Source: http://clinicaldevice.typepad.com/cdg_whitepapers/clinical-trials/
Timestamp: 2014-12-21 15:51:34
Document Index: 333241267

Matched Legal Cases: ['art 812', 'art 812', 'art 812', 'art 11', 'art 50', 'art 54', 'art 56', 'art 99', 'art 809', 'art 820', 'art 312', 'art 812', 'art 812']

CDG Whitepapers: Clinical Trials
The 2014 (Paper) CRA Handbook Is Here! A Medical Device Handbook for Regulatory and Clinical Research Professionals A Promotional Piece by Nancy J Stark, PhD.
Size and Storage of Investigational ProductsThe first big difference is with size and storage. Once I had a device the size of a breadbox. The IRB insisted the pharmacy keep the investigational breadbox-sized devices under double-lock and key, as was their practice with investigational drugs. But pharmacies don't have storage room for 100 breadboxes, and pharmacies don't dispense medical devices. The investigator had storage room, but no double-locked box for large devices. After weeks of negotiation--and costly delays to the investigation--the IRB agreed to allow the investigator to store the large devices in her office with a single lock on the door. The unique storage requirements of devices is unfamiliar to drug folks.
CRA Handbook 2014 I use the CRA Handbook as a desk reference for US regulations, a list of guidances, and regulatory and clinical requirements. When I traveled, I used it as a reference tool during meetings and for late-night hotel work. By the end of the year, my copy was dog-eared, filled with annotations, and colorful with Post-It tags. All my favorite paragraphs were marked. To learn more, go here.
Initiation of InvestigationsThe second big difference is that there are two levels of approval for study initiation in devices. In the US, device clinical investigations may be conducted under the abbreviated IDEs or under full IDEs (Investigational Device Exemptions). Abbreviated IDE studies make up 80-90% of the clinical investigations in the States, do not require FDA approval for initiation, and do not require a final report to FDA. There is no registry or list of abbreviated IDE studies. I'm getting my numbers from private interviews; for example, manufacturers of dermal contact products might do 100 clinical investigations a year on healthy, volunteer employees. While full IDE studies get all the attention, so-called 'non-IDE' studies are confusing to drug folks.
Adverse Effect ReportingThe third big difference between device and pharmaceutical investigations is with reporting of adverse effects and events. Adverse effects are device related, adverse events are not. Unless otherwise specified by the protocol, only USADEs (unanticipated, serious, adverse device effects) are reported to FDA. Not reporting anticipated adverse effects to FDA is befuddling to drug folks.
What's New in the 2014 Edition?Two major things changed in the regulatory world since 2011 and are reflected in the 2014 edition of the Handbook. The Declaration of Helsinki was updated to reflect the changes made in by the World Health Association in 2013, and 21 CFR Part 812.119 on investigator disqualification was expanded and strengthened. What's missing?
The Table of Contents 00 Foreword 01 CFR Part 812-Investigational Device Exemptions 02 CFR Part 812.20-Premarket Approval Applications 03 CFR Part 11-Electronic Records: Electronic Signatures 04 CFR Part 50-Protection of Human Subjects 05 CFR Part 54-Financial Disclosure 06 CFR Part 56-Institutional Review Boards 07 CFR Part 99-Dissemination of Information 08 CFR Part 809-In Vitro Diagnostic Products 09 CFR Part 820.30-Quality System--Design Controls 10 Expedited Review List 11 Risk Based Monitoring--The New FDA Guidance 12 Declaration of Helsinki (2013) 14 ISO 14155 (2011) Summary 15 Adverse Events and Effects 16 FDA Guidances
How do I get one?Go to our website.
The electronic version of the handbook is in the works. Julie is editing as fast as she can to get the electronic copy updated, functional, with working links and pretty colors. She expects it to be completed by June 2014. If you would like to be notified when it is ready, contact Peggy and have your name added to a notice list.
