CDG Whitepapers

A Strategic Approach to Protocol Design

A Whitepaper by Dr. Nancy J Stark, made available by Clinical Device Group

A former boss once told me this story. When I walk into his office he envisions me with a monkey on my back. As we begin our conversation the monkey jumps off my back and starts to create havoc, knocking papers to the floor, turning over the lamp, swinging from the chandelier, and kicking the waste can. My goal is to leave the office with the monkey on my boss's back; my boss's goal is for me to leave his office with the monkey on my back. When the conversation ends, the person who has something to do has the monkey on their back.

The same analogy can help you to write a protocol. The monkey is consensus on several key points about the study design. If you get consensus from the project team and top management, the monkey is on their back. If you have to start writing the protocol without agreement on these points, the monkey is on your back. With committed consensus, you can plan on 20-30 working days over a duration of 2-3 months to write a new protocol for a new technology. Without consensus it can take years.

Authority
To lay some background, let's look at the regulatory requirements for a clinical investigation. FDA regulations tell us that we shall have valid scientific evidence to support the safety and efficacy of medical devices. Valid scientific evidence [consists of] evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsible be concluded by qualified experts that there is a reasonable assurance of safety and effectiveness of a device under its conditions of use. So the purpose of a clinical investigation in the States is to provide reasonable assurance of safety and effectiveness for the investigational device. [1. 21 CFR Part 860.7(c)(1-2) (paraphrased)]

[08] Protocol & Trial Design Workshop on CD (March 2012)

A newly updated version of the Protocol and Trial Design Workshop is available on CD. The 4.5 hour presentation, consistent with both US and EU requirements, gives the backstory to each section of the protocol: why is it there, what are regulators looking for, is it important, can you omit it? You also receive a "fill-in-the-blank" protocol template with detailed instructions so you can focus on the creative work and leave the boilerplate in place. The well-researched course is designed and studio-recorded by Dr. Nancy J Stark. Click here for more information or call 773-489-5706.

For those of you concerned with clinical trials in Europe the path of authority is a little more complex. You'll begin with the Medical Device Directive which states the demonstration of conformity with the essential requirements must include a clinical evaluation in accordance with Annex X. [2. MDD 93-42-EEC I.6a)] A clinical evaluation is the assessment and analysis of [existing] clinical data pertaining to the medical device in order to verify the clinical safety and performance of the device. [3. MEDDEV 2.7.1 r3] If existing clinical data cannot verify safety and performance, then a clinical investigation must be done per ISO 14155 or the intended use reworded. The standard states that the justification for the design of the clinical investigation shall be based on the evaluation of the results of a clinical evaluation. [4. ISO 14155 Clause 5.3] This is the logic behind bringing a medical device to market in the EU via the literature route.

Start at the end
To leave the monkey on the project team's back, here are the key points on which you will want consensus.

Intended use
Intended use is a US regulatory term that refers to what you say in the labeling. It ties the physical device, and the words we use to describe it, into a single entity. [5. 21 CFR 801.4] Intended use is a broad concept—think verbs, function, and action. Consider the following examples:
[1] A neurostimulator is intended for stimulating the vagus nerve.
[2] An MRI scanner is intended for soft-tissue imaging using nuclear magnetic resonance.
[3] A fetal oxygen monitor is intended for monitoring oxygen in a fetus.

The intended use dictates the specialty we need in an investigator, say orthopedist or neurologist, and begins to define the subject population.

Indications for use
Indications for use are the diseases or conditions for which the device will be used. Choose diseases, conditions, or procedures that have accepted medical definitions. The indications for use dictate the subject selection criteria. [6. 21 CFR 814.20(b)(3)(i)] Consider the following examples:
    [1] A neurostimulator indicated for prevention of epileptic seizures.
    [2] An MRI scanner indicated for detecting structural abnormalities.
    [3] A fetal oxygen monitor (hopefully) indicated for determining if a C-section is warranted.

Consulting Services

CDG's experts are frequently engaged on a retainer basis to be available for phone calls, email exchanges, document review, good advice, or other consultations. We have experts in most medical device pre-approval issues, including market assessment, biocompatibility, regulatory, clinical evaluations, clinical investigations, statistics and sample size calculations, and audits. To discuss a Service Agreement, call or email us here or ask for Nancy at 773-489-5706.

Performance and device deficiencies
Performance speaks to the physical properties and operation of the device; for example, what range of light-waves does it emit, how hot does it get, do the buttons stick, how easy is it to use? Performance also speaks to the ISO concept of device deficiencies such as inadequacies with respect to the devices identity, quality, durability, reliability, or safety. The intended performance or concerns about lack of performance dictate several of the questions that you should include on the case report forms. [7. ISO 14155] Consider the following examples:
    [1] The neurostimulator delivers xyz amps.
    [2] An MRI scanner has good contrast resolution.
    [3] A fetal oxygen monitor detects oxygen levels in fetal blood.

Safety
Safety refers to the absence of adverse events to subjects and the absence of serious, unanticipated adverse events to caregivers or bystanders. [8. ISO 14155] Recording and reporting of adverse events varies with the host country (the country in which the study is being implemented) and with the study risk. Every protocol requires a "risk assessment". The risk assessment is often written in tabular format with headings of hazard, frequency, severity, risk, mitigation, and residual risk.

A hazard is an adverse event that may occur to a subject, or a serious, unanticipated adverse event that may occur to a caregiver or bystander. Frequency refers to the rate at which the hazard is likely to occur; it can be estimated on any convenient scale such as 1-100%. Severity refers to the intensity of the event, such as mild, moderate, or severe; a three-point scale is useful for estimation. Risk is a function of frequency and severity; you can use any meaningful mathematical relationship, in the example the two scores have been added. Mitigation refers to actions that are taken to lessen or prevent the risk; and because you are writing a protocol you’ll focus on measures that can be taken by the investigator. Residual risk is the amount of risk left over after all mitigation measures are taken. Residual risk can be described as minor, requiring an outpatient procedure, or hospitalization; or by any other meaningful scale. [9. ISO 14155] Clearly the safety questions on the case report forms will come from the risk assessment. In the US, the risk assessment may cause the IRB to see the study as significant risk. Consider the following examples for residual risk:
    [1] Neurostimulalton of the vagus nerve may cause headaches.
    [2] MRI scanner may expose technical staff to NMR.
    [3] Placement of fetal oxygen monitor sensors may injure fetal soft tissue.

Target market
Who is going to influence the buying decision about your device within the hospital or clinic structure? Often this person is a good choice for clinical investigator.

Major competitive products or procedures
Controlled, randomized trials are not usually required for medical devices in order to gain clearance in the US, and a comparison to competitors does not enter into the equation in the EU. Nevertheless, it is useful to know what your competitors are claiming, how they word the intended use and indications for use, what clinical trials they have done, what predicate devices they referenced, and the like. If you do decide to do a randomized, controlled study, a thorough knowledge of your competition will help you decide on what product or procedure to use as a control.

Claims
A claim is an assertion of truth about your product. The claims you want to make dictate the endpoints (clinical measurements that indicate device success or failure), outcome measurements, whether a study is comparative or single armed, and many other features of investigation. The team may list several claims they want to make about the device; limit your selection to two or three. If you're a new company go after the easy claims first to get experience in conducting studies, getting FDA clearance, and commercializing a device. If your firm is experienced you may feel comfortable going after more complex, but desirable, claims in the first investigation.

Frequently the project team will settle on the claims to be investigated. And then you'll begin writing the protocol only to find there is no good methodology for measuring success or failure, the sample size makes the study unaffordable, there are too few patients to maintain a reasonable recruiting rate, there is no market for treating such patients, or some other insurmountable problem. You go back to the project team, rework the wording of the proposed claims, and resume writing the protocol. This is the monkey creating havoc.

Clinical Trials Design
Stark NJ, Clinical Trials Design, Third Edition, Clinical Device Group Inc, Chicago, IL (2000).

This is one of the few books about writing protocols and designing trials that links them to the trial hypotheses and product claims. That simple sentence sums up the guts and substance of the book: first decide what you want to claim about your device, and then design a trial to investigate it. The concept is so important and so rarely discussed that the book has been translated into Japanese and Korean.

Still current, still relevant, and still a useful reference. It is intended for use by medical device manufacturers. Provided in a high-quality three-ring binder so you can add your own notes, illustrated, 300 pages. ISBN 1-889160-02-4. Table of Contents. $250 US.

Protocol Contents
There is no absolute format for a protocol, although FDA issued a guidance document in 1996, [10. FDA Statistical Guidance] and ISO 14155 contains an extensive checklist. Here is a suggested format that is a combination of the two:
[01] Cover page, Table of contents, Executive summary.
[02] Device description, photograph, accessories, description of comparator.
[03] Contention of SR or NSR regulatory status.
[04] Study objective.
[05] Hypotheses, primary and secondary.
[06] Endpoints and procedures, primary and secondary.
[07] Medical risk analysis.
[08] Study design.
[09] Subjects.
[10] Ethical considerations.
[11] Sample Size.
[12] Data collection.
[13] Control of study devices.
[14] Adverse event recording and reporting.
[15] Monitoring plan.
[16] Documentation.
[17] Central laboratories.
[18] Data management.
[19] Data analysis.
[20] Data monitoring board, Data safety monitoring board, Clinical events committee, if one will be used.
[21] Personnel Responsibilities.
[23] Return of unused inventory.
[24] Study registration and publication policy.
[25] Study cancellation.
[26] Definitions.
[27] References.
[28] Attachments.

Internal Approvals
Internal approvals are another great opportunity for the monkey to create havoc. But you can keep him in his cage by using a approval form that identifies and limits each function's responsibilities. For example, the project team leader reviews the protocol to ensure you have described the device accurately and you are investigating the right device; marketing ensures you are investigating the right claims, manufacturing reviews to ensure they can actually make the investigational device, the medical manager assures you have an accurate and complete risk analysis, regulatory assures you have identified the regulatory status of the investigational device correctly, statistics reviews the sample size and data analysis plan, and so forth. Only your manager has the privilege of global review.

References
[1] 21 CFR Part 860.7(c)(1-2) (paraphrased).
[2] MDD 93-42-EEC I.6a).
[3] MEDDEV 2.7.1 r3.
[4] ISO 14155 Clause 5.3.
[5] 21 CFR 801.4.
[6] 21 CFR 814.20(b)(3)(i)
[7] ISO 14155 Clause 3.15.
[8] ISO 14155 Clause 3.2.
[9] ISO 14971 "Medical devices—Application of risk management to medical devices" (2007).
[10] FDA's Statistical Guidance for Clinical Trials of Non-Diagnostic Medical Devices (1996).

