NORM BENDELL

Do you have a medical degree and want to work in the clinical research industry? Then most commonly, you might opt to be a principal researcher, recruiting and treating patients in human trials. Of course, your interests may not lie in research practice, and you might choose, instead, to design protocols, develop case books, or manage clinical projects—assignments typically conducted by physicians employed in pharmaceutical companies. However, what if you want to be involved in the treatment of study patients but don’t want to be the one delivering the treatment? Well, a specialized industry position exists that is suited for you: as a medical monitor (MM) at either a pharmaceutical company or a contract research organization (CRO).

If investigators treat research patients, coordinators assess them and record the collected data, monitors review the data and provide regulatory oversight, then what is left for an MM to do? Plenty, it turns out, because monitors and coordinators are not physicians, and the investigators do not necessarily have all the answers and rarely see the “big picture”. This is especially true in Phase III and IV studies, in which numerous investigative sites around the country jointly contribute to each clinical trial. As a result, the MM’s role can be described as lead physician for a research study.

Currently, most MMs are non-Americans who earned their degrees abroad and are not licensed to practice in the United States. This does not necessarily mean that these physicians lack medical knowledge; rather, it may simply be that various other constraints have prohibited them from completing the U.S. residency requirement necessary for licensing. Furthermore, although it is an overstatement to suggest that these individuals represent all MMs, it is certainly a fact that the position is one that many non-U.S.-trained doctors enjoy.

Support and training
A major role of the MM is to answer queries from investigators, coordinators, and research monitors. Because of their medical and study-specific knowledge, MMs are in a unique position to provide study-related training to research site personnel (e.g., instruction on how to conduct certain assessments or how best to increase a patient’s dosing). Further, because the MM knows what is happening at every investigative center involved in a multisite trial, he or she can provide across-the-board assistance that helps maintain a trial’s continuity. This job description may sound somewhat nebulous; the following examples are typical ways in which MMs guide research trials.

• Without realizing it, a site enrolls a patient who should have been excluded because of the presence of elevated liver enzymes. The MM is then called to determine whether the patient must immediately be terminated from the trial, and if so, what follow-up procedures (e.g., blood assay) should be conducted.
• Several sites report to the MM (either directly or through their research monitor) a significant rise in blood pressure for several of their patients. Because the MM recognizes that this is not an isolated situation, he or she can consult with physicians at the pharmaceutical company to determine what course of action should be followed for all sites: Alert them to carefully monitor blood pressure, discontinue patients whose pressure rises significantly, or treat patients with blood-pressure-lowering medications as necessary. The MM can suggest that the protocol be amended for all sites to exclude patients with known histories of hypertension.
• The clinical laboratory automatically faxes all blood assay results to the MM for every patient during a trial. As a result, the MM can monitor that aspect of every patient’s research experience in real-time and contact sites directly when values of concern are noticed. This is an additional safeguard for the enrolled patients and a secondary means of medical oversight.

Adverse events
Monitors must review patient records and the case report form (CRF) to verify that all adverse events experienced by patients during the course of a trial are properly and consistently documented at every visit. However, research sites pass a special class of events called “serious adverse events” (SAEs) to the MM for review. SAEs are strictly defined by the U.S. Code of Federal Regulations and include overdoses, life-threatening side effects, events that require inpatient hospitalization, and events that prolong hospitalization time.

Federal law requires that the FDA be notified immediately of all SAEs. In the typical notification process, a site faxes an SAE report (a standardized FDA form) to the MM, who reviews it for clarity and completeness and then faxes it either to the FDA or through the sponsoring pharmaceutical company (if the MM works for a CRO), who forwards it to the FDA.

The MM is involved in the process of SAE reporting for several reasons. As already mentioned, one is to ensure that the report is complete before it is sent to the FDA for review. In many cases, the MM must contact the research center directly to clarify aspects of the filing. The MM is also notified to ensure that every SAE is properly recorded in the CRF and that patients who experience SAEs are provided with proper, and if necessary ongoing, medical attention. A final reason for keeping the MM abreast of SAE reports is to ensure that someone is tracking the frequency and apparent causality of serious side effects for patients during a trial, so that appropriate action to protect them may be taken if warranted.

It should be noted that not all SAEs bear any relation to the study drug, and it is partly the responsibility of the MM to make certain that claims of connectivity are reasonable and that all serious events are properly reported regardless of causation. For example, a patient who falls and breaks a hip during a trial may have fallen as a result of dizziness caused by the medication or may simply have been trying to turn too quickly while roller-blading. Whether or not the experience was caused by the study drug, the MM must report it, because in both cases, the fall resulted in the patient being hospitalized.

Coding
A tedious part of the MM’s job is to review, and in many cases assign, codes for medical conditions, surgical procedures, and concomitant medications in the collected patient data. As described in a previous Clinical Trials Track department (August 2001, p 25), coding involves replacing informal terminology with specific, predefined synonyms as a means of clarifying research data. One reason for doing this is to prevent identical events, conditions, and medications from being redundantly tabulated in the statistical review (e.g., “stomach ache”, “stomach aches”, and “upset stomach” would be counted as three different kinds of adverse events in the side effect profile). Another reason for coding is to resolve unclear terms (e.g., whether a patient really had a migraine, as reported, or just a headache is an important medical distinction).

The codes used for medical conditions and surgical procedures come from a dictionary defined by the study-sponsoring pharmaceutical company that correlates thousands of common terms with their appropriate codes. Thus, for example, no matter how a site references a “headache”, the code entered will be the same. Similarly, names for nonstudy-prescribed medications are also coded. In this case, the World Health Organization’s “drug dictionary” is commonly used because it lists virtually every marketed medication by brand and generic name.

Near the end of every Phase III/IV trial, in particular, the MM must verify that the selected codes are properly matched to the terms reported in the CRF by the sites. It is not unusual for an MM to recode events or contact sites directly to verify their coding choices (e.g., “Did you really mean to code the event ‘headache’ as a ‘migraine’?”).

One more safeguard
No regulatory statute outlines the role or even establishes the existence of the MM; the evolution of the job is a result of the increasingly complex nature of clinical trials. As the study designs become more involved, particularly at the Phase III/IV level, having someone with a “big picture” view of the trial as it progresses helps safeguard the human participants. Specifically, the MM has “the pulse” of the trial by virtue of seeing laboratory reports as they appear; reviewing all SAE forms as they are submitted; and talking directly with sites, study monitors, and clinical project managers.

MMs are also needed because most monitors and project managers, and even many coordinators, lack medical training. Although monitors may understand the importance of excluding specific patients from a trial if they possess certain concomitant diseases, it is doubtful that they can fully appreciate the health-related consequences that exist for patients who are inappropriately enrolled in a study. As a result, the MM is key because he or she has both the educational training and trial-specific knowledge to render important medical decisions immediately rather than waiting until the data are collected and analyzed at the conclusion of a trial.