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Upcoming Events
September 9th 2010 07:30 AM
- Successful Office Kaizen Events
September 9th 2010 08:00 AM
- Sup 1: Fundamentals of Leadership for Manufacturers - St Paul
September 9th 2010 09:00 AM
- Sup 2: The Next Stage for Improving Performance for Manufacturers-Plymouth
September 9th 2010 01:00 PM
- Sup 1: Fundamentals of Leadership for Manufacturing - Plymouth
September 14th 2010 08:00 AM
- Results-Driven Sales Incentives
September 14th 2010 08:00 AM
- Fraud and Misconduct at Investigator Sites
September 14th 2010 01:00 PM
- Failure Mode and Effects Analysis (FMEA)
September 21st 2010 08:00 AM
- Project Monitoring- The Earned Value Method
September 21st 2010 08:00 AM
- Project Monitoring: The Earned Value Method & Project Management
September 21st 2010 01:00 PM
- Project Management for Product Development
Article Index
The Informed Consent Process - Protection of Human SubjectsArticle by: Diane Reid A Brief History of Research Ethics |
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Practical Adaptive Clinical Study Designs for Medical Devices Article by: Chris Mullin While the traditional clinical trial is supposed to be completely designed prior to study initiation, an adaptive design may be preferable as it allows for more flexibility. Adaptive designs have been the focus of recent attention due to the increasing pressure to speed products to market, new methodological developments, and new interest from regulatory authorities. |
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Local Snapshot: Nonin Medical, American Medical, Medtronic, and Myocor
Nonin Medical Inc. announces the release of the first and only wireless fingertip pulse oximeter to system integrators worldwide. The Onyx(R) II, Model 9560 fingertip pulsArticle by: Medical Device Alliance Nonin Medical Inc. announces the release of the first and only wireless fingertip pulse oximeter to system integrators worldwide. The Onyx(R) II, Model 9560 fingertip pulse oximeter enables patients to accurately monitor vital signs and remotely connect with their clinicians -- gaining independence to go about their daily activities. |
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The Search for the Perfect EmployeeArticle by: Pamela Wolfe Many organizations today are working "leaner" and trying to do more with less. This is true especially within clinical research as the number of trained professionals at certain career levels are not adequate for the number of trials being conducted. There are over 80,000 trials in process in the US right now. |
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Medical Device Manufacturing Regulations, Product Recall from the Field Article by: Thomas Pepin Situation: You have received customer complaints related to device failures which resulted in customer injury. Other complaints may not have resulted in patient injury, but were the result of a manufacturing non-compliance such as the device not performing per specification, packaged with an incorrect component, or missing important labeling. |
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Local Industry Snapshot: Vision Ease, Virtual Radiologic, St. Jude Medical Article by: Medical Device Alliance Vision-Ease's protective lens gets day in sun |
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The Many Aspects of Clinical Trials: Effective Site Monitoring Article by: Diane Reid What is Site Monitoring? |
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Noninferiority Clinical Trials Article by: Chris Mullin Most clinical trials are set up to show superiority -- that one course of action is better than another. Usually, the hope is that some new treatment is better than a control, and the objective is to obtain a significant p-value distinguishing the treatment from the control group. |
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Local Industry Snapshot: AGA Medical, SuperDimension, Medtronic Article by: Medical Device Alliance AGA Medical files for IPO |
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Medical Device Manufacturing Regulations - Product Recall from the Field Article by: Thomas Pepin Field actions are performed to protect the public from defective medical devices or for communication of important safety information related to the device or therapy. |
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Local Industry Snapshot: Atritech, St Jude Medical CVRx Article by: Medical Device Alliance Atritech looking for approval on heart device |
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Clinical Research Staff: Can We Win The Olympic Gold? Article by: Pamela Wolfe With Olympic spirit running high, it is easy to admire the dedication, skill and preparation the athletes go through. |
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Fraud: What is it? How to detect it? What to do about it? Article by: Diane Reid Fraud: What is it? |
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Single Arm Studies: Objective Performance Criteria or Performance Goals Article by: Chris Mullin Good science often requires a control group to provide evidence that an intervention is successful. In many clinical trials a control group is formed by randomly assigning patients to a new treatment vs. a standard of care or placebo control. |
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Selecting Clinical Study SitesArticle by: Frank Freedman The process of selecting clinical study sites is governed by two principles. When these two principles are followed, the study objectives are likely to be achieved.
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Bayesian Statistics: Fact And FictionArticle by: Scott Brown If you are involved in the conduct of clinical trials, you have probably heard of Bayesian statistics. Over the past several years, interest has grown dramatically in the use of Bayesian methods for the design and analysis of clinical trials; |
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The Many Aspects of Clinical Trials - Literature Review and Summary Article by: Diane Reid Why do a literature review? |
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Strategies for Publication PlanningArticle by: Joy Frestedt Medical communications have included publication planning for more than a decade. The tools of the trade vary widely depending on the number of projects included and the size of the budget allowed for this strategic focus. |
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Activity-Based Fees: Manage costs when outsourcing your clinical trials Article by: Ethan Rooney Managing your clinical trial budget is often challenging, and even more difficult when outsourcing clinical trial services. Most Contract Research Organizations (CRO's) prefer contracts that bill for their services on an hourly basis, or a fixed monthly "fee for service" across one or multiple cost categories (e.g. monitoring, site management, project management, data management, etc.). |
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Clinician of the Month: Carl Beaurline Article by: Pamela Wolfe After a 42 year career in quality assurance, regulatory affairs and clinical studies, one might think it time to consider putting it all aside and pass the time in a warmer climate, playing golf or enjoying what life has to offer outside the corporate world. For Carl Beaurline, his idea of enjoying what life has to offer is starting CMB Regulatory Specialties. In Carl's words "you want to give at least as much as you take, and I'm not done giving back yet." |
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Companies in the News: St. Jude Medical, Arkay USA, Transoma Medical Article by: Medical Device Alliance St. Jude gets FDA approval |
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(Statistical) Power To The People Article by: Scott Brown The statistical concept of power is a key notion in the design of clinical trials, but a sometimes misunderstood one. |
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Book Review: Both Texts are Solid Additions to Your Library Article by: Joy Frestedt Hello, I will be writing a recurring column for the Medical Device Alliance newsletter. My background includes over 30 years of research experience, including both academic and industry settings. I have worked for the University of Minnesota, Mayo Clinic, Medtronic and Johnson and Johnson, among others. |
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Companies in the News - Transoma, Inspire Medical and Apnex Medical Article by: Medical Device Alliance Transoma gets FDA approval for cardiac device. |
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Clinician of the Month: Jane Johnson with Transoma Medical Article by: Pamela Wolfe As Minnesotans, we have woken up to several snowy days in April and we are not necessarily happy. Jane Johnson, Clinical Research Project Manager at Transoma Medical, says she has enjoyed our winter and isn't complaining. |
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Local Headlines: Atritech, NeuroVasX, St. Jude Medical, GE Healthcare Article by: Medical Device Alliance Atritech raises $30M in venture capital |
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Subgroup Analyses: Good Science, Data Mining and the FDA Article by: Scott Brown The typical objective of a clinical trial is to demonstrate the beneficial effect of a medical therapy in a particular study population - the key being "in a particular study population." Deciding which patients to include in a clinical trial, especially one that involves a novel therapy, is one of the most important choices of the design stage. |
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The Nimble Workforce Article by: Paula Norbom The past twenty years have seen a dramatic shift away from an employee-based workforce to a more nimble and focused workforce. Contract staff can now provide 'just in time', 'just what is needed' skills for virtually every aspect of a company's business, from data entry to experienced high-level management. Independent contractors work in companies across the country in almost every industry, including the medical device industry. |
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Companies in the News: St. Jude Medical and Torax Medical Article by: Medical Device Alliance Torax Medical Inc. a firm that's developed a medical device used to treat acid reflux, has launched a key clinical trial. The Maple Grove company will test its device at 15 medical and academic facilities throughout the U.S. and Europe. |
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Clinician of the Month: Wayne Carlson Article by: Pamela Wolfe Dialysis... Just the word in most cases would be a conversation stopper, unless the conversation is with Wayne Carlson, Director of Clinical Services at Minntech. In fact, people all over the world frequently ask Wayne to talk about his knowledge of hemodialysis. |
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Companies in the News: Inspire Medical, Disc Dynamics, EV3 Article by: Medical Device Alliance Inspire Medical raises $17M in VC.Inspire Medical Systems Inc., a med-tech startup developing a device to treat sleep apnea, has raised $17 million in venture capital, the company announced Monday. |
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Need a Coach? Select wisely Article by: Ralph Jacobson Until recently, few people openly admitted that they had or needed a coach. Today, partnering with a coach is an accepted practice. Many people report improvement in their performance and yet others who engage in a coaching relationship fail to achieve the improvement they seek. |
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The Informed Consent Process - Protection of Human Subjects |
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A Brief History of Research Ethics Throughout history, great emphasis has been placed on professional conduct and responsibility of the physician, with regard to treatment of the patient. However, until very recent times, much information was concealed from the patient and the patient was not given any voice in diagnosis or treatment. Events such as the medical experiments in Nazi Germany, the Tuskegee Experiment, the thalidomide tragedy, and human radiation experiments have shaped the evolution of modern research ethics. The resulting regulations governing research involving human subjects, including present day informed consent doctrine, include the Nuremberg Code (1947), Declaration of Geneva (1948), Kefauver-Harris amendments (1962), Declaration of Helsinki (1964), U.S. Surgeon General policy statement and FDA regulations (1966), National Research Act, and Regulations for the Protection of Human Subjects of Biomedical and Behavioral Research(1974), The Belmont Report (1979), Human Radiation Experiments (DOE documents 1985), and "Common Rule" (1991). Certain federally sponsored and much privately sponsored research is subject to the regulations of the Food and Drug Administration. FDA regulations (revised 1996) and the provisions of the Common Rule are largely congruent, although some significant differences exist. 1 What is Informed Consent? Informed consent is more than a signature on a page. It is a documented process of communication. Drafting the Informed Consent Document - Getting Started Standard Operating Procedures (SOP) and FDA regulatory documents are the foundation of all activities related to clinical trials, and these documents are the authority with which to obtain site compliance with the investigational plan, including Informed Consent activities. Review your department's SOPs regarding required informed consent formats, elements, processes, and monitoring procedures, and regulatory documents such as 21 CFR Parts 50, 56, and 812. Review A Guide to Informed Consent, Guidance for Institutional Review Boards and Clinical investigators, for explanation of each section of 21 CFR Part 50. One important explanation found here states, "Subjects are not in a position to determine whether information provided is complete. Subjects may certify that they understand the statements in the consent document and are satisfied with the explanation provided by the consent process (e.g., "I understand the statements in this informed consent document)." They should not be required to certify completeness of disclosure (e.g., "This study has been fully explained to me," or, "I fully understand the study.")" Be aware of the status of any FDA Draft Guidance Documents that specifically address protection of human subjects. Drafting the Informed Consent Document - Basic elements In seeking informed consent, specific information must be provided to each subject. These basic elements of informed consent are listed in 21 CFR, Section 50.25. Briefly, the elements of informed consent state that the study involves research, and explains the purposes and duration of the research. Procedures are described, any experimental procedures are identified, any foreseeable risks or discomforts to the patient, along with potential benefits to the subject or others. Appropriate alternative treatments must be disclosed. The patient must be notified how confidential records identifying the subject will be maintained, and that the FDA may inspect the records. Explanations about compensation and medical treatments available in case of injury must be given, and where the subject can obtain further information, whom to contact for answers to pertinent questions about the research and their rights, and in the event of any research-related injury. The patient must be notified their participation is voluntary and that they may refuse to participate without penalty or loss of benefits, and that they may discontinue participation at any time. Consult the regulation for complete details and to determine if any additional elements apply. 2 Site Training Related to Informed Consent As you draft the Informed Consent document, plan how you will perform site training. Schedule and conduct investigator and site training, to include training on the Informed Consent process. The training agenda should include the following:
Monitoring Informed Consent It is vital to perform site monitoring early in the study, to identify any irregularities related to Informed Consent that may have occurred. A priority at every monitoring visit should be to examine the informed consent documents. Ensure that each informed consent document was properly executed and documented. Take inventory to make sure all informed consent documents, even those previously monitored, are present. Any changes to the study protocol may require changes to the informed consent document. Ensure that all documentation related to such changes, such as IRB approval for the change, and the new IRB-approved version of the Informed Consent document, is present in the Investigator File Failure to follow the Informed Consent process, as outlined in the Investigational Plan, and as required by the IRB, is considered to be protocol violation, as there is potential for increased risk, decreased benefit, and/or that the subject's rights, safety or welfare may be affected. In the event of such a protocol violation, consult the research agreement, and the IRB procedures for the institution, to ensure that the appropriate notifications are made and that any necessary corrective actions are taken. Such actions may include documenting the circumstances justifying the failure to obtain informed consent, notifying the patient of the irregularity in procedure. Typically, such a violation is to be reported to the IRB within five business days, or as soon as study personnel are notified of the violation. Documenting Interim Site Monitoring Complete a site monitoring report in accordance with your department SOPs. The report should include date(s) of the visit, name of sponsor/monitor, name and location of investigative site, name of investigator visited, statement of findings, conclusions and any actions taken to correct deficiencies noted. Changes on the horizon The FDA and Duke University have joined together as founding partners of a think tank, the Clinical Trials Transformation Initiative (CTTI), the goal of which is to modernize the clinical trial system. The CTTI will oversee specific projects to identify existing issues related to current practice, design models for improvement, and test the new models and compare them to the existing system. Conclusion Protection of human subjects starts long before the first study patient picks up their pen to sign informed consent for a clinical trial. Informed consent is a documented process of communication. All who are involved in clinical trials have responsibility for ensuring that the Informed Consent process is properly completed for each clinical trial patient. References 1 Information from this section adapted from National Institutes of Health and University of Nevada at Las Vegas - Office for Protection of Research Subjects 2, 3 Information from this section adapted from A Guide to Informed Consent We value your input! This article is the fourth in a series of articles relevant to specific tasks of medical device clinical trials. Our goal is to create a series that is of interest to a majority of readers. You are invited to e-mail comments, questions and suggested topics of interest. Stories of problems you have encountered, along with solutions that worked (or didn't work) are welcome. Reader input will be incorporated, where possible, in future columns on a related topic. Please indicate in your e-mail whether you would be willing to be interviewed for future columns, and include your contact information. You may e-mail your input to ksneen@mfrall.com.