Questions or Comments?
Please post your questions and comments below.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

 

 

Uptick in Clinical Evaluations

What Do Notified Bodies Want?

A Clinical Device Whitepaper by Nancy J Stark

We've seen an uptick in requests for clinical evaluations recently, and I thought it would be worthwhile to review the requirements. Where you begin depends on where you are now: 1) writing a clinical evaluation for a new, pre-approval device, or 2) writing a clinical evaluation for a device that is already commercial. In the first case, you are asking the question, "Do I need new clinical data for certification?" In the second case, you are bringing your documentation up-to-date.

Clinical evaluation reports for pre-certification devices
If you're still in the stage of designing your device, you begin by identifying its intended uses. Then you evaluate the existing clinical data to determine if it is sufficient to support safety and performance per the Essential Requirements of the MDD [1 MDD] or AIMD [2 AIMD], or if you need additional clinical data. If additional clinical data are needed you have the choice of revising the intended use or performing a clinical investigation.

Once you believe the data are sufficient, you convince top management to grant a CE Mark and sign the Declaration of Conformity to your previously certified quality management system. Finally, you will discover the truth when the Notified Body comes to make an inspection call.

Clinical evaluation reports for commercial devices
The more common situation is that your device is already on the market in Europe, and the Notified Body has informed you that its clinical evaluation is overdue or needs updating. They may give you a grace period, but you are expected to get busy. You follow the same process of evaluating the existing data to determine if it is sufficient to support safety and performance for the intended uses. Should the report conclude that the existing data are insufficient you are in a difficult situation: you'll need to suspend sales until additional data are acquired.

Because the consequences of determining the data are not sufficient are so financially significant for your firm, and the consequences of determining the data are satisfactory are so financially favorable, it is wise if the report writers are as far removed from the device designers as possible.

Resources
To write the report you need a team of at least three individuals: 1) a medical writer, 2) an information specialist, and 3) a statistician.

In addition you need a written procedure for how to proceed, a report template (useful, but not required), and access to literature databases such as Medline. Medline is easy to use, it is operated by the US National Library of Medicine and is available to anyone with a browser. Medline provides access to 5400 worldwide journals in 39 languages dating from 1947 to the present. And it is free.

Date Wheels for Clinical Evaluation Planning

A typical clinical evaluation involves the following steps and durations:
[1] Identify key questions—1 weeks.
[2] Identify databases to search—overlaps.
[3] Identify search scope, keywords, search strings—1 week.
[4] Review abstracts, discard with reasons—1 week.
[5] Acquire articles—2 weeks.
[6] Read articles—1 week.
[7] Weight articles for relevance, discard with reasons—overlaps.
[8] Weight articles for statistical validity—1 week.
[9] Medical writer summarizes literature—2 weeks.
[10] Review sponsored clinical trials, if any—0-2 weeks.
[11] Review risk management system & complaint file—2 weeks.
[12] Write final evaluation—1 week.

Date Wheels are a handy, pocket-sized calendar used by project managers to quickly plan simple schedules. If the clinical evaluation work begins on March 1, you can hope for a final report about three or so months later, or about June 1. Buy them here.

A Three-Legged Stool
First leg
The first leg of a Clinical Evaluation Report is an evaluation of the existing literature data. The Global Harmonization Task Force (GHTF) Study Group 5 document "Clinical Evaluation" coupled with MEDDEV 2.7.1 Rev 3, which is slightly easier to read, are the guidances that tell us how to do the literature evaluation.

Here's what the medical writer—working together with you—will do:
[1] Define the key questions.
[2] Identify the databases to search (Medline, Embase, MAUDE, Cochrane).
[3] Define scope of search and search strategies using a qualified information specialist.
[4] Scan the abstracts to identify articles for review.
[5] Acquire full-texts of articles.
[6] Weight the articles for technical significance, discard anything with a low weight.
[7] Have a statistician weight the articles for statistical significance, discard anything with a low weight.
[8] Review only those articles with the highest weightings; see averages below. The literature data are evaluated to determine if they support safety and performance of the device for its intended use. I like to prepare a separate literature review and attach it to the main clinical evaluation as an annex. The literature review annex has several required elements including the search strings used by the information specialist, a list of abstracts scanned, the articles reviewed, their weights and justification for those weights, and full-text copies of the articles.

Second Leg
The second leg of the evaluation is a review any existing clinical investigations that your firm may have sponsored. These data are reviewed separately from the literature because you have closer access to the details. The writer asks questions such as: "Was the Declaration of Helsinki followed?" or "Were adverse events resolved?" If not, those facts are noted in the report but the data are not used.

Once the writer is satisfied that ethical and administrative requirements were correct, he/she reviews the study results to see if they support safety and performance of the device for its intended use. I like to prepare a separate sponsored study review and attach it to the main evaluation as an annex.

Third leg
In the third leg, the medical writer comes to the most sensitive step of all; examining the complaint file against the risk management system. They review the file to see if complaint handling, as dictated by the risk management system, supports the safety and performance of the device for its intended use. I like to prepare a separate risk management review and attach it to the main evaluation as an annex.

The Clinical Evaluation
Finally, the medical writer takes the literature review, sponsored study review, and risk management review altogether and reaches an overall conclusion of whether the existing data support the device's safety and performance for the intended use, or if additional clinical data are needed newly. You know what happens if new clinical data are needed.

The Technical File
If the data are sufficient, the clinical evaluation is filed away in the Technical File, a written procedure describing the writer's strategy is incorporated into your quality management system, and you wait with baited breath until the Notified Body inspector comes.

Recently CDG conducted a poll on the average number of
articles used in a clinical evaluation. Here are the results.
Please add your two cents worth below.

How long, how much
There are only two questions in top management's mind: 1) how long will it take, and 2) how much will it cost. The answers are simple: "It depends." Let's say you have a very nice ultrasonic toothbrush and you intend to use it for cleaning roadside burns—the kind of burn you get when your motorcycle crashes and your skin scrapes against the pavement. The toothbrush is used to remove the dirt, grit, and tarmac from the wound. It's an unusual intended use and raises all kinds of questions about potential damage from the bristles, safety features to prevent over-brushing, effects of ultrasound on open wounds, comparing gum tissue to wound tissue, instructions for use, and so on. A clinical evaluation for cleaning wounds will take longer and cost more than a report for brushing teeth with the same device.

CDG can help
Clinical Device Group is poised and ready to help you with writing your evaluations. We have medical writers, information specialists, experienced statisticians, a written procedure, a standard template, and a proven process. Clinical evaluations written by our specialists have been reviewed by at least three different Notified Bodies and all have been accepted. We work collaboratively with a point-person on your side so that you are involved in the process every step of the way.

References
[1] Medical Device Directive 93/42/EEC.
[2] Active Implantable Medical Device Directive 90/385/EEC.
[3] Global Harmonization Task Force, Study Group 5, Clinical Evaluations. http://www.ghtf.org/sg5/sg5-final.html
[4] MEDDEV 2.7.1 rev 3. http://ec.europa.eu/enterprise/sectors/medical-devices/files/meddev/2_7_1rev_3_en.pdf

 
Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

 

 

 

 

 

 

Relationship Building in Clinical Trials

A Whitepaper by Dr. Nancy J Stark

Relationship building is an integral part of the successful implementation of any clinical trial. You need good relationships with investigators, study staff, your project team, your colleagues, your boss, and your subordinates in order to successfully implement any project. One thing is for certain: they are not going to change. If you want a good relationship you will have to adapt to them.

Myers and Briggs are great heroines and role models to me. Imagine two women psychologists during World War II. Katherine Cook Briggs and her daughter Isabel Briggs Myers had plenty of obstacles stacked against them. They had only master's degrees, they were women, they were playing in a man's world, yet they developed a personality tool that is still used seventy years later. These two did original research extending Carl Jung's theories to practical applications in the workforce.

Why did it matter? Women were entering the workforce en masse without a clue as to what they would be good at: office work (quiet and peaceful), factory work (noisy and lots of yelling), data work (numbers and logic), design work (color, texture, image, spacial relationships), or whatever.

In this whitepaper I will attempt to adapt the work of Myers and Briggs to the critical task of relationship building in clinical trials. I use layman's language because I am not a psychologist. If you are, feel free to add your comments, corrections, contributions, and rebuttals below.

Jungian Background
The theory of personality type originates from the work of Carl Jung, who proposed that people perceive the world through two different functions: 1) the 'rational' (judging) functions of thinking and feeling, and 2) the 'irrational' (perceiving) functions of sensing and intuition. Jung went on to propose that these functions are expressed in either an introverted or extraverted form. From Jung's original concepts, Myers and Briggs developed their own theory of personality types. [1. Myers-Briggs Type Indicator]

Risk-Based Monitoring for Medical Device Firms on CD

We offer training for medical device firms on risk-based monitoring on CD. The course covers the details of the FDA guidance 'A Risk-Based Approach to Monitoring', recommendations on using it for device studies, includes a sample monitoring plan and template, and features QnA addressing issues unique to device manufacturers. CDs are nice because you can stop and start them, share with your colleagues, and build a library for new hires. The well-researched course is designed and presented by Dr. Nancy J Stark. Click here for more information or call 773-489-5706.

Understanding Personality Types
Myers and Briggs saw that there are four essential steps in how people relate to the world: 1) we focus on the world of our choice, 2) we perceive information, 3) we judge the information, and 4) we present the information to the outer world with a characteristic attitude. We do each of these four steps as either introverts or extroverts for a total of sixteen possibilities. For the sensors among us, I've tried to represent the concept in a simple, colorful visual image. [2. Gifts Differing]

As children we learn how to survive in the world that we know first: family and parents. And those survival skills are our default personality throughout life. As we gain experience and mature we learn to move out of our preferred personality type and become skilled at all possibilities, allowing us to act appropriately in different situations. But when under stress we tend to revert to the survival skills of our childhood. If we understand our own personality types, and become adept at discerning the personality types of others, we can adjust our behavior to build the best possible relationships with our colleagues.

[1] Focusing on the World: Introversion or Extroversion
People prefer to focus on either the inner world of thoughts and ideas (introversion) or the outer world of people and things (extroversion). Introverts do their best work in their heads in reflection; extroverts do their best work in the outside world, in action. Our focus on the world effects dramatically how we live in the world. Only an introvert would sit alone in their office and write this whitepaper. An extrovert will be impatiently waiting to get to the practical applications.

