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]

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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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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

 

 

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

 

 

There is only one difference between registry studies and clinical studies: registry studies are observational and clinical studies are investigational. (When clinical studies are randomized they are called randomized clinical studies or RCTs.) To put it another way, in a registry study we tell the physician to treat the condition however they want—as sponsors, we are passive observers; in a clinical study we instruct the investigator to treat the condition in a certain manner—we are active researchers.

There is another, inevitable, feature of registry studies that I want to point out. The words "effectiveness" and "efficacy" are often misused, even by FDA. Effectiveness refers to how well a device performs as intended in the general population of patients and the general chaos of clinical practice. Effectiveness is measured in registry studies. Efficacy refers to how well a device performs in a setting of carefully selected patients and a carefully controlled protocol. Efficacy is measured in clinical studies.

 

Why do a registry study?
[1] Reimbursement data
One common reason for doing a registry study is to obtain data for reimbursement purposes. While CMS prefers comparative effectiveness data obtained from randomized clinical trials, such studies aren't always possible. 1. Definition of Comparative Effectiveness. There may not be a direct comparator for your new technology: the comparators might be an office procedure versus a surgical procedure or a device versus a drug. Imagine the complexities of comparing a device that emits a magnetic field intended to lower the viral load of patients with AIDS or hepatitis C to a multi-drug regimen. Or co-pay policies may be different for the comparators. Martin et. al. described an issue where a new (possibly more effective) drug costing $2000 per month was to be compared to an older drug being used off-label and costing $50 per month. There was concern that patients assigned to receive the expensive drug would drop out of the study. 2. Martin, et. al. In such a case, the sponsor would pick up the copay for every subject, no matter what their third-party coverage might be, in order to level the playing field.

[2] Post-approval effectiveness publications
Before adopting your technology most clinicians will ask about its effectiveness in the real world. Registry studies are ideal for obtaining effectiveness data. By allowing wide patient selection criteria you will include patients with multiple confounding complications, wide age ranges, various socioeconomic backgrounds, and differing healthcare attitudes. Learning how your technology behaves in these complex scenarios can provide valuable information to clinicians and important data for publications.

[3] Section 522
In certain circumstances FDA may require a post-approval study under Section 522 of the Food, Drug, and Cosmetic Act. The so-called Section 522 Postmarket Surveillance authority is limited to Class II or Class III devices the failure of which might lead to serious adverse health consequences, devices implanted for more than one year, life-sustaining or life-supporting devices used outside a device user facility, or devices used in pediatric populations. 3. Section 522. Registry studies are an ideal way to collect the broad surveillance data required.

[4] Off-label uses
Devices aren't always used the way we think they will be or in the populations we anticipate. In registry studies we—as sponsors—are not dictating how our device will be used, so there is always the possibility it will be used off label. Off-label use in a registry study is not a protocol violation since we don't specify in the protocol how to use the device in the first place. A review of how our device is actually used in real-world practice can provide valuable marketing information, hypothesis development for future studies, and indications for use development for future regulatory submissions.

 

How to do a registry study
Implementing a registry study is not much different than implementing a clinical study. All the basic elements of design, planning, and project management are present. There is a lack of consensus standards for registry studies so it is difficult to find guidance on how to do them. Your primary resource for information will be "Registries for Evaluating Patient Outcomes: A User's Guide, Second Edition" from the Agency for Healthcare Research and Quality. 4. Registries.

[1] Planning
In the planning phase, identify your stakeholders, the scope of data required, define the core data set (what do you need to know?), identify the patient outcomes or endpoints, define the target population (i.e. inclusion and exclusion criteria), and most importantly, get your funding. Funding may come from top management, venture capital firms, government grants, private grants, or other resources, but in the end we are all accountable to someone. Next you'll set up the registry team, determine if safety monitoring boards, IRBs, or other committees are necessary, and finally plan an exit strategy so you'll know when the study is completed.

[2] Registry design
In the design phase, the details of the registry study are worked out and a protocol is written. There are only a few options for study design:

a) Cohort designs follow over time a group of people who possess a characteristic to see if they develop a particular endpoint or outcome. 5. Registries, p38.

b) In case-control designs you gather 'cases' of patients who have a particular outcome or who have had a particular adverse event and 'controls' who have not, and then you look backwards to see what proportion had an exposure or characteristic of interest. For example, in the evaluation of re-stenosis after coronary angioplasty in patients with end-stage renal disease, investigators found both cases and controls from an existing PTCA registry. Alternatively, cases could come from the PTCA registry and controls from outside the registry (say, Medicare data). 5. Registries, p38 and p46.

