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Clinical Trials: The Search for Solutions The future has never looked brighter for people with Crohn's disease and ulcerative colitis. At least 10 new drugs for these diseases are currently being tested in human studies, according to the Pharmaceutical Research and Manufacturers of America. Many more compounds are in earlier stages of research and development. All told, "more than 50 companies are in various stages of testing drugs for these diseases," says William J. Sandborn, M.D., a gastroenterologist at the Mayo Clinic in Rochester, Minnesota. Dr. Sandborn is also chair of the CCFA Clinical Research Alliance, a consortium of medical centers that conducts clinical trials.
Of course, many of these experimental compounds ultimately won't pan out. "But let's say we get even five new drugs for Crohn's disease and ulcerative colitis in the next few years, which I think is very feasible," says Sandborn. "That's going to make an enormous difference in the treatment options that patients have available to them, and it will dramatically increase the likelihood that they'll be able to get well and stay that way. There are huge possibilities -- not only in the distant future, but also in the short term." Before any of these possibilities can be realized, though, there must be clinical trials -- research studies in human volunteers that investigate whether potential new treatments are indeed safe and effective.
Clinical trials are the core of the rigorous testing process that every new drug must go through in order to be approved by the U.S. Food and Drug Administration (FDA). They're also essential for studying new uses of already-approved medications. In short, carefully conducted clinical trials are the fastest, safest way of finding effective new treatments that may lead to significant medical advances. As this article was being written, the CCFA clinical trials database listed 468 clinical trials in 41 states, the District of Columbia, and four Canadian provinces.
From Lab Bench to Pharmacy ShelfBefore a new medication can be marketed in the United States, it must first make the long journey from lab bench to pharmacy shelf. Most compounds don't survive the demanding trek. Initially, researchers identify the target for a new medication, such as a particular molecule that's thought to affect the disease in question. They then screen thousands of possible compounds using computers or biotechnology to look for likely drug candidates. It's estimated that for every 10,000 compounds that are screened during this initial phase, only a few hundred make it to the next stage.
Next, those promising compounds enter preclinical testing. This involves extensive study in test tubes and in animals to evaluate each compound's safety and biological activity against the disease. Other testing looks at the practical utility of a compound, such as its manufacture, purity, shelf life, and formulation (for example, a pill or injection). On average, preclinical testing lasts one to three years. Out of every 250 compounds that enter this stage, only a handful make it through. For those that do, the drug company then submits an investigational new drug (IND) application to the FDA requesting permission to start testing in humans.
Once the IND is approved, clinical trials can begin. The trials are conducted in phases, each of which has its own unique requirements and purposes. - Phase I trials
These small studies, typically conducted in 20 to 100 healthy volunteers, determine the effects of a drug within the human body. The studies examine the drug's absorption, distribution, and metabolism. They also look at the side effects associated with increasing doses of the drug. The main purpose is to assess safety and determine a safe dosage range.
- Phase II trials
After the successful completion of Phase I trials, the drug advances to the next phase, in which it is evaluated for safety and effectiveness in 100 to 500 patients with the disease. These controlled studies provide preliminary information about how well the drug works against the disease in humans. They also identify common short-term side effects.
- Phase III trials
If the drug appears safe and effective in Phase II trials, it progresses to larger-scale testing in about 1,000 to 5,000 patients. These expanded studies usually test the new drug in comparison to a placebo or the standard treatment. They're intended to further confirm the new drug's effectiveness, determine its side effects, and define its appropriate use.
Once a drug successfully makes it through all three phases of clinical trials, the drug company files a new drug application (NDA) with the FDA. In the NDA, which contains all the data gathered so far, the company requests a license to market the drug for a particular use. An FDA team comprising physicians, chemists, statisticians, microbiologists, pharmacologists, and other experts then gives the study design, analyses, and results a careful review. The team's ultimate goal is to decide whether the drug's benefits would outweigh its risks for patients.