Follow us on twitter If the link doesn't work in your system, email us at cdginc@clinicaldevice.com or visit our website at www.clinicaldevice.com Posted at 04:50 PM in Clinical Investigation Plan, Clinical Investigations, Clinical Research Quality Management System, Clinical sponsors, Clinical Trial Procedures, Clinical Trials, CRO, FDA, Monitoring, risk-based monitoring | Permalink
Device contract research organizations (CROs) play a different role in the product development cycle than drug CROs, and it is unrealistic to expect a drug CRO to deliver the service a medical device sponsor needs. In the drug world a CRO is used more like a Kinko's or a dry cleaners: the sponsor drops off the protocol on Monday and picks up the report on Friday. The CRO acts independently and is legally responsible for the sponsor obligations identified in the contract. [1. 21 CFR Part 312.52] In the device world there is no possibility to legally transfer sponsor obligations to a CRO. The manufacturer may use the services of a CRO, but legal responsibility for sponsor obligations remain with the manufacturer. As a result, medical device CRO must serve as a consultancy; collaborating intimately with the manufacturer on sponsor responsibilities such as recording and reporting adverse device effects, investigator noncompliances, device deficiencies, investigator and study staff training to proper device use, and so forth. The device CRO-consultancy cannot act independently because the legal responsibility of their actions remain with the manufacturer. Choosing a device CRO-consultancyAs the manufacturer you should choose a CRO-consultancy that complements your corporate personality, fills the knowledge gaps in your organization, and makes themselves readily available to you. Here are some specific characteristics that you can evaluate. Device experience of top managementDoes the CEO have medical device experience? The career history and experience of top management sets the focus of any company. When you are interviewing a CRO, be sure to ask for the CVs of top management. Have they worked for medical device firms? Have they worked in clinical research or regulatory roles? Are they sensitive to the differences in regulations between devices and pharmaceuticals? Without device experience at the top, you are unlikely to get device experience at the level of implementation.
CDG Inc—A Device CRO Here to StayCDG is a small, networked CRO offering services in biological safety, quality design, clinical research, statistics, audits, reimbursement, and clinical evaluations for medical devices. We have many clients who use us as a consultancy—they call for advice when they want direction about how to proceed. We have been in business since 1990, and our President has been in the device industry since before Part 812 was final! Please call us to discuss consulting needs for your firm. Click here for more information or call 773-489-5706.
Size and powerHow big is the CRO in terms of number of employees or annual gross revenue? Little sponsors get swallowed-up by big CROs. If your project is small compared to the other projects the CRO is running you will be ignored when bigger clients have problems and demand attention. The disparity in size leaves you with no power to demand immediate help. Small CROs will value your business and are more likely to make themselves available to advise you.But in fairness, if you are a large device manufacturer you may be more comfortable working with a large CRO. Large CROs can bring more sophisticated electronic data tools, financial reporting tools, or other management advantages that small CROs cannot afford. Progressive slices of the pie—estimates and schedulesIn CDG's experience, device projects tend to be progressive slices of the greater pie. For example, the first project might be to review device biological safety, if that goes well we may be asked to review a protocol, and then to calculate an array of possible sample sizes, then to implement a study, and so forth. One project may turn into five projects or twenty-five project over time. In any case, once you settle on some specifications the CRO should be able to give you an estimate and schedule. I am using the word "estimate" to mean the number of labor-hours it will take to complete the project and the word "schedule" to mean the overall duration of the project. For example, it might require 40 man-hours to write a clinical evaluation over a duration of ten weeks. If the estimate and schedule are within 25% of the final cost and duration, the manufacturer has done a good job of planning and the CRO has done a good job of execution. But I promise you, there is no way the project will go to completion without a change in specifications. Who will do the work?It is key for the device manufacturer to ask, "Who will do the work?" Some large CROs have been known to show the CVs of device-experienced personnel during the negotiation phase, but then have another—device-inexperienced—individual actually do the work. It is understandable that personnel availability may change from the time a proposal is first discussed to the time the contract is finalized, but it is wrong to assign new individuals who don't have the necessary expertise. During project negotiations be sure to ask the CRO if they have the expertise to do the work. And then don't hesitate to object later if the assigned individual isn't as skilled, thorough, or knowledgable as you need them to be. From time-to-time every company makes personnel adjustments and it should not become a big issue.
