By Elizabeth Yoste

Before 1997, Virginia Garner, of Claremont, California, would brag that the last time she was in a hospital was the day she was born. Then she was diagnosed with chronic myelogenous leukemia. After unsuccessful treatments with interferon therapy, Garner was searching for hope.

“My doctor was about to pull me off,” she says. “I was at the end of my rope with interferon. I was completely defeated.” Researching on the Internet, Garner and her husband found hope in a clinical trial.

After discussing it with her doctor, she was referred to the investigators at UCLA who were conducting the trial.

“I didn’t even have to think twice.”

In 1999, Garner was one of the first patients to enroll in a phase I trial to receive an investigational drug called STI-571, now known as Gleevec® (imatinib mesylate). Today, the 58-year-old is still in remission. The drug has since been approved by the U.S. Food and Drug Administration (FDA) and is available for several types of cancer.

“I had no other options. I went into this trial with the idea that it was going to save my life. I had great hope that this drug would be a miracle. I’d be dead now if it weren’t for Gleevec.”

Ins and Outs of Clinical Trials

Gleevec is one of the few drugs that made it from the laboratory to cancer patients in the past decade. With only one in 5,000 drugs being approved by the FDA, the process is lengthy and complex, beginning with a compound or idea that then must pass multiple hurdles before the three phases of human testing can begin.

Before a drug even reaches human trials, researchers must determine the beneficial and harmful effects a drug has on living organisms in preclinical testing. Only five in 250 compounds make it through preclinical testing.

Phase I clinical trials usually involve a small number of patients. The primary goal of the trial is to determine how best to administer the drug, the maximum tolerated dose, and how often it can be given. Phase I trials can involve patients with different tumor types, allowing researchers to observe how the treatment works on various tumors. The drug regimen usually starts off very low and increases to determine the best dosage.

“Phase I cancer trials usually include volunteers with cancer who have limited therapeutic options or do not improve with standard therapies,” explains Ellen G. Feigal, MD, director, Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI). “And patients are carefully evaluated at each dose level for any signs of toxicity. Doses are only raised if the initial levels appear to be safe.”

Garner was hoping for a cure, but researchers were only looking at dosing.
“I was very lucky,” Garner says. “I was one of the first 38 people in the overall trial to take an effective dose.”

In those studies, the treatments are often new and have a low likelihood of benefit. Fortunately, there are now more drugs in early studies that are a better class of agents and offer greater benefit.

Phase II clinical trials focus primarily on how the treatment reacts to a specific tumor type that has demonstrated efficacy in a phase I trial. Sometimes, evidence in phase II is so significant that a drug may go through an accelerated approval process by the FDA, as Gleevec did, before completing the standard eight- to 10-year process. Clinical trials are still done to further test the drug after it becomes marketable.

In 2002, Iressa™ (gefitinib), a drug for advanced non—small-cell lung cancer patients, was accepted for accelerated approval after the FDA reviewed the results of a phase II study. Research showed that about 10% of 216 patients had tumor shrinkage of at least 50% with Iressa. Though the drug is still being tested in clinical trials, the FDA approved Iressa in May 2003 .

Patients enter phase III studies more often than early-phase trials because of the availability, high number of patients needed, multiple locations, and the better chance that the treatment will work. Often, phase III studies are held at different sites across the country and the data are pooled afterward.

A phase III trial may enroll hundreds to thousands of patients to determine effectiveness of the drug with large populations and if it is better than an existing treatment. These trials have passed rigorous testing and patients have a greater chance of receiving treatment that works.

During phase III trials, investigators randomly divide patients into groups that receive either the experimental treatment or the standard treatment. Researchers are thus able to compare them for toxicity, efficacy, and response.

Patients in a phase III trial may not receive the experimental drug and may not know which treatment they are given during a blinded trial. Those patients who are not randomized to the experimental treatment will receive the best standard treatment and care currently available.

If the clinical trial shows early significant results, either positive or negative, the trial may be stopped. In a positive situation, patients receiving standard treatment may be given the experimental treatment. In a negative situation, patients will be taken off the experimental treatment, and other treatment options will be considered.

Researching Clinical Trials

For patients who can’t wait for new drugs to finish clinical testing, their best option may be to join a clinical trial. One of the best places for patients to start their search is their physician, says Eric Rowinsky, MD, director of clinical research, Institute for Drug Development, San Antonio, Texas, and CURE editorial board member.

“I think the physician needs to get more involved,” says Dr. Rowinsky. It is the physician’s duty to find clinical trials for patients if they’re interested, he says, but many times, the burden falls on the patients themselves.

