Advance preparation is key to keeping clinical trials on track
Checklists are just one piece of the puzzle
Clinical trial coordinators can easily become overwhelmed by the myriad tasks they must perform during the study’s duration. But the key to keeping a drug or device trial or other research study moving is to do as much advance preparation as possible, say experts.
"A coordinator’s role at the site is multifaceted. The investigator relies on the study coordinator for all of the administrative aspects and many of the clinical aspects of the trial," explains Fred O. Smith, MD, a clinical trials consultant who helps institutions design and review study protocols. Smith is the co-author of two books, The Physician Investigator Handbook and The Clinical Research Monitor Handbook (both from Interpharm Press, 1997). "The logistics are at least a third of the job. And if the logistics of the trial are not planned prior to the first patient hitting the door, then the site will be behind all of the time and it will really hurt the study."
Well before enrollment begins, the coordinator must carefully arrange all of the services to be provided to participants at the site, and prepare an appropriate budget for the study.
"Many studies now involve the use of screening and diagnostic tests such as electrocardiograms, blood draws, lab analysis of the blood and other specimens taken, etc." Smith explains. "How will the specimen shipments be handled and what special requirements will be needed? Who, locally at the site, will be performing the different evaluation — the blood draws, EKGs, X-rays, etc. Where will the tests be interpreted? How will be transported to a central site, etc?"
The coordinator must establish, in advance, who will perform these services, how much that will cost, and where any specimens or other materials will be stored.
"There may also be electronic data capturing going on at the site that may require either the use of special computers or space on the site’s computer system may need to be allocated," Smith adds.
Coordinators must try to think of every detail involved in conducting a clinical trial and plan how each facet of the operation will occur.
"For example, transportation of clinical specimens needs to be arranged. Many specimens need to be frozen and contain dry ice during shipment. How will they get that dry ice? All of these kinds of arrangements need to be made by the study coordinator well in advance of the first patient showing up."
Taking the time to carefully prepare a sufficient budget is also essential, adds Laurie Czaplewski, RN, BSN, a clinical trial coordinator with the Mayo Alliance for Clinical Trials in Rochester, MN, and an ICU staff nurse with eight years’ experience.
"You have to review the study protocol carefully and develop a line-item budget that consists of everything that will be used for the study," she emphasizes. "Items that often get overlooked are office supplies, mailing supplies, office space, etc."
The coordinator must also make advance preparations for the amount of documentation and recordkeeping required by the trial, adds Chandra B. Louise, PhD, a pharmaceutical industry consultant who, with Smith, teaches the course, "Project Management for Clinical Trials" at PTI-International Inc. in New York City.
The study coordinator is responsible for maintaining all of the study documentation — particularly the study protocol, investigator’s brochure, and letters from the institutional review board stating the necessary approvals.
"Documentation is everything," Louise notes. "The coordinator is responsible for collecting all required documentation and forwarding it to the study sponsor, while keeping copies for the site."
In addition, the coordinator is responsible for maintaining files on each study participant, which contain the participant’s evaluations and other study data. Each participant’s file will typically take up an individual three-ring binder, Smith estimates.
"So, if you have a 53-participant site, you will need to set aside 53 three-ring binders and determine how you will maintain them and store them — both during the trial and afterward," he notes. "You have to determine where you will store 53 three-ring notebooks in a physician’s office. And once the trial is over, the files need to be stored, and arrangements need to be made for that as well."
Although it’s not mandatory that all of these preparations be in place prior to enrollment, experienced coordinators will ensure that all logistics are in place ahead of time.
"You don’t have to have the whole plan up front, but it is wise to do so," he notes. "Aside from saving time later, you are doing your budgeting process at this time. The budget is a matter of contract — and that is another set of documentation that must be maintained. The contracts between the investigator and study sponsor involve the cost of the storage of materials. You need to know ahead of time where you are going to store the stuff long-term and how to budget for it."
Many study sites have been burned by not calculating how expensive it will be to store an entire roomful of papers for three to 10 years, Louise adds.
Making a plan for patient recruitment
One of the biggest challenges to conducting a successful clinical trial is recruiting and keeping enough participants, both Smith and Louise advise. Almost every patient in the United States who is eligible and willing to be a clinical trial participant is already in one.
"There are not many naïve patients — that is our slang term for someone who has never been in a study," says Smith. "There are not that many unstudied clinical patients left. Our challenge is to reach the uncommitted and convince them that this is a good way to help others."
It’s imperative that study coordinators both design or help design good advertising and other recruitment tools and consider ways to keep participants interested once they agree to take part.
"A lot of clinical patients don’t want to participate because it takes a lot of time," Louise notes. "One of the things a lot of investigators try to do is make it as easy as possible for patients to participate and that is often another duty of the study coordinator."
If a participant must come in for a fasting blood level test, then the office offers some food after the check is over. Some sites have special chairs in the waiting room, or designated parking spaces close to the front door for study participants, Smith adds.
Coordinators must remember to get any recruitment tool or advertisement approved by the IRB and to keep a record of the approval, Czaplewski says.
It is helpful, though not essential, to have the recruitment tools approved by the IRB at the same time as the study protocol, but this isn’t always possible.
"Enrollment is often slower than expected," she admits. "It’s also important to be conservative when estimating the number of subjects the site anticipates enrolling."
