs. He was not a native English speaker and he then asked me to go over some documents that he wrote to check the English. I asked him what each document was for and he provided me with good explanations of various aspects of the regulatory process and I spent more and more time helping him with the FDA submission. The company got the FDA approval, began marketing it device in the US and was eventually bought out by the multinational medical device company Medtronic. I leveraged my knowledge of preparation of regulatory documents to find more gigs and soon had enough experience to be able to honestly present myself as a regulatory consultant. I established my own company Carmel Scientific where I offer regulatory consulting and medical and technical writing services. The VP regulatory affairs left the company to set up his own consulting firm and I have been working with him as a subcontractor for the past 17 years.
In my next entry I’ll compare the two fields and offer advice on how to make the switch.
Before a medical device can be legally marketed in most countries it must be approved by a regulatory body. In the US, marketing approval is granted by the FDA. According to the FDA, Medical devices are classified into Class I, II, and III. Regulatory control increases from Class I to Class III. The device classification regulation defines the regulatory requirements for a general device type. Most Class I devices are exempt from Premarket Notification 510(k); most Class II devices require Premarket Notification 510(k); and most Class III devices require Premarket Approval. In the majority of cases devices are submitted via the 510(k) route.
In Europe the device must receive a CE mark before it can be marketed. The CE mark is granted by a Notified Body which grants its approval based on documents submitted and an inspection visit. As with the FDA process, devices are classified into different categories based mainly on the potential danger that they may pose to patients.
If you’d like a deeper explanation of regulatory processes there are several excellent sites on the web that describe both the European and American regulatory systems.
As a freelance technical writer you may be called upon to write a User Manual or Instructions for Use (IFU) for a medical device. As most of you are aware, there is regulatory aspect to the writing of a medical device manual. The manual must be filed together with many other documents to receive marketing approval in the US, Europe and many other countries. This series of posts will help you to work with regulatory experts in producing a regulatory-compliant manual and keeping it in compliance.
I’d like to stress that, as I wrote in the previous paragraph, the person who is ultimately responsible for ensuring that the manual is written correctly from a regulatory standpoint is the either the regulatory consultant hired by the company or the company’s in-house Regulatory Affairs Director.
The following posts will get into more specific details about how to write a regulatory compliant manual..