For example, in 2004 Cordis began a registry designed to assess stenting outcomes in relation to the outcomes of their SAPPHIRE trial, which was used as the historic comparison group. The research question was to see if non-academic physicians would achieve the same level of success as the academic investigators used in the clinical study. The registry was conducted because of concerns by FDA and the Centers for Medicare and Medicaid Services (CMS), and involved 74 sites and 1493 patients. The large number of sites and subjects are characteristic of registry studies. 5. Registries, p38.

c) A case-cohort design is a statistical variant of a case-control study. Controls are sampled from a list of people, with each person having an equal probability of being sampled. 5. Registries, p38.

Help with Registry Studies

CDG is pleased to offer a five-hour workshop on designing and implementing registry studies for medical devices. Designed and recorded by Dr. Nancy J Stark, the workshop is a focused presentation of the AHRQ User Guide, adapted to medical device registries. You can find more information on our website. Scroll down to Registry Studies for Medical Devices.

If you're short on human resources and need to outsource the planning and implementation of a device registry study, please phone or email us at 773-489-5721 or cdginc@clinicaldevice.com. Dr. Stark will be happy to discuss a proposal.

[3] Selecting subjects and comparison groups
The target population is all the patients with a common disease or condition or a common exposure. For example, the target population might be all people with cataracts, all women with urinary incontinence, or all people who have been exposed to radiation for cancer treatment. Then broad inclusion/exclusion criteria are used to select a representative population of patients. One common feature of registries is that they have few inclusion and exclusion criteria, thus enhancing their applicability to broader populations.

Selecting comparison groups is more critical in observational studies than in clinical studies, because subjects have a choice as to which intervention they receive. The sickest patients may choose your technology, while less-ill patients may choose the comparator. The result will be an unfair imbalance in adverse events for the new technology. Key demographic factors—such as age, lifestyle, and disease advancement—are collected and statistically applied to help achieve equipoise.

Comparison groups may be "internal" (data collected simultaneously), "external" (data were collected outside of the registry, such as Medicare data), or "historical" (data collected under the registry protocol but not simultaneously). Comparison groups are essential when you want to distinguish between alternative procedures, assess the magnitude of differences, or determine the strength of associations between groups.

Registries do not need comparison groups when the purpose is to characterize the "natural history" of an intervention.

[4] What data should be collected?
Registry enthusiasts have their own language for many of the concepts we are already familiar with from RCTs. For example, they talk about "domains" of data, and by that they mean data should be collected from the personal domain (patient demographics, medical history, health status, and patient identifiers), the exposure domain (patient's experience with the technology or device), and the outcomes domain (primary endpoints, secondary endpoints, adverse events, and technology deficiencies.) In addition, you should collect information about potential confounders (say a drug being taken to treat the same condition as the study device). The collected data should relate directly to the purpose of the registry.

"Data elements" refers to the exact data that will be collected. Currently there are few, if any, broadly accepted sets of standard data elements for most disease areas, making it difficult to use external data as a source of comparison data. Look to the specialty societies to see if they have created clinical data standards that you can use as a guide for selecting data for collection. For example, the American College of Cardiology has created clinical data standards for acute coronary syndromes, heart failure, and atrial fibrillation. 5. Registries, p53. Whenever possible, tie your data elements to established terminology, such as Current Procedural Terminology (CPT) codes, International Classification of Disease (ICD-10), or events related to device deficiencies. 6. ISO 19218-1.

[5] Data Sources for Registries
Depending on the data sources required, registries may utilize certain personal identifiers for patients to locate the specific patients and link the data. For example, Social Security numbers (SSN), as well as a combination of other personal identifiers, can be utilized to identify individuals in the National Death Index (NDI). What peaks my interest is that data may come from many different sources: outpatient clinic records, inpatient hospital records, laboratory records, billing records, and even payer claims data! Data may come from medical chart abstraction, electronic medical records, institutional or organizational databases, administrative databases, death and birth records, census databases, or existing registry databases. For example, if you are developing a thermoebolization technology for treating liver cancer, you may want to access data from the Registry of Liver Diseases.

