Can "phase IV" trials work for you?

More physicians are signing up for these lucrative studies. Here are the benefits and pitfalls.

By Deborah Borfitz

At the 150-physician Sansum-Santa Barbara Medical Foundation Clinic in Santa Barbara, CA, pediatric allergist Myron Liebhaber is both doctor and researcher. Wearing his research hat, he may do little more than observe patients taking approved medicines. The work doesn't have the prestige of earlier phase clinical trials that test new chemical entities or new indications for existing drugs; nor is the pay as good. But it gives his patients access to medicines—often prior to formulary approval—at no cost.

Neurologist Louis Kirby has been doing clinical trials for a dozen years, abandoning private practice in 1996 to become a full-time researcher presiding over Pivotal Research Centers in Sun City/Peoria and Mesa, AZ. His preference is "marketing studies" that compare one drug compound to another to see which works better, faster, or is easier to use. Participants are relatively easy to find, because no placebo is involved. And while study results aren't always submitted to the FDA, they're often published and generate off-label use of a familiar drug.

The opportunity for office-based physicians to participate in these "phase IV" post-marketing studies is enormous, especially if they have a large patient base from which to draw suitable study subjects. Companies are increasingly compelled to do these studies as a condition of drug approval. For instance, the FDA might want to know how a drug can be used in combination with other commonly prescribed medications, or how children respond to the labeled dose. It also frequently mandates post-marketing studies for new drugs that treat serious and life-threatening illnesses and were approved under an accelerated review process.

Besides the pay—in some cases, thousands of dollars per patient—phase IV research can be a good place to start for doctors looking to break into research. Participation in simple trials and patient registries can prepare physicians for the rigors of randomized, controlled clinical trials, and there are fewer barriers to entry. But "this isn't child's play and it's not a hobby," cautions Marcia Angell, former editor-in-chief of the New England Journal of Medicine. "It takes expertise to do it well."

Does participation in phase IV trials make sense for you? Here's what you need to know.

What they are, what they pay

Pharmaceutical companies do a fair number of phase IV registry trials to learn how patients react to medical therapies in real, noncontrolled situations and to better understand physician practice patterns, says Kenneth Getz, president and CEO of CenterWatch, a Boston publishing company that provides news and information about the clinical trials industry. (CenterWatch is owned by Medical Economics' parent company, Thomson Healthcare.) The trials typically involve large numbers of participants, and are conducted in a variety of settings.

"Registry trials have played a major role in assisting researchers in understanding drug administration issues and patient compliance," he says. They can also increase physician awareness of an under-diagnosed therapeutic problem.

Myron Liebhaber is currently doing two registry trials, both focused on asthma. In one case, the sponsoring research organization is a subsidiary of a major HMO, and the intent is to follow the health insurance claims of subscribers. The other is a natural history study that follows asthmatic patients to assess their progress on "usual care."

"Those types of trials are becoming more common," Liebhaber says. "And they're fun. The sponsor does most of the work." Liebhaber's primary role is to go through the consent process with patients and document that they have asthma. Patients fill out their first symptom questionnaire in the office. "We fax all the information to the sponsor, and that's where it ends for us."

Subsequent asthma assessment surveys are mailed directly to patients. Still, Liebhaber is paid a flat fee of $500 for each of the 15 or so patients he enrolls. The hardest part, he says, is finding patients who meet the entrance requirements, including being at least 15 years old and new to the treatment modality.

On a per-patient basis, payment for phase IV trials tends to be lower than for pre-marketing research. But because so many patients are required, grant fees can add up quickly. "The data required is directly proportional to the pay," says Edward Morris, executive vice president of the clinical trials division of AAI International, a drug research firm in Wilmington, NC. Trials involving any type of invasive procedure also pay more.

"Doctors can expect to make a decent wage for their time, commensurate with what they'd be paid to see patients," says cardiologist Jonathan Seltzer, president of Applied Clinical Intelligence, a clinical research firm in Philadelphia, and director of clinical research at the Main Line Health Heart Center in Wynnewood, PA. On an hourly basis, the pay may well be better. "But they can't pay too well or it's considered coercive."

