Clifford Siporin, the president of Greystone Pharmaceutical Consultants, a contract research organization (CRO) in Parkland, Fla., has a challenge. His company is tracking down 2,600 volunteers to test a cholesterol drug for a biotech client, and it's taking more time than he anticipated.
"The protocol says you have to have a serum cholesterol of 220 to 260 based on three lab tests over a three-month period, one test per month," says Siporin. "So a patient comes in with 223 on the first test, so he qualifies. The next test is 226, so he still qualifies, but the next month he's at 264, so you've got to throw him out. This delays the clinical trial. It's still ongoing."
Siporin is not alone. The biotechnology and pharmaceutical industries face a host of headaches and growing challenges when it comes to recruiting volunteers for clinical trials. Company protocols are increasingly complex and require...
COSTS OF DELAYS CAN BE STAGGERING
The drug pipeline has grown by 15% a year over the last three years, up from 10% to 12% in previous years, according to Thomson CenterWatch. "The increase in the total number of drugs entering the pipeline appears to have affected firms' ability to recruit patients to clinical trials in this country," says Joseph A. DiMasi, director of economic analysis at the Tufts Center for the Study of Drug Development, and coauthor of a recent study on the economics of "me-too" or follow-on drugs. "The more drugs in development, the harder it is to find patients to recruit to trials."
Egilius Spierings, an associate clinical professor at Harvard Medical School, notes that protocols are becoming more and more specific with regard to the type of patients they want. "The list of eligibility and exclusion criteria is getting longer and longer, making it so difficult to find the right patient," says Spierings, who runs the MedVadis Research Corporation, a clinical trials research center in Wellesley Hills, Mass. "You sometimes wonder: Do these patients exist?"
The pharmacogenetic requirements of targeted drugs such as the breast cancer drug Herceptin, are making recruitment trickier, too. "Out of a random population of patients who present at your clinical door, you have to test all of them to find the subset of people suitable for the study,"says Reichert.
And because more Americans are taking medication in general, they are excluded from clinical trials that need medicine-free patients to avoid potential drug interactions. "The population is becoming more contaminated with medications," says Spierings. "It's not uncommon to find a patient who takes five or six."
All these factors contribute to companies needing more time to bring new drugs to market, adding to company costs. In the 1960s, it took 8.1 years to develop a new drug. By the 1990s, that number had risen to 15.3 years, or nearly double the time to do so, according to the Association of Clinical Research Professionals (ACRP), an Alexandria, Va.-based nonprofit that focuses on the education and training of clinical research teams.
The costs of delays can be staggering, says Siporin. "The average cost of a Phase III clinical trial ranges between $4 million and $20 million for one trial, and you have to run a minimum of two Phase III trials," says Siporin. "A delay for a drug that is to be a moderate success can cost a company $1 million a day in lost sales. A delay for a billion-dollar-a-year blockbuster product can cost upwards of $3 million a day in lost sales."
Well-publicized cases like Merck's withdrawal of its blockbuster drug Vioxx from the market last fall have also increased public distrust. "People are skeptical of the whole drug industry, and that affects the potential subjects for clinical trials," says Ric Ferraro, a former Harvard University professor and director of Clinical Monitoring Services at Bioforce Solutions, a Newton, Mass.-based company that works with pharma, biotech, and medical device companies.
CONTRACT RESEARCH ORGANIZATIONS
Some companies say they haven't had problems recruiting volunteers for clinical studies, particularly for uncommon conditions. For example, Genzyme, based in Cambridge, Mass., was able to recruit subjects for a clinical trial for a drug targeting Pompe disease, a rare and potentially fatal metabolic disorder. "There's nothing else out there, so the demand on the part of patients is extremely high to gain access to potential treatment," says Dan Quinn, a spokesperson for Genzyme.
Other companies, however, generally need more effort to find the patients they need. Annual spending on patient recruitment has nearly doubled over the past four years to more than $440 million per year, says Ken Getz, chair of the year-old Center for Information and Study on Clinical Research Participation (CISCRP), a nonprofit group in Boston that educates people about clinical research. Less than 6% of the total eligible population is participating in clinical research, but increasing advertising may not attract more patients. "The answer is not to spend more money to promote clinical research, because they're already doing that," says Getz. "We think the answer is [that] we have to do a better job educating and engaging the public and the volunteer community." To this end, CISCRP has launched a series of public-service announcements around the country about clinical research. The center receives funds from the pharmaceutical industry, foundations, and individual donors, according to CISCRP president, Roni Thaler.
In the past, academic medical centers ran most clinical trials, and physicians typically recruited the volunteers. Now, biotechs or pharmaceutical companies often use contract research organizations (CROs), which run and monitor trials for them, says Christopher Milne, assistant director of the Tufts Center for the Study of Drug Development.
