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Article Index
 Selecting Clinical Study Sites
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Article 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. Read More |
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Fraud: What is it? How to detect it? What to do about it?
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Article by: Diane Reid 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. Read More |
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Single Arm Studies: Objective Performance Criteria or Performance Goals
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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. Read More |
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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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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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Frank B. Freedman, Ph.D. is the Consulting Partner for Alliancz Medical Consultants, a company he founded in 1985. Formerly he was a co-founder of SciMed in Maple Grove and its first Director of BioMedical R & D. He also worked for Medtronic and Dacomed in product development, regulatory and clinical management positions. Dr. Freedman is currently an Adjunct Professor at the University of St. Thomas and Anoka Ramsey Community Colleague, where he teaches clinical research and medical device classes.
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.