Poll Question: How did you use a CRO last year, if at all? How did you use a CRO last year, if at all? Respond to the poll question and help us learn about our industry. Your answers are completely confidential and will be used only for my own research. The average responses will be posted in an upcoming whitepaper. Answer me here. —Nancy
Independent experts: one-person firmsMany of the finest medical device consultancies are independent, one-person firms. They have chosen an entrepreneurial lifestyle, preferring the independence of self-employment to the security of a routine paycheck. It is reasonable to ask what experience they have in the device industry, why they chose to work for themselves, and if they can commit to the duration of your project. I've had some interesting bosses over the years. When I decided to become a consultant in 1990, my soon-to-be-ex boss told me that "consultant" was a code word for "I'm unemployed." I took that as a challenge and knew that I would have to work at building a business persona. It was important that manufacturers perceived Clinical Device Group Inc as a company that was here to stay. When out-sourcing to a new independent expert, look for signs of someone trying to create a business: do they have a business name, business cards, a marketing effort, a website, a brochure, conference booths, speaking engagements, and the like? Look for people who have actually worked in the device industry and understand how devices are conceived, designed, tested, investigated, and commercialized. Independent experts run businesses themselves and will bring a sensitivity to the business needs of your organization. NetworksMany independent experts form relationships with other independents and work together to provide services to clients beyond their own specific expertise. Ask what services they can provide to you directly via employee or sub-contractor, and whom they can refer to you. They can often provide you with a full range of clinical and regulatory services just like any other full-service CRO through their strategic alliances. CommunicationsIf the experts are in a network, who is the project leader on their side? How will communications flow, knowing that the experts may live in different states? Will you have direct access to the project implementers? Think of the management model used in most organizations; the doer in clinical research is free to send an email to the doer in regulatory affairs, but the managers of both functions are copied to keep them in the loop. Who will bill whom? I follow a general contractor model: my sub-contractors bill CDG, CDG in turn bills the manufacturer. Do you need (or want) separate non-disclosure agreements (NDAs) from each sub-contractor? Occasionally manufacturers want NDAs from each sub-contractor, but more commonly the primary NDA requires CDG to have NDAs with each sub-contractor so that the requirement for confidentiality flows through. Contribution to the industry I have had an independent expert walk away from a contract in the middle of a project in order to take a job. I respect everyone's need for security, but it is dishonest for experts to present themselves as consultants who are here to stay, and then betray that promise. Businesses who are committed to their industries show it by finding affordable ways to demonstrate that commitment. CROs or consultant may offer public presentations, contribute written articles, participate in standards development, or find other ways to give back to the industry and to mentor younger persons. Looking at the CRO's commitment to the industry is one way to judge their staying power. Standing and reputation"Standing" refers to the reputation of the CRO or consultant in the eyes of clients and peers. For older CROs or independents standing may be self-evident; for younger CROs or independents you may want to ask for references. I have had the unusual situation of a client asking me if I agreed with the opinion of another consultant. I did not, and cited the regulations on which I based my opinion. For the manufacturer it was a question of whom to believe. It is useful if you have confidence in the advice the CRO is giving you.
Project Management for Clinical StudiesStark NJ,Project Management for Clinical Studies, Clinical Device Group Inc, Chicago, IL (2003). Probably the most overlooked aspect of device investigations, project management is absolutely essential if a trial is to be implemented on time and with care. The book follows the usual outline of any project: conception, planning, implementation, reporting, and close-out; but focusing on clinical research. It gives sample planning forms, Gantt charts, budgets, methods for cost analysis, reporting metrics, and sample CRO contracts. If you are in management you should insist your staff read this book, it is my personal favorite of all the books I've written. 290 pages, perfect bound, illustrated, ISBN 1-889160-09-1. Table of Contents. $250 USD.