The FDA's review of a standard NDA typically takes just over a year. But priority NDAs -- in which the drug, if approved, would represent a significant treatment advance -- are put on a fast track that cuts that review time in half. If a decision is made to approve the drug, it can finally be marketed. But study of the drug doesn't end there. Phase IV clinical trials are post-marketing studies that further explore the drug's benefits, risks, and optimal use. Among other things, such studies may look at the drug's use in specific patient groups, such as children and the elderly, or the drug's long-term impact on the disease and patient quality of life.
Safety -- First, Last, and AlwaysThe whole process would grind to a halt without the help of patients who volunteer to participate. Many such patients have already tried all the standard treatments. "They're at the point where their only options are to continue suffering and getting worse, to have surgery, or to enroll in a clinical trial," says Sandborn. By signing up, patients at least have a shot at trying one more alternative. Of course, not all study participants end up being assigned to the group that gets the experimental treatment. But even those who are assigned to a standard-treatment or placebo group often benefit from the excellent medical care they receive. All participants also get the satisfaction of knowing that they're contributing in a very real way to medical progress.
On the other hand, there's always some risk involved in being one of the first to try out a new medication. To minimize that risk, a number of safeguards have been put into place. Clinical trials are conducted according to a strict protocol, a study plan that's designed to protect participants as well as answer scientific questions. Before a trial ever begins, the protocol must be reviewed and approved by an institutional review board (IRB) -- a committee of physicians, researchers, community advocates, and others who watch out for the rights of study participants. Once the trial is underway, the IRB continues to follow the study's progress. Meanwhile, the FDA and the sponsoring company also monitor how the research is being conducted.
"What you have is a triple-check process," says Sandborn. Whenever a serious adverse event occurs, it's reported to the IRB and the FDA and the sponsoring company. Researchers at other study sites are notified as well. This kind of monitoring is continual, and if it appears that a worrisome trend may be developing, a group of experts will decide what steps to take next. Possible actions range from simply informing patients that a new risk has emerged to stopping the study altogether. Says Sandborn, "Especially in the last year or two, the monitoring system has been strengthened to protect patients and to be as forthright as possible with them about anything that might be a potential side effect. If something changes as we're going along, we tell them."
A Destination that's Worth the JourneyIt's a long road from the time when a drug is just a gleam in a scientist's eye to the time when it first appears on a pharmacist's shelf. Once you factor in the costs of all the compounds that fail to go the distance, it's estimated that the cost of launching a single new medication now exceeds a staggering $800 million. The whole process leading up to FDA approval takes more than 13 years, on average, and post-marketing clinical trials may continue for many years afterward.
Yet the destination is well worth the journey. When it comes to Crohn's disease and ulcerative colitis, "we're talking about serious diseases that can cause enormous problems in the lives of patients," says Sandborn. "But some of the new treatments coming forth are very exciting. If we let these clinical trials run rapidly and effectively-taking great pains to be as safe as possible, but getting the studies done -- I think we're going to see a number of new treatments soon."
Before I Sign Up...If you're a patient who's thinking about enrolling in a clinical trial, researchers are required to inform you about the study's potential benefits, risks, and inconveniences. The study's purpose and duration, required procedures, confidentiality provisions, and alternative treatments should also be clearly explained. In addition, your rights as a study participant should be described, and key contacts should be provided in case any questions come up later. Before you can enroll in the study, you'll be asked to sign an informed consent document stating that you've been provided with this information and voluntarily agree to participate.
Make sure you really understand what you're getting into before you sign up. Unfortunately, while some informed consent documents are clear and straightforward, others make a mortgage application look user-friendly! If you have any questions, don't hesitate to ask the study staff. Also, while you should take your role as a study participant seriously, keep in mind that this document isn't a contract. You can still withdraw from the study at any time.
To find out more about clinical trials in your area, visit www.ccfa.org/trials.
-- Linda Wasmer Andrews
Date Posted: January 13, 2006
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