Slow enrollment is the number one reason trials are delayed or take longer than planned, and that places enormous pressure on the coordinator. The coordinator must both recruit enough participants and ensure that proper informed consent procedures are followed and no one is unduly coerced, Louise says.
"It is unfortunate that a few sites succumb to the pressure and may start enrolling people who really do not meet the inclusion criteria or who otherwise should not be participating," Smith adds. "The overwhelming majority of sites are meticulous and honest And as a result, may fail to enroll rapidly because they quite properly only want those who are truly eligible to participate."
One of the biggest challenges for study coordinators is to refuse to enroll ineligible participants when the pressure is on, Czaplewski says.
"When I first started coordinating trials, I had people tell me, Just go ahead and enroll the patient’ when I knew the patient didn’t meet the criteria," she says. "Don’t get caught in that trap. You need to do what is right no matter who tells you otherwise. You have to remember the patient comes first. Coordinators make all the difference in the conduct of clinical trials."
If other study staff will also be enrolling patients, Czaplewski recommends making laminated pocket cards with the inclusion criteria printed on them. Study staff can use these as a checklist when enrolling patients.
Once the study is under way, it is a coordinator’s primary responsibility to ensure that any adverse events experienced by the participants are uncovered and properly reported, Smith adds.
"You have to find out whether they are getting headaches, is there any abnormality that showed up in one of the regular blood tests, or a change in an echocardiogram," he says. "Monitoring patient safety is the primary concern of coordinators during the later phases of the trial."
Keep in touch with investigators
Once the study begins, it can be difficult to maintain adequate communication with the investigator, Czaplewski adds. Scheduling meetings on a regular basis can help forestall any problems.
"To use the meeting time most effectively, keep a list with all of the issues that need to be discussed with the investigator," she says. "This time can also be used to have the investigator sign all of the documents that need their signature."
Reporting progress to the sponsor
During the course of the trial, the coordinator must also be scrupulous about promptly recording information and making the required reports back to the study sponsor, Smith adds.
"The whole purpose of a clinical trial is to get information about something, and that information has to be recorded somewhere," he states. "Today, even in the electronic age, it is usually recorded on paper somewhere. So the study coordinator has to make sure that all of the case report forms and all of the documents that record the results of the study are up to date."
This can be a very time-consuming task and it is very easy to fall behind, he notes.
"There may be 20-30 pages of information per patient per visit that must be recorded," he notes. "If you don’t record it promptly, it is very hard to bring that up from memory later."
Most coordinators also have to file weekly reports with the sponsor, which can present a whole new set of challenges.
"Throughout the course of the study and at the end, the site is filing reports to the sponsor," Smith explains. "But the sponsor may find inconsistencies in the data — like a birth date that is inconsistent with the reported age of a participant. When that happens, the sponsor generates a query and the site has to answer the query with the corrected information and keep track of all of those documents also. That can be a fairly big job to do, keeping track of all the queries and corrections."
Sometimes, site coordinators find themselves facing a slew of queries through not fault of their own, he adds.
"Sometimes the forms or questionnaires the sponsor uses are ambiguously worded. The coordinator may in good faith put down a series of answers that were not really what the sponsor was looking for, and then a whole dialogue ensues as to what they really meant by the questions, etc.," he explains.
This situation can sometimes be avoided, however, if the coordinators are proactive about contacting sponsors and asking questions about unclear wording of the case report forms, etc., says Czaplewski.
"It’s important to carefully review the instructions for filling out the case report forms," she adds. "If you have any questions, contact the sponsor or CRO [contract research organization] for clarification."
Study coordinators often find themselves in sort of a Catch-22 situation, with the more participants enrolled leading to even more paperwork that becomes more and more difficult to keep up with.
"You have to take the time to stay on top of things," Smith advises. "You will find that even the best sites have to stop enrolling for a time to allow the coordinator to catch up with the paperwork, unless they hire more study coordinators."
Don’t be afraid to alert the sponsor if things are really getting out of control, he adds.
"Sometimes, in the middle of a study, the sponsor will allocate an additional $3 million, say, to go for more advertising or recruit more participants in a study where enrollment is flagging, or money to hire more coordinators and provide more financial support to a site for that purpose," he says. "One of the key jobs of the project manager is to blow the whistle early when enrollment is not progressing properly so that remedial steps can be taken, if it is very important to get done on time."
Study sponsors, or even federal regulators, may want to visit a site to ensure that it is in compliance with applicable rules, or, in the sponsor’s case, that the study is progressing as it should.
In this case, the coordinators should just bite the bullet and set aside whatever time is needed to get all paperwork and documentation in order prior to the visit.
"Then you will have to put aside all of your other concerns for one day or two days or even three days and baby-sit the auditor while they go through your paperwork," Smith says.
Once the study is over, it is also the site’s responsibility to account for any unused study drug or devices that were part of the trial. In many cases, the sponsor will send a representative to oversee this process, as well.
"This is a biggie. If it is a study drug, every pill must be accounted for," Louise says. "It is the law and followed very closely. If it isn’t adhered to, the site can get into big trouble."
The coordinator and sponsor representative may together end up counting all leftover pills, for example, then ensuring they are safely shipped back to the manufacturer.