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An Engineer Takes on CE Marks and European Commercialization

Medical device companies have one primary goal: to develop, manufacture and market a medical device that addresses an unmet market need. While it’s a common goal, the medical device regulatory approval process can be confusing for design and development engineers. They may hear terms such as “safety agency,” “CE mark,” “Notified body,” “510K” and “PMA” tossed around by quality and regulatory professionals. Although these terms are likely somewhat familiar, their true meanings and proper application are not always clear to many of us who are part of the development process. 

To commercialize any medical device, the appropriate regulatory process must be followed. This process varies depending on the country where the device is intended to be marketed and sold. So, how do medical device companies obtain approval of their products in Europe, in the US, and in other countries around the world? This three-part series will address what engineers need to know from a design and development standpoint. 

The first installment of this series will provide details about the CE Mark process in Europe.

CE Mark, Commercialization of Medical Devices in Europe

To sell a medical device on the European market, it must first be CE-marked. A CE mark on a medical device means that the product meets the essential requirements designated in Annex I of the Medical Device Directive (MDD) 93/42/CE. The MDD is a European Regulation which is intended to harmonize the laws within the European Union which pertain to medical devices.

CE Mark – Device Classification

One of the first steps in the European regulatory process is to determine the appropriate classification of the device. The MDD classifies devices into four categories based on the amount of risk associated with the device : I, IIa, IIb, and III. These categories and some device examples are described in Table I.

Risk Level Device Examples
1 Low Cervical collars, hospital beds, wheelchairs, stethoscopes, wound dressings.
IIa Low-medium Hearing aids, diagnostic ultrasound equipment, electrocardiographs, infusion pump tubing, dental bridges and crowns.
IIb Medium-high Tracheal cannulae, long term corrective contact lenses, peripheral vascular catheters, high-frequency electrosurgical generators, most therapeutic/surgical ultrasound equipment.
III High Cardiovascular catheters, neuro-endoscopes, absorbable sutures, left ventricular assisting devices (LVADs), drug eluting stents (coronary or pulmonary).

There are several characteristics described in the MDD that determine device classification, including:

  • Duration of patient contact, either transient (<60 minutes); continuous (>60 minutes, <30 days); or long term (>30 days).
  • Degree of invasiveness, including noninvasive, invasive through a body orifice, surgically invasive,
  • Operative mode of action, either passive or active. In active mode the deivce depends on a source of electrical energy or other power besides gravity or the human body)
  • Effect on body, such as local (limited to area where the device is applied) or systemic, for which the effects of the device may be outside the area of application (e.g., via the circulatory or central nervous system).

Essential Elements, Regardless of Classification

Regardless of device classification, all medical device manufacturers must prepare the specific elements to submit to the regulatory body.

CE Technical File. A Technical File provides the summarized technical information about the device. If the device is Class III, the Technical File is called a Design Dossier. Some of the elements included in a CE Technical File or Design Dossier may include: risk analysis, design input specifications, design verification test results, biocompatibility test results, instructions for use, packaging and labeling documentation, and clinical data. The higher the device classification, the more substantive the information provided is required to be. A Design Dossier for a Class III device such as a cardiovascular catheter, for example, will generally include a significant amount of supporting clinical data, whereas the Technical File for a Class I or Class IIa device such as a wheelchair or a hearing aid may not include any clinical data.

Essential Requirements. The manufacturer must provide evidence that the device meets the essential requirements which are defined in Annex I of the MDD. Often this evidence consists of a line-by-line checklist of the requirements and an explanation of which requirements are applicable and not applicable to the device. For the applicable requirements, references are made to supporting quality system and device documentation such as SOPs, risk analysis, design specifications, and/or design verification test results (often to a European harmonized standard) which demonstrate compliance.

EC Declaration of Conformity. The manufacturer provides an EC Declaration of Conformity ensuring that the product meets the applicable provisions of the MDD.

Competent Authority Notification. When placing a device on the market, manufacturers must notify the Competent Authority of the country in which their business is registered and provide a description of the device. For medical devices of classes IIa, IIb, and III, a Competent Authority may request additional data such as labeling and instructions for use.

Post-Market Surveillance. Manufacturers must record, evaluate, and notify the surveillance authority of incidents as required per the MDD. They must review experience gained from marketed devices in the field and implement any necessary corrective action.

CE Mark – Regulatory Process

Once a device has been classified in accordance with the MDD, the regulatory strategy can be planned. The higher-risk the device, the more rigourous the regulatory process will be. The MDD allows for several different regulatory approval paths for each device classification. Table II describes some commonly used regulatory approaches for obtaining a CE mark.

Device Classification Risk level General regulatory process
I—nonsterile Low •    Technical File (self-certification; does not require review by a Notified Body) +
•    EC Declaration of Conformity
I—sterile or measuring function Low •    Technical File +
•    EC Declaration of Conformity +
•    Quality Management System compliant with ISO 13485 (or similar) +
•    Conformity assessment of Technical File & Quality System audit by Notified Body
IIa Low-medium
IIb Medium-high
III HIgh •    Design Dossier +
•    EC Declaration of Conformity +
•    Quality Management System compliant with ISO 13485 (or similar) +
•    Conformity assessment of Design Dossier & Quality System audit by Notified Body +
•    Notified Body exam/test/audit of product

Notified Bodies and Competent Authorities. A “Notified Body” is a private or public organization that has been accredited by an EU Member State to validate the compliance of a medical device to the MDD. A medical device manufacturer must select a Notified Body to act as an independent third party in the CE Marking process. Many Notified Bodies also provide quality management system certification to ISO 13485, as well as certified product testing, such as testing to the IEC 60601-1 medical device safety standard. Thus, it is possible for a device manufacturer to utilize a Notified Body to assess and provide validation of much of the commonly provided elements which are required for device CE marking.

