So you’re new to monitoring clinical research trials? Well, welcome. You’re probably starting out with little formal training, some knowledge of relevant FDA regulations, and a sense that the rules are just the tip of the iceberg. In addition, it’s likely that you aren’t certain what questions you should even ask about clinical trial monitoring. You are, however, not alone. Most monitors start their jobs in a similar state of confusion. Unfortunately, the job is difficult to delineate, since it is more art than science, more luck than skill, and more experience-driven than textbook-learned. Nevertheless, there are questions that can help you get started in the right direction. For example, what do monitors do and how do they go about doing it? What are the best ways to manage research sites, coordinators, and investigators? And most importantly, what is a monitor’s day-to-day job really like? What is the job; How is it done?
Put simply, the monitor’s responsibility is to “monitor the conduct of a research trial.” Thank you very much. But if you’re looking to the Code of Federal Regulations (CFR) for guidance, that’s about all you’re going to get. For example, there is no guide to assist monitors in selecting research sites (although they’re usually the ones to do it), there is no regulation that outlines the tasks appropriate for a site visit (but there is a necessary set), and there are no rules to dictate the frequency of such visits. Clearly, to monitor trials effectively, more than an understanding of job definition is necessary.
It goes without saying that monitors must know both the CFR and their assigned research protocols. After all, a large part of the monitor’s job is to advise and assist sites in conforming to FDA regulations while also helping them meet the requirements of particular research studies. Thus, a monitor should resolve general questions of patient eligibility, the use of concomitant medications, and problems with filing FDA and investigational review board (IRB) documents. It is also important that monitors anticipate upcoming study-related hurdles and necessary regulatory filings to help researchers meet those challenges.
Let’s now take a step beyond the regulations to consider a monitor’s other responsibilities. Generally, monitors help select research sites, train coordinators and investigators, review and collect research data, serve as patient recruitment consultants, verify the dispensation of study medications, and report the ongoing status of research trials. In essence, monitors serve both as communication conduits between sites and sponsors and as managers for individual research centers.
The meat of a monitoring visit, of course, involves the verification of a signed, IRB-approved, informed consent document along with a complete review of all research data collected for every enrolled patient. The data verification process involves comparing sources with case report form (CRF) documents. The source consists of a patient’s chart and contains every piece of medical information obtained before and during a research trial. The CRF, then, exists as a repository of information collected during, and specific to, a single research trial. So, it is the monitor’s responsibility to verify that the source data is precisely transcribed into the CRF. Two additional aspects of data review involve drug accountability and patient eligibility. The former requires monitors to physically count and compare all remaining study drugs with the site’s dispensation logs. The latter involves matching study participants’ medical histories with the inclusion and exclusion criteria relevant for a specified trial.
Beyond reviewing patient records, a good monitor will also take a global “snapshot” of how each patient is progressing during the trial. This snapshot is useful for confirming that a patient is receiving adequate care, the collected data is coherent, and the trial is progressing satisfactorily. If any of the elements of a snapshot seem questionable, however, it then becomes the monitor’s responsibility to discuss those concerns with investigators, coordinators, and even sponsors.
An unfortunate and often tedious part of any monitor’s job is making certain that the CRF data are entered according to the rigid requirements of a clinical database. By design, databases are unforgiving, and sites can easily wreak havoc simply by entering data improperly. For example, if the database is designed so that each patient is associated with a three-digit number, then entering a patient as “15” rather than “015” could result in hundreds of data queries. Therefore, monitors must be sufficiently familiar with both the clinical database and the CRF to help sites capture patient data in a way that is accurate but also meets the electronic specifications.