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Practical Adaptive Clinical Study Designs for Medical Devices |
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While the traditional clinical trial is supposed to be completely designed prior to study initiation, an adaptive design may be preferable as it allows for more flexibility. Adaptive designs have been the focus of recent attention due to the increasing pressure to speed products to market, new methodological developments, and new interest from regulatory authorities. Traditional studies have been considered more scientifically rigorous, but in certain cases, adaptive designs may be able to meet the regulatory requirements while increasing efficiency. Most of the published methods and examples of adaptive study designs come from pharmaceutical trials. Examples of adaptive characteristics of these trials include:
Clinical studies are often designed to demonstrate that the new therapy is superior to a control; these studies employ statistical superiority tests. Another type of study is one in which the goal is to demonstrate that the treatment is statistically similar to a control; these studies employ statistical non-inferiority tests. Non-inferiority testing is a reasonable approach if the performance of the therapy is not expected to be better than that of a control. However, when there is substantial uncertainty about the performance of the therapy, an adaptive hypothesis testing framework can allow for combined non-inferiority and superiority testing. Interest in adaptive sample size methods has grown as medical device trials have become, longer, larger, and more rigorous. The most common of these methods is the so-called "group sequential" design. This is a study where a large maximum sample size is planned, and if results on an initial group of patients are sufficiently compelling, the trial is halted early. Another adaptive sample size method is based on re-assessing the study design assumptions mid-trial and changing the sample size if these were found to be inaccurate. This is often referred to as an "internal pilot study" or a sample size re-assessment. Additional newer methods exist, but these are subject to statistical and regulatory controversy. Adaptive methods do require special consideration for use in medical device studies. First, it should be noted that medical device studies are usually small relative to pharmaceutical trials, and so adaptive methods may offer smaller incremental benefits. Also, the sample size for devices is often driven by an absolute minimum required to evaluate safety; this may exceed the sample size that could be used to demonstrate efficacy with an adaptive design. Finally, consideration of the interplay of enrollment time and endpoint assessment is crucial. For example, suppose a trial is designed to have an interim analysis based on the first 100 patients in the study. If, in the time required to obtain endpoint data on these 100 patients, a large number of additional patients are enrolled, much of the benefit of the interim analysis will have been lost.
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Local Snapshot: Nonin Medical, American Medical, Medtronic, and Myocor
Nonin Medical Inc. announces the release of the first and only wireless fingertip pulse oximeter to system integrators worldwide. The Onyx(R) II, Model 9560 fingertip puls |
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Nonin Medical Inc. announces the release of the first and only wireless fingertip pulse oximeter to system integrators worldwide. The Onyx(R) II, Model 9560 fingertip pulse oximeter enables patients to accurately monitor vital signs and remotely connect with their clinicians -- gaining independence to go about their daily activities. The innovative device combines Bluetooth(R) wireless technology with the revolutionary Onyx (R) line of fingertip oximeters to address rising health care costs and promote patient-friendly remote disease management. American Medical Systems Inc. named Anthony Bihl as president and CEO. Bihl, who has served as interim CEO of the Minnetonka-based urology products maker since January, will also serve on the board of directors and retain his current role as executive vice president and chief operating officer. Before joining AMS (Nasdaq: AMMD) Bihl was CEO at Siemens Medical Solutions Diagnostics. Medtronic Inc. said on Tuesday it has agreed to buy Restore Medical Inc. in a deal worth about $29 million. Medtronic will incorporate Restore Medical (NYSE:REST) into its ENT (ear-nose-and-throat) business. Restore Medical has about 57 employees, including roughly 27 workers in its sales and marketing division, according to securities filings made late last year. Medtronic said it doesn't expect to lay off sales staff. However, Restore Medical executives will not continue at Medtronic. Myocor's iCoapsys device was successfully implanted by an interventional cardiologist with the Minneapolis Heart Institute Foundation. The product is one of two Myocor devices designed to treat patients with mitral valve insufficiency caused by heart failure and coronary artery disease. It is the subject of the VIVID study, which was conditionally approved for investigational use by the FDA last year. The iCoapsys device offers patients with mitral regurgitation - who are not good candidates for major heart surgery - a less invasive option designed to treat the debilitating condition, according to Myocor.
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The Search for the Perfect Employee |
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Many organizations today are working "leaner" and trying to do more with less. This is true especially within clinical research as the number of trained professionals at certain career levels are not adequate for the number of trials being conducted. There are over 80,000 trials in process in the US right now. When the volume of work is up, we tend to rely on those who have proven to be competent and dependable. Employee burn-out is one of the silent killers of workplace productivity and morale. But, at what point does the increased workload (and never-ending 50-60+ hr work week) start to affect our key employees? At what point does 40-80% travel begin to become too much of a burden on one's life? When does the cost of an unfilled position begin to outweigh waiting for the perfect person, and hinder progress? When you begin to notice frustration, irritability, frequent illness or absenteeism, or an indifference to work in these key individuals, the point has been reached. And reaching that point is expensive! The costs to your organization increase. Healthcare expenditures for over-stressed employees are nearly 50% higher. Absenteeism hurts the bottom line directly. Finally, when your stressed employees have had enough and decide to quit, you are in an even worse situation. In fact, statistics show clinical research professionals tend to change companies and positions approximately every 2-3 years in the Twin Cities. This correlates to the employee burnout cycle (Figure 1). When one essential person leaves, this creates a tremendous workload increase for the remaining members of the clinical research department. On average, a position requiring previous monitoring experience can remain unfilled for several months, perpetuating the cycle and further burnout. A once otherwise happy employee becomes disillusioned and chooses to leave for a new opportunity. The organization now has two unfilled roles, and the cycle continues.  Figure 1: The Employee Burn Out Cycle There are ways to mitigate the intangible costs of rekindling employee motivation and the tangible costs of an insufficiently staffed workforce. An option to improve both issues at once is to take a critical look at your group and their roles. A key element is to determine which essential duties must be completed by a specific individual or skill level. Separate out those tasks which are routine or administrative. A new job description can be created. Although this may not be the role originally pictured, this position may be the solution to decreasing the burden on current staff. This new individual could be hired on a full or part-time basis for an undetermined duration. Additionally, the hire could be timeline specific for a project/specific research trial or a direct hire. There are several key benefits to approaching a staff shortage in this manner. First, the type of individual you now require may be easier to find since the qualifications are different. Using sources such as your HR department and working with local placement agencies who specialize in clinical research with available candidates, are great options to get the position filled quickly. Secondly, opening the door to a candidate who has a background in clinical research with the aptitude and ability to learn quickly allows you the opportunity to groom them for taking on additional responsibility as needed. An example we have seen many times is when intelligent, ambitious study coordinators who want to become monitors are overlooked. Although they do not have previous monitoring experience, they have the ability and aptitude to excel at it if given the chance to learn. A common pitfall many hiring managers fall into is looking for an individual who has done exactly the same role before. Taking a moment in the candidate's shoes, they are seeking a change to advance their careers with increased responsibilities and duties. If they are ambitious, taking a lateral move may look advantageous in the beginning. But when time goes by and the opportunity to advance is not presented, they will begin looking elsewhere. Therefore, considering a candidate who has potential and giving them the opportunity to shadow from time to time in areas of interest is a winning combination for the long term. The search for the "perfect person" can become a vicious cycle. This cycle reinforces the negative impact on remaining employees' productivity and morale. By taking a critical look at your organization and determining essential elements for each position, you can create a new definition for a supporting role. This redefines the "perfect person", and allows you more flexibility to find an individual. The tangible benefit is work is being completed successfully, and your key employee's burden is reduced. The intangible benefit is with more people doing the work and having supporting functions, morale and productivity improve, job satisfaction increases and the burn out cycle is halted.
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Medical Device Manufacturing Regulations, Product Recall from the Field |
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Situation: You have received customer complaints related to device failures which resulted in customer injury. Other complaints may not have resulted in patient injury, but were the result of a manufacturing non-compliance such as the device not performing per specification, packaged with an incorrect component, or missing important labeling. Each of these will give cause for consideration to remove the product from the field. 21CFR and ISO 13485 provide clear guidance regarding recalls. This article will be from a 21CFR FDA perspective. Part 7 of 21 CFR provides a framework for conducting a field action. One of the core required documents is the Health Hazard Evaluation (HHE). This document is an assessment of the patient risks from using the defective product. Ideally, the firm will have a documented "risk assessment" which should have been a core deliverable from the new product development process. This risk assessment documents all of the risks associated with device and manufacturing process failure. It will also define the respective countermeasures use in the device and or process to mitigate the risk. The HHE will describe the device and the intended use. The specific problem will be described along with the patient outcome. It will discuss the statistical probability of the defect occurring along with the probability of patient injury. Additionally, it will include all relevant labeling and instructions for use. The HHE should also document mitigating events and or conditions which will reduce the probability of patient injury. All HHE documents need to be reviewed and approved by individuals with sufficient education and authority to assess the medical consequences of the device problem. Ideally, a medical officer would approve the final HHE. The HHE will be the bedrock document used in generating any respective field action documentation package. It is also the core document that FDA will use in assessing the severity and classification of the field action. The next issue will continue with developing an administering a field action.
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Local Industry Snapshot: Vision Ease, Virtual Radiologic, St. Jude Medical |
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Vision-Ease's protective lens gets day in sun The "Today Show" featured Ramsey eyeglass-maker Vision-Ease as part of the Skin Cancer Foundation's effort to teach viewers how to protect their eyes and skin from harmful sun rays. The broadcast could not be timelier. Vision-Ease, which makes prescription and bifocal and trifocal lenses for eye doctors, LensCrafter, VisionWorld and Wal-Mart, recently launched a line of Coppertone polarized lenses that block UVA, UVB and glare from "High-Energy Visible Light." Ultraviolet rays are harmful and associated with eyelid cancer, cataracts and macular degeneration, said officials with the Skin Cancer Foundation, which recently endorsed Vision-Ease's Coppertone lenses and selected them to feature on the "Today Show" along with protective clothing and sunscreen products. Veronica Barlow, a spokeswoman for the foundation, said the Coppertone lens blocks 99 percent of the harmful radiation. "You won't find many companies our size getting their products mentioned on the 'Today Show,'" said Doug Hepper, CEO of the $125 million company that...read More Virtual Radiologic CEO wins entrepreneurial award A Minnesota CEO has been awarded the regional Ernst & Young Entrepreneur of the Year award. Telemedicine company Virtual Radiologic Corp. (Nasdaq: VRAD) CEO Sean Casey won the top entrepreneurial honor in the technology category for the Upper Midwest regional program Casey was selected by an independent judging panel made up of regional business, academic and community leaders. Casey accepted the award at a gala event on June 5 in Minneapolis. Casey is now eligible for consideration for the national program. Award winners in several national categories, as well as an overall national winner will be announced by the accounting firm in Palm Springs, Calif. on Nov. 15. St. Jude heart device wins European approval St. Jude Medical Inc. won regulatory approval in Europe on a new product used to treat cardiovascular diseases. Little Canada-based St. Jude (NYSE: STJ) won European CE Mark approval and will begin the European launch of its TigerWire Steerable Guidewire. The device is part of a family of guide wires that steer a catheter through peripheral arteries, helping doctors diagnose the severity of diseases or deliver treatment. The device's tip is designed to provide greater flexibility, which will be of use in complex procedures, the company said.