One common criticism of the European device approval process is that, because fees are assessed by Notified Bodies for many of its services, a Notified Body does not always fully act as an independent party.

A “Competent Authority” is a body which can act on behalf of the government of the Member State to ensure that requirements in the MDD are applied. It also appoints and supervises Notified Bodies, conducts surveillance of medical devices in its Member State, and evaluates adverse incidents related to medical devices.


While navigating the medical device regulatory process is never an easy task—particularly for a non-regulatory expert—this quick-reference should enable you to better understand how your designs and resulting documentation are being reviewed during each step of the process.

More from this series:

An Engineer Takes on FDA Clearance and Approval Processes

An Engineer Takes on Global Regulator Processes: Asia, Latin America, and More

Karen Brentnall is senior quality engineer at Stratos Product Development. She has 16 years in product development and quality engineering, during which she developed expertise in class II and III medical device product development. Prior to joining the quality and regulatory world, she worked for eight years as a mechanical design engineer. She has played an active role in the design, development and manufacture of numerous medical devices including the SuperSonic Imagine Aixplorer diagnostic ultrasound system, the Boston Scientific Rotablator rotational artherectomy system, several therapeutic catheter devices and LVADs, and a hemodialysis machine. Her expertise includes development and maintenance of documentation to support medical device regulatory submissions, including risk management, quality planning and verification. Her capabilities also include implementation and maintenance of quality management systems per the FDA medical QSRs and ISO 13485.

Weekly Vitals: St. Jude Medical Gets FDA Surprise, More Backlash

Bad press has plagued St. Jude Medical's ICD leads since the Riata recall in December and the company is now riding out the latest wave. During the past week, the company received a surprising order from FDA to conduct studies on the recalled Riata as well as the non-recalled Durata and other leads. Then, it was dealt another public blow upon the release of a study questioning the safety of its Durata lead, which St. Jude has fervently been promoting to deflect the bad press stemming from the Riata. Read about St. Jude's latest PR headaches and other top stories of the week in our roundup below.

Medical Device Recalls Hit 2-Year High in Q2 2012

The number of medical device products affected by recalls hit an eight-quarter high in the second quarter of 2012, exceeding 100 million units for the first time in nearly two years.

Though the 242 medical device recalls reported last quarter were down more than more than 12% from the previous quarter, 50% more units were affected, according to Stericylce ExpertRECALL (Indianapolis), a company that offers recall services to medical device manufacturers.

Perhaps most striking is the fact that of the 140 medical device companies affected by recalls in the 90-day period, one-third faced multiple recalls.

It’s a reminder that recalls can happen to any company—especially as more and more medical device manufacturers turn to outsourcing, says Mike Rozembajgier, president of recalls for ExpertRECALL.

“I think that the increase in outsourcing increases the complexity of the supply chain, and only adds to the complexity of putting appropriate quality systems in place,” Rozembajgier says.

In all, 123.5 million units were affected by recalls in the second quarter of this year. Year over year, the number of recalls rose 4% and the number of units affected increased eight fold.

Of all second-quarter recalls, three affected more than 10 million units. Class I recalls, for dangerous or defective products that could result in serious health problems or death, increased to 7% of all recalls, from 4% the previous quarter. Two-thirds of the medical device recalls in the second quarter affected customers in the United States and at least one other country.

For device makers, Rozembajgier emphasizes the importance of having recall plans in place in advance. Thanks to social media, the public is more aware of recalls than it was 20 or 30 years ago, he says, so how companies handle recalls can have a big impact on their reputations. And regulators are likely to keep a closer eye on the industry going forward.

“We can count on FDA to increase the scrutiny on the medical device industry,” Rozembajgier says.

Jamie Hartford is the associate editor of MD+DI. Follow her on Twitter @readMED.

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Cardiologist Proves to be Thorn in St. Jude’s Side for ICD Leads

Noted cardiologist Robert Hauser can't seem to stop giving St. Jude Medical palpitations. The embattled medical device manufacturer has spent the majority of 2012 in damage-control mode as it publicly dealt with the fallout from the recall of its Riata implantable cardioverter-defibrillator (ICD)  leads, the subsequent skepticism cast on its Durata leads, and the recent blow from FDA ordering the company to conduct studies on the Riata, Durata, and other leads. Yet despite the steady stream of bad luck and controversy, it appears that Hauser's outspoken criticism of St. Jude's ICD leads is at the heart of St. Jude's most significant PR woes, and it's starting to raise some eyebrows.

Since the recall landed St. Jude's faulty lead under the microscope, Hauser, a researcher and cardiologist at the Minneapolis Heart Institute, has led the charge against the medical device maker's Riata product while fueling fears about some of the company's related products, notably the newer Durata lead. In February, for instance, Hauser penned a perspective piece for the New England Journal of Medicine that held the Riata up as a representation of flaws in postmarket surveillance.

And so began a contentious relationship between the two that has endured throughout 2012. But the highlight of this war of words--or lowlight, depending on your view--occurred in a rapid-fire series of events stemming from a damaging study by Hauser published by Heart Rhythm titled, "Deaths Caused by the Failure of Riata and Riata ST Implantable Cardioverter-Defibillator Leads." Upon publication of the study, St. Jude demanded a retraction of the manuscript and strongly criticized the cardiologist's methods and findings; the request was denied. The company continued to publicly and aggressively question Hauser's study, which ultimately led to widespread criticism of St. Jude's handling of the whole situation.

In the wake of what the New York Times dubbed a scorched-earth defense,' St. Jude laid relatively low, staying out of the spotlight while striving to preserve and protect the reputation of its Durata lead.