Introverts organize the facts and principles related to a situation and are good at researching material, writing protocols, or designing investigations; extroverts organize the situation itself, including any idle bystanders, to get things rolling. Extroverts are good at implementing clinical investigations.

Help and advice is a phone call away

Sometimes you want to discuss an issue, but implement the solution yourself. If you want advice, a second opinion, or someone to talk to about clinical, regulatory, biological safety, or reimbursement strategies, sign us up as consultants. Email us here or ask for Nancy at 773-489-5706.

Introverts work out their insights slowly and carefully, searching for eternal truths. Extroverts have an urge to communicate and put their inspirations into practice. Can you imagine the annoyance of an introverted study nurse when an extroverted monitor bombards her with emails to give her the latest study updates; or the annoyance of an extroverted (and eager) investigator when an introverted monitor is slow to communicate the start date?

[2] Perception, Taking in Information by Sensing or Intuition
Perception refers to how you get information from the outside world into your head. People take in information either by sensing or by intuition. Sensing means to become aware of information by our five senses: touch, smell, sight, sound, and taste. Intuition means to become aware of information through the unconscious. With intuition we incorporate our ideas or associations to what we sense with lightning speed and seemingly without logic.

Discuss a new device with a sensing person and they may tell you it is too lightweight, it is smaller than the current model, the materials aren't sturdy enough, but the display panel is clear and easy to read—all the information taken in by their senses. Sensing people are well suited for the demands of clinical trial monitoring. Practical and matter-of-fact, they see the world as it is rather than as it should be. They are often good project managers, following the project with Gantt charts, spreadsheets, drawings, flowcharts, and data. If both you and the investigator are sensors you may focus too closely on the details and lose sight of overall progress.

Hand an intuitive person the same device and they may answer, "This reminds me of my grandmother. She used this kind of device every day when I was a kid, we'd check in on her to make sure it was functioning properly and then play a game of checkers." Instead of focusing on the device, your intuitive colleague focused on her associations with it. [3 Tieger]

Intuitive people often have inspired product ideas, clever solutions to problems, or make associations that no one else would see. Intuitive people are good at picking up undercurrents, they know when a situation is 'off' even if they can't exactly tell you why. If both you and your investigator are intuitives, you may have imaginative conversations but not notice some study problems.

I had an extroverted, sensing boss who had a rule that we could present no more than three possibilities to him. If he asked you what went wrong, you had better not give him a list of five things. If he asked you for a recommendation, you had better not have more than three. His intuitive, data-loving subordinates were terrified.

“Readers who are sensors will tend to confine their attention to what is said here on the page... readers who are intuitive are likely to read between and beyond the lines to the possibilities that come to mind.”

[3] Judging, Processing Information by Thinking or Feeling
Judging refers to how you process the information you take in. Thinkers use a logical process aimed at reaching an impersonal finding. Feelers use an emotional process of viewing information in a personal, subjective manner.

The thinking protocol writer may make a list of all the data elements they think are necessary to meet the purpose of the new clinical trial. As they develop the protocol they use their list of data elements as an absolute guide. They are not swayed by pleas from marketing to include questions they have already dismissed as unessential or exclude questions because "it is knowledge we would rather not have." Thinking writers may try to collect too much data in a clinical trial—oblivious to the impracticality.

If, as a member of the project team, you want additional data elements included in the study you should listen closely to the thinking writer's rationale for omitting them, be respectful of their reasoning, and use facts and data that relate back to the trial's purpose to persuade them to make the change. Thinking people objectify situations—dealing in facts, figures and data; they do not respond well to insincere flattery. (My husband is even suspicious of sincere flattery, I only tell him he has done a good thing when I know he already thinks so himself.)

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Our professional monitors are experienced in risk-based monitoring of device studies (because that's how device studies are often done), they know how to work with all personality types, their goal is to worry so you can sleep at night. Our Network Staff has been involved in dozens of device trials and hundreds of issues; their extensive knowledge can solve your problem de jour. Click here to request a proposal for clinical research services from CDG or phone 773-489-5706.

A feeling person may make a list of data elements but it will have little influence on the final protocol design—the decision to collect data is made because it “feels” right. The decision is made first, and a rationale is developed later. A thinking monitor who is ill-at-ease with the site's data collection should be delicate with a feeling investigator who is confident the device works, but they should not back down. They should challenge the data with facts while being thoughtfully respectful of the investigator's mode of processing information.

Another consequence of thinking and feeling personalities is how they relate to each other. Feeling people subjectify situations—anticipating how facts, figures and data will affect the people involved. A feeling monitor (such as myself) might have difficulty enforcing an important requirement, say, for dating an informed consent, because it causes too much inconvenience to the investigator. The feeling person’s prime motivation is harmonious relationships, not regulatory compliance. A sensing boss has no difficulty pointing out the monitor's deficiencies.

“A reader who first considers whether an idea is consistent and logical is using a thinking process. A reader who first considers whether an idea is pleasing or displeasing, supporting or threatening, is using a feeling process.”

[4] Attitude to the World: Perception or Judgment
Our attitude in presenting information to the world is a reflection of which personality type is more strongly developed, perception or judgment. Attitude or "face" refers to how you present information back to the outside world. For extroverts, attitude is a reflection of the personality type that is dominant. For introverts, attitude is a reflection of the personality type that is subordinate because they reserve their favored, dominant preference for the more highly prized, inner world. In other words we know exactly what extroverts think and we never know what introverts think.

People with perceptive attitudes maintain an open mind regarding situations, continuing to seek additional information that can broaden and deepen their understanding. If pressed, they will disclose the facts, but they will refrain from telling you what it means or predicting the outcome. Perceptive people make others feel safe and accepted, and are valued members of any project team because they keep an open mind. Project managers with perception attitudes may be reluctant to move the action forward. They are more likely to delay conclusions or fail to act at all. They can be positively frustrating to bosses who who are at a critical decision-point.

Persons with judging attitudes shut off their perception (at least for the moment) and make a judgment. They may not have all the facts, but they can certainly tell you what they mean. Monitors or project managers with judging attitudes will have strong opinions about the value of a project, work product, piece of data, or whitepaper; and will freely share that opinion with listeners. They are more likely to come to wrong conclusions, a positively frustrating behavior to bosses who want to be sure before acting on a recommendation. But judgers are an essential component of a well-functioning project team; they bring issues to closure and move the project to the next step.

The Queen of Hearts in Lewis Carroll’s classic novel Alice in Wonderland had a typical judgment attitude (as well as being an impatient extrovert). “Off with her head, we’ll have the execution now and the trial later!” she said.

“Readers who are still following this explanation with an open mind are using perception, readers who have decided by now that they agree or disagree with me are using judgment.”

Putting It to Practice
The most important step in building relationships is the first one: know thyself. To help you get over the embarrassment of digging so deep into your psyche, I'll tell you that I am an introverted, sensing, feeling, judger (an ISFJ.) I live in my head, which is far more fascinating to me than anything going on outside; furthermore you will never know what I really think. I take in information by my senses: are there data-gaps, are the facts consistent, do I trust the source, do I need more information? I am a feeler, use the wrong word (mismanagement versus bad economy) and your conversation with me is over. And I am a judger, I have an opinion about almost everything, a quality essential for writing whitepapers or editorials.

Happily we are not stuck on home base. With time and experience I have learned to behave like an extrovert, make a rare intuitive leap of logic, be objective in my assessment of a situation, and withhold judgment until the facts are in—at the cost of a great deal of psychological energy. The hallmark of maturity isn't balance, but being able to move freely from one extreme to the other as the situation demands.

The next step is understanding your colleagues. Changing them is not your goal or your business, and anyway it won't work. The goal is to build relationships that will facilitate the successful completion of your trial. If you're working with an introvert be respectful of their privacy; if you're working with a extrovert enjoy the excitement. If your working with a sensor be prepared with facts and details, if with an intuitive go for the big picture. If your working with a thinker be logical in your presentation, if with a feeler never, never, never say "you". If your working with a perceptive be patient while they work through information on their own, if with a judger you may want to slow them down. The best project teams have someone of every personality type.

Relationships are complicated by supervisor/subordinate, client/consultant, parent/child, wife/husband, boyfriend/girlfriend, addiction, religion, politics, culture, heritage, wealth, and so much more; there is no one simple answer to building good relationships. But understanding personality types and adjusting our own behavior to meet the needs of our colleagues in order to meet the goal, is something we can all do.

References
[1] Myers-Briggs Type Indicator, Wikipedia, the free encyclopedia.
[2] Isabel Briggs Myers with Peter B Myers, Gifts Differing, Understand Personality Type, Davies-Black Publishing, Palo Alto, CA, (1980).
[3] Teiger PD, Barron-Teiger B, The Art of SpeedReading People, Little, Brown & Company, New York (1998).


Questions or Comments?
Please post your questions, comments, contributions, and rebuttals below.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

Risk-Based Monitoring—The New FDA Guidance

An Op-Ed by Dr. Nancy J Stark

FDA's draft guidance, "An Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring" (August 2011) references the ICH-GCPs six times. The ICH-GCPs were written in 1996 by pharmaceutical sponsors and regulators from the US, Europe, and Japan. It is 15 years old and is showing a few signs of age—there is no discussion of central data management or electronic security issues, for example. But because the phrase 'good clinical practice' is in the public domain, ICH was free to adopt it as part of the title of document E6, "Good Clinical Practice: Consolidated Guidance." The Center for Drugs published the guidance in the Federal Register giving it high standing in the regulatory community.

Although used by device manufacturers, the guidance does not work well. It's description of an Investigator's Brochure is chemically-centered not mechanically-centered, investigational devices are stored and dispensed but never installed, there is no mention of training an investigator to use the investigational product, there is no mention of software-controlled devices or software collected data, no mention of caregiver or healthcare provider safety; in other words, for medical devices, the ICH-GCPs are inadequate and out-of-date.

ISO 14155 'Clinical investigation of medical devices in human subjects—Good clinical practice' (2011)—the internationally definitive document for medical device clinical studies—is not mentioned even once; yet the international standard was closely harmonized with ICH-GCP to promote international continuity. I could live with the lack of acknowledgement in FDA's guidance if the same FDA Office hadn't taken such a heavy hand in writing the ISO standard. It is wrong to insist on practice-changing language (such as moment of consent versus moment of enrollment) and then turn your back on the work product as FDA seems to have done.

