Trials and tribulations

Effective recruiting for clinical trials requires a commitment to educating patients and physicians

Jeffrey Bouley
Certainly, the global market for clinical trials is huge, with Visiongain placing its worth at about $10 billion in its report The Clinical Trials Market 2006 and noting that revenues from clinical trials had increased by nearly 15 percent in the previous year. But even with Visiongain's predictions of an "extended period of healthy growth," it is a market that faces many challenges, with business intelligence firm Cutting Edge Information noting in 2004 that some 80 percent of clinical trials are delayed past their original deadlines—with 85 percent to 95 percent of those delays coming from patient and site recruitment challenges.

And with agencies like the U.S. Food and Drug Administration (FDA) expressing ever-growing concern about safety issues, things aren't likely to get any easier.

"The FDA is under increasing pressure, which can complicate the clinical trial recruitment process," notes Dr. Lou Vaickus, chief medical officer at Tolerx Inc., a Cambridge, Mass.-based biopharmaceutical company that is currently initiating a Phase III clinical trial of otelixizumab in new-onset type 1 diabetes. "The FDA is somewhat disconnected from the clinical trial process—but are still held accountable if something goes wrong. As a result, and somewhat out of necessity, they've put new requirements in place and tightened their regulations to ensure that the data they are reviewing is accurate. As part of that, the FDA wants larger databases—and larger databases mean companies need to find more patients for clinical trials."

There are no easy answers to the challenges of trying to fill those slots in clinical trials, but those who are in the thick of it—whether conducting trials or recruiting for them—insist that education is a key component. And it is not just potential patients who require this education, but physician investigators as well.

The access problem

Although type 1 diabetes is much more rare than type 2 diabetes, Vaickus notes that one advantage is that it is primarily a disease of Caucasians—who represent the vast majority of clinical trial participants in this country. Type 2 diabetes, on the other hand, hits heavily in African-American and Hispanic populations as well as among obese people of all races, so one might think that would make patient recruitment easier—and help diversify the patient base for trials.

But while the prevalence of the disease is much greater for type 2 diabetes patients, he admits, many of those patients—because of economic, racial or other reasons—may lack access to healthcare systems that would refer patients into clinical trials. Thus, reaching those patients with information about why they should—and how they can—participate in trials can be difficult.

Dr. William H. Thies, vice president for medical and scientific relations at the Chicago-based Alzheimer's Association, knows this problem all too well, having 20 years of experience conducting clinical trials, about evenly split between cardiovascular trials and Alzheimer's disease trials.

"The number one challenge to all trials is the understanding, or lack thereof, among the general public about why you are recruiting for clinical trials, what is the process involved, what happens when you participate and why is it important for you to participate," Thies says.
 
People don't think about the importance of clinical trials in producing the medications they use any more than they think about what goes into making the semiconductors that allow them to use personal computers and cruise the Web, he says, and it's up to pharmas, the government and physicians to correct that.

"We can perfectly design all the studies we want and get all the infrastructure and support in place, but if we don't have everyday folks willing to come in and be a part of it, the whole thing breaks down unalterably," Thies asserts.

Is there a doctor in the house?
Another challenge is that pharmaceutical companies, contract research organizations and others conducting clinical research can identify a big population somewhere that is good for a trial, but then the next challenge becomes, "who, if anyone, is in that area that has the experience as a clinical investigator to conduct it?" notes JeanMarie Markham, CEO of Clinlogix LLC, a Pennsylvania-based global clinical research service organization.

"Often it is very difficult to find potential investigators that have been schooled in clinical trials or how to run them," Vaickus says. No matter how excellent they are as physicians, if they don't have specific skills in conducting trials—such as understanding the FDA's needs or GCP, GMP and GLP compliance—it isn't cost effective to use them. And if they lack dedicated staff and other resources to conduct trials, that makes them even a more risky prospect. "The pharmaceutical companies have to go with the investigators that already know what they are doing and do it well," he says.

Pharmaceutical companies are quick to note that it's not their job to train physicians how to do clinical trials, Vaickus adds, yet the lack of training among physicians—and thus their lack of ability to participate in trials directly—puts a damper on patient recruitment.

"As for the issue of who would pay for such training, that really goes both ways," Markham points out. "If the trial is important enough, it might be worthwhile for a sponsor to help pay for potential investigators to get the training they need. But on the other hand, physicians who are interested in doing clinical trials get involved both to benefit patients who might want to access a new therapy and also as an additional revenue stream to their practices. So there is some incentive for them to invest in their own training by getting a consultant to help them through the process or becoming part of a site management network through which they can access people with experience who can guide and mentor them."