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The Many Aspects of Clinical Trials: Effective Site Monitoring |
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What is Site Monitoring? Site monitoring is the task, and all related activities, of ensuring that the investigator and site personnel are conducting a clinical investigation according to plan and regulations. Site monitoring begins at or soon after the first enrollment of patients in a clinical trial. If the sponsor's monitoring personnel are not present at the time of first enrollment, efforts should be made to make a site monitoring visit very soon thereafter. Errors and misunderstandings caught early may be corrected before the errors are multiplied by the number of patients enrolled. Usually, only minor discrepancies are found at monitoring visits, and these are then corrected, ensuring complete and accurate data is collected to support the device being studied. However, there are occasions in which serious non-compliance is found or fraud may be suspected or detected, and this often surfaces during a site monitoring visit. FDA Guidelines Related to Site Monitoring The remainder of this article includes a brief overview of the relevant FDA regulations, especially 21 CFR 812.46, and the related FDA Guidelines for Monitoring of Clinical Investigations. It is a good idea to periodically review the regulations and guidelines, noting and incorporating any recent changes. The FDA regulation requires that a sponsor monitor the progress of a clinical investigation and secure compliance with the study protocol. The regulation also addresses what to do in the event of unanticipated adverse events or serious non-compliance.1 The FDA Guidelines, while not legal requirements, reflect principles recognized by the scientific community and represent a standard of practice that is acceptable to FDA. A sponsor who selects different procedures for monitoring a clinical investigation may, but is not required to, submit those procedures to FDA for review and comment to avoid the possibility of employing monitoring procedures that FDA might later determine to be inadequate. The FDA Guidelines address the topics of selection of a monitor, written monitoring procedures, pre-investigation visits, periodic visits, review of subject records, and record of onsite visits.2 Monitor Selection Generally, monitors should be selected with education and training appropriate and relative to the device being studied. Monitors may be employees of the sponsor, or they may be qualified persons contracted to perform the monitoring tasks. Monitors need not be qualified to diagnose or treat the disease or condition under study, but someone in the direct line of review of study data should be so qualified. The number of monitors may vary based on number and location of investigational sites, number of patient records to be examined, type of device, complexity of study, and other factors.2 Written Monitoring Procedures The sponsor's Standard Operating Procedures should be sufficiently detailed to cover the general aspects of clinical investigations, and may be used as the basis for the monitoring plan, supplemented by more specific or additional monitoring procedures, as needed. Written procedures ensure the quality of the study and that each person involved in the monitoring process carries out the appropriate tasks.2 It is helpful to develop a monitoring checklist tool to ensure that all tasks are carried out at each site monitoring visit. Site monitoring should be addressed in every Investigational Plan. It is important to determine and state which percentage of medical records will be monitored, and when they will be monitored. This is discussed in more detail in the section below, "Review of Subject Records". Pre-Investigation Visits The pre-investigation visit is the optimal time to establish expectations about study compliance, monitoring procedures and frequency, and correspondence between visits such as data queries to clarify information or obtain data obviously missing from the case report forms. Thorough, effective training and frequent communication should result in site monitoring visits that are straightforward, with no surprises. If appropriate, share the monitoring checklist tool with site personnel with whom you will work during monitoring visits. This provides an at-a-glance overview of the scope of each monitoring visit, and will assist the site personnel to focus on critical tasks and information required for successful completion of the investigational study. More detailed information about pre-investigation visits may be found in the January 2008 Medical Device Alliance Newsletter article entitled Investigator and Site Training. Periodic Visits The FDA guidelines indicate that the sponsor is responsible for assuring, throughout the clinical investigation, that the investigator's obligations are being fulfilled and that the site remains acceptable for the clinical investigation to continue. It is important to determine that the investigator remains actively involved in the study activities and has not delegated responsibility to non-designated personnel. The sponsor should schedule site monitoring frequently enough to ensure that complete and accurate records are being kept, and that all IRB activities, such as protocol change approvals, reports of unanticipated adverse events, and annual renewals are being completed in a timely manner. 2 Sponsors often require investigative sites to submit copies of IRB correspondence as it occurs - site monitoring of these documents then becomes a simple matter of ensuring that the site file is complete. Other types of interim communication between sponsor and investigative site can also guide the monitor in determining which additional activities or retraining may need to be conducted at the next site visit. Review of Subject Records The FDA states that during a periodic visit, the monitor should compare a representative number of subject records and other supporting documents with the investigator's reports to determine that information is complete, accurate, and legible, that missing visits and patient compliance issues are reported, and that informed consent is properly documented.2 The sponsor may wish to designate this representative number of subject records as a percentage, as it may be difficult to project the number of patients who will ultimately be enrolled at a given site. At the monitoring visit, if site compliance is found to be lacking, it may need to be increased, perhaps to even 100% monitoring. Such situations should be rare with early and thorough training and monitoring. The monitor may encounter situations when inheriting a study in which previous monitoring has been inadequate or non-existent. Most monitors, and even some site investigators, have a story or two to tell about these situations. Such a situation often requires that the monitoring plan and budget be increased to allow for additional, sometimes intensive site visits. I was surprised and dismayed at one site to be told that other companies' clinical study monitors stayed only an hour or so each day they were visiting - the site was unprepared for our monitoring team to actually be performing monitoring activities! Unfortunately, we discovered enough lacking that we had to move to 100% monitoring at that site until the deficiencies were corrected. Record of On-Site Visits On return to the office, ensure that a complete record of the on-site visit is prepared and filed, including information such as visit date(s), name of sponsor monitor, site investigator, site personnel, and the findings, conclusions and actions taken to correct any deficiencies noted during the visit.2 We value your input! This article is the fifth in a series of six articles relevant to specific tasks of medical device clinical trials. The topic for the final article in this series will be: "Fraud: What is it? How to detect it? What to do about it?" Stories of problems related to fraud, which you have encountered, along with solutions that worked (or didn't work) are welcome. Reader input will be incorporated, where possible. Please indicate in your e-mail whether you would be willing to be interviewed for the column, and include your contact information. You may e-mail your input to ksneen@mfrall.com. References This article is quoted or paraphrased frequently from the following documents: 1 21 CFR 812.46 Monitoring Investigations 2 FDA Guidelines for Monitoring of Clinical Investigations
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Noninferiority Clinical Trials |
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Most clinical trials are set up to show superiority -- that one course of action is better than another. Usually, the hope is that some new treatment is better than a control, and the objective is to obtain a significant p-value distinguishing the treatment from the control group. But this isn't always the case. Some trials only need to show that the new treatment is as good as an accepted one. In this case, the "control" group is an active control, and the new therapy doesn't have to be superior (though if it is, so much the better). In a case like this, it's sufficient to demonstrate what statisticians call noninferiority: that the new treatment is no worse than the old one. Demonstrating this with clinical evidence is a relatively recent concept, and reams of statistical literature are devoted to the topic of how to do it right. For instance, imagine that you have two therapies which are equally effective, and you test them in a randomized trial. Thanks to the workings of chance, it would be a minor miracle if the two groups had identical outcomes, so one of the treatments will end up looking better, even if only by a little. Since in reality there's no difference between them, it's a 50-50 shot which one that is. How do we make a statistical judgment about the results? One way would be to say that if we fail to see a significant p-value when comparing the two groups, then they must actually be the same. That reasoning doesn't hold water, though, because a nonsignificant p-value means either that there really is no difference or that the study was underpowered -- that is, the sample size was too small. That leads to the temptation to deliberately undersize the trial to fail to find a significant difference, which is obviously poor science. Instead, we say that "no worse" really means "not too much worse" -- not worse enough to provoke clinical concern. This concept is the heart of noninferiority testing, and it starts with a number that defines how much worse is too much. The idea is that the new treatment has to get close enough to the old one to convince observers that the difference between them isn't clinically meaningful. In a statistical analysis of this type, we test whether the new treatment is within the "noninferiority margin" or "delta" of the old one -- that is, whether it's "not too much worse." Setting up such a trial isn't necessarily any more complicated than a traditional superiority design, and noninferiority is well-understood by most regulatory bodies. The most important thing is that the noninferiority margin must be established in advance. This is usually done by clinical reasoning, although statistical and regulatory precedent can come into play. Consult your friendly neighborhood statistician to help determine if a noninferiority design is plausible for your trial, and if so, how to start setting it up.
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Local Industry Snapshot: AGA Medical, SuperDimension, Medtronic |
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AGA Medical files for IPO AGA Medical Holdings Inc., which makes medical devices that treat structural heart and vascular diseases, has filed to go public. According to securities filings filed Friday, the IPO by the Golden Valley-based company could fetch as much as $200 million, though AGA said that price was used to calculate registration fees and could change. AGA makes a device called the Amplatzer, self-expanding mesh that is inserted into blood vessels to repair defects in the heart or vascular system. AGA plans to use the proceeds from the IPO to repay debt and to pay accrued and unpaid dividends, as well as for working capital. SuperDimension completes $22.3M in financing Medical technology company superDimension has completed a $23.3 million round of financing, it announced Monday. Minneapolis-based superDimension, which develops minimally invasive interventional pulmonology devices, said that it has treated more than 3,500 patients. The company's first product, the inReach System, helps doctors detect and treat lung cancer early by translating a CT scan into a three-dimensional map of the lungs. A computer displays the image, along with arrows leading a physician through the lungs. Medtronic Debuts Study of Migraine Treatment Device Medtronic Inc. is presenting findings from a study of its new device to treat chronic migraines at a conference in Boston. Fridley-based Medtronic (NYSE: MDT) said it conducted a study, called the Occipital Nerve Stimulation for the Treatment of Intractable Migraine. In the study, the company implanted electrodes in patients, a treatment designed to stimulate the occipital nerves. Medtronic said the study, which was conducted at nine centers over three months, showed positive change in the number of headache days patients had per month and lessened overall pain intensity. The company said that over 28 million Americans suffer from migraines and lose about 157 million workdays each year.
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Medical Device Manufacturing Regulations - Product Recall from the Field |
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Field actions are performed to protect the public from defective medical devices or for communication of important safety information related to the device or therapy. A thorough Health Hazard Evaluation (HHE), reviewed by the medical officer, drives this process and guides the management team for determining if product must be recalled or important safety information distributed to the customers. The FDA will consider either of the above to be a recall. A field action plan must be developed which will document the process and include formal executive approval. Several items need to be developed or assembled as supporting material for the field action. It is important to note that all assumptions must be supported with a formal technical reference. The following are additional components of a successful field action. Corrective Action: Both FDA (21 CFR) and the International Community (ISO 13485) will expect that all field actions are supported by a CAPA (Corrective Action Preventative Action). Something went wrong which resulted in the need for a field action and the CAPA process will document the Investigation, corrective action, and preventative action. Consignee report: This is a comprehensive list of all affected customers who will be contacted regarding the action. FDA will ask for this list and perform follow up effectiveness checks to assess if the action was properly communicated to customers. Labeling: This includes all packaging labels, inserts, instructions for use, and any other material which may be shipped with the product to the end customer. Regulatory approval references: These are the PMA or 510K approval numbers which were assigned by FDA when it was approved the device for distribution. Communication letter: This is the formal letter, authored and approved by senior management, for communication of the field action to the health care professional. It must include enough information to fully inform the physician of the situation, associated patient risks and required action. Customer reconciliation record: This is a record to document that the health care provider communication occurred. The next issue, Product recall from the field part 3, will address execution of the field action and notification to FDA.
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Local Industry Snapshot: Atritech, St Jude Medical CVRx |
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Atritech looking for approval on heart device Atritech Inc. is filing for pre-market approval application for a new heart device for people with atrial fibrillation, it said Monday. Plymouth-based medical technology firm Atritech's Watchman Left Atrial Appendage (LAA) closure technology is designed to stop blood clots from entering a patient's blood stream, thus preventing stroke. The company recently completed a trial of the device in 800 patients at 60 centers in Europe and America, it said. It began the study in 2005. CEO Jim Bullock said in a statement, "This is a significant event for our company. We are thrilled to have completed this expansive and important trial and delighted to be one step closer to providing patients a compelling alternative to warfarin therapy." FDA OKs St. Jude chronic pain device St. Jude Medical Inc. has received regulatory approval to market a device used to treat chronic pain, the company said Wednesday. The neurostimulation device, dubbed EonC, uses electrical pulses to prevent pain signals from reaching the brain. It will be used to treat patients who suffer from chronic back pain due to a failed surgery. The device also features a long-lasting battery, the company said. CVRx wins $84M in financing The Brooklyn Park-based company will use the funds to continue developing a product it has invented to treat high blood pressure. In October, the Business Journal reported that CVRx's Rheos Baroreflex Hypertension Therapy System, an implantable device designed to control hypertension, or high blood pressure, won approval for marketing in Europe. The company's product is intended for patients who have not been helped by medication. Investors in the latest round of funding include New Jersey-based Johnson & Johnson Development Corp. and Menlo Park, Calif.-based New Enterprise Associates Inc. To date, total investments in the company are upwards of $209 million.
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Clinical Research Staff: Can We Win The Olympic Gold? |
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With Olympic spirit running high, it is easy to admire the dedication, skill and preparation the athletes go through. They spend years trying to find the right methods and combinations to perfect their technique with the assistance of coaches, teammates and even a little scientific help. Their goal is to win an Olympic Gold Medal. In clinical research we may spend years developing protocols, running trials and preparing submissions for that elusive "gold", FDA approval. Do we want our team to look like the USA's men's swimming relay team, with seamless transitions back and forth with a CRO? Do we consider a track athlete who has trained in the US and then returned (with new knowledge and skill) to compete for their home country, in essence using offshore options with US training? Or, do we want our team to be flawless like the Chinese women's synchronized diving team, where we keep all functions in-house, with the option of using trained adjunct staff? In today's global economy and instant technological communication, the options for clinical trials and research have expanded for both pharmaceutical and medical device sponsors. Let's look at three.