The draft guidance draws heavily on the ever-increasing presence of electronic data collection. A really cool EDC system can spot a lot of site problems before the human eye ever gets to the data. But these systems are expensive (think in terms of a $1M for a modest study) and unaffordable to small start-ups.

Finally, it was the Offices of Compliance from CDRH, CDER, and CBER who wrote this guidance. While they promise us the inspection manual will be promptly updated to match the guidance, they do not make assurances that the reviewers in the Office of Device Evaluation will follow along. Sponsors are strongly urged to get buy-in on the monitoring plan from reviewers before initiating a clinical trial.

While device manufacturers can use the new guidance to their benefit, often to defend existing practices, they should make certain FDA's Office of Device Evaluation buys into any IDE monitoring plan.

 

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Risk-Based Monitoring—The New FDA Guidance

A Whitepaper by Dr. Nancy J Stark

In August of 2011 FDA released a draft guidance document titled "Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring." At first I was very excited because the monitoring guidelines had not been updated since the 1988 "Monitoring of Clinical Investigations." But then, as I began to consider the ramifications of implementing the new guidance for medical device investigations I started to have mixed feelings. The first part of this whitepaper is a factual review of the draft guidance with ideas about how device manufacturer's can take advantage of it. The second part (next blog) is an op-ed expressing my views about what it will mean for the device industry. [1.Risk-Based Monitoring Guidance] [2. Monitoring of Clinical Trials]

Two points stand out as noteworthy before we begin: 1) the draft guidance was written by the Office of Compliance not the Office of Evaluation, and buy-in from an IDE reviewer is uncertain, and 2) the draft guidance addresses itself to drugs with a mere mention of devices as an afterthought, so most concepts have to be 'retrofitted' to device needs.

Part One: Review of Guidance
Risk-Based Monitoring
The draft guidance is based on the premise that most sponsors conduct on-site monitoring visits every 6-8 weeks with the goal of source verifying 100% of the data 100% for 100% of the subjects. It uses this premise to argue that sponsors will save money by moving to risk-based monitoring because such a move will result in fewer monitoring visits. Risk-based monitoring probably will result in fewer on-site visits for big pharmaceutical firms, who may be 'conducting hundreds to thousands of trials in locations around the world'. [3. Quality Management in Clinical Trials] But start-up medical device companies have never monitored as heavily as the guidance assumes and, in that sense, the principles risk-based monitoring won't save on monitoring costs.

The guidance suggests that we use fancy statistical algorithms and analyze real-time data as it comes into electronic data capture systems to identify high-risk sites or high-risk data. The algorithm could be something like 'Risk Priority Number = severity x likelihood of occurrence x detectability'. A Risk Priority Number is calculated for each identified risk. When high-risk sites or data exceed a trigger, they merit immediate, onsite monitoring visits. [3. Quality Management in Clinical Trials]

CDG's Risk-Based Monitoring Course on CD—Available Now!

Training on risk-based monitoring is now available from CDG! The course covers the details of the FDA guidance 'A Risk-Based Approach to Monitoring', recommendations on using it for device studies, include a sample monitoring plan and template, and features QnA addressing issues unique to device manufacturers. The well-researched course is designed and presented by Dr. Nancy J Stark. Click here for more information or call 773-489-5706.

High risk sites and high risk data
A high-risk site is a site with a high probability of having a problem; the 'symptom' might be that they are enrolling at a slower or faster rate, experiencing a higher or lower rate of adverse events, or having a higher rate of non-compliances than other sites. For example, one site I worked with suddenly stopped enrolling subjects altogether. The sudden change in enrollment pattern should have triggered an on-site monitoring visit. We eventually learned the site had enrolled the same subjects in multiple trials and compromised everyone's data. The site stopped enrolling because they were being audited by other sponsors for fraud.

High-risk data might be a particular type of event or outcome that is a 'symptom' of a problem with the study. For example, a high rate of post-procedure embolism might indicate a poorly trained investigator or a problem with subject selection.

The guidance suggests that any site in the start-up phase of the study is a high-risk site and that on-site monitoring should be performed at every site in the study's early stages.

Device companies can adopt the same principles using low-cost methods. Have the sites fax or scan the case report forms to the monitor once a week for off-site monitoring (i.e. remote monitoring). With one trial and maybe 100 subjects, a monitor can easily examine the case report forms manually for high-risk sites or data without the need for statistical algorithms.

Critical data and processes
Critical data and critical processes are the types of data and processes most likely to be high risk. Critical data include: [1] evidence that the subject really exists, [2] evidence that subject has the disease or condition being studied, [3] evidence that IRB approval was obtained, [4] evidence that informed consent was signed before the intervention or procedure, [5] endpoint data that address the hypothesis, and [6] serious adverse device effect data. For each study you'll need to make a unique list of endpoint data and adverse device effect data that is critical.

Critical processes include [1] the process of obtaining informed consent, [2] the intervention or procedure, [3] timely reporting of regulatory non-compliances or study deviations, [4] timely correspondence with a data safety monitoring board (if one exists), and the like. Because studies vary so much from each other, you'll need to make a unique list of critical processes for each one.

Critical data and processes are most likely to be high risk and should be checked for closely during the off-site monitoring process.

CDG has monitors experienced in risk-based monitoring

Our outsourced monitors come in with the attitude of service, impermanence, and an enthusiasm for the new; they are accustomed to off-site monitoring and problem spotting. They also carry a breadth of experiences that can help solve the issues de jour. Click here to request a proposal for monitoring services from CDG or phone 773-489-5721.

Methods of monitoring
Next the guidance considers two different methods of monitoring; on-site monitoring and 'centralized monitoring', meaning the real-time analysis of data by an application running on a server in some data management center.

I propose that for device studies there are four methods of monitoring: [1] on-site monitoring, [2] off-site monitoring of faxed or scanned case report forms, [3] off-site monitoring of electronic ally captured data, and [4] off-site monitoring of source data that has been captured by the device (usually in vivo or in vitro diagnostic devices.) Often data card is changed out on-site and the data card analyzed off-site. Sometimes the data card may transmit data electronically via the internet—consider a digital camera used to take photographs of the procedure. In the future, of course, it may even be possible to remotely access electronic medical records.

The idea, then, is to use the most expensive method of monitoring (on-site) for sites or data or processes that are critical and high risk and to use less expensive methods of monitoring (off-site or remote) for sites and data that are less so. It is a welcome concept to device manufacturers who are cash-starved and looking for ways to economize.

Triggers
The idea of a trigger is that some server at a data management center somewhere is programmed to alert you if critical data or a critical process has become high-risk; i.e. has the value or frequency of a critical data element or critical process step changed in such a way as to demand attention. Indeed, if hundreds or thousands of sites are reporting data every day, you will need a program to screen the information for anomalies or outliers.

But since most device firms are doing only a few studies at a time, having the case report forms faxed or scanned to the monitor for remote viewing is an inexpensive alternative. The monitor checks the forms for, [1] completeness (no missing data), [2] contemporaneousness, [3] legibility, [4] logic, [5] adverse device effect reports. The forms can be checked for everything except source verification. The monitor issues and resolves queries for any issues observed. Most triggers are found by simple observation.

Then the case report forms are forwarded to the data center where the data are entered into a local (often non-networked) computer. Here the data may be statistically analyzed to see if a site, data element, procedure or process step is at risk and merits an unscheduled, on-site monitoring visit.

Monitoring Plan
A monitoring plan should be developed for every study. This requirement is not new to sponsors conducting IDE studies or European studies under ISO 14155, but the guidance makes clear recommendations for the format. I recommend you develop a template for a separate document that can be referenced in the protocol, and don't make the monitoring plan a part of the protocol itself.

Section One—Study Description
As a separate document, the first section describes the protocol, investigational device, purpose of the study, and other obvious reference information. You need to describe, [1] the monitoring approaches you will use for the study, [2] criteria for determining the timing, frequency, and intensity of planned monitoring activities, [3] specific activities required for each monitoring method employed during the study, including
reference to required tools, logs, or templates, [4] definitions of events or results that trigger changes in planned monitoring activities for a particular clinical investigator, and [5] identification of possible deviations or failures that would be critical to study integrity and how these are to be recorded and reported.

A second opinion is a phone call away

Sometimes to you want to discuss an issue, but implement the solution yourself. If you want a second opinion about clinical, regulatory, biological safety, or reimbursement strategies, sign us up as consultants. Email us here or call Nancy at 773-489-5721.

Section Two—Reporting
Section two of the monitoring plan should discuss the communication of monitoring results to management, review boards, and regulatory bodies. It should describe the format, content, timing, and archiving requirements for reports and other documentation. For example, if the monitor receives case report forms by fax or email, it makes sense to require, say, a weekly or monthly report. Section two should discuss the process for appropriate communication of the findings to management, review boards, and regulatory bodies.

Section Three—Noncompliances
Section three of the plan should discuss the management of noncompliance. How, and who, will follow up with investigators found to be non-compliant with the regulations, protocol, or IRB requirements? If non-compliances persist will the site be retrained, terminated from the study, or will some other action be taken? If protocol deviations are detected you need a plan for root cause analyses. Problem-solving has always been a part of a monitor's responsibilities in device trials and it may require an on-site visit to really assess the problem. I have had the root cause to be such simple things as the data transcriber needing spectacles, a three-hole punch, or a dedicated phone line. Eyes-on may be the only way to detect such problems so they can be solved.

Section Four—Training
Section four of the monitoring plan should describe specific training for monitors and internal data auditors, especially with the detection of triggers and recommendations for on-site monitoring visits. For device studies, I recommend section four also discuss training plans for investigative site personnel. This section should also describe plans for random quality audits.

Section Five—Amendments to Monitoring Plan
Section five describes the process for amending monitoring plans. What events may require review and revision of the monitoring plan and establish processes to permit timely updates when necessary?

Much of sections Two to Five can be incorporated into the clinical research quality management system. By developing procedures for off-site monitoring you won't have to repeat them in every monitoring plan.

References
[1] 'Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring' FDA, August 2011. http://www.fda.gov/downloads/Drugs/.../Guidances/UCM269919.pdf
[2] 'Guideline for the Monitoring of Clinical Investigations' FDA, January 1988.
[3] 'Quality Management in Clinical Trials', March 2009, Clinical case series from Pfizer.