Bidding ProcessA bidding process is a process where the submits a bid for a job or project. The process requires strict specifications for the project (i.e. the sponsor must know exactly what they want) and works well for "cookie-cutter" investigations. The idea is that bids are obtained from several potential suppliers and the "best" bid is accepted, where "best" is some combination of people, resources, and cost. It's a personal choice on the part of CROs, but I rarely participate in bidding situations. I have put many hours of original research and considerable proprietary business practice in a bid, only to have the project go to another party and my proprietary information used as a learning tool for the cheaper firm. In one case the sponsor decided not to out-source at all, but to do the clinical trial in-house based on what they learned from the bids they solicited. If you use a bidding process, it's important to play fair and ethically. Sponsors and manufacturers get reputations among CROs, too; and you don't want to risk being in a situation where no-one of quality will contract with you. Capabilities meetingLarger CROs will often travel to the manufacturer's site and make a capabilities presentation. Smaller CROs will often host a capabilities meeting, but the cost of travel is the burden of the manufacturer. Most frequently the meeting takes place by teleconference. No matter how it is arranged, the CRO should be able to make a presentation reviewing their company history, business model, service capabilities, technology capabilities, and resources. If I travel to a conference I may learn, say, four new things. If it cost me $2000 in travel expenses to attend, then a new piece of information costs me $500. As a CRO, I have an unspoken rule of thumb. I will give away two new pieces of information to a potential client to establish credibility, but no more. As the manufacturer, you are engaging the CRO in conversation so as to assess their knowledge, confidence, organization, and corporate personality. You should expect to learn a couple of new things during the meeting. Website, brochure, company information, referencesThere are many ways for a CRO to present their capabilities with professional, take-home, printed materials. Whether it is a simple file folder, a four-color glossy, or an electronic brochure, you are looking for a material that describes the CRO's organization, presents its vision and mission, describes it scope of services, and tells you who they are. References[1] 21 CFR Part 812.32 Transfer of obligations to a contract research organization.
Posted at 10:52 AM in Clinical sponsors, Clinical Trials, Consultant, CRO | Permalink
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 BackgroundThe 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 CDWe 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 TypesMyers 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]
[1] Focusing on the World: Introversion or ExtroversionPeople 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 awaySometimes 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 IntuitionPerception 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 FeelingJudging 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.)
CDG knows risk-based monitoring for device studiesOur 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 JudgmentOur 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, PhDPresident, Clinical Device Group Inc
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, PhDPresident, Clinical Device Group Inc Posted at 03:06 PM in Clinial Investigations, Clinical Research Quality Management System, Clinical sponsors, Clinical Trial Procedures, Clinical Trials, FDA, Monitoring, Regulatory-Medical Devices, risk-based monitoring | Permalink
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 GuidanceRisk-Based MonitoringThe 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]
High risk sites and high risk dataA 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 processesCritical 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.
Methods of monitoringNext 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.
TriggersThe 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 PlanA 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 DescriptionAs 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, includingreference 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
Section Two—ReportingSection 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—NoncompliancesSection 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—TrainingSection 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 PlanSection 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?
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. Posted at 02:36 PM in Clinial Investigations, Clinical Research Quality Management System, Clinical sponsors, Clinical Trial Procedures, Clinical Trials, FDA, Investigative sites, Monitoring, Regulatory-Medical Devices, risk-based monitoring | Permalink
Conflicting missionsUniversities, 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)
[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.
[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.
ISO 14155 "Clinical investigation of medical devices in human subjects—good clinical practice" (2011)
[H] Intellectual propertyIntellectual 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.
[I] Indemnification and insuranceIndemnification 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.
[J] Subject injuryWhile 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.
[K] Best effortsConsultants (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.
[N] SignatoriesIndustry 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.
ConclusionSponsors 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.
References1. 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.
Why do a registry study?[1] Reimbursement dataOne 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 publicationsBefore 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 522In 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 usesDevices 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 studyImplementing 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] PlanningIn 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 designIn 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:
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.
[3] Selecting subjects and comparison groupsThe 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.
[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.
[5] Data Sources for RegistriesDepending 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 PrivacyThe 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.
[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.
[8] Data collection and quality assuranceThree 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.
[9] Adverse event reportingFor 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.
[10] Analysis and InterpretationStatistical 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.
ConclusionDon'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.
References1. 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.
Reimbursement strategiesA 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.
The challenge of new 510(k)'d technologiesIsn'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.
Reimbursement decision processThe 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.
CoverageCoverage 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)
.....Registry studiesRandomized 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.
Codes, codes, codesThere 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.