There are costs associated with meeting study requirements, and they can add up, says neurologist Louis Kirby. "By the time you go through all the processes—qualifying patients, doing consent and regulatory paperwork, talking to patients, doing study procedures, and perhaps attending an investigator meeting—it can cost $3,000 to $5,000 per study," he says.

Liebhaber points out that physicians tend to be naive about many of the regulatory requirements. "You need to store records for a certain period of time, for example (in some cases, up to 15 years), and all medications have to be properly stored and accounted for."

There are also safety concerns. "Phase IV is the arena in which we really find out if a drug is safe or not safe," says Seltzer. "A side effect that happens only 0.03 percent of the time may not even be seen until then." That's why it makes sense to seek indemnification from pharmaceutical companies, adds Kirby. Would-be investigators should also check with their medical malpractice carriers to ensure that research-related claims are covered.

Staff support is crucial, particularly in getting a study launched, says Liebhaber. The Sansum Clinic, which supports about a dozen part-time investigators, has a full-time secretary and three full-time nurses devoted to research. Pivotal Research Centers, with three full-time investigators, has a staff of 35.

The controversy surrounding phase IV trials

According to the New England Journal's Marcia Angell, most phase IV studies are unworthy of the term "research." "Phase IV studies are the fastest growing component of the clinical trial enterprise and much of it amounts to bribing doctors. Essentially, doctors are paid to put their patients on the sponsor's drug. There's often no legitimate scientific purpose for the study. To a large extent, doctors buy into the fiction that they're doing 'research' because it's lucrative to do so."

Kenneth Getz of CenterWatch adds that drug companies conduct certain post-approval clinical trials as a means to bolster drug sales and tap new markets. "Registry trials have become particularly popular for blockbuster drugs and 'vanity' drugs looking to build large physician or patient communities," he says.

The multispecialty Sansum Clinic works hard to avoid the controversy. Doctors here routinely reject "research" opportunities offered up by pharmaceutical sales reps, says Liebhaber, medical director of research. "We don't go looking for phase IV studies," he says. "They just come to us. Not a week goes by that we're not solicited one way or another. They pay doctors to use a drug under the guise of phase IV research. It's a very small sum, $50 to $100 per patient, and that's another giveaway."

Often criticized are those studies that take a comparative look at similar drugs already on the market or test off-label prescribing practices and attitudes about a single drug, says Getz. The criticism, he says, isn't entirely warranted because such studies sometimes "provide extremely valuable information about medical innovations, how they are adopted, and creative ways that they are being used to improve people's lives," he says.

"One way doctors can avoid being involved in poor quality studies is to take a critical look at the hypothesis being tested, the inclusion/exclusion criteria, the endpoints, and the statistical methodology," says Douglas Massey, vice president of clinical operations at Pharmacia (now Pfizer).

The FDA will get tougher

"The FDA's previously relaxed attitude toward post-marketing studies will be changing," Seltzer predicts. "Drugs can no longer be assumed safe once they're marketed." Far fewer drugs are being approved and used in Europe first, and tragedies during pre-marketing studies have also created demand for greater patient protections during the entire research process.

The FDA is finalizing industry guidance on how to implement a 2001 regulation on post-marketing study commitments and is working on a database to track them through completion. The most recent iteration of 1992's Prescription Drug User Fee Act, meanwhile, should funnel more funds to post-approval safety activities. All of this will translate into more "real studies" and less schmoozing of physician investigators. Doctors can also expect to read more journal articles about post-marketing study results.

In the world of clinical research, phase IV trials are the least complex and about as safe as they come, Seltzer says. "If you screw up, someone doesn't die." But at any phase, research is "not easy." Three out of four physicians who do clinical research do only one trial. "You have to finish it on time, do it well, not be sloppy, and pay attention to people—and you have to be personally interested in those issues. Nothing makes for successful research like having the doctor involved."

How to participate

Interested in getting involved in a phase IV clinical trial? To find out about ones that might interest you, check out clinicaltrials.gov, developed by the National Library of Medicine. Using the Web site's "Focused Search" you can search for phase IV trials by a number of criteria, such as location, disease, age of patients, and type of sponsor (industry, government, or university).

The author is a freelance writer based in Vero Beach, FL.

Deborah Borfitz. Can "phase IV" trials work for you?

Medical Economics

Jun. 6, 2003;80:58.