[6] Ethics, Data Ownership, and Privacy
The principles of ethics, data ownership and privacy are the same for registry studies as they are for clinical studies. You need IRB approval to conduct the study, HIPAA waiver to access patient medical records, a financial agreement with the institution regarding payments, data ownership and publication rights, and assurances of patient privacy.

Consider the case study of the National Oncologic PET Registry, a registry developed to collect data about PET scans in cancer management with the goal of obtaining expanded CMS coverage for PET scans. The registry was to be conducted at hundreds of hospitals and free-standing PET facilities. The sponsor's believed the registry was not subject to IRB approval because it was being "conducted by or subject to the approval of Department or Agency heads" for the purpose of evaluating a "public benefits or services program." CMS agreed. One week before starting operation the Office of Human Research Protections (OHRP) issued a letter of disagreement. The study was put on hold while the sponsors contemplated the difficulty of obtaining approval from hundreds of IRBs. Ultimately OHRP conceded that only the registry was engaged in research and study needed to be approved by only a single IRB. 5. Registries, p84.

[7] Recruitment
Recruitment of sites becomes a major issue in studies the breadth of registries. Sites must be paid fair-market value for their time and must see a benefit to their operations if they are to join and actively participate in a registry. This is especially true if the registry study is to include community physicians or high-volume specialty centers, as well as academic centers. Community physicians are more likely to participate if the registry is viewed as a scientific endeavor, is endorsed by leading organizations, led by a respected opinion-leader, provides useful self-assessment data to the physician, or helps meet other physician needs such as maintenance of certification, credentialing, or pay-for-performance programs.

Patient recruitment presents the same challenges as clinical studies. The best success comes from recruitment by the patient's own physician. It also helps to communicate that registry participation may help improve care for future patients, to provide written materials in language easily understood by the lay public, keep survey forms short and simple, and provide incentives such as newsletters, reports, and modest monetary compensation.

[8] Data collection and quality assurance
Three sets of documents, together, form the system for data collection. The first is the case report forms, be they paper or electronic. These are the forms whereby data is gathered in the field, entered into coded fields, and transmitted to a data management center. The second is a data dictionary which contains a detailed description of each variable used in the registry. For example, the question may be: "Do you smoke?" And smoking may be defined has having smoked tobacco within the last year. The third is the set of data validation rules. These are logical checks on data entered to look for inconsistencies such as males taking birth control pills.

A data management manual should be developed to define how missing data will be handled, how invalid entries will be handled, how data will be cleaned, and what level of error will be accepted. The manual should describe how data will be tracked and coded, how query reports will be generated and resolved, and how it will be stored and secured. Finally, the data management manual should describe a quality assurance system for data entry and registry procedures.

[9] Adverse event reporting
For device and device procedure registries, adverse event detection, collection, and reporting is the same as adverse event reporting for any other post-approval setting. It begins with the "becoming aware" principle; i.e. the clock for reporting adverse events starts at the moment the investigator becomes aware of symptoms or events reported by the patient or signs such as out-of-range laboratory results reported by a lab, or from the moment the manufacturer learns of an event from an investigator.

Investigators are responsible to report serious injuries to manufacturers within 10 days and to FDA within 10 days if the manufacturer is not known. Investigators are responsible to report deaths to both the manufacturer and FDA within 10 days. 7. 21 CFR 803. Interestingly, if an adverse event occurs with a comparator device the investigator must report the event to the comparator's manufacturer. Manufacturers have 30 days to report deaths, serious injuries and malfunctions to FDA, and 5 days to report events that require remedial action to prevent an unreasonable risk of substantial harm to the public health. Events are logged into the Manufacturer and User Facility Device Experience Database (MAUDE).

[10] Analysis and Interpretation
Statistical analysis of registry data is no different than statistical analysis of clinical data. There are a couple of points that deserve mentioning, though. First, you'll need to determine how closely the actual study population represents the target population. Second, there should exist a statistical analysis plan for how the data are to be analyzed and interpreted. And third, there should exist a plan for how to handle missing data.

Conclusion
Don't be misled, registry studies are not cheap, second-rate clinical studies. They are easily as complex and costly than the exalted RCT. What they are is different. They are observational studies that asses a technology's ability to achieve its intended use in the real world. They are used when alternative technologies don't exist, are outdated, or perhaps unethical.

