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Article Index
 The Many Aspects of Clinical Trials: Effective Site Monitoring
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Article by: Diane Reid 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. Read More |
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Noninferiority Clinical Trials
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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. Read More |
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Local Industry Snapshot: AGA Medical, SuperDimension, Medtronic
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Article by: Medical Device Alliance 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. Read More |
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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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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.
The Medical Device Alliance has captured a synopsis of local medical device companies in business journals and publications. Please send your press releases to ksneen@mfrall.com or call 763.533.8239.