But the Hauser-St. Jude feud resurfaced this past week. On the heels of FDA's surprising edict ordering St. Jude to conduct studies on several of its leads, including the Riata and the Durata, and recommending that Riata patients receive x-rays, the company saw its stock slide by 4%. Adding to this new wave of bad press, Hauser and his colleagues released a new study in the journal EP Europace that questioned the safety of the company's prized Durata lead.

Using data collected from the MAUDE database, Hauser and his colleagues claimed that Optim, a silicone-polyurethane copolymer that coats the company's Durata lead as well as the Riata ST lead, did not prevent lead abrasions as intended or promoted. In "Failure of a novel silicone-polyurethane copolymer (Optim) to prevent implantable cardioverter-defibrillator lead insulation abrasions," the researchers conclude: "Riata ST Optim and Durata ICD leads have failed due to insulation abrasions. Optim did not prevent these abrasions, which developed less than or equal to four years after implant. Studies are needed to determine the incidence of these failures and their clinical implications." The problems identified were not the same issues encountered with the recalled Riata lead, however.

Hauser has been actively making the rounds to promote his study during the past week, speaking with a number of media outlets and opining about St. Jude's leads. "How good is this Optim insulation, which St. Jude said protects against outside-in abrasions?" he said, according to the Minneapolis Star Tribune. "It turns out, there are a lot of abrasions." Hauser additionally told the New York Times, "There is no need to use this lead until we have more confidence in its performance." He also announced plans for a multicenter study to further investigate the rate of abrasion in Optim-coated leads.

A reputable researcher in the field and respected cardiologist, Hauser is likely pursuing the investigation with the best interest of patients in mind and with sound methodologies. But this whole situation is beginning to seem a bit...personal.

"You mean to say they don't love me? " MedCity News reported that Hauser joked when asked about the situation, adding that the company didn't send him a valentine this year. "I really don't care. That's not why I do this."

And it's true that he shouldn't pull any punches when examining legitimate safety issues and exposing defects or flaws that put patients at risk. But his media exposure, tone of some public comments, and strong focus specifically on St. Jude's products comes off as a bit biased against the company, regardless of whether there is any or not.

Back in April at the height of the Heart Rhythm brouhaha between St. Jude, Hauser, and Medtronic, for example, we took a reader poll on which party's public image was suffering the most. The majority vote of 44% indicated that all three parties, including Hauser, weren't doing themselves any favors in the public court of opinion. And in June, I received an interesting email from a former defibrillator lead designer that speculated that Hauser, former president of CPI, could hold a grudge against the former competitor or may simply enjoy publishing articles and getting media attention. While these assessments are purely opinion based and not grounded in any fact, the truth remains that this contentious interaction between Hauser and St. Jude is beginning to raise eyebrows. And that's not a good sign.

It will be interesting to see how this latest round of research and accusations plays out between the two. But in the meantime, I'll leave you with an interesting point brought up by the reader from whom I received the Hauser email in June. "We said years ago that the reliability [in ICDs] is as good as it will ever be and will only go down from here, and we were right," he wrote. "The most interesting question to ask is: How good is good enough and how bad is still ok? This seems like a simple question, but it has deep ramifications for design, build, and use of defib leads, and is a very difficult question to answer. It involves technical risk, business risk, and reputation risk, and is very difficult to wrap your arms around. Of course, at some point the FDA and the legal system gets involved, but often too little and way too late." --Shana Leonard

President of Ireland Delivers Scathing Critique of US Healthcare System, Tea Party

A two-year old debate between Irish President Michael D. Higgins and conservative broadcaster Michael Graham has found a new lease on life on the Internet and is approaching 500,000 views on YouTube. Give it a listen, and you will understand why: Higgins' passionate oratory is irresistible, regardless of where you stand on the Affordable Care Act.

"A social floor below which people would not fall, that is the future," he proclaims. "Even the poorest people in the great country that is the United States should be entitled to basic healthcare."

Higgins spent some time in the United States in the 1960s as a professor, and he has some trenchant observations on the notion that people working two or three jobs should lack healthcare coverage, while an elite enjoys the best medical care in the world.

Spend four minutes in the company of this masterful, passionate orator.


Ortho Implants: Replacing Polyethylene on Metal with Diamond on DiamondGiven the aging population, hip and knee implantations are expected to grow by 700%, according to Vohra. Approximately 20 to 50% of Baby Boomers are getting joint replacements. To meet this growing need, the UAB researchers hope that existing orthopedic implants, such as those based on zirconium or polyethylene on cobalt-chromium, will be replaced with diamond-on-diamond implants displaying improved wear and longevity characteristics.For more information on this technology, click on the 'Next Photo' button above to view the next slide.

Unbeknown to many, Alabama’s largest city is an important hub for a variety of medtech-related companies, university research efforts, incubator activities, and government research expenditures. Among Birmingham’s seven key economic sectors, high-tech jobs, specifically those in the biological and medical technology fields, are targeted for expansion under Blueprint Birmingham, the Birmingham Business Alliance’s strategic plan for the region.

Here's the full story.

What's in a Medical Device's Name? For Patients, a Lot

Patients with chronic diseases spend a lot of time with their medical devices. Those with type I diabetes, for example, are tethered to their insulin pumps day and night. All that time together results in a close relationship between patients and their devices.

I got an idea of just how close those ties can be when I stumbled upon this Reddit thread about naming your medical devices. It was started by someone struggling to christen a new OmniPod personal diabetes manager. The user wrote:

I tend to name all of my super expensive devices since they are on me all the time and I know I'm not the ONLY person who is weird this way."