Clinical Research Organizations (CROs) can be a good option for creating your team. The critical initial question for a sponsor is the value - cost to use a CRO vs. available time and resources. How quickly do the trials need to be completed? How many monitors and CRAs do you currently have in your organization? How many trials are you currently running? Do you have the expertise to run a trial of the magnitude proposed? What would the cost of lack of manpower, learning curve or increased stress on your current staff be? If the answers to these questions are not favorable, then the value of time and resources likely far outweighs the cost. A critical part of using a CRO is the flow of information being as seamless as in the men's swimming relays. Ultimately, you are putting your faith and trust into the CRO that you have chosen to get the job done. In essence, the sponsor is the "coach". The coach and the CRO team must work together to perfect their craft, communicate often and work towards a common goal. A newer option for US sponsors is outsourcing trial management to a non-US group. In fact, it seems almost every continent now has the ability to conduct FDA compliant trials, including Europe, Latin America, Australia, Africa, Asia and India. Many US CROs have offshore arms in these countries as well. Some have the capability to run a trial from start to finish, while others specialize in data management. An important question for a non-US based CRO group would be whether their capabilities are truly comparable to a US-based CRO, and what expertise level they have to conduct FDA compliant studies? Sprinter Richard Thompson competed for Trinidad after training in the US at LSU, and won silver in the men's 100m sprint. Was the level of training he received good enough to accomplish his goal? If he had trained with the US team, could he have achieved gold? Although some CROs have US-based training, one might question whether this is sufficient to handle and manage the inevitable hurdles encountered with the FDA throughout the course of a trial. Communication and expertise are critical elements when working with an OUS-based CRO or data management group. If they have a proven track record, ability and reputation for achieving FDA compliance and approvals, they are a viable option. The most traditional option for conducting a clinical trial is for the sponsor to staff and run the trial from start to finish. Many choose this option, as their ability to control all proceedings is highest. A major drawback, as alluded to earlier, is available manpower. With today's lean organizations, there may not be enough staff trained within the clinical research department to take on an entire additional trial. This is often the number one issue for many sponsors when evaluating trial needs. Fortunately, the other two options listed above can assist in resolving this issue. One effective method for rectifying lack of available staff is to work with an agency that specializes in recruitment of clinical research professionals by hiring additional staff directly or for trial specific needs/timelines. One benefit is that you are generally working locally, and the agency can address your detailed qualifications in terms of what type of talent you require. Here you are trying to achieve the synchronization of the Chinese women's diving team. With all elements of the trial managed and controlled in-house, it would seem you could accomplish this. By expanding your current staff on a direct, contract or temporary basis, the benefit is that the added person is right there working with you day in, day out. You can synchronize your efforts and become a well-bonded team, aware of every internal move happening, and hopefully end up making a very little splash. The make-up of clinical research teams or any team within an organization is a critical element in the success of any trial "going for the gold". Good leadership will act as your coaches and both internal and external team members will keep the goal in mind with every action. Carefully evaluate the trial itself and the options for clinical trial staffing. Whether your team decides to use a US CRO, an OUS-CRO or simply supplement current staff using local resources for trial specific needs, all roads can be paved with gold and FDA approval achieved.
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Fraud: What is it? How to detect it? What to do about it? |
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Fraud: What is it? The topic of research fraud always seems timely. There is usually a prominent story in the media at any given time, about research personnel who have breached the trust bestowed upon them. But what is fraud? Fraud may take various forms, including but not limited to fabrication, falsification, and omission. One legal reference defines fraud as follows: All multifarious means which human ingenuity can devise, and which are resorted to by one individual to get an advantage over another by false suggestions or suppression of the truth. It includes all surprises, tricks, cunning or dissembling, and any unfair way which another is cheated.1 While the above seems to imply intent, it is likely that some instances of fraud begin with a biased researcher's misguided efforts to bring a product to market which they view as clearly beneficial to a patient population. Intention, or lack of intention, is difficult to prove, and likely would not hold up well to legal and regulatory scrutiny. If fraudulent activity occurs at the investigational site, your company may unwittingly become a party to fraud, unless the clinical team remains vigilant, and takes appropriate action when necessary. Whether there is intent or not, there may be another element at work when fraud is committed. The Association of Certified Fraud Examiners cites a report which states, "Not all psychopaths become fraudsters, but some fraudsters are psychopaths". The report discusses how these aberrant characters can infect organizations and provides ways to deal with them. 2 The U.S. Food and Drug Administration (FDA) states that, "In FDA's investigations, which began as inquiries into illegal gratuities and questionable data submissions, the agency discovered broad patterns and practices of fraud in the applicants' abbreviated new drug applications. The discovery of this extensive pattern of fraudulent data submissions prompted FDA to develop a program (1) to ensure validity of data submissions called into question by the agency's discovery of wrongful acts such as fraud, untrue statements of material fact, bribery, and illegal gratuities and (2) to withdraw approval of, or refuse to approve, applications containing fraudulent data."3 Maintaining personal and corporate integrity, and effective monitoring of clinical sites are imperative to bringing safe, effective products to market and keeping them there. Fraud: How to detect it? The first indication that fraud is occurring may be rather elusive. It may be a gut-feeling, a remark from site personnel, or data that varies significantly from what is seen at other sites or in the literature. It may come in the form of a request that just doesn't sit right. It is vital to pay attention to such indications! Medical device clinical research personnel visiting the clinical site are the most likely persons to first detect fraud, if it exists. However, the entire clinical team needs to be trained about fraud and remain vigilant. Standard Operating Procedures should include identified internal channels of communication for personnel to report suspected fraud or other discrepancies, both internally and at the clinical sites. Proactively discuss fraud within the clinical team, and be sure all personnel are aware of any related company policies and procedures. I certainly don't recommend going into a clinical site "looking for trouble". Neither should clinical personnel allow themselves to be lulled into complacency based on the reputation of a site or investigator. A neutral alertness is required. With some experience, it will become second nature to ask the question, "does this seem like an honest mistake which can simply be corrected, or does this seem like an 'odd' mistake - one not likely to occur if the person has engaged both their faculties and their integrity. Fraud: What to do about it? If fraud is suspected, it is important not to take an adversarial stance. Utilize monitoring procedures, examine relevant documents, and ask clarifying questions. Document your discovery and all actions. If possible, make copies of any documents which raise questions, and take those back to the clinical team for discussion and determination of any action that may be required. Under these circumstances, one discovers quickly if their clinical team and their company will back them up. This can be a fearful time, compounded by the real or imagined threat of employment termination should your concerns be unfounded, ignored - or worse - should you find that others in your company are complicit in the fraudulent activity. At a time like this, we hone our definition of personal integrity and it is to be hoped that we refine the definition honorably. Considering the potential ramifications of threat to public safety, erosion of the public trust, tarnishing of personal and company reputation, the choice seems clear. Integrity is the number one priority. And really, would you want to work with anyone - be they an investigator, other clinical site personnel, clinical team member, or an entire company - if you should find yourself in a "whistle-blower" situation and you lose? If that should become the case, one must decide if any further action can be taken, outside of the corporate structure. In my own experience, and the experience of colleagues who have shared their stories with me, we have been taken seriously and appropriate action has been taken. The outcome can be very rewarding, in knowing that your belief in your company's integrity is justified. Conclusion The results of research studies can be valid only if all parties maintain integrity. The future of medical research is jeopardized by fraud, the prevalence of which will result in potentially unsafe or ineffective devices getting to the marketplace, with all the implicit harm to patient health and safety and erosion of the public trust. We are charged not only with maintaining our own personal integrity in these matters, but also with being the guardians of the study data, so that public trust is justified, and patients - and their doctors - may have confidence in their decision to use our products. References 1Black's Law Dictionary, 5th ed., Henry Campbell Black, West Publishing Co., St. Paul, Minnesota, 1979 2 Fraud Magazine 3 FRAUD, UNTRUE STATEMENTS OF MATERIAL FACTS, BRIBERY, AND ILLEGAL GRATUITIES; FINAL POLICY This article is the sixth in a series of articles relevant to specific tasks of medical device clinical trials. You are invited to e-mail comments, questions and suggested topics of interest. Stories of problems you have encountered, along with solutions that worked (or didn't work) are welcome. Reader input will be incorporated, where possible, in future columns on a related topic. Please indicate in your e-mail whether you would be willing to be interviewed for future columns, and include your contact information. You may e-mail your input to ksneen@mfrall.com.
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Single Arm Studies: Objective Performance Criteria or Performance Goals |
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Good science often requires a control group to provide evidence that an intervention is successful. In many clinical trials a control group is formed by randomly assigning patients to a new treatment vs. a standard of care or placebo control. On occasion, a randomized study may not be feasible. For example, patients and/or physicians may not be willing to forgo the use of the device. In other situations, randomization may be considered unethical. In such cases, an oppropriately designed and executed single arm trial may provide reasonable assurance of safety and efficacy. In a randomized trial, a direct comparison of the treatment and control groups allows for a straight-forward assessment of the success of the treatment. A difficult question arises in a single arm study: what do you compare against? The obvious answer is that you compare with the past performance of other treatments, i.e. an historical control. There are two general statistical approaches frequently used to evaluate a single arm trial. The first and most well-known is a comparison against an Objective Performance Criteria or OPC. The canonical example comes from heart valves. Many heart valve studies have been based on a comparison of prospectively collected adverse event rates against an accepted benchmark, the OPC. If a study demonstrates that the adverse event rates are comparable (i.e. statistically non-inferior) to the OPC, we have reasonable assurance of safety and efficacy. OPCs are generally based on a wide body of published literature for a well understood disease and treatment. In some cases, the existing literature may be too small or outdated to properly define an OPC. In these cases, a so-called Performance Goal may be more appropriate. This is still just another benchmark that a device is compared against, but it is no longer considered to be "objective". However, using a benchmark still allows for a formal statistical comparison which provides some scientific credence. Performance goals may be especially appropriate for novel devices intended to treat poorly understood diseases or life-threatening diseases where no alternative treatment exists. The concept of a Performance Goal was discussed in the fall of last year at a meeting of the FDA Circulatory System Device Advisory Panel. There, a reviewer from the FDA defined a performance goal as "A fixed value to which [a] device's performance is compared to". They then laid out some of the distinctions between OPCs and Performance Goals. Interestingly, they noted "it is neither a superiority nor non-inferiority comparison". By this, they implied that the appropriate claim for a device that has met a Performance Goal is that the "pre-specified Performance Goal was met", not that the device was superior or non-inferior to the Performance Goal. Performance Goals may have one advantage over an OPC that is not immediately apparent. As a comparison against an OPC is usually a non-inferiority comparison, one may need to provide justification for both the OPC itself and a non-inferiority margin. In contrast, a comparison against a Performance Goal may only require the justification of one number, the performance goal itself.
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Selecting Clinical Study Sites |
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The process of selecting clinical study sites is governed by two principles. When these two principles are followed, the study objectives are likely to be achieved.
First, the appropriate type of study sites should be established. If the study design involves evaluation of a truly new and unproven therapeutic medical device, then university sites should be selected with physicians whose specialty includes the medical condition treated by this new device. If the study is designed to demonstrate that nurses can reliably obtain valuable diagnostic data using a new (but scientifically proven) point-of-care instrument, then rural community hospitals (where obtaining such data from a clinical laboratory instrument is problematic or time-consuming) should be the selected sites. Site Selection Example Gone Astray Against the better judgment of the clinical department, marketing insists on having a world-renown surgeon be the first investigator for a new surgical implant. This surgeon missed most of the training session scheduled for him. He also seemed to lack the ambidexterity required to successfully implant the device. But, marketing insisted. A very serious complication occurred during his first implant. The clinical project schedule was delayed by more than six months, the time it took to interest this physician to participate in the study and then realizing that he would not implant another device. But, the implant proved safe and effective in the sponsor's clinical study and was successfully introduced into the marketplace. Once the type of clinical study site required is determined, several factors should be considered to maximize the likelihood of obtaining quality and timely clinical data.
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Bayesian Statistics: Fact And Fiction |
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If you are involved in the conduct of clinical trials, you have probably heard of Bayesian statistics. Over the past several years, interest has grown dramatically in the use of Bayesian methods for the design and analysis of clinical trials; although the full-scale use of Bayesian methods was once difficult because of computational requirements, advances in computing power and the development of software dedicated to Bayesian analysis have made its use feasible even for large trials. Bayesian methods make use of prior information to help draw inferences from data. Under this analysis framework, new data can be combined with existing information about a device -- often, that information comes from the results of previous trials -- to help meet regulatory thresholds. This concept, sometimes called borrowing strength, means that if good prior data are available, a new study can be smaller and shorter. Because of this, and also thanks to FDA's recent embrace of Bayesian methods, they have gained an almost-mystical reputation in some corners. Bayesian analysis produces smaller trials with more flexible analysis options. Bayesian trials are faster, cheaper, better. They make traditional studies look like a Ford Model T parked next to a Lamborghini Countach -- so what are we waiting for? Well, hold on. Bayesian statistics are not a panacea. Used properly, they may save time and resources compared to traditional analyses, but the price is typically a longer and more involved negotiation with FDA, and their results use unfamiliar terms like "posterior probabilities" and "credible sets" which may need explaining to reviewers or panelists. What's more, not every statistician is versed in Bayesian methods (though many who are can be found both in industry and at FDA). And finally, used indiscriminately, Bayesian analyses may save no time or money at all. The most advantageous use of Bayesian methods comes when a device is similar to previous ones, especially when a history of clinical trials exists for similar therapies. Using the "prior information" concept, Bayesian analysis can then lean on the results of existing studies for evidence, though some new data are still required -- FDA will rarely permit a new device approval without at least some prospectively-collected outcomes. Having said that, strictly speaking you don't need prior information to design a Bayesian trial. Even a study of a first-of-its-kind device can be designed in a Bayesian way, but the benefit over traditional statistical methods is less. In this case, prior data are replaced by what is called a noninformative prior, which is a sort of computational placeholder that permits the Bayesian crank to be turned without using prior information. One reason to do this is that the size of a trial is heavily dependent on the size of the anticipated device effect, and when a good guess at the effect size cannot be made, Bayesian methods can be useful in designing a trial without a fixed up-front sample size. It's also worth noting that FDA only accepts part of the Bayesian framework. For instance, Bayesian statistics do not acknowledge the concept of "Type I" error; this occurs when we find a statistically significant result simply by chance even though the device being tested does not truly work. But controlling Type I error is part and parcel of FDA's statistical tradition, and the agency will demand that a Bayesian analysis behave reasonably on this front. Deciding what is meant by "reasonably," and agreeing on what statistical work is needed to demonstrate this to FDA are part of why Bayesian designs normally require more time to set up, and take longer to get agreement from regulatory bodies. In short, under the right conditions a Bayesian analysis can be an attractive option for a clinical trial, but to find out if it's right for you, let FDA know that you're considering a Bayesian design and be sure to contact your friendly neighborhood statistician for advice.
