A Whitepaper by Nancy J Stark, PhD
It may be a coincidence, but it seems to me that the device industry emerged from a long sleep after the August 31, 2010 CDRH Webinar on Preliminary Internal Evaluations of the 510(k) process. The webinar entertained questions from the audience regarding two preliminary reports published by: 1) the 510(k) Working Group, and 2) the Task Force on Utilization of Science in the Regulatory Decision-Making Process. Both groups were comprised of representatives from across CDRH to assess the challenges faced by Center management and staff in the 510(k) process and to assess how effectively science is used to evaluate 510(k)s.
One recommendation of the 510(k) Working Group was to "define the term 'clinical data' in order to foster a common knowledge among review staff and manufacturers about what constitutes 'clinical data' ". Recommendations by the Task Force on...Science... were to "continue to engage in the development of...international consensus standards, which, when recognized by FDA, could help establish basic guidelines for clinical trial design, performance, and reporting," and for the Center "to expand its ongoing efforts related to clinical trials...to include clinical trials that support 510(k)s". Possibly the most significant and repeated recommendation made in the reports was to improve the overall quality of clinical trials.
Good monitoring is essential
Think about what happens in a clinical trial. A manufacturer located in one state or country contracts with an investigator in another state or country to conduct a clinical trial that may last from a month to as long as several years. Like all human beings, investigators lose interest in the trial, deviate from the protocol to experiment with their own ideas, enroll subjects in competing studies, or generally misbehave, without regular eyeball contact from the sponsor.
Monitoring is the mechanism by which a sponsor remains engaged with an investigator. Monitors are the individuals charged with maintaining that eyeball contact.
Types of monitoring visits
Clinical trials are implemented in 'project management' phases of prestudy design, study initiation, implementation (duration) and close-out. Monitoring activities are often designed to parallel the process of the clinical trial. While the transition from one phase to another is not carved in stone, I've tried to describe transition points that are commonly used and easy to conceptualize.
Pre-investigation or assessment visits are intended to select investigators and prepare sites for the study. They are better perceived as a process in which the capabilities and business relationship of the sponsor and investigator are established.
Both FDA and ISO envision this as a time for sponsors to assure that investigators understand the investigational nature of the device, the requirement to wait for IRB approval, the need for informed consent, agreement that records will be created and made available for monitoring, and that contractual obligations are mutually understood and agreed to. This is also the time during which budget agreements and financial arrangements are made between sponsor and site. The period of time may take several months, visits, phone calls, and email messages and can be thought of as spanning from project conception to first subject consented.
The main focus of the initiation process is investigator and study staff training. Training may begin with an investigator's meeting if there are many investigators involved in the study. Or investigative sites may be trained one at a time and may include practice on simulated patients or live animals. The importance of training the investigator to device use cannot be over-emphasized. Even investigators familiar with your type of device will need to review special features, materials, software, hardware, instructions for use, and protocol requirements. Misuse of an investigational device by an investigator may come back on the sponsor as a failure to adequately train the user and may be considered an adverse event.
During this phase the monitor will set up record-keeping systems by building Investigator Regulatory Binders, Coordinator's Study Manuals, Subject Binders, Source Document Verification Logs and sponsor files.
It is a common practice for subjects to be consented but not considered enrolled in a study until they have passed subsequent screening procedures and been exposed to the device. But the practice of viewing consent and enrollment as separate events is now frowned on by FDA. They are concerned that subjects may be consented, and then dropped from the study without documentation about why. The preferred viewpoint is that consent and enrollment take place at the same moment. Then if a subject later fails screening, the reasons are documented and the subject is exited from the study. Study initiation culminates when the first device is placed on the first subject.
Routine monitoring visits
A routine monitoring visit is an on-site visit in which the monitor observes the process of the study, compliance to protocol, compliance to regulations, completeness of documentation, and verifies accuracy of data on the case report forms against source information. Case report forms should be verified for accuracy, logic, completeness, legibility, and contemporaneousness; electronic forms should be checked for traceability (i.e., who filled out the screen.) Monitoring should take place on a periodic basis, but I suggest you allow no more than 2-3 days of work to accumulate at a site.
Monitoring requires an extensive skill set. It requires an intimate knowledge of clinical regulations and company procedures, knowledge of the device function and possible malfunctions, knowledge of the disease or condition being studied, the ability to solve problems and work independently, and the ability to write a comprehensive and lucid report that captures the progress of the study and action items for the future.
Monitoring Reports >> Action Item Database >> Open Action-Item Checklist
Monitors need a special kind of personality. They should be people who can work with busy sites, who love data, who can sift through pieces of information and fit them together, who do not leave details unaddressed, and who cannot tolerate an unbalanced checkbook.
Off-site monitoring is an alternative to travel when a site is known as well-organized. Data can be transmitted by fax, pdf, or electronic means and checked for everything but accuracy to source files.
Close-out visits deal with ending issues and have the goal of making the site inspection-ready. All open action items are addressed, open queries resolved, and reports filed. Close-out visits are like filing income taxes, if you've done a good job of record-keeping all year long the close-out visit will go quickly; if not, it could take days.
If you liked the whitepaper, take the workshop
If you liked this whitepaper, then take the workshop. The learning objective is to review the skills of monitoring in order to help assure quality in clinical trials. This is an intermediate level course, participants are expected to have a basic knowledge of clinical research and device regulations. Sign up here or phone us at 773-489-5706.
A quiz, of course
The five-hour workshop is following by a half-hour online quiz, taken on your own time within the following two weeks. The quiz is designed to test your learning of the concepts discussed in the lecture and your ability to apply those concepts to real-life issues.
You will receive, we will discuss
[x] Printable PowerPoint slides.
[x] Clear example distinguishing intended use, indications, claims and warning.
[x] Monitoring procedures and templates.
[x] Recent monitoring warning letters.
[x] A graded quiz with immediate test results.
[x] One computer connection for one learner (each learner must log-in individually).
[x] Certificate of Attendance and 0.55 CEUs.
[x] A copy of the CRA Handbook 2010 (electronic) with registration by October 13, 2010.
Who should attend
[x] Clinical research associates.
[x] Managers and directors of clinical research.
[x] Start-up companies planning their first clinical trial.
Dr. Nancy J Stark is President and Founder of Clinical Device Group, a CRO and consulting firm that has been in business since 1990. Her curriculum vitae can be found at www.nancystark.com.
[x] Personal computer.
[x] Internet Access.
Date, time, registration
The 5 hour workshop will be presented on Wednesday, 20 October 2010, at 11:00 Central Time. Event materials will be distributed the day before the workshop. Or you can take the event later by CD or OnDemand. Sign up at here or phone us at 773-489-5706.
Nancy J Stark, PhD
President, Clinical Device Group Inc