Others replied with the monikers of their own medical devices. One user sent in a photo of an Animus OneTouch Ping named GLaDOS. Other names for insulin pumps included the Count, Megatron, Prometheus, and Donald Pump. Another user pledged to name his or her pump after a superhero:

I am going to name mine Batman, it's got a black suit and I can never find it."

Glucometer names included Marceline the Glucose Machine, Li'l Dracula, and Lester the Tester.

Jamie Hartford is the associate editor of MD+DI. Follow her on Twitter @readMED.

Medical Device Marketers Need to Act With Precision | Medical Device Podcast

It’s somewhat hard to believe. But in 2010, the pharmaceutical industry eliminated 43,334 jobs. Stop and think about that. Over 40,000 people received the infamous pink slip!

Okay, so you might be thinking, “But that’s pharma; I’m in medical devices. I’m safe.” Think again, my friend. Regulatory timelines are long. PMAs and 510ks are incredibly expensive. Venture capitalists are white-knuckling their cash. Oh yeah, don’t forget about the 2.3% medical device tax and the Sunshine Act.
With that in mind, it’s paramount that medical device marketers and sales people begin to stretch. As in…stretch your mindset. Think outside the box. Employ aggressive, non-traditional avenues. Are you with me? Okay then…
Enter Bob Harrell, VP of Marketing for Appature, a technology company that provides a cloud-based relationship marketing software platform for pharmaceutical and medical device companies. Before joining Appature, Bob served as Director of Integrated Marketing at Shire. Bob’s 20 years in the pharmaceutical industry began in hospital sales for Merck, followed by field sales for Astra Merck. He then assumed a variety of positions with increasing responsibility at Astra Merck and AstraZeneca headquarters, including product communications manager, director of field communications, and director of strategic communications.
Enjoy our conversation. Better yet, don’t just sit in the audience. Employ just one of the principles we discuss and you’ll have a fighter’s chance against the headwinds that face the healthcare industry.
This is what you can do next:
1) You can download the mp3 file of the interview by clicking here.
2) You can listen to this interview and all of the other Medsider interviews via iTunes.  
3) If you prefer text, read the transcript the interview with Bob Harrell below:
Interview with Bob Harrell of Appature:
Scott Nelson with You were recently quoted as stating, “The industry can no longer rely on the blunt instrument of mass campaigns to reach customers…” Where are medical device customers…” Where are medical device companies missing the boat when it comes to marketing strategies?
Bob Harrell with Appature: Since the 1940s, there has been mass marketing via TV, as well as print and radio, for cigarettes, soap etc., and that was state of the art at the time. Markets were greenfield, consumers were easily influenceable, and mass marketing had a big return.
This was also the case in pharma during the age of the ‘detail men,' that is, men who exclusively educated doctors on the details of the product. This was at a time when access to the doctor was easy and sales reps were viewed as the primary and trusted source of information about products. Then came the 90s where we had the sales force arms race. By the 2000s, there was nearly a rep for every valuable doctor in the U.S. That, of course, was unsustainable, which is why you’ve seen sales forces decline in the intervening years.
At the same time, doctors got busier, managed care took more control, and technology began to enable self-service for key information about products. So life sciences companies found themselves with a broken model. Sales reps are extremely expensive when you consider fully-loaded costs. And when the number of calls per rep decreases, you end up with a crazy cost per call. Currently, a large portion of docs enforce “no see” policies with sales reps, and most others are very hard to reach. Well over 75% of calls end at the sample closet (no interaction) and only a small fraction result in more than two minutes of dialogue. So let’s say the fully loaded cost of a rep is $200-250,000 and they get a total of nine to 15 minutes a day actually communicating with a target doc. That doesn’t work, except in the cases where doctors have a legitimate interest in new products (and a knowledge gap exists) and you’re dealing with the most productive/valuable docs (i.e. the very top decile or two of Rx writers).
So assuming we still need to have commercial influence with customers to drive market share, what’s the alternative? For the last 10 years, pharma and medical device marketers have been ramping up non-personal (i.e. print, direct mail) and digital (i.e. Web, e-mail, e-detail) programs.
This can backfill the rep influence to a certain degree, but not entirely. The truth is that the total ‘pie’ of customer attention and influence has shrunk. We can substitute digital and non personal promotion for rep access in some instances, but the sum total of our influence will still be less – replaced by self-service, managed care edicts, etc.
That means that there is more pressure on margins for pharma and medical device marketing departments. It’s harder to get ROI. Think of it this way: financial services and consumer packaged goods have lower margins (by a long shot) than pharma, but they still have huge marketing budgets. Presumably they are not doing that with a goal of continuously losing money.
What’s different? Well, fundamentally, they have greater sophistication in their marketing capabilities. They use technology, data, 1:1 content and offers, etc. They measure and optimize daily and/or weekly to squeeze the maximum return out of every marketing dollar.
Bottom line: we have to ask ourselves, as pressures on our business continue to mount, is it reasonable to think that a life sciences marketer–and/or his or her budget – can survive using the blunt instrument techniques perfected in the 1940s through 1980s–when making a profit on an approved product was like shooting fish in a barrel and the Internet was still the stuff of science fiction novels?
Scott Nelson: First, I love your comments about the increased cost per call of a pharma and/or medical device rep. In addition, you mentioned that the 'total pie of customer attention and influence has shrunk.' With that said, why aren’t more pharma and medical device companies taking advantage of the sophisticated technology we have today?
Bob Harrell: I would say that it is a function of a few different items:
1.) Awareness and/or understanding, or lack thereof, regarding the changing environment and 2.) The fact that this kind of marketing is fundamentally more sophisticated, complex, and dependent on a set of IT/process capabilities that, for the most part, do not exist in pharma and medical device companies. They haven’t had to exist. I joke that John Wanamaker’s famous quote ‘I know I’m wasting half of my marketing budget, I just don’t know which half’ could be adapted to the old days of pharma as ‘I know I’m wasting 90% of my marketing budget, but I just don’t [have to] care.’