Clinical Trial Agreements

A Whitepaper by Nancy J Stark

Clinical trial agreements (CTAs) are the legally binding agreements between a sponsor and an institution (site) as to how certain business and property rights will be dealt with between the parties. These agreements are separate from Investigator Agreements and Confidentiality Agreements and are not regulated by FDA or disclosable to FDA. CTAs are important because they allocate risk, responsibility, financial support, and obligations of the parties; and they protect the rights of the parties.

Usually the sponsor presents an initial draft of the agreement to the institution, and then each of the terms and conditions are negotiated by the party's attorneys. Agreements follow a typical format of: preamble, acknowledgements and responsibilities, term and termination, payment and reimbursement of costs, HIPAA and patient privacy, publication, data ownership and use, intellectual property, indemnification and insurance, subject injury, best efforts, waiver of consequential damages, miscellaneous (export controls, governing law, and dispute resolution/arbitration/mediatio, exhibits), and signatories. (1. Perry-Northwestern University)

 

The most common problem areas are publication, data ownership and use, intellectual property, indemnification and insurance, subject injury, best efforts, and signatories. In the text below I explore these problems and solutions suggested through various model CTA templates. (2. Weill Medical College of Cornell.) (3. UIDP) (4. MAGI) (5. Arizona template) (6. IOM template)

Conflicting missions
Universities, teaching hospitals, and other not-for-profit institutions are grounded in the principles of academic freedom and the discovery and sharing of information. Furthermore, in order to maintain a tax-exempt status, they must fulfill certain duties such as education of students, creating generalizable knowledge, or dissemination of knowledge. (7. Guiding Principles)

Sponsors, manufacturers, and other for-profit firms have commitments grounded in creating value for their shareholders, providing useful goods and services, and expanding the state of the art. They contribute to society by developing and providing new technologies to ease the medical conditions of mankind, but they must be profitable to survive.

Since neither party can live without the other, the challenge is to find contractual language that supports the mission of each within the constraints that limit them.

[F] Publication
The publication clause outlines who can publish what, and when. The clause is important to industry because they need to hold early developmental information confidential until the design of the device has matured into a functional, manufacturable, and marketable configuration. Revealing information too early, or revealing the wrong information, may allow your competitors to learn from your mistakes. Sponsors are also concerned about the accuracy of reporting, both of data and of product descriptions. And for multi-center studies, solutions are needed that allow for a complete manuscript incorporating results from all sites, and which pre-determines the order of authors.

Conversely, a non-profit institution needs to publish new knowledge. Publication creates recognition of the investigator's efforts, allows results to be used in future trials, enhances the site's prominence, contributes to public knowledge, and allows graduate students to use the data for their theses.

A typical industry draft clause might say, in essence, "Institution shall submit to Sponsor a copy of any proposed publication at least 90 days prior to submission for review and approval."

Compromise language suggested by the University of Arizona is, "Sponsor has no objection to publication by Institution of the results of the Study based on information collected or generated by Institution, whether or not the results are favorable to Sponsor. However, to ensure against inadvertent disclosure of Confidential Information or unprotected Inventions, Institution will provide Sponsor the opportunity to review any proposed publication or other type of disclosure at least thirty (30) days before it is submitted for publication or otherwise disclosed. If any patent action is required to protect Inventions, Institution agrees to delay the disclosure for a period not to exceed ninety (90) days from the date Institution initially submitted the proposed publication, or other type of disclosure, to Sponsor for review. Institution will, on request, remove any Confidential Information before disclosure.

If Study is part of a multi-center study, Institution agrees that the first publication is to be a joint publication covering all centers. However, if a joint manuscript has not been submitted for publication within twelve (12) months of completion or termination of Study at all participating sites, Institution is free to publish its results separately…." (5. Arizona template)

[G] Data ownership and use
Data ownership and use is another common sticking point. Sponsors may argue that they "own" the data because they have paid for it, but Institutions counter that they cannot retain their non-profit status if they engage in contract research or "work-for-hire". Institutions want to protect the right to use study data for non-commercial, research, development, and educational, purposes.

A typical industry draft clause might read, "All study data shall be the sole and exclusive property of Sponsor."

MAGI offers this compromise clause, "Site owns all Source Documents. Sponsor owns all Sponsor Data. Site owns all Specimens and Genetic Data, and grants Sponsor access to such property only for purposes of the Study. Sponsor and Site may freely use their own data subject to Subject consent and IRB approval. In addition, Site may freely use Sponsor Data after first multicenter Publication is published or Sponsor waives right to a multicenter Publication. Sponsor has no right to Site’s pre-existing biological samples, genomic database, or other proprietary database." Sponsor Data is defined as, "Study lab test results, CRFs and other reports completed by Site or Investigator per the Protocol, Agreement or other written instruction by Sponsor, excluding Source Documents and Genetic Data. Specifically excludes results derived from analysis of data." (4. MAGI)

ISO 14155 "Clinical investigation of medical devices in human subjects—
good clinical practice" (2011)

What makes this ISO 14155 training so special? The author served on the Editing Committee of Working Group 4, the inner circle of individuals who put finger-to-keyboard and wrote the standard. In this three-hour recorded training Dr. Stark discusses the standard in a topic-by-topic format; identifying what is new, what were the controversies, and what was the Working Group's thinking in adopting the language it did. It is this background information that helps you apply the standard appropriately to your study.

You can buy this newly released training on CD on our website cdginc@clinicaldevice.com or by phoning 773-489-5706. Private training from Dr. Stark is also available.

[H] Intellectual property
Intellectual property is a little different than data ownership, in that it covers who has the right to obtain a patent, or own an invention, development, or discovery.

A typical industry draft clause may read, "Any inventions made as a result of Institution's performance of this Agreement will be disclosed promptly to Sponsor and shall be deemed the property of Sponsor." But again, the sale of information is at cross-purposes with the non-profit mission of the institution.

The University of Arizona offers this compromise clause, "Inventorship of any inventions, developments, or discoveries, whether patentable or not (collectively referred to as "Intellectual Property"), resulting from the performance of the Study, shall be allocated according to U.S. Patent law (Title 35 U.S. Code) in effect at the time the Intellectual Property was created…." (5. Arizona template)

[I] Indemnification and insurance
Indemnification is language whereby one party agrees to protect another against an anticipated loss or damage; insurance is a policy through a third-party which guarantees payment to cover the costs of loss or damage. Although FDA does not require sponsors to carry insurance to cover the possibility of loss or damage to the Institution resulting from the study, most Institutions will have insurance requirements for sponsor-initiated clinical trials. In the event a sponsor in unable to meet the insurance requirement, the study will probably undergo a clinical risk assessment via which the institution attempts to assess the likelihood of loss or damage.

A typical industry draft clause might read, "Sponsor shall indemnify and hold harmless Institution from any damages and liability that are caused by Sponsor's negligence."

A compromise clause might read, "Sponsor shall indemnify, defend, and hold harmless Institution from any damages and liability that arise out of the proper administration of the Study device, Study-required procedures, Sponsor's use of the results, or Sponsor's negligence or breach of the Agreement."

[J] Subject injury
While indemnification and insurance have to do with loss and damage to the Institution, the issue of subject injury has to do with loss and damage to the subject. Sponsors readily agree to provide subject injury coverage if it is determined the injury is related to the investigational device, but who gets to make the determination? Good clinical practice tells us the principal investigator makes this determination.

Some sponsors like to add a clause that they will not pay for injuries until insurance is billed and denied. But billing third-party payors, whether Medicare or private insurance, should be at the Institution's discretion. If the injury is related to the medical device there should be no billing.

Some sponsors are concerned with injuries that are, in fact, attributable to the underlying illness. A solution is to qualify underlying illness by saying, "to the natural progression of the underlying illness."

Some sponsors try to limit their liability if the injury is attributable to the negligence of the study subject or the failure of the study subject to follow the instructions of the Principal Investigator. But such thinking is contrary to current ethical standards. Subjects are donating the use and study of their bodies for other people's gain; there may be little or no benefit to them beyond the satisfaction of contributing to the world's knowledge. Either the institution, sponsor, or third-party payors should bear the cost of their injury regardless of it origins.

IOM's suggested language is, "The Sponsor shall reimburse actual and reasonable medical expenses incurred in treating any injury or illness to a Study Subject that is directly related to the administration of the Investigational device or the proper performance of any other procedure, each in accordance with the Protocol and the Sponsor’s written instructions to the Institution (or to the extent that the Sponsor’s written instructions conflict with the Protocol, the Sponsor’s written instructions to the Institution only). The Sponsor is not required under this Section to provide compensation for (a) other injury- or illness-related costs (such as lost wages), (b) medical expenses that are paid for by a third party (provided that neither the Institution nor the Study Subject shall be obligated to seek reimbursement from a third party insurer), (c) medical expenses that are incurred as the result of a violation of the Protocol or other misconduct or negligence, in each case by any agent or employee of the Institution (including the Study Staff), or (d) medical expenses for injury or illness unrelated to the Investigational Device and unrelated to the proper performance of any other procedure required by the Protocol or Sponsor’s written instructions to the Institution." (6. IOM template)

Arizona offers a simpler suggestion, "Should a subject suffer any adverse effect caused by the Study drug/device/biologic, the Study procedures, or laboratory work required by the Protocol, Sponsor will pay for all medical and hospital costs required for the diagnosis and treatment of such adverse effect." (5. Arizona template)

[K] Best efforts
Consultants (such as Clinical Device Group) know that research projects are dynamic. No wise Institution, consultant, or research contractor should agree to work under time, cost, and performance constraints. Deadlines and results cannot be guaranteed. Furthermore, work product is constrained by the laws and standards of the United States.

One might think the Sponsor is left defenseless, but this is not the case. Institutions will agree to a "best efforts" clause, a contractual provision which requires the institution to use its highest efforts to perform its obligations and to maximize the benefits to be received by the sponsor. Sponsor's are obligated to terminate a site's participation in a study if non-compliances to protocol or regulations are discovered. And sponsors always have the right to terminate a study for business or ethical reasons. Cost overruns, project delays, or non-performance (of investigator or device) are all legitimate business or ethical reasons for terminating a study or an institution's participation in a study.

[N] Signatories
Industry sponsors sometimes don't realize the employee-employer relationship between investigators and investigative sites and they propose to have the investigator sign the CTA. They're also concerned about the performance of the investigator because of their financial investment in the trial.