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—CPTThe 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)
....Step 2—ICD-9-CMThe 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.
....Step 3—HCPCSHCPCS 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.
Council on Technology and InnovationThe 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)
PaymentPayment 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)
ConclusionFDA 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
[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!
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 SAEsThe guidance takes the odd approach of dividing SAEs into two categories: a) those that require prompt remedial action, and b) those that do not.
ObservationsA 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.
[3] MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and Notified BodiesThe 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.
DistinctionsThe 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.
Differences between US and EUThe 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.
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Nancy J Stark, PhDPresident, Clinical Device Group Inccdginc@clinicaldevice.com
[5] Improper use of recognized standards—require a summary of testingSection 514(c)(1) of the Act describes the possibility of using, as part of a 510(k) submission, consensus standards that have been entirely or partially recognized by FDA. This section states, “[FDA] shall, by publication in the Federal Register, recognize all or part of an appropriate standard established by a nationally or internationally recognized standard development organization for which a person may submit a declaration of conformity in order to meet a premarket submission requirement or other requirement under this Act to which such standard is applicable.”
[6] Incomplete information—how much is enough?Current regulations require 510(k) submissions to provide "data to support the statement" regarding substantial equivalence to a predicate device. Under PMA regulations, PMA applications are explicitly required to contain a summary of all information known concerning the safety and/or effectivenes of the device under review. FDA's concern is that submissions may contain biased information, including only clinical or scientific information that supports device equivalency.
Working Group recommendationsThe Working Group recommends that 21 CFR 807.87 be revised to explicitly require 510(k) submitters to provide a list and brief description of all scientific information regarding the safety and/or effectiveness of a new device known to or that should be reasonably known to the submitter.
[7] Type and level of evidence neededThe reviewer's first step is to determine if the device and predicate have the same intended use. However, once this is done, most devices have either different indications for use and/or different technological characteristics than the predicate, and FDA may want data to show that any differences have not altered the intended use or significantly affected the safety and/or effectiveness of the device. In most cases data from bench and/or animal testing is sufficient to complete the argument of safety and effectiveness, but in some cases the Agency wants additional data.
Working Group recommendationsThe Working Group recommends the agency develop guidance defining a subset of devices, i.e. Class IIb devices, for which clinical information, manufacturing information, or post-marketing information would be typically necessary.
[8] Clinical informationThe Working Group acknowledges there is common misunderstanding as to what constitutes clinical data. Yet within the space of four paragraphs on pages 76-77 of the report the Working group refers to "clinical information", "clinical data", "clinical evidence", "clinical investigation", and "clinical study". According to CDRH staff, submitters sometimes cite the definition of “valid scientific evidence” together with the “least burdensome” provisions of the Act, claiming that it is sufficient for them to provide any type or level of evidence that meets the definition of “valid scientific evidence” with the lowest possible level of burden, even if such evidence fails to provide "reasonable assurance" of safety and effectiveness.
Working Group recommendationsThe Working Group recommends a “Class IIb” guidance provide greater clarity regarding the circumstances in which the agency will request clinical data in support of a 510(k), what type and level of clinical data are adequate to support clearance, and to define clinical data. Would this mean that all IVD 510(k)s are Class IIb?
[9] Postmarket informationCDRH feels that for certain devices, including novel or particularly complex technologies, it is not feasible to conduct a large-scale clinical trial prior to clearance [does this mean such devices are now cleared without adequate clinical data?] They feel it is necessary to collect additional data after clearance in order to better evaluate the safety and effectiveness of a device over a longer time period, or in a wider patient population.
Working Group recommendationsThe Working Group recommends the Agency seek greater authority to require postmarket surveillance studies as a condition of clearance for certain devices.
[10] Manufacturing process informationWorking Group recommendationsBecause 37% of device recalls are associated with manufacturing problems, the Working Group recommends CDRH develop guidance to provide greater clarity regarding what situations may warrant the submission of manufacturing process information as part of a 510(k), and include a discussion of such information as part of its “class IIb” guidance. The Working Group further recommends the agency seek authority to withhold clearance on the basis of a failure to comply with good manufacturing practice requirements in certain situations.