References
1. Draft definition, prioritization Criteria, and Strategic Framework for Public Comment.
2. Identifying and Eliminating the Roadblocks to Comparative-Effectiveness Research, Martin et.al., New England Journal of Medicine, June 2, 2010.
3. Food, Drug, and Cosmetic Act, Section 522 Postmarket Surveillance.
4. Registries for Evaluating Patient Outcomes: A User's Guide, Second Edition. Agency for Healthcare Research and Quality, 2010.
5. Registries for Evaluating Patient Outcomes: A User's Guide, Draft. Agency for Healthcare Research and Quality, 2006.
6. ISO/DTS 19218-1 Medical devices—Hierarchical coding for adverse events—Event type codes (2010).
7. 21 CFR 803 Medical Device Reporting.

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

A Whitepaper by Dr. Nancy J Stark and Dr. Dan McLain

There are commonly three scenarios in which manufacturers call on CDG for biocompatibility help: a) FDA has raised questions about the safety tests you performed, b) you disagree that you need sensitization, genotoxicity, or carcinogenicity tests, or c) you have a new device and don't have a clue as to what tests to do. Can an expert opinion help?

Materials and the manufacturing process
We usually think about biological safety when selecting the materials for a new device. Many materials may be under consideration for a particular component. The mechanical properties, manufacturability, availability, aesthetics cost, as well as biological safety issues, are all considerations in the material selection process.

Often manufacturers believe they are using "common" material in their medical devices, but when challenged by FDA to give reasonable assurance of the material's safety they cannot offer specifics. You must establish the material is comparable after your manufacturing process. This is why biological safety tests are performed on final manufactured product. Some companies use final manufactured devices, others run a coupon of the material through the manufacturing process to get a material that is representative of the final process.

Back in the day—when one of us started working in the device industry—there were no recognized standards for device biological safety testing. Manufacturers floundered around looking for tests that seemed applicable. I once used US Pharmacopoeia (USP) tests for drug containers when developing a new syringe. Even today, suppliers and manufacturers sometimes assume that materials which meet USP Class V or VI requirements are sufficiently safe for device applications. (1 USP)

 

 

Step Two: "The Matrix"
Because of its long history, most manufacturers base their biological safety testing on "The Matrix". In 1986, regulators from FDA, the UK, and Canada published the Tripartite Biocompatibility Guidance. The guidance built upon standards that had previously been published by AAMI, ANSI, ASTM, and others. It looked at materials based on the type of tissue the material contacted and the duration of that contact. Then a testing category was recommended for each combination of contact and duration. The problem with the Tripartite Guidance was that nearly every category of biocompatibility test was recommended for nearly every combination of material contact and duration (198 out of a possible 240 categories were recommended.) (2 Tripartite) There were other problems too: it didn't tell you how to handle whole devices, and it didn't apply to metals or ceramics.

In 1992, the International Standards Organization (ISO) published ISO 10993 Part 1 "Guidance on selection of tests". The standard was part of a series of biological safety standards, but Part 1 included a matrix similar to the contact and duration matrix of the Tripartite Guidance. The major difference was that far fewer categories of tests were recommended (117 out of 240). (3 ISO 19003-1 Selection of Tests) This matrix was not accepted by FDA.

  

1995 brought us The Matrix as American manufacturers know it today. It is found in FDA's General Program Memorandum G95-1. (4 G95-1) With clairvoyance and foresight FDA modified the matrix presented in a version of the ISO 10993-1 standard that would not be published for another two years. (5 ISO 10993-1 Testing and Evaluation) The goal was to harmonize the agency's biological safety policy with the expectations of the international community. In the modified matrix, an additional 36 categories of tests are "suggested" for manufacturers to consider (for a total of 153 out of 240).

Step One: ISO 10993 Part 18 'Chemical characterization of materials' (2005)
A more ethical and efficient practice is to chemically characterize materials and compare them to materials in existing clinical use before performing animal tests. This is done in conformance to ISO 10993-18 'Chemical characterization of materials' (2005) and it should be done before the matrix is even consulted. (6 ISO 10993-18)

To put it in context, the chemical characterization of materials justify the performance or omission of animal biocompatibility tests, just as clinical evaluations justify the performance or omission of human clinical investigations.