A typical industry suggestion for the signatory clause is, "This Agreement is entered into by and among Sponsor, Investigative Site, and Principal Investigator." But if you think about it, an investigator—as an employee of the institution—has no legal authorization to sign the CTA.

A compromise clause is, "This Agreement is entered into by and between Sponsor and Investigative Site. The Principal Investigator shall conduct the trial as an employee of the institution and not as a party to this Agreement." Then the Principal Investigator is asked to sign the Agreement to indicate their understanding and intention to comply.

Conclusion
Sponsors and Institutions both have a vested interest in performing clinical research, and each party has much to gain from the process. By thinking through the issues and appreciating the needs of the other party, it is possible to come to an Agreement that is fair, balanced, and meets everyone's needs.

References
1. My thanks to Sean Perry, JD, Sr. Contract and Grant Officer, Office for Sponsored Research, Northwestern University, Chicago for his insights into this topic.
2. The format is taken from Clinical Trial Agreements, Weill Medical College of Cornell University, Office of Clinical Trials Administration. Contact CDG for link.
3. University-Industry Demonstration Partnership (UIDP), National Academy of Sciences, http://sites.nationalacademies.org/PGA/uidp/PGA_060368.
4. MAGI Model Clinical Trial Agreement, https://www.magiworld.org/standards/.
5. Template for Clinical Trial Agreement, University of Arizona Board of Regents, http://www.orca.arizona.edu/ctas.html.
6. Template for Clinical Trial Agreements, Developed by Jim Snipes, Covington & Burling LLP for the Institute of Medicine, April 2009. Contact CDG for pdf copy.
7. Guiding Principles for University-Industry Endeavors, National Academy of Science and the National Council of University Research Administrators and the Industrial Research Institute, April 2006.

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

 

 

Reimbursement Strategies for New Technologies

A Whitepaper by Dr. Nancy J Stark and Dr. Vincent Jaeger

Reimbursement strategies
A reimbursement strategy is a plan for: 1) working in clinical research to design studies that show "medical benefit" and "added value" to secure coverage; 2) identifying codes for new technologies (i.e., drugs, medical devices, medical and surgical procedures and services); 3) working with the FDA to phrase the intended use and indications for use to fit coverage and coding; and 4) presenting the clinical trial data to the Centers for Medicare and Medicaid Services (CMS) for reimbursement approval. Ideally, reimbursement strategies must be part of the early-on process of development for every new technology. Unfortunately, most manufacturers wait until they launch their product or are faced with resistance from Medicare before they begin to formulate a pathway toward reimbursement.

Reimbursement is the primary driver to profitability of a new technology in that it assures the all-important revenue stream that keeps a company viable. Medicare, by far the largest third-party payer, is limited by the Social Security Act to only cover technologies that are "reasonable and necessary" for diagnosis or treatment of diseases, conditions or injuries. (1 Social Security Act) In this whitepaper, Dr. Vincent Jaeger and I will review only the Medicare reimbursement process with the understanding that, because of its size and influence, private payers will usually adopt the same or similar coverage, coding and payment policies.

The challenge of new 510(k)'d technologies
Isn't it interesting that one of FDA's missions is to foster medical device innovation, (2 FDA & Innovation) but CMS has no parallel mission to reimburse it? Approximately 5000 510(k)s are cleared by the FDA each year, and most of these represent incremental improvements to medical devices and other technologies already on the market. Medicare’s bundled payment systems, i.e., diagnosis-related groups (DRGs) for inpatient care and ambulatory payment categories (APCs) for outpatient services, allow payment for incremental improvements without additional clinical evidence. Most 'new' technologies fall into the bundled payment system and do not face a full reimbursement challenge.

 

Although it is often possible to make a substantially equivalent argument to the FDA and gain 510(k) clearance to market a new technology, the technology may not meet Medicare's bundled-payment requirements or qualify for reimbursement. Some start-up manufacturers don't realize that it can take 3-4 times as long or more to gain CMS coverage as it took to get 510(k) clearance and that approaching the necessary activities to gain reimbursement in a sequential manner will unquestionably add to the overall timeline. The most serious obstacle facing manufacturers is not gaining FDA approval, but securing a positive reimbursement decision by Medicare.

Reimbursement decision process
The term reimbursement is used to describe activities related to the mechanisms by which patients have access to medical technologies through their health insurance payer. The elements necessary for reimbursement are: [1] coverage; [2] coding; and [3] payment. (3 Innovators' Guide) It is most important that a strategic plan is begun early in product development to ensure a positive coverage and reimbursement outcome. It is imperative to develop parallel regulatory, clinical and reimbursement paths that address the needs of both the FDA and the payers who ultimately control the technology’s marketing destiny through their policy-making decisions. Hospitals and physicians may use the device, but public and private payers reimburse and they set the rules.

 

Coverage
Coverage refers to the terms and conditions under which Medicare and private payers will (or will not) provide payment for drugs, services, procedures and medical devices. Coverage is the first, and unquestionably the most important, component of the reimbursement process. The decision for or against coverage of a new technology is directly related to the presence of valid scientific evidence from well-designed comparative clinical trials published in the peer-reviewed medical literature. The evidence must support the medical device’s effectiveness in substantially improving health outcomes over existing technologies. Over the last twenty years a system for ranking the quality of evidence has been developed and is known as evidence-based medicine. (4 Jaeger) Randomized, blinded, controlled clinical trials designed to overcome the many possible sources of bias rank as the highest quality of evidence. Testimonials rank as the lowest quality of evidence. (5 Evidence)

In May 2000 Medicare published a Notice of Intent (NOI) proposing a set of criteria to be used for determining which items and services are reasonable and necessary and therefore eligible for coverage. (6 NOI) The NOI proposed that technologies must demonstrate "medical benefit" as well as "added value." But just how medical benefit and added value should be measured remains controversial.

.....Registry studies
Randomized controlled trials (RTCs) for new technologies are sometimes difficult to conduct because physicians, surgeons, interventionists and patients are often reluctant to compare the new technology to an existing standard of care. And blinding device studies is usually an impossibility.

In these circumstances, registry studies, conducted according to the Agency for Healthcare Quality and Research (AHRQ) "Registries for Evaluating Patient Outcomes: A User's Guide", lend themselves well to comparative studies for commercial medical technologies. (7 Registry User's Guide) (8 Stark) Registry studies have been successfully used by manufacturers to gain CMS coverage. (9 CMRI) A registry study is research carried out in a prospective, observational manner in which subjects with certain shared characteristics are studied, and ongoing and supporting data over time is collected on well-defined outcomes of interest for analysis and reporting. Investigators are instructed to select and use 510(k) cleared devices as they would in their normal practice. The protocol refrains from dictating treatment or follow-up care. The value is that objective, observational data comparing new technologies to other technologies already being used can be gathered. These effectiveness data address benefits, outcomes, complication rates, adverse events, and deficiencies in real practice settings.

Don't be misled, a well-controlled registry study costs about the same as a well-controlled clinical trial. It requires a protocol, case report forms, informed consent, IRB review, monitoring, data collection, data analysis and a final report. The regulatory advantage is that the study is exempt from the Code of Federal Regulations (CFR), Title 21, Part 812 - Investigational Device Exemptions.

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Codes, codes, codes
There is no lack of codes. There are current procedural terminology (CPT) codes used primarily to identify medical and surgical procedures and services performed by physicians and other health care professionals. ICD-9 (International Classification of Diseases, 9th Revision) codes, used in both the inpatient and outpatient settings, convey a patient’s diagnosis(es), and provide the medical justification for the episode of care for which the provider is filing a claim. There are ICD-9 procedure codes primarily used by hospitals to identify and define procedures performed during an inpatient stay. Codes for diagnosis related groups (DRGs) are a classification system developed by Medicare as part of the prospective payment system for inpatient care. There are T-codes for emerging technologies, as well as nondescript codes (-99 codes) to identify new medical technologies until a specific code is assigned. Healthcare Common Procedure Coding System (HCPCS) codes are intended to report supplies, medical equipment and services that are regularly billed by suppliers, not physicians. (10-Clark) ICD-10 will add a new complexity to the mix in 2013.

In other words, code sets have been created to accurately describe and convey information between the various providers of healthcare and payers about medical diagnoses, procedures, products and services rendered to patients. These codes, when placed on a claim form, operationally link coverage to payment. When seeking reimbursement, it is better for the manufacturer to have an existing CPT code that adequately describes the procedure which is recognized by payers as valid for payment levels acceptable to physicians.

  

No Codes?
If there is no existing code which adequately describes the new medical technology, application for creation of a new code must be made to the appropriate committees within CMS and the American Medical Association (AMA): ICD-9 diagnosis codes to CMS, CPT procedural codes to the AMA, and HCPCS codes to CMS. New code applications are received on strict deadlines and take a long time for approval, which certainly is a major factor in the long delay for reimbursement approval by Medicare.

....Step 1—CPT
The first step in obtaining codes is to apply to the American Medical Association (AMA) for a CPT code. The AMA first developed and published CPT in 1966. The first edition helped encourage the use of standard terms and descriptors to document procedures in the medical record, helped communicate accurate information on procedures and services to agencies concerned with insurance claims, provided the basis for a computer oriented system to evaluate operative procedures, and contributed basic information for actuarial and statistical purposes. (11 AMA & CPT codes)

 

To ensure that physician services across all specialties are well-represented, the AMA established the Relative Value Scale Update Committee (RUC). Annually, the RUC makes recommendations regarding new and revised physician services which are then accepted, rejected or modified by CMS. As such, the RUC significantly influences the relative value units (RVUs) of CPT codes and, as a result, how much physicians are paid. The impact of the RUC becomes even more important when one considers that Medicaid and private payers tie their fee schedules to Medicare's.

The first step in obtaining a new CPT code is to make application to the AMA, specifically, to the Department of CPT Editorial Research and Development. The AMA staff reviews all applications to evaluate their coding suggestions. If they determine that the request is a new issue, or significantly new information is received on an item that the CPT Editorial Panel reviewed previously, the request is referred to appropriate members of the CPT Advisory Committee. If the advisors concur that a new CPT code should be added or a change should be made to an existing CPT code, the application is approved. If two or more advisors disagree, the issue is referred back to the CPT Editorial Panel for resolution. The Panel meets three times each year, evaluates approximately 350 new technologies and deletes those procedures that are outmoded.