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The Many Aspects of Clinical Trials - Literature Review and Summary |
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Why do a literature review? Performing a literature review should be one of the first steps taken when planning a clinical trial. A good literature review is the very basis of your research, and is a platform on which to base the argument that your new device merits investigation. The literature review will help you build a knowledge base, and will provide the historical and theoretical context within which you will frame your research. This will enable you to define questions that may not have occurred to you previously, or that might arise as you conduct your research. Your focus will be clarified and possibly narrowed. The prevailing experts in the field will quickly become apparent. You will also gain a greater knowledge base of any competitive devices already on the market or being developed. Where to start? Getting started with a literature search is somewhat easier than it used to be, due to the advent of powerful internet search engines such as MedLine, PubMed, Medscape, MedBot and many others. The referenced article below provides specific search tips.1 Use of Google and other general search engines is also helpful. With a little practice, you will quickly become adept at honing your search terms. Full or partial abstracts can often be accessed as a result of internet searches, although access to full articles usually requires a paid subscription. Medical librarian services are perhaps the quickest way to obtain a list of articles related to your research. Some brainstorming with team members will help define a list of search terms to be used, and undoubtedly the medical librarian will have helpful suggestions to offer. Locally, the Bio-Medical Library at the University of Minnesota is one such service.2 Once you have a list of potential articles, meet with your project team to identify the articles that will result in a credible literature summary. Realize that the final summary will likely be used by various disciplines within your company and become part of an FDA submission. For FDA submission purposes, articles related to research conducted in the United States should be clearly identified as an important subset of the entire review and summary. Next, order any printed articles, or locate the applicable professional publications in your company's library. How to proceed? Anticipate that each article read and summarized will take about one hour of time. Depending on the number of articles and their complexity, a literature review can seem to be a daunting task, sometimes with hundreds of hours of reading. You must also deal with the challenge of how to organize the summarized materials. During the first pass through the articles, log the title, authors, journal, page numbers, and obvious main topics. Decide which type of software program would lend itself better to your particular summary. I usually create tables in Microsoft Word, and at the end of the project I copy them into Excel for ease of sorting by the end user. Along the way, discuss any questions with your project team and any external clients who may need to have input to the process. Then begin reading the articles in whatever order makes the most sense for your project goals. For example, a recent literature review and summary I performed was quite comprehensive. Indications for use included pediatric heart surgery, carotid endarterectomy in elderly patients, and detecting seizure activity in the general population. For this project, it made the most sense to sort and read the articles by indication for use. For other projects, it may be more appropriate to read the articles in chronological order by publication date, or read all articles by the most prominent publisher in the field. Assign an identifying number to each article as a reference point, such as 1996-01 or 2008-22 (if organized chronologically). Review the articles, making special note of pertinent data such as device name and model number, indication for use, type of clinical trial, number of patients, operative variables, adverse events, and outcomes. It is helpful to create a column for each individual type of data summarized, so the end users are able to view this information at a glance. A column for comments is helpful and can be done in narrative style. Look to the abstract of the article as a starting point for writing the narrative summary. There is no point paraphrasing important information or "re-inventing the wheel". The authors undoubtedly chose their words carefully, and while it would be defeating the purpose to include large portions of the article, the abstract can be pared down or added to, as the need dictates, to give a complete yet succinct summary of the article. You will also want to make note in the narrative column, in bold, of any anomalies you notice in the article, such as data discrepancies or obvious lack of adherence to good clinical practices. This will help the end user give the appropriate weight to the data summarized for such articles. Once all the articles are reviewed and summarized, write a short report to accompany the tabular or spreadsheet content. This report will describe how the summary was conducted, the number of articles reviewed, main findings, and tables showing the distribution of articles by country, indications for use, and other applicable factors. Who should do the literature search? A medical librarian or experienced consultant can probably provide the quickest finished product. If the clinical team takes on this task, it will be important to set a specific schedule, being realistic about the time required, and faithfully commit an hour or two per day to the task. Conclusion Performing a literature review and summary can seem a bit overwhelming, especially if it is added to an already overflowing work schedule. But taking the project step by step, as described above, and using the services of contract personnel when feasible, will get the project completed on time, allowing the clinical team and the manufacturer to move on to other important tasks of the clinical trial. As new literature is written and published, the cycle comes full circle. Each clinical trial starts with the literature. When research results are complete, or important discoveries are made, new literature is written, thus becoming part of medical history. References 1 Researching Medical Literature on the Internet 2 University of Minnesota Bio-Medical Library
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Strategies for Publication Planning |
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Medical communications have included publication planning for more than a decade. The tools of the trade vary widely depending on the number of projects included and the size of the budget allowed for this strategic focus. Entire companies are dedicated to providing services in this area and larger companies often have publication planners/managers on staff. The value of publication planning is in communicating important messages to your customers at the right time. In the medical world, the "gold coin of the realm" in publication currency is the peer-reviewed, top-tiered, high impact factor journal or the keynote speaker platform presentation at a well-attended international meeting. All publication types should be considered when planning a publication strategy. Properly timed publications can help to drive recognition, teach new techniques or even support adoption of new technologies. Having a solid platform of previously published information can build an image of a new product even before the product is launched. The key thought leaders who help to develop the product concepts and to test the product in a clinical trial usually speak about the work at various meetings before the published, citable article is available for dissemination. All of these types of claims must be supported by solid clinical evidence and the publication plan needs to share this evidence in an ethically appropriate manner. The nuances separating effective from less effective publication planning are found in understanding and mapping out the number, type and sequence of presentations to be attempted, the venue for each presentation, the training and experience of each presenter and the timing for the presentation. Publication planning involves pro-actively making choices about key messages (e.g. trial data), target audiences (advocates, physicians, patients, experts), venue selection (conferences, journals, websites, press releases), and timing. The goal is to communicate with a purpose.  Figure 1: The Cycle of Publication Planning Guidelines are available to help: Good Publication Practice (GPP), Uniform Requirements from the International Committee of Medical Journal Editors (ICMJE) and information from the Committee on Publishing Ethics (COPE). This document does not attempt to discuss the ethical issues of funding for research disclosures, whether marketing should be driving the publication process or who is actually doing the planning or medical writing (e.g. ghost writers), etc. Rather, the goal of this article is simply to define publication planning and to provide some generic examples (a simple flow chart and some template forms) that might be used to start a publication plan. The discussion about developing the publication strategy (what needs to be achieved) and tactical plan (how to achieve it) is often started by the marketing team in order to communicate key clinical and product messages in the marketplace. The strategy is to get specific clinical data communicated quickly, efficiently and effectively to the right audience at the right time. The plan defines each specific communication/publication, when it will occur, who the audience will be, what exactly will be communicated and how the individual communication/publication fits into the overall picture for the product and the company. An important point to remember is that a public communication is just that, public. In other words, once released, the published work becomes a citable reference. The safety and efficacy of the product can be used to support the product; however, this information is available not only to clients, but also to competitors, regulators and other individuals worldwide. Recent guidelines and discussions requesting full disclosure of all research data makes these publication planning efforts all the more important. Another important point is that one publication plan is not right for all products or even for the same product at a different point in time. Each publication plan should address the specific communication needs at the time the plan is developed and the plan will need to change as the timeline unfolds. The art of publication planning involves understanding the relationship between the data that is available, the time the data becomes available and the audience that will hear the data at that time. In other words, the goal is to get the right message to the right people at the right time. WHAT AREAS SHOULD A PUBLICATION PLAN ADDRESS?
WHAT ACTIONS ARE COMMON IN PUBLICATION PLANNING?
WHO MIGHT BE ON THE PUBLICATION PLANNING TEAM?
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Activity-Based Fees: Manage costs when outsourcing your clinical trials |
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Managing your clinical trial budget is often challenging, and even more difficult when outsourcing clinical trial services. Most Contract Research Organizations (CRO's) prefer contracts that bill for their services on an hourly basis, or a fixed monthly "fee for service" across one or multiple cost categories (e.g. monitoring, site management, project management, data management, etc.). These two contract models are the most common in our industry today, and offer the least risk for the CRO. Unfortunately, both of these models can create a misalignment between CRO incentive and customer goals. The longer the project continues, the more the CRO will bill the customer. While there are circumstances where these contract models are reasonable and fair, as clinical trials become larger in scope and more complex in design, the likelihood of cost over-runs becomes greater when using "hourly-based" or monthly "fee for service" based contract models. This happens because as the project increases in scope, so does the uncertainty and variability of work, effort and expenses. I cannot recall ever working on a clinical trial of any significant size that didn't have changes or in some way deviate from the original plan. Additionally, during the bidding process, we must remember that a CRO is trying to maintain profit, but at the same time price their services competitively in order to win the sponsor's business. This can often lead to the temptation of underbidding the project, and subsequently correcting for this error by issuing "change orders" or re-negotiating the contract once the sponsor is committed to the vendor, and the prospect of changing vendors is much less desirable. The sponsor must consider the impact to their customers (physicians, hospitals), possible delays to the project, and the additional hassle of selecting a new vendor. Cost over-runs that result from situations like the one described above can lead to significant frustration, and make sponsors more hesitant to outsource their clinical trials. However, there are ways to collaborate with your CRO to negotiate and structure contracts to avoid cost over-runs and have better control of your budget. For the purposes of this article, I will focus on a unique approach to structuring your contract model. Activity-based fees or Activity-based billing, is a contract model that you should consider using for either small or large clinical trials. Activity based billing means that the CRO will invoice the customer in direct proportion to the activity or work completed in a given timeframe (typically monthly). For example, the number of sites activated / supported, data queries issued or resolved, Case Report Forms reviewed or entered are all good examples of activities that can be measured, tracked and reported, and thus are ideal for determining CRO payment. By establishing units of meaningful work, and establishing a value for the completion of each unit of work, the study sponsor is now in an excellent position to pay for only the work or activity they need completed. Activity-based billing may be used in conjunction with monthly fee for service cost categories as well, resulting in a hybrid contact model (some categories activity-based, others flat fee for service). Whenever possible, using activity-based models is preferable if for no other reason than scalability. Clinical trials are often very fluid, especially in the early stages of a project. For example, the number of sites you plan to include in your trial may change between the time you complete your CRO contracting and the time enrollment ends. You may have planned to provide 100 sites for the CRO to manage, but end up with 87 before the trial even begins and 72 sites by the time it ends. Used correctly, Activity-based models are ideal for managing this variability. In the example above, a CRO and Sponsor could agree on a cost for the monthly management of a site. Once this cost is established, the contract may not need to be changed in order to accommodate either small or large changes in scope, because the CRO would bill in proportion to its activity in a given month. In this case, the activity is the management of a certain number of sites. Another form of activity based billing is a milestone-based contract. A true Milestone-based contract also achieves the sponsor's goal of controlling costs, and establishes a direct relationship between the work to be performed and dollars paid. Milestone-based contracts are most common with large, multi-center trials where the Sponsor and CRO have a good relationship and mutual understanding of the project and work required. True milestone-based contracts are rare, and should not be confused with a deferred payment plan. A true milestone-based contract is one where the CRO works with the Sponsor upfront to determine a reasonable timeline and value for the services to be performed. The CRO then commits to a pre-determined total cost, and meaningful project milestones, and agrees to be paid some partial amount each time a milestone is reached. Notice how this contract model requires the CRO to fully understand the project scope, as they must be prepared to share risk with the Sponsor that is not present in a traditional hourly-based or fee for service contract model. There are several other ways to help control costs and manage your clinical trial budgets when outsourcing. Including a maximum payment clause in your contract is always a good idea. There is no substitute for frequent and clear communication between sponsor and CRO. Focus any opportunities to reduce the number of cost-categories to include only those that you absolutely need. The more cost categories you create, the more you will need to manage throughout the trial. All of these are good things to remember when outsourcing, however, I believe the best way to control your clinical trial budget is to ensure that both the sponsor and CRO have a concrete mutual understanding of the contract model, and how that contract is interpreted in response to different situations. Activity-based billing is one of the best tools you have to create a scalable and fair contract. Hopefully this article provides you with a new billing mechanism to consider and discuss the next time you negotiate a contract with a CRO.
