Veteran researchers' advice to new researchers
Times have definitely changed for CT industry
One of the major changes the clinical trial (CT) industry has undergone involves study design, according to a researcher who has been in the business for more than three decades.
"Studies are being designed in a very different way now than they originally were designed," says Roy Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, TX. Fleischmann also is the co-medical director of the Metroplex Clinical Research Center in Dallas.
"When I started doing studies, they were designed to ask a question and answer that question," Fleischmann says.
The inclusion/exclusion criteria was straightforward and made it easy to enroll. Now phase I, II, and III studies are designed with very narrow exclusion/inclusion criteria, so they are very difficult to enroll, Fleischmann explains.
"Some exclusion criteria make it virtually impossible to deal with," he adds.
Another change has been that in the past the phase I trials all enrolled healthy volunteers. Now there's a movement to use people who have the disease that's being studied, he notes.
While this is a positive change, the sponsor companies have decided to have phase I studies look at efficacy, as well as safety and pharmacodynamics, Fleischmann says.
For this reason, the inclusion/exclusion criteria have become more narrow: Instead of a healthy volunteer, you need to find a person with the disease, but then you also need to find a person with the disease who meets more stringent criteria.
"So you take the person with active disease and try to put that person in a phase I study, and it becomes an impossible study to enroll," he adds. "A phase I study should look at safety, pharmacokinetics, and dynamics, which is what it's traditionally designed to do."
For all these reasons, Fleischmann advises new researchers to be very careful about how they select protocols.
"I will look carefully at a protocol and not do any protocol in which I don't feel we have the patient population for doing the study," Fleischmann says. "Then I'll speak to the sponsor company and advise the company as to why I'm not doing that protocol."
Investigators need to speak up more so that sponsors will learn why their studies have such difficulty with enrollment, he notes.
For example, suppose an investigator is looking at a drug for rheumatoid arthritis and the protocol's criteria require that the patient be placed on methotrexate and have an incomplete response to methotrexate, Fleischmann says.
"That seems reasonable, and then the protocol says that the sedimentation rate has to be elevated a certain amount," he adds. "When you look at those patients what you see is that even though they don't have a complete response, the chances are that they have a normal sedimentation rate."
For investigators, the question is how they should deal with that circumstance.
One answer is for investigators to educate sponsors about this problem and to suggest that the protocol design be changed to look at other markers of activity, Fleischmann says.
"You don't need the sedimentation rate," he adds. "If the company makes those changes then the protocol can be changed appropriately and effectively, if they don't make the changes, then you can't do the study."
In some cases, the changes can't be made because a particular lab value is needed for efficacy, so there's always a trade-off, he notes.
Fleischmann offers these tips on how to improve a new CT site's success rate:
• Learn keys to analyzing protocols: "You have to really check into your patient population and assess it," Fleischmann says. "You cannot guess that you have the patients for a study — you have to know it."
For instance, investigators should look at the patients who have the disease being studied and the major inclusion features and estimate how many of these people will want to be enrolled in a study, he says.
Often, when new investigators are asked by clinical research organizations (CROs) or sponsors how many patients they can put into a study, they'll estimate a high number.
"They say, 'I have 100 patients,' and the truth is they probably have 10 patients, and of these five will want to go into the trial," Fleischmann says. "There has to be a correct assessment by the [sponsor] company and the investigator."
And once an investigator determines an accurate number of potential enrollees, it's important to stick with that estimate and not give-in to pressure, even if it means losing the contract.
"We have had studies we didn't get because the company says, 'We have 47 sites that say they can do all of this in a month, and you say it will take you a year,'" Fleischmann says. "The answer is that it will take those sites a lot longer, and that's why there are difficulties with enrollment."
If Fleischmann is going to turn down a protocol, he always tells the sponsor why he's turning it down.
"I say, 'This is the reason why I can't do it,'" he says. "That should help all sites because I do have a lot of experience and know what the protocol should cost, so when I am negotiating for me, I'm negotiating for everybody else at the same time."