....Step 2—ICD-9-CM
The second step is to apply to the Coordination & Maintenance Committee at CMS for an ICD-9 code. (12 ICD-9) This Committee provides a public forum where thoughts and comments are given; however, no decisions are made. All final decisions are made by the Director of the CDC’s National Center for Health Statistics (NCHS) and the CMS Administrator. Tentative agendas for the scheduled meetings are usually posted one month in advance.

Applicants can make presentations at these meetings, describing the clinical issues of their products. The participants at the meeting are encouraged to ask questions concerning the clinical and coding issues and to offer recommendations to those applicants requesting a change. Recommendations concerning proposed code revisions can be made either at the meeting or in writing before the end of the comment period. Final decisions on code revisions are made through a clearance process within the Department of Health and Human Services.

....Step 3—HCPCS
HCPCS is a standardized coding system that is used primarily to identify services (such as ambulance services) and durable medical equipment (DME), prosthetics, orthotics, and supplies (DMEPOS). These codes are primarily used by medical suppliers, so they are typically not costs that get passed through a physician's office. HCPCS coding is intended to be used to identify DMEPOS and formulate fee schedules in a consistent manner for billing purposes. "Level III" HCPCS codes refer to Medicaid and other state and local codes.

The preliminary step in the process for recommending a modification to the HCPCS coding system for DMEPOS is to contact the Statistical Analysis Durable Medical Equipment Regional Contractor (SADMERC). (13 Level II) CMS contracts with SADMERC to provide assistance to the public in determining whether or not a HCPCS code exists which describes the new product. If none is found, an application form for a new code, a cover letter outlining the new code request and a brief summary of why the code is needed should be submitted to CMS, together with the FDA letter confirming 510(k) approval, data supporting clinical effectiveness, and product brochures and/or booklets. Samples of the device can be included with the application. Once the application is received, the product is placed on an agenda and reviewed by a panel whose membership includes representatives of Medicare, Medicaid, and private insurers. These informal, public meetings permit interested parties to make oral presentations or to comment in writing regarding the coding issues.

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Council on Technology and Innovation
The Council on Technology and Innovation (CTI) at the Centers for Medicare & Medicaid Services (CMS) oversees the agency's cross-cutting priority on coordinating coverage, coding and payment processes to enable CMS to more efficiently identify high value technologies and services that will improve healthcare quality and the lives of Medicare beneficiaries. (14 CTI) CTI is developing the capacity to better prepare for new kinds of medical innovations. The agency recently issued a revised guidance on Coverage with Evidence Development (CED). (15 CED)

Payment
Payment refers to the amount of monetary compensation provided to the physician and other healthcare professionals who use the new technology. It is important to realize that Medicare pays for the procedure associated with a medical device, not for the device itself. Medicare’s inpatient and outpatient prospective payment systems include provisions designed to provide an extra payment amount for certain new technologies. To merit such additional payment, the new technology generally must represent a substantial clinical improvement relative to existing technologies and meet specific cost thresholds. (16 Innovator's Guide)

Conclusion
FDA approval, clinical trial outcomes data, the presence of appropriate coding and payment levels are vital for reimbursement of new technologies. The quantity and quality of the outcomes data arrived at by randomized controlled trials (RCT) or an observational, well-controlled registry study will dictate the decision for or against reimbursement. Products with explicit reimbursement pathways to increase revenue are more likely to be used by providers than products with limited or no coverage. As improper coding is often the cause of Medicare’s delayed or denied payments to providers, manufacturers must make certain that an identifying code is clearly available for placement on the insurance claim form. The somewhat long and drawn out timeframe for coverage can be reduced if a thoughtful reimbursement strategy is implemented at the earliest stages in product development.

References
(1 Social Security Act) Title XVIII, The Social Security Act of 1965, sec. 1862(a)(1)(A).
(2 FDA & Innovation) http://www.fda.gov/downloads/MedicalDevices/NewsEvents/WorkshopsConferences/UCM192268.pdf.
(3 Innovators' Guide) https://www.cms.gov/CouncilonTechInnov/Downloads/InnovatorsGuide5_10_10.pdf.
(4 Jaeger) Cost Effective Analysis and Medical Device Utilization (Nov 2009).
(5 Evidence) http://en.wikipedia.org/wiki/Evidence-based_medicine.
(6 NOI) Federal Register 65, no. 95 (16 May 2000): Proposed Rules, 31124–31129.
(7 Registry User's Guide) http://www.effectivehealthcare.ahrq.gov/repFiles/PatOutcomes.pdf.
(8 Stark) Registry Studies for Medical Devices - Workshop (Mar 2010)
(9 CMRI) https://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=228&ver=16&NcaName=Magnetic+Resonance+Imaging+(MRI)&bc=gQAAAAAAIAAA&.
(10 Clark) Device Case Studies for Reimbursement Codes (Nov 2008).
(11 AMA & CPT Codes) http://www.ama-assn.org/ama/pub/physician-resources/solutions-managing-your-practice/coding-billing-insurance/cpt/cpt-process-faq/code-becomes-cpt.page.
(12 ICD-9) https://www.cms.gov/ICD9ProviderDiagnosticCodes/03_meetings.asp
(13 Level II) https://www.cms.gov/MedHCPCSGenInfo/Downloads/2012HCPCSApplication.pdf
(14 CTI) https://www.cms.gov/CouncilonTechInnov/01_overview.asp
(15 CED) http://www.cms.gov/coverage/download/guidanceced.pdf
(16 Innovator's Guide) https://www.cms.gov/CouncilonTechInnov/Downloads/InnovatorsGuide5_10_10.pdf

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Getting to First-in-Man Studies

Last month I had the opportunity to attend the CRT2011 meetings in Washington, DC. My purpose was to report on the March 1 "Workshop with the FDA" on device development in the US. My whitepaper today is to combine the cardiovascular message from "Workshop with the FDA" with significant findings published by AdvaMed in a November 2010 publication titled "FDA Impact on US Medical Technology Innovation." I hope to take a deeper look into the why behind the what, and then hopefully propose a way forward.

The Device Development 'Ecosystem'
When I talk about innovation, I am referring to either the conception and invention of new devices or to incremental improvements to existing devices. When I talk about development, I am referring to the bench, animal safety, pre-clinical and clinical studies that occurs before FDA clearance or approval or EU certification. When I use the adjective "clinical" in this paper, I am referring to human studies. By the way, the 'ecosystem' is the new buzzword for global device development, including regulatory, economic, and resource availability effects.

  
While the US is still the leader in medical device innovation, development has largely fled to other continents. Most first-in-man studies are done in Europe, Asia, Latin or South America. The reasons are a ready patient population, modern hospital facilities, and English-speaking physicians trained in Western medicine and good clinical practices.

But all of this begs the question, how is it that it is easier to get first-in-man trials approved in countries outside the US?

First-in-Man Approval in the US
In the States, first-in-man trials require the same review process as any other clinical trial, which means you must get an IDE from FDA if the device is significant risk. While FDA reports an average of 27 days to get IDE approval from time of IDE submission, and six months if you count from first communication, Advanced reports an average of 14 months to get an IDE approval from the time of first communication with FDA. The long lead-time results in costs and delayed revenue stream that venture capital firms are becoming unwilling to fund.

  
First-in-Man Approval in the EU
In many European countries the Ethics Committees (ECs) have the real control over approval for clinical trials; the National Authority is only notified of the trial's initiation but doesn't take an active review role. The Notified Body serves as the inspection arm and reviews certification sometime after the device is commercialized. This means the level of review for first-in-man studies rests in the hands of the Ethics Committees, which are usually local and most certainly not funded or trained to the level of FDA.

I can't find any figures for the time required from first EC submission to initiating the first-in-man study, but AdvaMed reports that a 510k-level device requires an average of only seven months to certification. When you compare the benefits of earlier revenue stream with the inconvenience of implementing studies on the other side of the ocean, it is small wonder that American manufacturers have moved their development process to Europe.

 

The Global Harmonization Task Force
As an aside, the Global Harmonization Task Force (GHTF) has attempted to close the gap between continents but it lacks regulatory teeth. Its documents are written with more hope than how-to, (Medical devices should be designed and manufactured in such a way that...they will not compromise the clinical condition or safety of the patients....), and an Australian report says GHTF is closing shop and will reopen as "regulators only."

The Flight of Device Development
Both the speakers at CRT2011's Workshop and the report from AdvaMed draw a disturbing picture of the flight of medical device development to Europe. Sean M Salmon of Medtronic (VP and General Manager, Coronary and Peripheral) said he does 95% of his clinical trials outside the US, "why bother with FDA?" He acknowledged that US investigators feel left out and that he, too, is frustrated with the US system. But exceptional competencies exist around the world and there is no reason to restrict clinical studies to the US.

As device development moved to Europe and to other countries, US investigators fall increasingly behind the curve. One trend is the development of international relationships between US and outside-US hospitals (example) whereby American physicians can participate in international clinical trials by practicing outside the country.

So if manufacturers have found a way to go to Europe and elsewhere, and investigators are finding a way to go to Europe and elsewhere, where does that leave the American patient? According to the Medical Tourism Association, medical tourism is one of the fastest growing industries within healthcare. Traveling to another country to receive healthcare is the pathway of choice for many Americans seeking leading-edge care. Many insurance companies, such as Aetna, the Blues, WellPoint, and others, have implemented medical tourism pilot programs to support such care.

The workshop with the FDA can be summarized in a few simple statements:
[1] Device development has moved to Europe.
[2] US investigators are following.
[3] Device availability is delayed two-to-five years in the US.
[4] Medicare reimbursement doesn't necessarily follow FDA clearance/approval.
[5] Patients are following the new technologies through medical tourism.
[6] As development leaves the US, innovation and jobs will follow.
[7] The device industry is struggling under Healthcare Reform's federal excise tax on sales.

FDA's Response
Next at the workshop it was FDA's turn to speak. Dr. Ashley Boam (Branch Chief, Interventional Cardiology Devices, CDRH, FDA) summed FDA's position up simply: "Bring us better pre-clinical data."

Pre-clinical Strategies
In addition to ISO 10993 biocompatibility testing, preclinical animal testing to investigate potential harms to humans before doing first-in-man studies may be necessary. Such testing is often done in large animals in order to mimic clinical use of the device. You need to select a species whose anatomy can receive the device or provide reasonable feedback regarding human use.