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Clinician of the Month: Carl Beaurline |
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After a 42 year career in quality assurance, regulatory affairs and clinical studies, one might think it time to consider putting it all aside and pass the time in a warmer climate, playing golf or enjoying what life has to offer outside the corporate world. For Carl Beaurline, his idea of enjoying what life has to offer is starting CMB Regulatory Specialties. In Carl's words "you want to give at least as much as you take, and I'm not done giving back yet."  To date, Carl's career has spanned 4 decades of growth and learning as each new opportunity arose. He began working at Medtronic as an electrical technician and had the opportunity to work on the design and testing of the first pacemaker. It was also his introduction to quality assurance as a department supervisor. One day, serendipity intervened, and he ran into Earl Bakken coming out of the elevator. Earl asked him to look into the Cooper Committee, and Carl's career in regulatory affairs for medical devices had begun.Carl moved onto SciMed, where in 1978 with Art Anderson's help, he did a retrospective study and obtained one of the very first 510K approvals. With a solid background in clinical research under his belt, he then joined St. Jude Medical. Under the mentorship of Carl Bruch, a 20-year FDA veteran, he was able to learn valuable skills in interacting with the regulatory body. As part of a review board, he led the initiative for Walt Lillehei's quest to educate and communicate physician to physician. Carl gained more new dimensions to include in his repertoire. At this juncture in Carl's career, he changed direction and ventured to work with Jim Grayback, a former coworker turned entrepreneur. Carl gained intimate knowledge of the trials and tribulations of being part of a medical device start-up. At GV Medical, the device for peripheral vessels and coronary arteries was a technical success but a commercial failure. At Comedicus, in the midst of a feasibility study for a pericardial access device and while working with phenomenal surgeons, physicians and lab technicians, the company ran out of money. Later, At ACIST Medical, he again focused on his quality roots until the company was acquired. Carl then went onto Compex Technologies, focusing on electro-stimulation for pain management in a regulatory capacity. He was persuaded to take the position partly because the company was going to be building a new facility in Minnetonka which would significantly lessen his commute from Chaska to New Brighton. Ironically, 3 days after Carl joined the company, they were acquired and the company moved to Shoreview, a few miles even further down the road, where he worked for several more years. As a fellow coworker said "A long drive to paradise is better than a short drive to hell". With this comprehensive background and a love of what he does, especially the opportunity to improve human welfare, Carl has created his own company. Now he can't imagine doing anything else. He feels every day is a new opportunity and experience, always interesting and challenging. Since his clients are relying on his expertise, it really pushes him to stay abreast of and be on the leading edge of his field. To facilitate this, Carl has returned to school to obtain a business degree and RAC certification to combine with his technical background. It will enable him to help companies understand how what he does from a quality and regulatory standpoint can help the financial well being of the company. He can answer the question "How much is it costing you to do it this way and what will it cost to improve it?" Additionally, an integral attribute of a good consultant is the ability to build relationships, create trust and gain credibility. Over the years, Carl has been able to interact with many people and develop long lasting professional associations. He believes it is important in two facets. The first is to create a client base that can rely upon him to help whenever they outsource projects. The second is to develop a network of other professionals who can assist him when clients require expertise beyond his scope. Although, early on in life, Carl thought as many do, that they know it all! Years ago he learned these reciprocal relationships are essential to knowing who has information and where to find it to help others. In the world of quality, clinical and regulatory, understanding the roles of various engineering disciplines and how they each contribute to product development is essential. Carl is passionate about making sure these relationships are not neglected. He states that if the engineering departments can't interact with the clinical and regulatory areas, it can cause delays and decreased revenues. Carl enjoys being the point person to make these connections, and fosters the collaboration and communication to break down the silos. In Carl's opinion, a key way to accomplish this is to be involved in professional associations. He says "Don't be afraid to get involved in professional societies and industry associations; it gives you a whole different perspective on things; you share your experience." You learn from other people on committees as well as at seminars and workshops. Carl likes to interact with people who are very skilled, talented and specialized. They can drill deeper and discuss challenges, learn new areas and share information on how they solved problems. "Giving as much as you take" is truly a lifelong philosophy for Carl Beaurline. Through his collaborative nature and hard work, Carl shares his time and expertise. As an independent consultant, although Carl learns a great deal from every project he is fortunate enough to be able to work on, the contribution Carl gives to a company requiring his skills is always equal if not greater. He "isn't done giving back yet."
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Companies in the News: St. Jude Medical, Arkay USA, Transoma Medical |
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St. Jude gets FDA approval St. Jude Medical Inc. has received regulatory approval to market a system used to implant cardiac devices, the company said Thursday. The product makes it easier for physicians to connect a cardiac defibrillator to the leads that transmit electrical signals to the heart. The product requires that only one connection be made between the parts, whereas competing systems often require three connections and multiple sets of screws. Having fewer leads in the body can reduce risk to a patient's health, the company said. Little Canada-based St. Jude (NYSE: STJ) will launch a "limited release" of the product in the near future. It will begin a full rollout later in 2009. ARKRAY USA Receives FDA Clearance on GLUCOCARD(R) 01-mini Blood Glucose Monitoring System GLUCOCARD(R) 01-mini is the first blood glucose monitoring system specifically designed for those who want high-end technology and an economical price with interchangeable face plates. ARKRAY USA, Inc., the 5th largest Blood Glucose Monitoring Company in the world, announced 510(k) clearance from the U.S. Food and Drug Administration for the GLUCOCARD® 01-mini Blood Glucose Monitoring System. This new system requires no coding, displays results in 7 seconds, requires a tiny 0.3 micro liter sample size, and was developed to use the same affordable test strips as the downloadable GLUCOCARD® 01 system that launched in 2008. GLUCOCARD® 01-mini has AST and features pre/post meal flags. Most notable, the GLUCOCARD® 01-mini is the only system on the market that features interchangeable faceplates so users may personalize the look of their monitoring system. It also features an easy-to-read display. The GLUCOCARD® 01-mini is distinguished by its leading edge design and technology. Recent clinical data showed GLUCOCARD® 01-mini to be highly accurate, precise and easy-to-use. "ARKRAY is excited to announce a new addition to our growing line of GLUCOCARD® blood glucose monitoring systems. The GLUCOCARD® 01-mini system follows the GLUCOCARD® brand image of sleek, compact, and discreet. The GLUCOCARD® 01-mini is unlike other glucose monitors in the market, it features interchangeable face plates," said Jonathan Chapman, President of ARKRAY USA, Inc. "An assortment of faceplates are available, we anticipate making exciting changes to this category by possibly adding a free face plate to each test strip carton and hope to soon make design software available on our website (http://www.glucocardusa.com) so that our customers can make their GLUCOCARD® 01-mini as unique as they are." Transoma gets FDA approval for cardiac device Transoma Medical Inc. has received U.S. Food and Drug Administration approval for its Sleuth AT implantable cardiac-monitoring system, the follow-up to its original Sleuth product that launched in 2007 . The Sleuth products help physicians diagnose patients with recurrent, unexplained fainting and abnormal heart rhythms more quickly, while also minimizing paperwork and practice workload, Transoma said in a press release Wednesday. Sleuth AT allows physicians to use the program with electrocardiogram (ECG) data to help monitor the efficacy of prescribed therapies. The products can be used to detect cardiac arrhythmias such as atrial fibrillation, ventricular tachycardia, bradycardia and supraventricular tachycardia. Atrial fibrillation is the most common arrhythmia, affecting approximately 2.2 million Americans. Transoma is a privately held medical-technology firm based in Arden Hills.
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(Statistical) Power To The People |
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The statistical concept of power is a key notion in the design of clinical trials, but a sometimes misunderstood one. Power is the probability of seeing a statistically significant result on an endpoint under a given set of assumptions - assumptions about the anticipated size of the treatment effect (the treatment-control difference, if you're running a randomized trial), the variability in the data, and the study's sample size. Power takes into account the natural unpredictability of patient response; even an effective therapy doesn't work for everybody, so there's always some chance of failing to meet study goals even under the best circumstances. With that in mind, more is better, as the saying goes. Larger treatment effects produce greater power, as does a bigger sample size. On the other hand, high variability is the enemy of power. More variation in the data makes it harder to demonstrate a statistically significant effect because the noise overwhelms the signal in the data. Power should first be discussed before the trial begins. Most trials incorporate one or more primary endpoints for which a statistically significant result is desired, usually in the form of a p-value below the magic cutoff of 0.05. Since success or failure on the primary endpoint goes a long way toward the success or failure of the trial as a whole, it's critical to design a trial whose primary endpoint you can "win" statistically. That's what power is about -- making sure there's a satisfactory chance of meeting the endpoint by hitting statistical significance. The way this usually works is that after an endpoint is selected, reasonable guesses about treatment effect and variability are obtained from the literature or from a previous pilot or feasibility study. Then for a given sample size, the resulting power can be calculated. Of course, this is usually done in reverse: the desired power is identified, and from there the needed sample size can be found. Power for a primary endpoint is traditionally set at 80%, though there's no statistical requirement for this. Some trials use 90% or even higher numbers, though again more power requires a bigger study. Setting power below 80% is usually perceived as producing unacceptably high risk -- after all, a trial with 70% power has nearly a one-third chance of failing its endpoint even if the assumptions about treatment effect and variability were reasonable, just due to random chance. You will sometimes hear a trial referred to as being underpowered or overpowered, often after the results are in hand. Used indiscriminately, saying that a study was underpowered has little meaning, since the term can be applied to almost any trial which missed its endpoints. In this context, calling a study underpowered is sometimes meant to suggest that better results (such as a significant p-value) would have been seen if the trial had been larger, but this is rarely an effective debating strategy with FDA or manuscript reviewers. Overpowering is the opposite concept. With a large enough trial, even miniscule effects can be detected in a statistical analysis, and an overpowered study is one which hit its endpoint statistically but showed a treatment effect that was clinically uninteresting. This is not often seen in device trials, since keeping studies to a reasonable size is typically a priority for practical reasons. The most important thing to keep in mind is this: most of the rules of study design and data analysis, especially in a regulatory setting, are designed to protect the public from ineffective or unsafe therapies. Predefined primary endpoints, statistical analysis plans which set out the rules in advance, blinding, the need for significant p-values as convincing evidence -- these are all intended to prevent ineffective or unsafe therapies from reaching the marketplace. Those things all try to control the risk of a false positive -- a study which seems to show that the device works when in reality it doesn't. Power is different. Power is arguably the one thing in statistical analysis which protects the sponsor of the trial by trying to avoid a false negative -- a study which fails to show that a device is safe or effective even though it really is. The moral of the story is to think carefully about power. If a power analysis suggests that more patients are needed than is practical to give reasonable assurance of a successful outcome, consider the options carefully. Maybe the treatment effect will be bigger than you think, or maybe the variability will be less; in either case the power will be higher and the required sample size lower, potentially making for a workable study design. This can sometimes be justified by limiting the scope of the investigation to those patients who are deemed the very best candidates for intervention, or by choosing a more homogenous study population to limit variability. But proceed with caution! Trials which fail to meet their endpoints usually do so because the treatment effect was smaller than anticipated, sometimes due to overoptimism in the design phase. So when confronted with a difficult situation, resist the temptation to assume the best-case scenario, step away from the table and (if you haven't already done so) contact your friendly neighborhood statistician for advice.
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Book Review: Both Texts are Solid Additions to Your Library |
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Hello, I will be writing a recurring column for the Medical Device Alliance newsletter. My background includes over 30 years of research experience, including both academic and industry settings. I have worked for the University of Minnesota, Mayo Clinic, Medtronic and Johnson and Johnson, among others. I started Frestedt Incorporated last year to offer full service clinical, regulatory and quality support to companies needing experienced individuals to provide a wide range of services on a consulting basis. Over the years, I have found that good reference books are critical to teach and build competent teams, so I decided to start this column with two books that I have used and found helpful both in practice and in the classroom. For our first two books, I selected Bert Spilker's classic "Guide to Clinical Trials" and John Gallin's "Principles and Practice of Clinical Research." Both texts are helpful to those learning how to conduct clinical research as well as standard references for those of us who have been doing research for decades. The Spilker text (published in 1991 and 2000) is a definitive guide, covering topics over 130 chapters in a dozen parts. Most notable is the opening section on designing clinical trials, followed by writing protocols and conducting "special" trials in areas like pharmacoeconomics and orphan drug products (a particular area of expertise for Dr. Spilker). The reason that the opening is so notable is the practical advice to questions like "Can a Pilot Trial Become a Pivotal Trial?" In my experience, the rapid pace of industry rarely allows a lot of time to think and carefully plan a series of trials and how they fit together. Often we try to run before we can even walk and we find that we need a pivotal trial before we even know if the device or drug will work for the use indicated and we have little to no pilot data to determine a solid sample size. This text goes on to cover topics about planning, conducting, analyzing and publishing data from clinical trials as well as the active oversight required to conduct multiple ongoing clinical trials. I have used the Gallin text in a class entitled "Understanding Medical Research." We started this class, just as the text does, with the historical perspective of clinical research and branched out to include ethical, regulatory, and legal aspects. We then jumped around among the chapters on Biostatistics, Epidemiology, Quality of Life, Economics, and Protocol Development. The class found parts of the text quite easy to read and other parts a bit more challenging. We thought the templates and forms in the chapter on data management were quite applicable to research activities today. Of specific interest are chapters on Institutional Review Boards, Data Safety Monitoring Boards, Data and Data Management and the special needs of small and large clinical trials. Each of the chapters are written by experts from places like the NIH, NHLBI and NCI. If you don't have these two textbooks already, both texts are solid additions to your library
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Companies in the News - Transoma, Inspire Medical and Apnex Medical |
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Transoma gets FDA approval for cardiac device. Transoma Medical Inc. has received U.S. Food and Drug Administration approval for its Sleuth AT implantable cardiac-monitoring system, the follow-up to its original Sleuth product that launched in 2007. The Sleuth products help physicians diagnose patients with recurrent, unexplained fainting and abnormal heart rhythms more quickly, while also minimizing paperwork and practice workload, Transoma said in a press release Wednesday. Sleuth AT allows physicians to use the program with electrocardiogram (ECG) data to help monitor the efficacy of prescribed therapies. The products can be used to detect cardiac arrhythmias such as atrial fibrillation, ventricular tachycardia, bradycardia and supraventricular tachycardia. Atrial fibrillation is the most common arrhythmia, affecting approximately 2.2 million Americans. Transoma is a privately held medical-technology firm based in Arden Hills. Two local med-techs vie in sleep-apnea market Suddenly, the Twin Cities seems like a hotbed for research into implantable devices that might tame sleep apnea. Inspire Medical Systems of Brooklyn Park says it expects to begin implants in the United States this month of an investigational medical device designed to use electrical stimulation to prevent the closure of the upper airway while people sleep. Such a treatment, the company hopes, could help people with obstructive sleep apnea – a common condition in which recurrent blockages of the upper airway can disrupt a patient's sleep, reduce oxygen levels in the blood and contribute to other health problems. Hennepin County Medical Center is one of a handful of U.S. hospitals that will be part of a government-approved study to test the company's device in a small group of patients, Timothy Herbert, the president of Inspire Medical Systems, said Monday. Last month, officials with Roseville-based Apnex Medical – a startup that's also developing a "neuromodulation" device for sleep-apnea patients – said they expected doctors outside the United States would perform the first implant with their investigational system this quarter. The technology behind Inspire Medical's device was first developed at Medtronic, where Herbert worked on the project. The startup was formed in 2007 when the intellectual property and technology behind Medtronic's device was licensed and spun out to Inspire Medical. "At the time, this is something (Medtronic wasn't) focused on," Herbert said. Medtronic maintains a minority ownership position, he said, and provides contract manufacturing to Inspire Medical Systems. The sleep-apnea devices of both companies consist of a pulse generator that is surgically implanted in the chest and a wire that delivers electrical stimulation to the hypoglossal nerve in the neck. That nerve leads to the tongue. Inspire Medical's device uses a pressure sensor to monitor a patient's respiratory effort during sleep so that nerve stimulation can be timed to match respiration. Patients are given a programming device to turn the system on at bedtime and off during nonsleep hours. The stimulation is sufficient to trigger a nerve response but not so great that it disturbs a patient's sleep. Beyond Inspire Medical and Apnex Medical, a Canadian company called Victhom Human Bionics Inc. also is developing technology for a neuromodulation device to help sleep apnea patients. Apnex Medical says it has been backed so far by $16 million in private-equity financing; Inspire Medical did not say how much money it has raised.