But you can’t go from 10 mph in the pace/capability level of your marketing to 100 mph overnight. It’s an evolution–one that requires significant and sustained commitment of people, dollars, and organizational focus. Why should I do it if I don’t see the need for change or if, today anyway, I am still making lots of money–thank you very much–doing it the old way? To that I would say you may be right, but given the lead time to grow this kind of capability and marketing sophistication, you may well find yourself flat footed in 2-3 years, even if things seem okay today.
Remember Wile E. Coyote from the Road Runner cartoons? He would always chase the Road Runner off the cliff, and only when he saw that he was hanging out over mid-air would he realize that he should have taken a left turn 100 yards back. But by then it’s too late. Thankfully for Wile E. Coyote, he could magically regenerate after a fatal fall like that. Not so sure I’d take that gamble as a pharma or medical device marketer today.
Scott Nelson: Will the external market forces–i.e. the medical device tax, Sunshine Act, decreased reimbursement, etc – help pharma and medical device companies step up their game when it comes to more sophisticated approaches…approaches that are enabled by systems like Appature Nexus?
Bob Harrell: Precisely. It really is a situation of evolve or die right now. Some commercial people in the industry, both sales and marketing, are still operating under the illusion that things will continue as they have, albeit with a bit less money and a bit more scrutiny. Not true. To use another analogy, you can think of mass marketing as the old days of blunt instruments (cave-man marketer), or sticks and knives (post cave-man marketer). I grew up in Texas, and people there were, of course, fond of the phrase ‘don’t bring a knife to a gun fight.' Marketers who hang on to the old model of one-size-fits-all, untargeted, non data-driven, nonoptimized, nontechnology-enabled marketing will find themselves not just unprepared to compete in this era, but fundamentally unarmed in an ever increasing war for market share. That’s a bad place to be.
Scott Nelson: I agree with you wholeheartedly. In fact, in 10-15 years, I have a feeling there will be plenty of pharma and medical device marketers that look back and think, 'How in the hell did we operate like that?'
In the time we have left, I’d like to discuss some of the challenges that the Appature platform helps to solve. Perhaps you could briefly elaborate on the following challenges and frustrations that pharma and medical device companies face specific to the following topics:
Bob Harrell: Our technology has been designed from the ground up to address the key pain points outlined below. Specifically:
Problem #1: My data is siloed. I can’t establish a complete view of the customer.
Nexus 360 provides a flexible database that quickly integrates all your disparate data sources to create a clean view. It also includes maintenance tools such as MDM (master data management) so that you can very quickly get a 360 degree view of the customer, who can very quickly get a 360 degree view of the customer – who they are, what their preferences are (including opt-in and opt-out for customer service and compliance purposes), how you have contacted them, etc. A single version of the truth for every customer.
Problem #2: I’m unable to measure ROI on our marketing efforts. I have no idea how our marketing campaigns are performing.
Nexus Insight enables real-time reporting and analysis on the fly as needed. Easy-to-configure reports, ability to explore data right at your desktop with a simple user interface (i.e. the marketer can do it himself, not relying on IT or a marketing service provider), and the ability to easily export a clean feed to your marketing analytics team for deeper ROI analysis through SAS or a similar tool. The other component is A/B testing (which, embarrassingly, most marketing campaigns in pharma and medical devices do not include) that is enabled through a good campaign plan, driven by a database, campaign management engine, and reporting/analysis tool.
Problem #3: We’d like to expand our reach to those hard-to-see physicians.
This is fundamentally about planning robust campaigns that contain enough touchpoints to create ‘surround sound’ with physicians. If I don’t reach them through the journal ad, how about search words via SEM? If not that, how about a KOL webinar, or an e-detail? What about a microsite within Medscape? Banner ads within online journals or professional association sites? Messages embedded in starter kits? Content delivered through the sales reps via iPads? Materials we provide to patients (i.e. ‘talking to your doctor’ worksheets) that they in turn bring into the doctor visit? I could go on, but those are a few examples.
Problem #4: I want to personalize our messaging and avoid redundancy, eliminate duplicates, etc.
Again, this is dependent on a strong database and campaign management tool. You need to manage opt-in and channel preferences automatically via business rules; set limits on the number of contacts a doctor or consumer can receive in a given week or month. We already do this with online media and banner advertising via frequency capping, so why don’t we do the same thing with our other communications? (Hint: it’s because we’ve had neither the need nor the capability to do so in the past. Appature as a company was built from the ground up to address exactly these kind of gaps.)
Problem #5: How do we break through the noise and hear what our customers are saying?
We do not build social media tools into our core product but do integrate with third party tools such as Radian6. This enables us to capture this kind of intelligence and incorporate it into an intelligent database.
Scott Nelson: Great information, Bob. Before we conclude, is there anything you’d like to leave the audience with that we haven’t discussed?
Bob Harrell: Yes, one last point. I think of the current situation in the industry very simply as a marketing maturity curve. Imagine a graph where the Y-access is pressure on ROI and margins, and the X-axis is channel and customer complexity. As margin and ROI pressures go up, and as customer and channel complexity go up, marketing sophistication must go up as well. In this context low sophistication can be defined, on the low end, as uncoordinated push tactics, and on the high end, as performance-based, data-driven marketing. Historically, pharma has been in the lower left quadrant (low pressure, low sophistication), the same place financial services and consumer packaged goods industries were with their marketing in the 1960s. Now there truly is a burning platform for change for life sciences marketers to move up and to the right on the maturity curve as margin pressures continue to mount. It would be great if it could be easier but it’s just not. Don’t bring a knife to a gun fight. In our business today, it’s evolve or die (or at least atrophy).