There is no single, prescribed protocol for preclinical studies. Instead the intended use of the device is reproduced as best as possible. The potential harms from the device are identified from the literature or prior experience, including biological harms, mechanical harms, electromagnetic harms, software harms, harms from human error, or harms from any other source. Finally a protocol is developed to investigate the device's safety and performance. The species of animal, sample size, endpoints and pathology must all be justified. The protocol should be approved by an Animal Care and Use Committee and implemented in conformance with ISO 10993-11 "Systemic toxicity" Section 6. FDA favors the involvement of an experienced toxicologist in the development of the protocol and the final report.

For example, an embolization system was evaluated in a rabbit model, a thrombectomy device was evaluated in porcine whose arteries had been injected with fribrin-laden thrombi, a robotic spinal surgical system was evaluated in a porcine model, but I could find no accepted animal model for evaluating joint surface repair or osteonecrosis.

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CDG Can Help with Pre-Clinical Strategies

Dr. Dan McLain, convener of ISO 10993-11, is available to assist with pre-clinical strategies for your device. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

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Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

ISO 14155 (2011) Good Clinical Practices for Medical Devices Is Here

It's time to update your procedures!
Coming into force very, very soon.

The International Standards Organization (ISO) has finally done it. Earlier this week they published the good clinical practices for medical device clinical investigations: ISO 14155 "Clinical investigations of medical devices in human subjects—good clinical practices" (2011). You can buy your very own copy at www.iso.org for 158 Swiss francs, search for 14155.

 

Once the standard is harmonized via publication in the Official Journal of the European Union it comes into force immediately; it will be tough, so you should start updating your procedures for European studies now. What's the "proof" that enforcement is immediate? And what will it mean for your study? Read on.

No phase-in period—the tedious proof
You can take my word for it, or you can follow the tedious proof presented in the next paragraphs to convince yourself about the enforcement date. We will look only at the Medical Device Directive (MDD); you can follow the same logic for the Active Implantable Medical Device (AIMD) directive on your own.

Annex ZA of the standard
Annes ZA of the standard states: "Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the normative clauses of this standard confers, within the limits of the scope of this standard, a presumption of conformity with the relevant Essential Requirements 6a of that Directive and associated EFTA regulations."

Which means—in American English—once the standard is cited in the Official Journal, you will meet the Essential Requirements of the MDD for clinical investigations if you conform to the standard.

Essential Requirements of the MDD
Turning our attention to the MDD, in Article 3 we read:

"Article 3
Essential requirements
The devices must meet the essential requirements set out in Annex I which apply to them, taking account of the intended purpose of the devices concerned.”

And in Article 4 of the MDD paragraph 2, we read:

“Article 4
2. Member States shall not create any obstacle to:
— devices intended for clinical investigation being made available to medical practitioners or authorized persons for that purpose if they meet the conditions laid down in Article 15 and in Annex VIII,”

And in Article 5 of the MDD, paragraph 1, we read:

“Article 5
Reference to standards
1. Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes [sic, published] in the Official Journal of the European Communities; Member States shall publish the references of such national standards.”

Harmonized standards
You can check the MDD at ec.Europa.eu to see if the standard has been harmonized to the directive. Scroll down on the page to see the long list of harmonized standards. As of today, the 2003 versions of the clinical investigation standards are still in force. I'm told it takes 5-6 months before the a new ISO standard is cited in the Official Journal and harmonized to the directive.

 
 

Frequently asked questions—my guess at the answers
Your Notified Body is your final arbiter for enforcement of the new ISO standard for ongoing studies. A good rule of thumb is that the standard applies to your investigation from the time it is harmonized and going forward, but does not apply retrospectively to activities that are already completed.

[1] When the standard comes into force, what happens to clinical investigations that are currently enrolling?

The new rules will apply to the remainder of the investigation. This means investigators and study staff must to be trained to the new standard and their heavier responsibilities, new data forms for collecting device deficiencies should be created, and the like. It may be useful to develop an educational pack for the Ethics Committees.

[2] When the standard comes into force, what happens to clinical investigations that are completed (last subject is out) and I am analyzing the data?

The final report, i.e. clinical investigation report, should follow the format and content of the standard.

[3] When the standard comes into force, what happens to clinical investigations I am setting up? Let's say I have investigators and sites, and I have EC approval, but I have not yet enrolled the first subject?

Your clinical investigation procedures and quality management system should be updated now to meet the intense requirements of the new standard. Because you haven't enrolled subjects yet, you can expect to redo most of your administrative set-up if it wasn't done in conformance to the new standard.

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CDG Can Update Your Procedures

CDG was actively involved in writing ISO 14155 (2011). We understand the intention behind the words and can help explain standards-speak in a way you can understand. We can review your procedures, provide recommendations to bring them into conformance, or write additional procedures if needed.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or cdginc@clinicaldevice.com.

 

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

European Medical Device Update

A Few Items of Note about Device Regulation in the European Union

Life keeps moving along in Europe in spite of the snow and closed airports. Here are three important medical device regulatory issues you'll want to address in the new year.

[1] No phase in period for ISO 14155 "Clinical investigation of medical devices in human subjects—good clinical practices"
If the stars align, Jupiter stays in the heavens, and my cat stops catching birds, ISO 14155 may be published in the first quarter of 2011. But don't wait around for the big event. Implementation will be immediate and there is no phase in period!

The convener recommends all sponsors start updating their clinical investigation procedures now. However, updating your procedures is a little bit difficult because the final draft of the standard is not available for purchase on the www.iso.org website. ISO.org lists the standard as being under publication (stage 60.00) but provides no means to add it to your shopping cart.

 

The same is true for the Association for the Advancement of Medical Instrumentation at www.aami.org, which has inexplicably truncated the title to "Clinical investigation of medical devices for human subjects" and left off the declaration of "good clinical practices". AAMI claims identical equivalency to ISO 14155/Ed.3 (edition 3?), and states the draft is not available 'outside of committee'.

CDG can update your clinical procedures to ISO/FDIS 14155

Clinical Device Group is a corporate member of AAMI, a member of ISO TC 194, and has access to the final draft versions of ISO/FDIS 14155 "Clinical investigation of medical devices for human subjects—good clinical practices". While we can't provide you with a copy of the unreleased document, we can review your existing procedures and make recommendations to bring them into conformance. Our style is to work collaboratively with point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5706 or cdginc@clinicaldevice.com.

 If you don't work for one of the thirty or so firms who pay corporate dues to AAMI, are members of TC 194, and have access to the final draft standard, you will have to figure out another game plan. You might consider hiring a CRO with access to the final draft to update your procedures for you.

2] MEDDEV 2.7/3 Serious adverse event reporting under the amended Directives
The European Commission published MEDDEV 2.7/3 "Serious Adverse Event Reporting under 90/385/EEC and 93/42/EEC" in December 2010. Although the guidance is voluntary, you are strongly urged to follow it. The guidance uses the ISO/FDIS 14155 definitions of adverse events and effects, and recommends that all serious adverse events (SAEs), device deficiencies that might lead to SAEs, and any new findings regarding existing SAEs, be reported to every National Competent Authority (NCA) in which the investigation is being conducted.

Two categories of SAEs
The guidance takes the odd approach of dividing SAEs into two categories: a) those that require prompt remedial action, and b) those that do not.

SAEs that require prompt remedial action to mitigate an imminent risk of death, serious injury, or serious illness should be reported immediately but no more than 2 (two) calendar days to the NCAs using the Reporting Form provided in the guidance Appendix. SAEs that do not require prompt remedial action should be reported no more than 7 (seven) calendar days. The MEDDEV 2.7/3 guidance and an Excel spreadsheet of the Reporting Form are provided on CDG's website.

Observations
A serious adverse event that occurs at a US site should be reported to every European NCA in which the investigation is also being conducted. CDG recommends that investigations in the US and EU be administered and managed as separate studies because: 1) it is difficult to meet the reporting requirements of two different regulatory entities in the same investigation, and 2) it is difficult to justify pooling data given the differences in medical practice. Patients in countries with socialized medicine tend to be farther along in the disease process before receiving medical care than patients from countries with for-profit medical care.

The guidance makes no mention of reporting serious adverse events to Ethical Committees. It doesn't discuss sharing of data between National Competent Authorities. It doesn't address setting up a European database of serious adverse events. And it doesn't address making the SAE reports available to the public. As much as we have complained about a lack of transparency and organization at FDA in recent whitepapers, Europe has a long way to go before it catches up.

[3] MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and Notified Bodies
The European Commission also published MEDDEV 2.7/4 "Guidelines on Clinical Investigation: A Guide for Manufacturers and Notified Bodies" in December 2010. Again the guideline is not legally binding, but it reflects the thinking of the European Commission and what manufacturers can reasonably expect from their Notified Bodies.

Distinctions
The guideline tries to clarify the European distinctions between clinical data, clinical evaluation [reports], and clinical evidence. The logic is not obvious, so I've designed a graphic to help sort it out.

 

Clinical data are numbers, values, measurements, and the like, taken from the literature, sponsored clinical investigations, and other reports such as complaint history files and risk management systems.

Clinical data are assessed, analyzed, and written up in clinical evaluation reports.

Clinical evidence is both the original clinical data (numbers and values) and the clinical evaluation report.

If the clinical evidence is sufficient to establish the safety and performance of a device for its intended use, then the manufacturer may declare conformity to the essential requirements and proceed to market the device. If the clinical evidence is insufficient to establish safety and performance, the manufacturer may withdraw the claim or proceed to a new clinical trial in an effort to generate data to substantiate the claim.

Differences between US and EU
The fundamentals of good clinical practices haven't changed and are not much different between the US and EU. The new ISO 14155 standard was written to harmonize as close as possible with the existing ICH-GCPs; so if you are an experienced clinical research professional there will be no surprises. But there are some differences in implementation.

The first difference is the heavy level of adverse event reporting in Europe. Even for European Class I and IIa devices, all adverse events are reportable to sponsors, Ethics Committees, and NCAs; and all serious adverse events—device related or not—are reportable to NCAs within 2-7 days. In the States, for significant risk devices, only adverse device effects are reportable to sponsors, IRBs, and FDA (unless FDA requires more for a particular investigation); and for non-significant risk devices, adverse device effects are only reportable to sponsors and IRBs.

The second difference will be the increased emphasis on risk management in the clinical investigation process and figuring out how to apply ISO 14971 "Application of risk management to medical devices" to clinical investigations.

Got feedback?
If you have comments, disagreements, or additional information, please post them below. I look forward to hearing from you.

Happy New Year,

Nancy J Stark, PhD
President, Clinical Device Group Inc
cdginc@clinicaldevice.com