An Introduction to Clinical Trials: Patients Take Part in Searching for the Cure

The lure of the phrase "new medication" is a strong one for people with chronic disease. The prospect of a drug that has not yet been tried brings hope that this drug will be the cure, or at least alleviate some pain and suffering. As such, calls to participate in trials of new medications result in a multitude of responses. The decision to participate in a clinical trial, however, is an important one. It is best made with a full understanding of the process of drug development and the patient's role therein. This process can be a lengthy one; according to the Tufts Center for the study of Drug Development at Tufts University, it takes an average of 15 years for an experimental drug to go from lab to patient.

In the Beginning

New medicines are born in the laboratory, and may endure years of laboratory and animal studies before human subjects even enter the picture. Researchers begin by testing compounds (drug preparations involving several ingredients), adding them to enzymes, cell cultures, or cellular substances to see which combinations improve the compound's performance. Computers can facilitate this effort, enabling scientists to simulate enzymes and design compounds that might work.

If a compound succeeds in the test tube, it's time to test it on animals. Researchers generally test drugs on two or more species, because the agent might affect each differently. These tests determine any toxic side effects of the drug, and its safety at various doses. Animal testing also helps researchers to see how a drug is absorbed into the bloodstream, and how quickly it is excreted.

Trying it Out on Humans

Once the drug proves successful in animal testing, clinical trials begin in humans. According to Tufts, five in 5,000 compounds that undergo preclinical testing make it to human testing (and one of those five is approved).

Stephen B. Hanauer, MD, Professor of Medicine & Clinical Pharmacology at the University of Chicago, and chairman of CCFA's newly created Clinical Alliance, explains the four phases of clinical trials.

"The drug must go through phase I testing in humans (usually healthy men) to demonstrate safety at the projected dose range and to determine how the drug is metabolized in humans," says Dr. Hanauer. "Phase II trials are the pilot trials, testing a dose or two in patients with the proposed disease. If these are promising, then phase III trials demonstrate safety and effectiveness in larger trials involving dozens to hundreds of patients.

"In the U. S., if two large trials are positive, the drug can be presented to the FDA in a New Drug Application (NDA). If approved, the drug can then be marketed for the specific indication (e.g., to maintain remission in ulcerative colitis). However, once approved, doctors can prescribe for any indication."

Following approval, a company must submit periodic reports to the FDA that include information on any reported adverse reactions. Phase IV studies are sometimes required to extend the prior indication at different doses, dose schedules, or formulations.

FDA drug approval is speeding up, says Dr. Hanauer. "Since the manufacturers have had to pay a user fee [funds that the FDA has been charging since 1992, and is using this fee to hire more reviewers to assess applications], the approval process has moved much faster. There are essentially no new drugs that are awaiting approval more than 12 months."

Dr. Hanauer explains that the process differs somewhat for biologic therapies, which unlike synthetic medications, are derived from living organisms. These include the new immune-based treatments that are causing some excitement among IBD researchers, such as anti-TNF. "For biologics, the two-trial rule does not necessarily apply, but the evidence of safety and efficacy has to be quite robust," he says. It is in this new area that CCFA is taking a tremendous role, by funding basic research that is leading to the creation of immune-based therapies.

Setting Standards

The rules and regulations of a clinical trial are designed by the sponsor. This usually is a pharmaceutical company, although research institutions and health organizations also fund investigations. The sponsor designs a protocol--a detailed description of how the trial should be conducted--for clinical investigators, the physicians who conduct the trial from various locations.

The protocol will describe the type of trial involved. Often, preliminary trials are open label, meaning that patients receive the experimental medication at a dose that is known to the patient and the doctor. In controlled trials, some participants receive the trial drug while others receive a placebo (a harmless substance that looks identical to the drug on trial).

"You do not need a placebo," says Dr. Hanauer. "But it is easier to show a statistical difference in a smaller group of patients when comparing to a placebo than when comparing to an approved drug. This takes less time and less patient exposure to a potentially useless or harmful drug."

Other factors help ensure a fair investigation. Many trials are randomized, meaning patients are randomly assigned to receive either drug or placebo. Studies also can be double-blinded, meaning that neither patient nor physician knows whether drug or placebo is being taken, or at what dosage.

According to FDA regulations, an institutional review board, (IRB) made up of healthcare professionals from the facility where the trial is taking place, keeps tabs on that entity's involvement in the trial. The IRB makes sure that all FDA and protocol regulations are adhered to, and reviews patient recruitment, advertising, and potential risks.