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Clinician of the Month: Jane Johnson with Transoma Medical |
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As Minnesotans, we have woken up to several snowy days in April and we are not necessarily happy. Jane Johnson, Clinical Research Project Manager at Transoma Medical, says she has enjoyed our winter and isn't complaining.  She even mentioned we could blame the long winter on her if we would like, as she moved back to Minnesota after a 20 year absence. One would think this wouldn't be the case- with her transition from Southern California to Minnesota this past year. A location change was not the only transition Jane experienced in moving back to the Twin Cities. Educated as an RN/BSN, her 12 year career in research on the West Coast encompassed working for a CRO and a large biotech company with abundant resources, primarily pharmaceutical in nature. Moving back home forced a shift in her career, as Minnesota is known as one of the few medical device clusters in the US focusing on cardiovascular technologies. She had great interest but very little experience in this area. Additionally, Jane made the transition to joining a smaller organization with local emphasis. For Jane, the years spent working in California provided her with flexible and versatile skills she uses each day to be successful.
It is these skills and more that have enabled Jane to be successful, adaptive and flexible with each new challenge she has faced in her career. Her hope is that as Transoma Medical grows, she will one day be able to take on a leadership role and balance her portfolio of responsibilities to again include strategic direction, team management and clinical study management. The skills she has gained through her diverse career will go a long way to helping her achieve this goal. Versatility and adaptability enable one to embrace the challenges their career may hold and be proactive at making that challenge an interesting transition. I guess this can also be said for embracing a long Minnesota winter as well.
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Local Headlines: Atritech, NeuroVasX, St. Jude Medical, GE Healthcare |
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Atritech raises $30M in venture capital Medical-technology firm Atritech Inc., which is developing a device to keep patients with atrial fibrillation from suffering a stroke, has closed on $30 million in financing, the company announced Thursday. The Plymouth-based firm will use the funding to wrap up clinical trials and begin marketing its product in Europe. Thomas, McNerney and Partners, a venture fund based in Minneapolis, led the round of financing. Split Rock Partners in Eden Prairie and previous investors, including Prism Ventures, Tullis-Dickerson and Vector Group, also participated. Atritech's device, dubbed Watchman, helps prevent blood clots from forming in the heart and migrating to the brain. The company is targeting patients who suffer from atrial fibrilation, or an abnormal heart rhythm, who are at greater risk of suffering a stroke. Atritech's device would help patients avoid having to take blood-thinning medications. The company, which has raised about $75 million in capital over the past three years, applied to the U.S. Food and Drug Administration for regulatory approval of the product last summer. Med-tech firm NeuroVasX gets OK to sell device in Europe Medical-technology firm NeuroVasX Inc. has received regulatory approval to begin marketing a device used to treat brain aneurysms, the company said Wednesday. The company's device uses a polymer material designed to fill an aneurysm, preventing it from bursting and causing damage to the brain. Such aneurysms now are often filled with tiny coils. NeuroVasX reported its device is superior to that treatment, as it uses a simpler process and fills the aneurysm more completely. Maple Grove-based NeuroVasX already has applied for regulatory approval to sell the device in the United States. The firm has raised more than $13 million in financing since its founding in 1997. In December 2007, it raised $8.5 million through a private placement. St. Jude Medical and GE Healthcare launch new product St. Jude Medical Inc. and General Electric Co.'s health care business have co-launched a product that helps cardiologists measure vascular functionality. The new product combines a new GE Healthcare software program with a St. Jude medical device called PressureWire Aeris. It is designed to allow physicians to measure fractional flow reserve (FFR) without time consuming setup. FFR is an index that determines which individual heart blood vessel is responsible for obstructing blood flow. It is used by cardiologists to direct coronary interventions and assess treatment. Little Canada-based St. Jude (NYSE: STJ) acquired the PressureWire device in December through its acquisition of Swedish cardiovascular device maker Radi Medical Systems. GE Healthcare is a $17 billion division of General Electric (NYSE: GE), based in Fairfield, Conn.
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Subgroup Analyses: Good Science, Data Mining and the FDA |
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The typical objective of a clinical trial is to demonstrate the beneficial effect of a medical therapy in a particular study population - the key being "in a particular study population." Deciding which patients to include in a clinical trial, especially one that involves a novel therapy, is one of the most important choices of the design stage. To put it simply, the patterns of disease are complicated, and patients who are candidates for investigational therapies are often the most complicated of all. These are typically people for whom established therapies have not worked, and who have few or no other choices. They often have widely different disease states and assorted comorbidities, and knowing in advance how a new therapy will work for each of them is impossible. Obviously, then, a great deal of effort is invested in figuring out the "right" patients for a study. Sometimes that effort is rewarded with a successful trial: good results from the statistical analysis, a compelling clinical justification and in regulatory situations, a thumbs-up from FDA. Other times -- well, you know what they say about the best-laid plans. When a trial fails to meet its clinical or statistical objectives, an attempt to understand what went wrong is the next step. For the sponsor, this is the right thing to do. When a great deal of time and money have been invested in a trial, it makes little sense to look at unappealing results, shrug one's shoulders and start from scratch. The obvious first question: what if we studied the wrong patient group? Specifically, what if there is a smaller group of patients in the trial who benefited, even if the overall population didn't show it? Welcome, then, to subgroup analysis. It's a natural thing to do from a practical standpoint, but fraught with difficulties both in a regulatory and a statistical sense. FDA tends to regard subgroup analyses as "hypothesis-generating," not as standalone evidence. That's partly because many subgroup analyses result from post hoc findings - analyses developed after the data were observed, as opposed to those prespecified in a study protocol. For instance, a recent paper by Hernandez et al. (Am Heart J. 2006 Feb; 151(2):257-64, "Subgroup analyses in therapeutic cardiovascular clinical trials: are most of them misleading?") found that among a selection of 63 randomized controlled trials, 39 reported subgroup analyses with 26 of those reporting on more than five subgroups, but only 14 - less than a quarter of all studies examined -- involved "fully prespecified" subgroups. This is probably unavoidable. Few sponsors can afford to make a trial large enough to permit powering of subgroup analyses. And if it were believed that therapeutic benefit would only be present in a subgroup, why include anyone else in the study in the first place? Rather, subgroup analyses are often motivated by the unexpected - we see something interesting in the data and react accordingly. From FDA's standpoint, though, the problem is bias - the increased chance of finding a false positive result by sifting through many possible analyses. This is why it is typical to prespecify study cohorts, primary endpoints and statistical methods - to prevent too much data mining, derisively called "data dredging." While data mining can produce findings of merit, it can be difficult to tell the difference between a real effect and spurious one under such circumstances. FDA isn't alone in its concerns. The New England Journal of Medicine recently published guidelines for reporting subgroup analyses in its pages (http://content.nejm.org/cgi/content/full/357/21/2189); the acknowledgements in that article include many well-respected statisticians, reflecting the interest in the issue and the importance of extracting the most scientific value from a clinical trial without stepping over into the murk. What to do? Despite potential misgivings, subgroup analyses are often important to interpreting the results of a clinical trial. Though a subgroup analysis may not carry the day by itself, it can provide valuable insight for future trials. For that matter, subgroup analysis may be useful in a pooled analysis across multiple studies, such as with a Bayesian trial design. As always, when in doubt contact your friendly neighborhood statistician for suggestions on how to proceed.
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The Nimble Workforce |
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The past twenty years have seen a dramatic shift away from an employee-based workforce to a more nimble and focused workforce. Contract staff can now provide 'just in time', 'just what is needed' skills for virtually every aspect of a company's business, from data entry to experienced high-level management. Independent contractors work in companies across the country in almost every industry, including the medical device industry. According to the U.S. Bureau of Labor Statistics, independent contractors increased 10% between 1995 and 2005, and made up 7.4% of total employment, with 81% over age 35. 82% of these independent contractors preferred their work arrangement to a traditional job and indicated that increased independence was a significant component of their satisfaction. In the current economy, contract staffing is a critical element in the strategic planning of any company and perhaps even more important for small or midsize businesses. A company that cannot quickly and effectively re-direct resources in response to changing business and market needs will fall behind and may ultimately fail. Risk Management There is no doubt that the largest single operating expense for any company is payroll and related costs. The effective use of human resources goes right to the bottom line. Companies with too many, too few or the wrong people may pay a high price. Overstaffing Change in business demands creates the risk of having excess employees. An independent contractor workforce can easily and cost effectively adapt to changing needs. For example, a local medical device firm increased permanent staff during three proposal processes, but ultimately did not "win" any of the proposals. An employee of only four months was laid off, resulting in a loss of recruitment and training costs associated with that employee, not to mention the effect on the morale of remaining employees. Hiring an independent contractor would have provided much more flexibility. Understaffing For staffing gaps due to illness, resignations, or extended vacations, independent contractors with a like skill set may be able to fill in seamlessly. A local emerging medical device company requested a Sr. Clinical Research Associate when a current employee resigned. An independent contractor with a complementary medical device technology background was sourced and placed in the interim position within a week, and was able to cross train with the employee who was leaving. Right staffing One of the greatest benefits of contract staffing is the ability to tap into a world of talent and experience when you need it, but only for as long as you need it. For opportunities outside normal business or process improvement initiatives, the best decision may be to hire a skilled and experienced independent contractor instead of incurring delays and costs involved in recruiting, hiring and training a new employee or re-training an existing employee. A local medical device start-up needed to develop a quality system. Rather than hire a full-time resource, they looked to an independent contractor with over 20 years of experience. He developed a quality system the company could utilize as they proceeded through their product development process. Another company implementing a new ERP system hired independent contractors to help with integration and documentation of new process flows. For these companies, tapping into the right talent at the right time was critical to their ability to grow. Perry Parendo of Perry's Solutions, LLC says it can be a slow process for organizations to understand "right staffing". An organization first contracted with him when their product development project had their "back against the wall". After years of development, and well into the test cycle, product performance was not satisfactory. To compound the problem, a large amount of custom manufacturing equipment was purchased to prepare for production, and process development was well underway. Perry created a series of tests using Design of Experiments that determined with confidence that a design change was needed. From these DOE test results, the product was redesigned, and Perry continued his involvement with testing. Using strategic testing without the prior constraints, the project came together quickly and objectives were achieved in 3 months. Due to this success, the organization asked for early development assistance from Perry for the next project. The working dynamic was very different, with the focus on answering the following questions:
A strategy and project plan was created to address those questions so that another crisis situation could be avoided. "While I can help when they hit the wall," Perry says, "it is much easier and smoother for the company when they involve me early to expose the potential gaps to reduce risk". Productivity With the right talent in the right job, productivity will increase. It is common for a company to focus staff on the core mission and outsource non-core activities. When a local urology medical device company needed reimbursement expertise, a staffing agency helped them quickly find a senior reimbursement expert to efficiently answer their questions. Companies can gain productivity by offloading job posting and candidate screening to meet their staffing needs, while freeing up existing staff to work on income producing activities. With a ready reserve of qualified talent, an agency can speed up the placement process and provide a candidate pool carefully selected to meet a company's specific, current needs. Capital Efficiency Companies must be fluid in the size of their workforce. Hiring experienced full-time employees is a commitment. Recruiting fees, vacation, sick leave, unemployment insurance, workers compensation, and payroll taxes typically represent approximately 20% of an employee's base pay. And this doesn't include bonuses! If the hire doesn't perform as planned or business needs change, costs of terminating an employee include severance, vacation pay out, effect on unemployment insurance ratings, and possible negative impact on morale. Hiring contract talent can lead to significant cost avoidance, as illustrated in Perry's Design of Experiments testing, but there are other cost savings. Contracting eases the administrative burden by spreading out costs and creating a sort of assured performance period, helping ensure a mutual match. If eventual permanent placement is the end goal, contracting is an affordable way for both sides to "try before you buy." For short term engagements, there are few cost effective solutions as easy to employ. The trend toward a workforce as adaptable as the world is changeable will continue. CareerBuilder's "2009 U.S. Hiring Forecast" published on December 30, 2008 states that "28 percent of employers anticipate hiring freelancers or contractors to support their business as they wait for the economy to bounce back." The companies that thrive will be those who consider all workforce options, including contract staffing through an ongoing relationship with an experienced agency.