Finally, monitors must complete a written report of each visit for the sponsor’s files. The purpose of this report is to notify the project management team of the activities conducted, progress being made, difficulties encountered, and any issues of concern at each visited site. The reports are often in check-box format, with space for comments at the end. These comments, like any scientific paper, should be written in the third person past tense, and they should include only facts: no guesses, no thoughts, and no theories. This is extremely important as these reports become a part of a sponsor’s official study file, may be used to affect investigator payments, and are commonly considered when choosing sites for participation in future research projects. In addition, site visit reports are legal documents that provide the FDA with verification of a sponsor’s diligence in monitoring investigative trials. As a result, monitors must word these reports carefully and seriously.
MANAGING A RESEARCH CENTER
Being a good monitor means, in large part, being a good manager. It means planning ahead in case problems arise, developing strong communication with research personnel, and observing everything that occurs at a research center. Observation skills are particularly important because, for example, a suddenly stressed staff may be an early warning sign of internal problems that could contribute to sloppy data collection, or a dwindling number of patients in the waiting room might signal an impending enrollment problem. So, to manage them effectively, a monitor must continually be aware of all facets of their sites.
The most difficult situations to manage fall into two categories: site personnel issues and study conduct issues. Personnel issues predominate, and generally, all other concerns eventually devolve into them. These problems are political and delicate. They may involve an untrained coordinator or an investigator who can’t get along with the staff. Unfortunately, the monitor often gets caught in the middle of these disputes, and it is here, more than anywhere else, that the monitor’s management skills must come forcefully into play. Rapport, communication, training, and patience are usually the keys to resolving these situations. Often, monitors must bring their concerns directly to the principal investigator. Although this may be uncomfortable at times (especially if the investigator appears to be the problem), ultimately, it is the monitor who is in charge of each study, and issues that can affect research conduct must be addressed. The good news is that investigators understand this and are generally willing to act on a monitor’s concerns.
Extreme issues that require strong action occasionally occur. The worst of these, of course, involve investigative negligence or fraud. In these situations, the keys are to watch, listen, document, and discuss: watch what is happening at the sites (maybe you’ve misinterpreted something); listen to what research staff tell you (maybe they’ll confirm your suspicions); document everything you see so that both you and your superiors have records to back up any claims; and always discuss the problems you see with the coordinators, investigators, and project managers. It is important to avoid jumping to false conclusions. But it is equally important to express legitimate concerns. Chances are that if you feel something is amiss, it probably is.
BIOETHICS IN CLINICAL TRIAL MONITORING
Bioethics is the study of the ethical issues emerging from advances in biology and medicine. It is also moral discernment as it relates to medical policy and practice. There is strong bioethical policy when monitoring clinical trials and a sound Trial monitor must have these principles at the tip of the hand. Bioethicists often refer to the four basic principles of health care ethics when evaluating the merits and difficulties of medical procedures. Ideally, for a medical practice to be considered “ethical”, it must respect all four of these principles: autonomy, justice, beneficence, and non-maleficence. The four principles cover the facet of participants’ safety and trial efficacy. Any bridge in the four will surely lead to erroneous monitoring. As a Trial Monitor, you must focus on these four principles while monitoring, check for deviation from the four and make necessary corrections without neglecting your documentation because anything not documented in never done.
MONITORING AS A LIFESTYLE
To be a good monitor involves juggling quite a few balls: regulatory and protocol requirements, study conduct issues, supervisory concerns, and data management matters. All of this, of course, must be conducted while traveling from hotel to hotel and from city to city. Monitoring can become an all-consuming endeavor, and the repetitiveness of travel is often the most difficult ball to juggle. Coordinating business meetings, air travel, rental cars, frequent flyer miles, hotels, and even deciding what to pack are inherent challenges of the job. The solitary lifestyle can also foster feelings of loneliness. Many coordinators, however, befriend their monitors and spend time outside the office with them during their visits. Thus, trips that involve working with these site personnel are more relaxing than others. In fact, those who find monitoring enjoyable like to travel and routinely build friendships with investigators and coordinators. But more than anything else, the rewards they cite come from participating in clinical trials at a “global” level—from helping to guide new medications to market and directly affecting the safety and health of study participants around the country.
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Last modified: May 25, 2018