Many patients have turned to the Internet, as well as support groups, pharmaceutical companies, and cancer organizations, to find out about clinical trials. When researching clinical trials, patients should know their exact diagnosis and medical history. Knowing this information will make it easier to navigate the eligibility criteria.

Unfortunately, no one site lists every single trial being conducted, and many times information can be outdated, which is why a doctor’s ability to serve as a researcher, teacher, and liaison to his or her patients is so important. Without the physician’s input, patients may not understand the risks involved, the added effort and expense, and whether they are eligible for the trial.

Gloria Oliver asked her doctor about clinical trials when she was diagnosed with non-Hodgkin’s lymphoma (NHL). When her doctor learned of a clinical trial testing an experimental treatment of high-dose Cytoxan® (cyclophosphamide), Oliver hadn’t even finished her first line of standard chemotherapy. She eagerly jumped at the chance to enter the phase II trial and was the first patient enrolled in the trial at Johns Hopkins Cancer Center.

“This was an opportunity to try for a cure,” says Oliver.

As Oliver’s doctor explained to her, standard chemotherapy was not a cure for her NHL. Eventually, the cancer would return. That spurred Oliver to look for a clinical trial. Oliver was given a high dose of Cytoxan—also used in standard treatments—that was more than nine times stronger and administered differently than the standard treatment.

Nervous about the clinical trial process, Oliver had questions. But she says her doctors answered every question and explained what was to go on during the trial.

“I was very interested in what the side effects would be, chances for a cure, whether I would lose my hair, the long-term effects,” she says.

Although it’s too soon to tell whether the trial was a success, Oliver said her test results were good, the experience was positive, and she would have no doubts about going through the process again.

Who Pays?

The sponsor of the trial will usually foot the bill for the actual drug and special tests required by the clinical trial. It is usually up to the patient, however, to pay for the cost of routine care, such as outpatient visits, the hospital stay, travel, and any other expenses.

Hildy Dillon, vice president of Patient Services Disease Program, The Leukemia & Lymphoma Society, suggests patients be proactive by inquiring in advance what costs will be covered and what costs the patients and/or their insurance carriers can expect to incur. Patients need to have a clear discussion with the clinical trial healthcare team about what participant costs will be covered by their insurance before joining a trial.

If an insurance company refuses coverage of particpant costs, if possible, appeal before the trial begins. Many insurance companies will acknowledge a written letter by a doctor on the importance of the drug to a patient’s well-being and care. Recently passed legislation in several states requires insurance companies to cover all clinical trial costs to participants.

Since 2000, Medicare covers routine costs acquired in patient care during trials, especially ones sponsored by the NCI. There are also several organizations and government agencies, including the National Children’s Cancer Society (www.children-cancer.com), Mercy Medical Airlift (www.mercymedical.org), and Angel Flight America (www.angelflightamerica.org) that can help with other costs or travel arrangements.

What’s Right for You

Since pharmaceutical companies usually carry the high expense of providing the actual treatment, many patients worry they will be taken off the drug once the trial ends. Dr. Rowinsky says that although this does not happen often, patients should ask before entering the trial.

“We won’t even take on a study if there is any prospect that the patient will be stuck [without the drug],” Dr. Rowinsky says. Although some studies limit the number of courses due to cost, a shortage of the drug, or FDA mandates, many doctors do not take on studies if there is a chance the study will close, especially if patients are still benefiting from the drug, he says.

If a trial has this stipulation and the drug is working, patients can discuss options with their doctor or contact the drug company and the FDA to continue the drug on a compassionate use basis. Some drug companies also have programs where experimental drugs are supplied for non-research use. Much of this information can be found in the informed consent document, a requirement for any clinical trial before a patient is admitted.

Patients should read the informed consent document thoroughly, says Dr. Feigal. “It includes discussion of the study’s purpose, what will happen in the research study, potential risks and benefits, and the voluntary ongoing nature of participation.”

If patients do not understand a part of the informed consent form or have any questions about their treatment, they should ask before enrolling.
Also, Dr. Feigal encourages patients to continue asking questions throughout treatment. Patients should be aware of new information during the trial that might affect their decision to continue the study. Patients have the opportunity to withdraw from a trial at any time.

The potential benefit, risk, and added responsibility of being in a clinical trial must be weighed during the decision-making process. Garner advises other patients to learn as much as they can about their disease and the trials they are interested in before joining.

“Just do your homework, and research what the trials are all about,” she says. “Go in with what questions you have and if you feel good about it, go for it.”