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Companies in the News: St. Jude Medical and Torax Medical |
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Torax Medical Inc. a firm that's developed a medical device used to treat acid reflux, has launched a key clinical trial. The Maple Grove company will test its device at 15 medical and academic facilities throughout the U.S. and Europe. Torax's device supports a muscle that, when weakened, allows acid to seep out of the stomach. The firm is targeting patients who haven't been helped by drugs, which can relieve pain but don't necessarily prevent acid from damaging the body. Torax estimates that about 19 million people in the U.S. suffer from acid reflux disease. The company has raised more than $10 million in venture capital from venture firms including Minneapolis-based Thomas, McNerney & Partners. Medical-device consultancy opens in Bloomington Emergo Group Inc. announced it has opened an office in Bloomington. The Austin, Texas-based medical-device regulatory consulting firm opened the office Friday. Mike Johnson is the office's director of business development. The company decided to locate an office in the Twin Cities because of the concentration of medical-device companies here, said Chris Schorre, a spokesman. Johnson is the only employee in the Bloomington office now, but the company plans to hire more people when the economy improves, Schorre said. St. Jude Medical wins FDA approval for defibrillator lines St. Jude Medical Inc. on Monday said federal regulators have approved a pair of cardiac defibrillator product lines. The Promote Plus and Current Plus defibrillators, approved by the U.S. Food and Drug Administration, include features that allow doctors to customize therapy for patients with heart arrhythmias and heart failure. St. Jude (NYSE:STJ) said the new products also have a smoother header configuration to make the defibrillators more comfortable for patients, as well as provide more visibility at the connector site, where the thin wire that delivers electricity to the heart is connected. Cardiac devices such as defibrillators are big business for Little Canada-based St. Jude, which reported a 14 percent jump in earnings in its first quarter. The increased profit was partly fueled by strong sales gains in St. Jude's cardiac device business units. Sales of cardiac-rhythm management products, such as pacemakers, rose 7 percent to $676 million in the first quarter. Implantable cardiac defibrillator sales increased 9 percent to $394 million, while pacemaker sales climbed 4 percent to $282 million.
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Clinician of the Month: Wayne Carlson |
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Dialysis... Just the word in most cases would be a conversation stopper, unless the conversation is with Wayne Carlson, Director of Clinical Services at Minntech. In fact, people all over the world frequently ask Wayne to talk about his knowledge of hemodialysis. He started his career as a Dialysis Technician over 30 years ago. Since then he has spoken to audiences world wide, keeping them entertained and interested using personal experiences and stories from throughout his career.  When Wayne began in hemodialysis, he recalls it was a niche therapy with no Medicare funding. As time went on and he became the Director of Operations for the Regional Kidney Dialysis Program, dialysis evolved as a mainstream therapy and the funding followed. A unique highlight in Wayne's early career involved setting up regional dialysis programs on two Indian reservations in South Dakota. He found that the resident's thoughts and culture were much different than he was used to. It was very challenging to implement the project, even in a community with a high mortality rate. He was eventually able to get the project up and running and is proud to say it is still going strong today. Wayne fulfills a very different function today, yet still uses the experiences from his early days. He joined Minntech's marketing department a dozen years ago after being recruited by a colleague. He moved on to become a product manager and faced an interesting challenge in that there have been few technological advances in renal since the 1980s, due to a lack of reimbursement for such projects. The only areas to pursue growth were focused on cost savings. He then became the Director of Clinical Services. Again, Wayne faced distinctive challenges in that they were supporting very mature products. Clinical Services was to run clinical protocols for new development. It was a difficult role when they didn't require a great deal of support. As a result, over time the clinical group evolved. The group evolved into a very multi-faceted role within Minntech. Wayne described it as the liaison between the customer and sales, the customer and manufacturing and manufacturing and sales. The group also determines business ramifications. Wayne spends time talking to customers, then developing programs that look like education and training. In reality, it is product support from a clinical affairs perspective, under the guise of customer support. When we spoke, Wayne was excited about a new project with a very tight deadline. He couldn't share all the details of the project, but he had been working hand in hand with a key customer. Had we not clearly established his clinical role; one might have mistaken Wayne as a marketing department member. His team had been working diligently to develop a creative educational piece to convey product information per the customer's specific requirements. What he showed me was a mock up of a children's book, brightly colored with a simple message. It was being presented to the client's executives about 24 hours later, as the first phase of a multi-component project. It was not at all what one would have expected from a clinical department, yet it was fabulous. Wayne emphasized that challenging projects could be accomplished primarily due to his colleagues. With this team, he never has to question if things will get done or the quality of the work he can expect. He has a high confidence level because everyone's motives are in the right place. Wayne also mentioned that even with Minntech's hierarchical structure, if someone had a passion to do something, and had the ambition to run with it, they were encouraged to do so. Status and position within the company don't play a significant role. Of course there are the usual limitations set by the FDA or stakeholders, but the "Just Do It" attitude prevails. This works well in a company considered large in size, but designed with agile business units. Things are done expeditiously when you have a team of three who manage $60 Million dollars worth of product and get decisions made without a lot of bureaucracy. Concepts can be sold quickly and projects moved along without a lot of delays. Wayne's attitude regarding pursuing one's abilities fits nicely with Minntech's corporate philosophy. He believes you can be your own worst enemy if you pigeon hole yourself. Rather, he recommends you create your own definition, develop different skill sets, and thus expand your horizons. In the end, it will benefit both the employee and the company, because it moves one in a direction to embrace work beyond what has traditionally been done. In fact, Cantel, Minntech's parent company is supporting development of new technologies in infection control, an area that is a passion for Wayne. He believes it is an unrecognized need. How did the organisms get to your body and how do you get rid of them? There are currently different protocols as to how to deal with C-diff versus another organism. Do you use soap and water or alcohol? Wayne feels there is an immense amount of knowledge in acute care facilities not compiled yet. He sees it as the start of a whole new area dedicated to infection prevention. This new development exemplifies both Wayne's and Minntech's "Can Do" philosophy, and allows him to get in on the ground floor of a new venture. Wayne's enthusiasm regarding the future of dialysis and infection control are easily conveyed through his vibrant personality. He told me how he presented to a room of over 500 people on the obscure topic of "Dialyzer Reprocessing", at a renal conference in China. They all held onto his every word, then he realized it was because he was the last speaker before the prize drawing. Meeting Wayne in person, that is hard to believe. With his years of experience, he can make any topic exciting. This is why he is a perfect fit for the Clinical Services group, dedicated to providing creative support for products from a clinical affairs perspective.
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Companies in the News: Inspire Medical, Disc Dynamics, EV3 |
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Inspire Medical raises $17M in VC.Inspire Medical Systems Inc., a med-tech startup developing a device to treat sleep apnea, has raised $17 million in venture capital, the company announced Monday. Synergy Life Science Partners, a venture-capital firm in Portola Valley, Calif., led the round of financing. Previous investors, including Kleiner Perkins Caufield & Byers, US Venture Partners and Medtronic Inc., also participated in the round. Brooklyn Park-based Inspire Medical spun out of Medtronic in 2007 and its CEO, Tim Herbert, formerly worked as senior director of ventures at the company. Dr. Glen Nelson, a former vice chairman of Fridley-based Medtronic and a previous CEO of Park Nicollet Medical Center, also is an investor. Inspire Medical will use the capital, to be disbursed in two parts, to fund clinical trials. The company's technology sends an electrical impulse to a nerve in order to keep a patient's airway open during sleep. The device could become an alternative to the standard treatment for the disorder, continuous positive airway pressure (CPAP). Patients undergoing that treatment must wear a mask while sleeping. Inspire Medical is not the only med-tech company in the Twin Cities developing devices for treating sleep apnea. Fridley-based Apnex Medical Inc., which is using electrical stimulation to treat the disorder, closed on $16.1 million in venture capital two years ago. CE Mark Extended for Disc Dynamics' DASCOR Disc Arthroplasty System Expansion of Intended Use Now Includes Posterior-Lateral and Endoscopic Approaches EDEN PRAIRIE, Minn.--(BUSINESS WIRE)--Disc Dynamics, Inc., a leading developer of minimally invasive treatment options for low back pain caused by degenerative disc disease (DDD), announced that the CE Mark received in the European Union for its DASCOR® Disc Arthroplasty System has been expanded to incorporate a posterior-lateral surgical approach, as well as an endoscopic approach. "DASCOR is the only motion preservation technology that can be delivered through multiple surgical approaches," said Steven Healy, president and CEO of Disc Dynamics. "Surgeons can now match the preferred surgical technique with the patient's anatomy." The device consists of a two-part curable polyurethane and an expandable polyurethane balloon that is inserted into the disc nucleus space after the desiccated nucleus has been removed. The balloon is then injected with a flowable polymer, which creates a complete, patient-specific implant that conforms to the shape and size of the disc space. In the U.S., Disc Dynamics is currently completing its IDE feasibility clinical study. Medtech Ev3 acquires California firm Chestnut Plymouth-based medtech Ev3 Inc. has purchased a California firm developing a new method for treating brain aneurysms. Ev3 (Nasdaq:EVVV) said Tuesday that it's making an upfront $75 million payment for Chestnut Medical Technologies Inc. of Menlo Park. About 30 to 40 percent of the payment is in cash, with the rest in Ev3 common stock. Ev3 said it will pay an additional $75 million if and when Chestnut receives U.S. Food and Drug Administration approval of its Pipeline Embolization Device for treating aneurysms. Ev3 doesn't expect to make the payment until 2011. A cerebral aneurysm is a ballooning of blood vessel in the brain that can cause stroke and even death if it ruptures. The Pipeline device, which has already received European approval, is designed to treat an aneurysm with a minimally invasive technique that diverts blood flow away from the weakened blood vessel. Robert Palmisano, president and CEO of Ev3, said in a news release that the Chestnut's product will "benefit the large number of patients suffering from brain aneurysms that currently are not well treated with either surgical or endovascular techniques." Chestnut's top executive, Dr. Aaron Berez, described Ev3 as an "ideal partner to accelerate the rapid diffusion of our products around the world." The acquisition is expected to close in the next 45 days.
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Need a Coach? Select wisely |
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Until recently, few people openly admitted that they had or needed a coach. Today, partnering with a coach is an accepted practice. Many people report improvement in their performance and yet others who engage in a coaching relationship fail to achieve the improvement they seek. Coaches may become frustrated when their coachees disregard the prescribed regimen. Often disappointment is the result of a poor fit between the expectations and capabilities of the coach and the needs of the coachee. Personal leadership development support tends to fall into three buckets: coaching, advice, and counseling. Each is appropriate for a different need, requires different professional skills from the person providing the support, and requires various levels of involvement from the person being helped. If these are not properly defined and aligned up front, positive results won't be achieved. Coaching People typically seek coaching support because an aspect of their behavior tends to subterfuge their effectiveness. The realization for the need to make a change typically originates from the perceptions of several stakeholders. The work of the coach is less about developing insight and more about engaging the person to improve specific behaviors. The domain of the coach is to work on specific behaviors. The objective is to help the coachee develop a broad repertoire of behaviors so that they can choose the right response to the right situation. Ultimately the identified stakeholders determine whether the specified objective has been met. During the selection interview, the coach determines whether the motivation to undertake the process of behavior change is present. The coachee must determine whether there is chemistry between the two parties and whether they will make the commitment to trust one another. If they agree, the coachee's role is to acquire and listen to the feedback of critical stakeholders and follow the coach's prescribed practices to improve the targeted behaviors. Example exercises may include writing down thoughts, trying out new behaviors and actively soliciting and following up on feedback. In partnership, the coach and coachee set up one or two specific objectives to address over a specified time period. They develop a contract that specifies the role each party plays in the process with specific actions to be taken when an aspect of the relationship is violated. The contract may be openly shared with others. The coach is likely to work with the individual more intensely at the start of the relationship. Coaches work with people who freely engage in the relationship–they typically don't work with people who are on a performance improvement plan where coaching is the last step of an exit strategy. Advice You may find yourself in situations in which you have insufficient knowledge. You may distrust the quality of input from those around you or feel uncomfortable admitting to your peer or superiors that you need further information. Therefore, you seek external counsel from those who have the requisite experience or the specialized knowledge. You look for specific suggestions on how to deal with situations. The input sought is not about making significant behavior change. It is about developing a response to a specific situation. Indeed, you may seek advice regarding the same issue from several people. Advisors may work on an informal basis or work under a more defined project arrangement. Ultimately you choose whether to act in accordance with the provided advice. The responsibility of the advisor is to ensure a proper grasp of the situation, to undertake the necessary homework, and to provide an unbiased and honest assessment and suggestions. The advisor should not take a personal affront if you choose an alternate course of action. Rather, success is determined whether you find the information presented by the advisor as having added value. Counseling Life and relationships are imperfect. Being human often means having to confront those issues that my have surfaced early in your life. Usually you can move beyond them and function adequately. Yet when issues of past relationships continue to impact your current behavior and relationships or when you struggle to find deeper understanding, it may be necessary to seek the support of a professional counselor. Typically this person has years of professional preparation and certification from a state agency. The backgrounds of these individuals may be in social work, psychology, psychiatry, or religious leadership. Clients may see counselors for several sessions to several years. The emphasis is to understand how personal issues and relationships from the past impact current life. Counselors spend more of their time focusing on establishing insight and understanding. The work is typically deeply personal and thus confidential and private. Most counselors are trained to work in the realm of one-on-one situations such as marriages and parenting; they are less capable of dealing with the complexities and peculiarities of organizational life. What is right for you? The needs of most people don't fall neatly within one of the three buckets of coaching, advice, or counseling. So how to you determine the person who is right for you? Here are three thoughts to help you make the appropriate selection.
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Chris Mullin is a Principal Statistical Consultant with The Integra Group, providing statistical expertise to the medical device and biotechnology industry. Contact him at 651 - 270 6442.