Calling All Patients

The clinical investigators that conduct drug trials have special considerations when choosing patients. "To get a drug on the market, you have to show it works," says Dr. Hanauer. "Ideally, you could give it to anyone, but you have to pick a population of patients who you anticipate will demonstrate a reliable response. This is based on the information from the pilot trials. Generally, you do not want patients to be so sick that they are not likely to improve, nor so mild that they won't show much improvement. It's often not the patients who need the drug the most, but rather, patients who you think will respond the most."

The process of picking patients for clinical trials of medications for IBD will get easier with the creation of CCFA's Clinical Alliance, a nationwide registry of IBD patients and trials. "It will facilitate enrollment into trials by making available patients with numerous disease conditions," says Dr. Hanauer. "For instance, at IBD centers, we see mostly patients with severe or refractory disease. Many trials need patients with mild to moderate disease. The Alliance will have different layers of centers, from the Regional Centers (mainly teaching hospitals) to their satellites (local gastroenterologists)."

Choosing Trials

Enrolling in a trial is a careful process for the patient as well. CCFA plays a part in bringing trials to the attention of potential participants, via sources such as its Web site. Either way, the patient should discuss participation with his or her physician, and that physician should be kept posted about the patient's progress in the trial.

"Your physician should counsel you on the potential benefits and risks of the trial," cautions Dr. Hanauer. "Doctors should have 'equipoise' in entering patients into trials. In other words, if they do not feel it is in the best interest of the patient, or if they feel that one therapy is superior to another, then they should not be enrolling patients. These are trials. We are testing whether the drug works...not knowing that it works."

Patients enrolling in a trial are closely monitored throughout by the clinical investigators. On the first visit, the patient should be ready with a list of questions and concerns:

  • What is the purpose of the trial and how long will it last?
  • Who is the sponsor?
  • Who has reviewed and approved the trial?
  • What kinds of tests and treatments are involved?
  • Will there be any pain or discomfort?
  • What are my treatment options, other than this medication?
  • What are the advantages and disadvantages?
  • How often will I be examined?
  • What side effects may occur?
  • Will the treatment be free?
  • If I am harmed, what treatment would I be entitled to?

The FDA protects patient rights by demanding that people enrolled in trials sign an informed consent form. This requirement mandates that the researcher provides adequate information about the study and responds fully to participants' questions. The investigators must be certain that the patient understands all risks and responsibilities and is aware of other treatment options.

The View from a Patient

If a patient qualifies for participation in a clinical trial, and is comfortable with the risks involved, the experience can be worthwhile. Kerrie Gallaga, a woman from Illinois who has suffered from Crohn's disease for 13 years, recalls her participation in a recent trial of IL-10, an anti-inflammatory protein that is derived from the immune system.

"I was having one of my biggest flare-ups--problems for more than six months," says Mrs. Gallaga. "Nothing was working. I was so tired of being on prednisone, I was ready to try anything."

Mrs. Gallaga found out about a study on the Internet, and contacted her gastroenterologist for information. "He was excited about it, and didn't believe that there would be a lot of risk involved," she says.

Next, Mrs. Gallaga contacted the clinical investigators conducting the study at an Illinois hospital. "There were pages and pages of information to read before giving consent," she says. "They told me that there were no guarantees, and that they would pay for everything--including parking. If anything went wrong during the study, they would pay for the necessary medical care."

Mrs. Gallaga was told that her chances of getting a placebo were small, as four out of five people were getting doses of the medication. Her biggest trepidation was in administering the medication with needles, but she overcame this fear quickly. "I've been stuck with enough needles to figure it out," she says.

The distance to the site of the investigation was somewhat of an inconvenience. "I had to take a half day off, every two weeks, because the appointments were so far away," says Mrs. Gallaga. "I had to tell my boss, because I didn't want him to think I was interviewing! The hardest part was getting there, but I liked the people that I was working with and I was happy to get on the meds. I didn't have to stop taking my other medication, so I had nothing to lose except time." The trial lasted 28 days, with 28 days of follow-up, and then six months of follow-up by phone. Patients reported their progress in journals daily.

All in all, Mrs. Gallaga reports positively on her experience. "When I first started, I felt relieved, and happy to be doing something," she says. "It did not seem as disruptive as prednisone." She noticed improvement in her symptoms soon after beginning the regimen.

Although the study is over, if Mrs. Gallaga relapses during the follow-up period, she will be provided with the experimental medication. The study results will not be available for some months.

"It was a good thing to do," she says. "Even if wouldn't have helped me, it might help someone else."

For further information, call Crohn's & Colitis Foundation's IBD Help Center: 888.MY.GUT.PAIN (888.694.8872).

The Crohn's & Colitis Foundation provides information for educational purposes only. We encourage you to review this educational material with your health care professional. The Foundation does not provide medical or other health care opinions or services. The inclusion of another organization's resources or referral to another organization does not represent an endorsement of a particular individual, group, company or product.

About this resource

Published: May 1, 2012

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