Happy trials to you

ILLUSTRATION: NORM BENDELL

Managing clinical research trials is difficult at best, and project managers at contract research organizations (CROs) who perform above the so-called crisis management level are rare. This absolutely does not need to be the case; unfortunately, however, many clinical trial managers are unprepared for their roles. They often lack leadership skills, don’t know enough about the nuts-and-bolts of clinical research, aren’t well versed in regulatory requirements, and focus too much on the “big picture” rather than planning the necessary details. In addition, pressures from numerous directions can often overwhelm them.

The biggest hurdles, and most complications, arise during Phase III/IV efficacy and safety trials. Early phase studies often encounter many of the same problems, but because the patient populations are smaller, the number of investigative sites generally limited to just one or two, and the studies narrower in scope, the research programs tend to be relatively easy to manage. Therefore, this article will primarily address the larger Phase III/IV research programs.

Previous articles in Clinical Trials Track have considered the problems with recruiting patients, training research personnel, and developing well-designed study protocols and case record books. However, if every aspect of a trial is well crafted but the management is shoddy, the entire project will ultimately suffer. A badly run study will not automatically result in failure, but reaching conclusions will take longer, budgets will be exceeded, and the toll taken on the participants will be greater.

Getting ready
The keys to managing any project, and clinical research is no exception, involve planning, planning, and planning. Unfortunately, most project managers at CROs seem to believe that a study simply will conduct itself if people and resources are thrown into the mix. The result of this thinking is often that detailed planning doesn’t begin until after the trial is under way.

Certain key elements, particularly the budget, must be considered carefully before a trial starts. Quite often, in an attempt to win business, CROs—which handle much of the Phase III/IV clinical testing—underbid their projects. Enormous problems can arise when insufficient staff, patient enrollment issues, database alterations, protocol amendments, and other miscellaneous situations create unexpected costs. Thus, it is critical that the manager who bids a project understands its unique requirements and components.

One of the most important aspects of planning for a study is selecting the monitors and sites. It is not uncommon for monitors to cover multiple trials concurrently. However, it is important that sufficient staff training occur for each study; specifically, monitors must be fully briefed on the therapeutic area and the nuances of each project. It is also critical that the number of full-time monitors (or full-time equivalents) be chosen carefully; too often, the number of monitors that begin a trial is insufficient, forcing new monitors to be added later at a cost of time, money, and experience. In addition, if monitoring requirements are not sufficiently established at the outset, the overall team dynamic suffers, and a toll is taken on the existing monitors who must work additional hours until new employees are identified and trained.

Monitors are important to the site selection process, and sufficient resources must be allocated at the start of the trial to allow a proper number of site visits and assessments to occur quickly. It is critical that the feedback about these sites be taken seriously (e.g., a monitor may determine that a site can accommodate a study but recommend that only an experienced monitor be assigned to manage the site because of a perceived need for additional support and guidance). Finally, the monitors who make the final site selections should be involved in monitoring those centers whenever possible.

Once the sites and monitors are selected, the project manager must schedule the investigators’ meeting and initiate the submission process to the investigational review board (IRB). (Often, if the necessary paperwork is not sent to the IRBs immediately, significant time may be lost waiting for the boards to convene and provide their required approvals.)

Ultimately, it is up to the project manager to verify that the clinical database—the electronic repository of all collected research data—is developed and fully tested before the first patient enrolls. If database integrity is not ensured up-front, delays can ensue when errors are caught only after large quantities of data are collected.

Finally, in studies that mandate the use of codes for concomitant medications, adverse events, and medical histories, the medical monitor—who, among other things, will ultimately review the codes—should be selected and a schedule for reviewing the codes during the trial should be put in place (instead of waiting for the trial’s conclusion before conducting this critical review).

Running the study
Once a trial is under way, problems invariably surface. Site coordinators will change, and new ones will have to be trained; protocol amendments will be issued, which must be approved by the IRBs; and drug accountability and record keeping details will need to be addressed. But these occurrences are relatively routine.

A manager must be prepared for more significant concerns, however, such as patient recruitment and retention problems, monitor “burnout”, database errors, and negligent or fraudulent investigational sites. These difficulties and the manager’s responsibility in addressing them are described here.

Enrollment and retention. The manager should track enrollment and patient dropout rates in an attempt to identify slow-enrolling sites quickly. Furthermore, the monitors should be consulted about strategies to combat perceived problems before they become significant. Finally, if it turns out that the protocol (or its amendments) limits the patient population beyond what was originally expected, the manager might need to approach the sponsor with possible solutions and/or protocol amendments.

Monitor burnout. One of the fastest ways for a manager to lose monitors may be to ignore their stresses, complaints, and concerns while proudly telling them what good jobs they’re doing and how “empowered” they are to affect their jobs. Managers must be aware of the number of patients each monitor is responsible for reviewing, special circumstances specific to their sites, and the physical distances between the investigators they manage. In general, sites should be assigned geographically (to limit travel exhaustion), and no monitor should be overloaded with patients or “difficult” sites. Further, since the monitors have first-hand knowledge of how a study is progressing and what trouble spots exist, a manager must include them in all planning and ongoing conduct meetings for their studies; the opinions of the monitors should be requested routinely and acted on quickly. Put simply, communication, trust, and a flat management style are critical to the organizational success of any research project.

Database problems. Project managers should develop effective guidelines for handling computer-generated queries concerning data that do not fit the database design. No matter how much testing occurs before a study starts, errors happen, and developing an effective plan to deal with them is key.

Conduct issues. Project managers must be ready to assist monitors in any way possible to resolve issues involving research conduct. This may mean sending internal quality assurance officers to a site, giving the monitor extra time to train investigative staffs, or even suspending or terminating a site’s participation. Suspension or termination may be politically difficult if a problematic site is sponsor-chosen, and it may be legally cumbersome because of the inevitable accusations of negligence or fraud. This action is one of the unpleasant tasks a project manager sometimes must undertake.

In addition to these responsibilities, a CRO’s project manager must serve as a communication link between the sites and the research sponsor. Once a study begins, sponsors often place unrealistic demands on CROs; and it is the responsibility of the manager to buffer those demands and, if necessary, refuse them. It is critical that the sponsor’s requests be considered carefully so that sites and monitors are not overwhelmed by any additional responsibilities.

Three keys
Project managers have three principal roles:

1. to act as liaisons between those actively conducting research studies and the sponsoring pharmaceutical companies,
2. to plan each trial so that it runs smoothly, and
3. to get out of the way so that it actually can.

Part of planning involves bringing the parties who will contribute to the study together early and often. It also means understanding what must be accomplished to complete the project and knowing the monitors, investigators, coordinators, and other research personnel. Ultimately, it is the manager who must guide each trial to its conclusion, under budget, and with the least amount of stress forall parties.