• Push for a fair budget: Another recent problem involves tighter research budgets as pharmaceutical companies are clamping down on costs and CROs also are trying to cut costs.
"But if you don't make the study worthwhile to investigators, why should they continue to do studies?" Fleischmann asks.
"Especially if an investigator is doing it for the first time, it takes a lot of time," he says. "You have to meet with monitors, do informed consent, all of the study specifics, look at documentation, double-check coordinators and labs, and it takes a lot of time."
When physicians can spend 15 minutes with a patient and earn $100, why should they spend a half hour on a study and earn $50, Fleischmann asks.
"There are a lot of CT budgets that come out like that, and many of them are not worth doing because the investigator is not being compensated appropriately for the time put into the study," he adds.
Fleischmann will tell a sponsor that the study will cost XX amount, based on cost data, and if the sponsor wants him to do the study they'll have to pay for these costs.
"They agree or don't agree, and if they don't agree, I don't do the study," he says.
• Don't rely on CRO for recruitment advertising: Sponsors sometimes shift the burden of recruitment advertising to CROs, and this typically is not a good idea, Fleischmann says.
"Ninety-nine percent of the time, the CRO does a bad job of it," he says. "A CRO has never helped me enroll a single patient."
If a sponsor hires a patient recruitment company, then that could work out well. But the best solution might be to press the sponsor for enough in the advertising budget for the CT site to do its own recruitment, Fleischmann says.
This means that investigators should know what local advertising costs are. For example, a newspaper advertisement in Dallas might cost $4,000. So if the pharmaceutical company offers to pay $1,500 toward advertising, the investigator should show the sponsor the true costs and negotiate for more, he explains.
Fleischmann's CT site is in the top 25% in enrollment, and often the site is the top enroller for a study, he notes. Retention also is high.
"I have a study we started in 1993 with 20 patients," Fleischmann says. "We now have 12 patients in the same study; some patients died over the past 15 years, and some moved, but if they didn't die or move, they're still in the study."
• Work to make site a top performer: Unfortunately, the clinical trial industry still doesn't reward its top performers as well as do other industries, Fleischmann notes.
"If I was going to use a corporate lawyer for something, I could get one for $50, $100, or $200 per hour, but my expectation is that the $600 per hour person should take less time and get a good result because he has more experience," he says. "The $50 per hour attorney will take a lot of time and not get very good results."
Top performing CT sites also should be paid more for their expertise and performance record, but it doesn't work that way, he says.
"Not every site should be paid the same thing," Fleischmann adds. "But nobody does it that way."
Still, the industry is changing, and CT sites should work toward making themselves top performers for their own benefit, if not for the potential for higher compensation, he says.
"You should have rock solid GCPs [good clinical practices] in place," Fleischmann says. "By and large, 90% of your GCPs should be perfect, as opposed to being a new site that doesn't know what GCP is."
And new CT sites and investigators should be entering the research field for the right reasons, such as improving the medical field and patient care practices, as opposed to thinking they'll improve profits, he says.
Back in the 1980s when there were fewer drugs available and patients often would enroll in studies simply because they had few available treatment options, the enrollment was far easier to accomplish and the pay seemed reasonable, Fleischmann says.
"I could do a biologic study, enrolling 25 patients in three months because it was a worthwhile study for them to do," he explains. "And if I had a budget where I made $1,000 per patient I could make $25,000 on that, and it was worth the effort as a business."
Now, the same study might take two years to enroll 25 patients, and to make $25,000 in two years is not very profitable, Fleischmann says.
"The real reason for doing studies now is to try and help patients now and in the future by developing safer and more effective drugs," he says.
"If you don't want to do that I don't think you should be doing clinical research," he adds. "But once you decide to do it, then you should be paid fairly for it."
The key to success is to find the right study for the right patient, Fleischmann says.
"If you do that, everything else is fluff," Fleischmann says. "Right drug, right study, right patient — it's going to work."
One of the major changes the clinical trial (CT) industry has undergone involves study design, according to a researcher who has been in the business for more than three decades.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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