Glucose Monitoring and the Economy: Q&A with GlySure's Chris Jones

Fortunately, GlySure had solid medical data to support the company’s developmental efforts. “What drew me to GlySure was this unique opportunity where the outcomes data already exist,” Jones says. “There was a seminal paper done in 2001 by Greet Van den Berghe that showed if you tightly control glucose you get these phenomenal outcomes—a 34% reduction in mortality and a near 50% reduction in sepsis, for example.” For hospitals these prospective outcomes result in “$1500 savings per patient in the U.S. and €2300 per patient in Europe,” he says.

"I think it’s fair to say there’s probably more money available in the U.S. than there is anywhere else in the world right now," Chris Jones, GlySure.

Launched in 2006, GlySure is readying the commercial introduction of its continuous intravascular monitoring system for tight glycemic control in ICUs. Using an optical fluorescence sensor licensed from Beckman Coulter, the device could treat some 8 million patients annually, according to the company. The projected positive outcomes, estimated $2-billion market, and encouraging clinical test results have attracted $19.5 million in venture capital funds to GlySure.

A veteran of more than 20 years in the medical device industry, Jones was CEO of Tensys Medical from 2005 to 2008. At Tensys he oversaw the development of the first continuous, noninvasive blood pressure monitor. Before working at Tensys, Jones, who has a BS in molecular biophysics and biochemistry from Yale, spent nine years at Tyco’s Nellcor division, where he served most recently as vice president of marketing for pulse oximetry and critical care businesses. He also spent six years in sales and marketing management at BioGenex Laboratories.

On a “four-cities-in-five-days” business trip to the U.S. Jones called MDDI from his IP lawyer’s office in Minnesota before leaving for a Chicago visit with board members and a red-eye flight back to Oxfordshire. He discusses how GlySure benefited from the Indian clinical trials, the trend toward making devices that cut hospital costs, the developmental advantages of competition, the effect of the 2008 downturn, and related matters.

MDDI: In March GlySure announced the results of an ICU pilot trial in India. What do the results tell you about the company’s direction?

CJ: Those results are really the culmination of about 18 months of work we’ve done in intensive care. We now have over 106 patients trialed in the ICU. Those were the culmination of a lot of iterative developments that demonstrated the ability to monitor a diverse range of intensive care patients with different conditions—sepsis patients, cardiac patients, respiratory patients—and monitor them from admission through discharge.

Having done that, we’re now in the process of scaling up our manufacturing and finalizing the commercialization of the product. We were using some prototype systems in early pilot trials. Now we’re finalizing all the product integration and preparing for regulatory trials, with CE trials coming up this fall and discussions with FDA over the scope and nature of our U.S. regulatory trials. We hope to start those early in 2013.

MDDI: Your description touches on something that a lot of device companies are doing, which is seeking regulatory acceptance in Europe first. GlySure is based in the UK, obviously, but what are the pros and cons of getting a CE mark before tackling FDA approval in your view?

CJ: More and more you’re seeing a lot of medical device companies executing a Europe-first strategy because it is easier to get a CE mark these days than it is to get 510(k) or PMA clearance, depending upon the device you’re working with. For us we think it’s a huge advantage being on the ground in Europe already in that we don’t have to build any extra infrastructure there, we can do the trials in our backyard and get our feet wet in the market over there while we then build toward the U.S. FDA trials and ultimate U.S. commercialization of the product.

MDDI: Does it help that you get a CE mark first? Does FDA take that into account during regulatory scrutiny?

CJ: That’s an interesting question. I think it can help if you design your European studies correctly you can use them to answer questions that FDA may have and that data can be part of IDE or pre-IDE submissions when you’re discussing with FDA the nature of the U.S. trials. All that data you can present to and discuss with FDA that will ultimately help you reach agreement on what the U.S. trials should look like.

MDDI: Regarding the trials you did conduct, were there aspects that you found particularly challenging as far as the ICU patients you mentioned?

CJ: In terms of the trial design itself the most challenging aspect is that we have a device that monitors around the clock. It’s a continuous glucose sensor. If you’re going to run the device you then have to make a decision about whether you want to run the device 24/7 and have staff to do that during your trials or whether you just want to run it for 8 hours during the day and then turn it off and turn it back on the next day.

We really wanted to understand the performance of the device in a real-life, real-use situation, so we set up the trial where we were running the device and running the study 24 hours a day from admission to discharge in the ICU. We’re drawing blood to do comparative measurements throughout that time. Setting up the staffing and the management of the trial around the clock is a logistical challenge, and it would be much easier if you had to do one day shift. In the end you wind up with data that is much more representative of what you’re going to see when you’re running for 24 hours a day on patients with a commercialized product.

MDDI: Running the trial around the clock requires a bigger budget obviously.

CJ: Absolutely. It costs more money to run it that way.

MDDI: And you didn’t hesitate?

CJ: That’s part of the reason we ended up doing our early trials in India, because the costs were significantly lower there. You have to have all the same quality systems in place and all the same patient safety measures in place. The first volunteers we had for our testing were ourselves—our CTO, our chief chemist, and myself—so we knew the device was safe before we went into ICU testing.

Going over to India, we were able to do it at a lower cost, and the regulatory approval process was much faster, so we were able to save significant time and money by doing it overseas.

From here we’re gearing up to start our CE trials. We’re hoping to do those in Europe this fall, and if all goes well then we’ll be launching the device in Europe early in 2013 and at the same time we’re in discussions with FDA right now over U.S. trials. We’re hoping to define those this year so we can begin our FDA trials early next year.