Source: Thomson CenterWatch's 2004 Year in Review
In 1991, academic medical centers ran 80% of US clinical trials; by 2002, they ran only 30%. "CROs picked up most of that business. CROs are believed to be involved in about 70% of projects for new molecular entities in the US," says Milne. He estimates that 400 of the world's 1,000 CROs are based in North America, another 450 are in Europe, and the rest are scattered about the globe.
Worldwide CRO spending grew from $7.9 billion in 2001 to $10.4 billion in 2003. In 1993, doctors or nurses referred 65% of study volunteers to clinical trials; today, 75% of patients refer themselves into clinical trials using the Internet or other contacts, says Dan McDonald, vice president of Thomson CenterWatch.
The Web is just one method in a growing arsenal of tools being used to recruit volunteers. In 2004, at least 1,500 organizations listed trials online, according to McDonald. More than 75% of research centers actively enrolling patients list their clinical trials online, and 60% expect to increase their online usage during the next three years, according to a CISCRP survey. Other approaches include reaching out to patient support groups and community centers. On May 21, CISCRP is organizing a free, one-day program for the public on clinical research, to be held at Northeastern University in Boston.
"People give their time and instead, they're called guinea pigs," says Thaler. "We believe they should be thanked. Clinical research participation is the underpinning of the whole medical research system."
FINDING THE RIGHT PATIENTS
Volunteer recruitment problems in the United States and Europe are pushing clinical trials overseas, and many trials are taking place in the former Soviet Union, Australia, India, and Japan, according to Thomas L. Adams, president and CEO of ACRP. "We're growing overseas at about 8% a year." Although there is no shortage of patients in such countries, he says, there is a problem finding enough trained people to conduct the trials.
Adams notes that international trials can require a dizzying array of regulations and requirements, which can be a challenge for industry. Clinical trials conducted outside the United States need to take FDA regulations into account, as well as International Conference on Harmonization guidelines, which were created to harmonize rules and regulations between the United States, Europe, and Japan. In Europe, it's the EU's clincal trials directive. "If you think of clinical trials across Europe, they have 22 different sets of rules," Adams says. "So the European directive tries to harmonize what they do in the EU because it's different in every country. It drives everybody nuts."
Facts about Clinical Trials
• One out of every four volunteers drops out of a study after it begins, according to CenterWatch.
• In 2001, 402 different drugs were in cancer trials, according to a survey by Pharmaceutical Research and Manufacturers of America.
• Fewer than 5% of patients with cancer participate in clinical trials, according to the National Cancer Institute. If 10% participated, studies could be completed in one year instead of the three to five years that studies currently require.
• From 2001 to 2004, the number of people who say they've had a chance to participate in a clinical research study increased from 13% to 19%, according to Harris Interactive, May 2004.
As clinical trials go global, ethics in developing countries are a growing concern, causing debate about possible exploitation, coercion, and poor understanding by trial volunteers because of language differences and other problems.
In March, critics accused the FDA of violating international ethics by proposing that certain guidelines that protect patients do not apply to some clinical trials conducted overseas. Currently, FDA rules require that clinical research conducted as part of a new drug application be conducted under the Declaration of Helsinki or local laws, whichever better supports patients. The Helsinki Declaration, created by 82 national medical associations, says patients in clinical trials must have access to drugs after the study, and limits some uses of placebos.
But the consumer group Public Citizen and other critics accused the FDA of trying to weaken patient protections by proposing that clinical trials overseas that are not being conducted as part of a new drug application be exempt from the declaration, and be required only to meet good clinical practices.
Spierings of MedVadis says ethical concerns at home have prompted him to seek volunteers outside his own clinical practice, although it's much more difficult to find patients this way. Participation in clinical trials is voluntary, but patients may feel subtle pressure to participate if a trusted advisor such as their doctor asks them to sign up, he says.
To build public trust in clinical trials, Ferraro, a former professor at both Harvard and Tufts Universities and a 30-year veteran of clinical trial research, says researchers should pay scrupulous attention to ethics. "You are not supposed to coerce people into getting into studies, so you have to be careful about the incentives you offer," he says. "The second issue is informed consent: making sure the subject really understands why they're doing the study and what's involved, and what's been published about previous studies of a particular drug, especially in animals."
Ferraro, who set up a master's degree program in clinical investigation in 1996 at the Massachusetts General Hospital's Institute of Health Professionals in part to address ethics problems, says an effort is underway to certify the companies that recruit patients for clinical trials. While physicians conducting clinical trials may advertise in newspapers, some larger patient recruitment firms buy databases and "harvest people with different diseases, and get into their phone numbers and mailing addresses," contributing to public unease about the process, he says.
Diana Anderson, president of D. Anderson & Company, a patient recruitment firm in Dallas, and the author of two books on recruiting and retaining patients in clinical trials, predicts that the volunteer recruitment problem is not about to go away.
"The whole patient recruitment concept is still fairly new to the industry," says Anderson. "I think there will continue to be more of a focus not only on recruiting patients, but how can we keep them so the clinical trial can be completed."