If medical schools did more to educate medical students about the potential financial benefits of trials and gave them some basic education about what they need to know to conduct trials, that could go a long way toward easing the problem, Vaickus suggests.

Also, professional medical societies and academic institutions would do well to step outside of their academic mindset and start giving more attention to research on drug development, instead of just non-pharmaceutical medical research. As far as Vaickus is concerned, clinical trial investigators are specialists in their own rights, and it's time they were recognized as such—not that he is aware of any such progress on that front yet.

"There is a notion that physicians involved in clinical trials are just out there helping the pharmaceutical companies to profit. But in fact, clinical trial investigators have to have very specific knowledge and conduct their work under very stringent guidelines and regulations," he points out.

In addition to recognizing physician investigators as specialists, more pharma and biotech companies need to recognize that patient recruitment has itself become a specialty over the past five to 10 years—non-medical though it may be, notes Leslie C. Lilly, principal consultant with Clinical Research Consulting Services in Concord, Mass.

"There are many companies who now provide services to assist companies with patient recruitment," she says, but many companies haven't traditionally appreciated how labor-intensive it is to do good patient recruitment work and the skill that is involved. That is changing, though, and she says that many large companies have started to build such expertise in-house.

In the end, patient education, physician training and better leveraging of recruitment resources will pay off, says Markham. "Cycle time is a big concern in drug development, and the mantra is 'How do we decrease cycle time?' Probably the biggest hindrance is patient recruitment."

Going global

Diversity among patients participating in clinical trials is a challenge, notes JeanMarie Markham, CEO of Clinlogix, one that saw the U.S. FDA issue guidance at the end of the '90s that it wanted to see more diversity in clinical trials.

"At the time, about 80 percent of participants were predominately white males," she recalls. "FDA wants more diversity in clinical trials because different people of different races in different areas and cultures react differently to treatments. This, in part, is a driver of the push for more global trials."

Cost, of course, is another concern, and CenterWatch has estimated that 20 percent to 30 percent of global clinical trial activities are being conducted in developing countries, with China and India being especially attractive targets because of the billions of untapped patients they represent. But at the same time, companies have to consider whether a more cost-effective patient population is always the right one, notes Dr. Lou Vaickus, chief medical officer of Tolerx Inc.

"There was a pneumonia trial I recall that got to a pivotal trial stage and the p value wasn't significant. But when they took out the Eastern European patients, the p value suddenly was significant," he says. "Now, that may have been a coincidence or not, but they had to start over. So even when patients are plentiful, you have to ask if they are the right patients, or is the database polluted in some way that is going to skew your results."

Alzheimer's factor
Clinical trials for Alzheimer's disease can pose special patient recruitment challenges, notes Leslie C. Lilly, principal consultant with Clinical Research Consulting Services, not the least of which is making sure you are really getting informed consent from patients with compromised neurological function.

But perhaps the more daunting problem is the sheer scale of Alzheimer's disease in the clinical trial space in the years to come, says Dr. William H. Thies, vice president for medical and scientific relations at the Alzheimer's Association. Alzheimer's, he says, is a key emerging disease for the next 40 years, given the aging population, particularly in the Western world.

As Dr. Lou Vaickus, chief medical officer at Tolerx Inc. notes, any time several companies are tackling trials for the same "hot" disease, competition for already scarce patients complicates recruitment. But Thies says the problem with Alzheimer's is even more dire.

"Limiting amyloid accumulation is the most mature theory in turning Alzheimer's into a manageable chronic disease," Thies says. "But many kinds of molecules will modify amyloid accumulation and each of the big companies has several different types locked in their vaults. But they're waiting to see if limiting amyloid accumulation actually works before they start thinking of clinical trials. If a study shows soon that amyloid is the key, my worry is that we'll open a floodgate and have 30 or 40 trials starting at once in a few years, and the system simply cannot handle that."

Vast majority of patients would do a clinical trial again
Finding enough participants for clinical trials is a challenge, but bringing them back might not be. More than 90 percent of study volunteers report that they would do it again, according to the 2007 National Survey of Study Volunteer Experiences conducted by CenterWatch, a Boston-based company providing information services used by patients; pharmaceutical, biotechnology and medical device companies; CROs; and research centers involved in clinical research around the world. Moreover, 85 percent said they would recommend a family member or friend participate in a study.

Survey data show the Internet and media (26 percent and 30 percent, respectively) as the primary sources of public education about trials, with the Internet's role in education increasing steadily each year since 2004.

Sixty-four percent of volunteers reported they did not learn about clinical trials from their doctor, and just one out of five considered their physician to be "very knowledgeable" about trials. According to CenterWatch, physicians not directly involved in trials simply aren't educated about them, and don't have time to explore whether a trial is available and appropriate for one patient. DDN

Jeffrey Bouley

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