MDDI: As far as your personal career path, what factors convinced you to move to the UK and GlySure?

CJ: I’ve spent my whole career in medical devices and diagnostics, and my last job in the U.S. was CEO of Tensys Medical, which developed a continuous, noninvasive blood-pressure monitor for use in operating rooms. That was a turnaround [operation]. We revamped the product, relaunched it, and managed to sell that company in 2008, so I was looking for my next opportunity.

During my career at Nellcor and then at Tensys the trend that I noticed more and more is that in order to get new technology out in the market it wasn’t enough to have something that was a little bit better or a little bit faster or a little bit easier to use. You needed to be able to show not only a clear, compelling clinical benefit but also to show hospitals how they could save costs. The whole health system is creaking against the cost pressures that it’s up against, and if you want a device to be adopted quickly these days you need to be able to show not only a benefit for the patient and clinicians but also the financial benefit to the hospital.

What drew me to GlySure was this unique opportunity where the outcomes data already exist. There was a seminal paper done in 2001 by Greet Van den Berghe that showed if you tightly control glucose you get these phenomenal outcomes—a 34% reduction in mortality and near 50% reduction in sepsis, for example—all of which turns into savings for the hospital that has been published in prospective outcomes data showing $1500 savings per patient in the U.S. and €2300 per patient in Europe. So, the fact is there was this huge pent-up demand that would enable hospitals to realize the benefits of tight glycemic control, and the opportunity existed to not only improve patient care to make the nurses’ jobs in the ICU easier but also to deliver hospitals the cost savings they needed.

It was that combination of sort of the Holy Grail of medical devices these days, which is both quality improvement and cost savings that convinced me it was an opportunity I wanted to be a part of.

MDDI: The company licensed the optical fluorescence technology from Beckman Coulter. How did the company work out that licensing agreement?

CJ: Our founder [Barry Crane] saw the opportunity, had deep experience in developing intravascular sensors, and was looking for a chemistry that was specific for glucose. This was one that he identified, and he approached Beckman Coulter. They are in many ways focused on the laboratory analyzer market, so it was a market that they were not going to pursue directly and we were able to negotiate a fairly standard medical device license with a royalty payment to enable us to have access to that technology for this market.

MDDI: How long is the agreement?

CJ: It was an exclusive license for the lifetime of the patents, and recently we were able to convert that into a purchase agreement where we bought the patents outright and now own them ourselves.

MDDI: So you’re at the IP attorney’s office. How is your IP portfolio doing?

CJ: Quite well. We just put out a press release a couple of weeks ago; we had a new patent of our own issue on our core calibration technology, which is essentially getting accurate measurements right at the point of care. As I said, in the past six months we’ve been able to finalize the purchase of that core IP from Beckman Coulter so those two things together have been some really nice progress for us on the IP front this year.

MDDI: GlySure has at least three device competitors with this capability for warding off hypoglycemia in ICU patients. From a business standpoint you talked about moving ahead this year and into next, how do you balance getting to market versus making sure you’re developing the very best product you can?

CJ: First of all, you’ve got to have product that is reliable, accurate, and safe. You can’t cut any corners on that. It’s just the classic truism you only get one chance to make a first impression. We’ve been developing this product with the target and goal of the ICU in mind and developing a product that is going to integrate easily and seamlessly into ICU practice.

For me this is a big market opportunity. It’s a [product] opportunity that clinicians have been [anticipating] for a decade now. My experience says in anything new it’s often useful to have multiple companies out there developing a market together, and collectively you can grow things faster than any one company can on its own. We’re quite confident that we’ve got the optimum solution for use in intensive care. It’s always a balance between trying to get there as quickly as possible and also making sure that you’ve got the right product when you come out. There’s no sense coming out too soon with a product that doesn’t make customers happy, so you’re much better off giving them something that is easy to use and accurate the first time around.

MDDI: One of the three main components in GlySure’s device is the sensor monitor. Can you elaborate on how long that runs?

CJ: There’s a standalone monitor. It’s a typical razor-razor blade system with a disposable patient-dedicated sensor because it’s a blood-contacting device. With the sensor itself…I think 106 hours is the longest patient we’ve been on, which has purely been a function of just how long patients have been in the ICU while we’ve been running the trials. We’re hopeful that we can extend it even farther than that. Our goal is to have a product that you can put into a patient and leave it throughout the duration of the patient’s stay in intensive care.

MDDI: Is that capability a major challenge or is it within reach?

CJ: I’m very confident it’s within reach. Our in vitro testing has shown the ability to monitor for five to seven days, so I believe it’s really a matter for us of finding the patients who are going to stay that long in the ICU and demonstrating what we can do. There’s been a lot of work in development going into the design of the sensor to allow it to be resident in the bloodstream without biofouling or thrombosis or clotting, but having done all that work we’re pretty confident we’re going to be able to continue to extend that time if we’ve got patients who stay in the ICU for longer and longer.

MDDI: Do you have a price point in mind for the product at this point?

CJ: It’s a little too early. We’re not on the market yet, so that’s not something that we’re talking about at the moment.

MDDI: But you’d have to design it with some sort of sweet spot in mind.

CJ: You always want to design it to keep the cost as low as possible so that you can offer a significant benefit to the hospital. We design it with cost in mind but we haven’t set the cost yet.

MDDI: GlySure has received about $19.5 million in venture capital funding since the launch. How would you describe the investment climate in Europe and the U.S. at the moment?