  

Chemical characterization is the accepted method for comparing one finished, manufactured material to another in order to make the argument that they are clinically equal or that one material is no worse than a currently used material. The methodology has been developing over the years and was described in detail in a book by Dr. Stark in 2003. (7 Stark) The characterization is done in the following manner.

[1] Qualitative information
Describe the material and its intended purpose within the device. The description includes qualitative information such as supplier name, common name, chemical name, batch or lot number, visual and physical characteristics such as color, hardness, flexibility, and chemical family, and other specifications. The intended use of the material (type of tissue contact, duration of contact, and function) are also described.

[2] Material equivalence
The new material is compared to an existing material that is used in a device with the same clinical exposure; the device can be a commercial device from your own firm or it can be from your competitor. You can readily visualize a spreadsheet or database listing each material in the device and comparing it to another known material. If you have sufficient information for an expert to make a toxicological risk assessment you can stop here.

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Expert Opinions and Consultation for Biological Safety

Dr. Dan McLain, is an internationally renowned medical device toxicologist. His position as convener of ISO 10993-11 is evidence of his global stature. Dan is available to assist with pre-clinical strategies and chemical risk assessments for your materials and devices. 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.

 

[3] Quantitative data
Quantitative data will be needed if a sound risk assessment cannot be made purely on qualitative information. This means a thorough knowledge of the chemical composition, additives, manufacturing residues, and leachables must be obtained through analytical and physical chemistry. The goal is to determine the amount of identified chemicals (such as monomers, anions, radioactive elements, and the like) that are present in the final, manufactured material.

[4] Quantitative risk assessment
In the quantitative risk assessment the amount (in µg, Gy for radiation, or other unit of exposure) of identified chemicals are compared to existing toxicological information, rather than to another material. The objective is to determine which, if any, of the chemicals in the material might be harmful at the calculated exposure.

[5] Estimate clinical exposure
Finally the amount of potentially harmful chemicals, the 'dose', is compared to the clinical dose a patient might receive in a lifetime, a procedure, or other unit of time. Such a comparison seeks to show that the maximum dose of a chemical one might receive is acceptable in light of the lowest dose that could case medical problems. Detailed methods for risk assessments are discussed in ISO 14155-17 'Methods for the establishment of allowable limits for leachable substances' (2008). (8 ISO 10993-17)

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"The Matrix" Is Available as a Mousepad/Notepad

CDG's talented graphic artists have reconfigured The Matrix and printed it on a high-quality mouse-grade paper pad. Now you can always have The Matrix at your workstation, in plain sight where you can find it. You can quickly look up the test categories needed while the boss is quizzing you on the phone. And at ten sheets to the pad, you can take notes on the conversation (or doodle), tear off the sheet, and keep it safe in the technical file.

Find it here, or contact Peggy at 773-489-5706 or cdginc@clinicaldevice.com.

Consider these examples, they are intended to illustrate the kind of issue you'll be addressing: a) Let's say you have a metallic implant that you clean by washing with perchloroethylene. Known to be highly volatile, but also highly toxic, you must ask if enough perchloroethylene remains on the metal implant to preclude its use as a cleaning agent; b) Let's say you make a wound dressing that contains a potassium salt. You know that potassium affects cardiac function and in sufficiently high concentrations could put a patient into cardiac arrest. You must ask if sufficient potassium can leach out of the dressing and into the wound to affect cardiac function.

References
(1 USP) United States Pharmacopeia.
(2 Tripartite) Tripartite Biocompatibility Guidance G87-1, (1987).
(3 ISO 10993-1 Selection of tests) ISO 10993-1 Biological evaluation of medical devices: Selection of tests (1992).
(4 G95-1) "Use of International Standard ISO-10993-1 Biological Evaluation of Medical Devices: Evaluation and Testing", G95-1 (1995).
(5 ISO 10993-1 Evaluation and Testing) ISO 10993-1 Biological evaluation of medical devices: Evaluation and testing (1997).
(6 ISO 10993-18) ISO 10993-18 Biological evaluation of medical devices: Chemical characterization of materials (2005).
(7 Stark) "Biocompatibility Testing & Management" Fourth Edition, Nancy J Stark, Clinical Device Group Inc, 2003.
(8 ISO 10993-17) ISO 10993-17 Biological evaluation of medical devices: Methods for the establishment of allowable limits for leachable substances (2008).

Questions or Comments?
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