CJ: Ever since 2008 it’s fair to say it’s been challenging in both the U.S. and in Europe, and I think it’s also fair to say there’s probably more money available in the U.S. than there is anywhere else in the world right now. There is a very active start-up device and pharmaceutical community in Europe. There’s a lot of innovation going on over there, and there’s a lot of grants and government support. There is a building venture community in Europe, but it’s nowhere on the size, scale, or amount of funds in the U.S. right now.

MDDI: You mentioned that GlySure saved money by conducting clinical trials in India. Given the funding environment, what key decisions did you make to keep the project moving forward?

CJ: When I got to the company in 2008 it was right when the financial crisis was hitting. There was a very clear signal that the bar for investment had gone up, and people really wanted to see proof of concept and fundamentally see human data before doing follow-on investments. So for us part of the decision to go overseas was that the cost-per-patient [figure] was significantly lower in India than it was in Europe or in the U.S. The other was that the regulatory approval timelines and processes to begin a study were several months faster over in India, and every time we modified the product and went back to restart testing we saved that couple of months of regulatory time.

Over all, it probably saved us nine to 12 months of development time in being able to do our testing faster in India than we could have in either the U.S. or Europe at that early stage. It was absolutely critical to surviving the lean years when investment was very tight and getting to the point of having human proof of concept that enabled us to close that Series C round at the end of last year and bring some new investors into the company.

MDDI: What personal or professional adjustments did you have to make moving to a start-up from an established company?

CJ: It’s a classic trade-off. At a big established company you’ve got incredible resources at your fingertips to rely on. It’s one of resources versus speed and focus. You give up some of the resources, and you have to be much more efficient. But the benefit you have is the incredible power of focus in that you’ve got one project that everybody in the company is aligned around. That can allow you to do things much, much faster than at a large organization, where you may have resources but you’ve also got more layers of bureaucracy and approval and people to get aligned around decisions.

It is much more focused and faster to change direction, and in some ways I compare it to running an oil tanker versus running a speedboat. But you still have to learn to keep a light hand on the tiller. Just because you can make really rapid decisions doesn’t mean you want to do that all the time. You have to use that speed and nimbleness in the right way and keep it focused on the project and the outcomes you want.

MDDI: Broadly speaking, what differences in the business climate or mode of operating, if any, do you see between working in the U.S. and the UK?

CJ: You see many more similarities, I think, than differences. When it comes to commercialization there are big differences in the healthcare systems and the reimbursement and the way products are paid for. And there are obviously the big differences that we talked about in terms of the regulatory approval and CE versus FDA.

In terms of running a start-up, attracting people, and doing venture-based medical development, I was pleasantly surprised by the entrepreneurial nature of the culture and the country that I walked into and the number of resources that were available. So I’ve been very pleased. And from a business perspective I haven’t seen a lot of internal differences in the way companies, and start-ups in particular, operate.

Sidebar: Air Show Disaster Elevates Luer Connector

Compounding the magnitude of the disaster were the lack of coordination between civil and military authorities, and the incompatibility of the luer and Record connectors used on intravenous catheters by the American military and German paramedics. Largely in response to the Ramstein disaster, the luer style became the global standard and the Record connector fell into disuse. However, a single standard wasn't codified until 1995.

The Ramstein Airbase 1988. Incompatibility of the luer and Record IV connectors contributed to emergency response complications following the disaster. 

Over the next couple of decades, luers became the standard connector in enteral and gastric, urethral and urinary, limb cuff inflation, and neuraxial device applications. Their ease of use and low cost moved the product from clinical settings to home-based care environments. This continued expansion counter intuitively weakened its foundation as a simple solution for a complex world.

The connections were simple and secure — but also potentially very risky. The European Committee for Standardization (CEN) Report CR 13825 in 2000 stated, “In a coronary care unit there are as many as 40 connectors on the devices used with a single patient.”

With the same connector being used simultaneously in vascular, enteral, respiratory, epidural, and intrathecal applications, the possibility of misconnections between these applications has always existed. The probability of misconnections grows exponentially with increased applications and types of users, and the consequences can be deadly. That's why new standards mandating separate, incompatible connectors for different applications are nearing adoption.

Although hundreds of millions of procedures are performed each year without incident, any misconnections are still far too many. And the widespread use of standard luer connectors is the reason for misconnections. Devices, components, and materials that are used within a specific application will continue to come from different suppliers, so standardization within, but not across, applications will be the best solution.

The process of developing new standards for small-bore connectors began in 1996 when the Association for the Advancement of Medical Instrumentation (AAMI), stated that “enteral feeding tubes should not be Luer Lok compatible.” In 1997 the standard designated BS1060-3 stated “Luers should not be used with NIBP [non-invasive blood pressure] systems.”

AAMI, with a broad range of industry, healthcare organization, FDA and academia participants worked to develop two standards. The first disallows compatibility of enteral and parenteral connectors. Specific dimensions, tests, and acceptance criteria for a new enteral connector were to be expressed in a second standard. AAMI/ANSI ID 54 is still in effect today and recognized by the FDA but without any additional FDA action; no second standard has been developed.

In 2000, CEN BTTF 123 was formed in Europe to address the issue. In 2006 it proposed that a joint working group (JWG) be formed for “the development of standards for small-bore connectors for liquids and gases in healthcare applications under the Vienna agreement with ISO TC 210 administrative lead.” Responsibility was officially moved to ISO TC210 JWG4 in 2007.

JWG4 subsequently released ISO 80369-1:2010, which “provides the methodology to assess non-interconnectable characteristics of small-bore connectors based on their inherent design and dimensions in order to reduce the risk of misconnections between medical devices or between accessories for different applications and to reduce the risk of misconnections between medical devices with 6% Luer connectors, and all other non-Luer (6%) connectors that will be developed under future parts of this series of standards.”

Return to the main article, "The Life and Death of the Luer."