What is a Clinical Trial?

At A Glance • A clinical trial is a research study that tests how well new medical techniques work in people. • The different types of trials include observational and randomized controlled trials (RCT). A RCT is considered to be the most reliable way to learn whether a certain test or treatment works. • Screening trials evaluate new tests for detecting cancer and other health conditions in people before symptoms are present. The goal is to determine whether the screening test saves lives and at what cost. • Patients should consult their own physicians for assistance in interpreting what clinical trial research results may mean for them.

A clinical trial is a type of research study that tests how well new medical techniques work in people. Individual research trials are designed to answer scientific questions and to find better ways to prevent, screen for, diagnose or treat a disease. Clinical trials vary greatly in size: from a single researcher in one hospital or clinic to an international multicenter study with several hundred participating researchers on several continents.

Every clinical trial has an action plan, or protocol, for conducting the trial. The plan describes how the study will be conducted. Each study has rules about who can and cannot participate. These rules are called "eligibility" criteria and they describe characteristics that must be shared by all participants.

In the United States, an independent committee of physicians, statisticians and members of the community called an Institutional Review Board (IRB) must approve and monitor the action plan to ensure that any risks to participants are minimized and are worth the potential benefits.

Different Types of Research Studies

Observational Studies

There is a distinct difference between observational studies and randomized, controlled trials. In observational studies, researchers monitor a group of people for a period of time without trying to change their lives or provide special treatment and then draw conclusions about the frequency or course of disease in the group. However, only further research can prove the findings of observational studies.

Randomized, Controlled Trials and Blind Studies

A randomized, controlled trial (RCT) provides the most compelling medical evidence and is considered to be the most reliable way to learn whether a certain test or treatment, works. Randomized means each study subject is randomly assigned to receive either the new treatment being studied or a placebo, which is either a fake treatment or the available standard of care to which the new treatment is being compared. Patients who receive the placebo treatment serve as the control group, which allows researchers to isolate and study the effect of the treatment received by the other group.

A blind study means the subjects involved in the study do not know which they receive—the study treatment or placebo. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent researchers' biases from affecting the results.

Types of Clinical Trials

There are different types of clinical trials depending on their goal, including:

• treatment trials to test the effectiveness of a new drug or procedure and
• screening trials to test new ways of detecting cancer or other health conditions in people before they have any symptoms.

Treatment Trials

Current Trials Online The National Institutes of Health (NIH) maintains a current list of clinical trials being conducted throughout the United States and in 154 other countries online at www. clinicaltrials.gov. Nearly 53,000 trials sponsored by NIH, other federal agencies and private industry are listed in the database. The National Cancer Institute lists cancer-related trials at www. cancer.gov/clinicaltrials.

Randomized, controlled clinical trials are separated into different phases based, in part, on the number of participants, and the interim goals for each phase.

• Phase I trials are the first step in testing a new approach in people. In these studies, researchers enroll a small number of patients (fewer than 100) at a few centers and evaluate safety issues, watching closely for any harmful side effects.
• Phase II trials usually include 100—300 patients. The study drug or treatment is given to this larger group of people to see if it is effective and to further evaluate its safety.
• Phase III trials are randomized, controlled multicenter trials involving large patient groups of 300—3,000. The study drug or treatment is given to this larger group to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
• Phase IV trials are conducted to further evaluate the long-term safety and effectiveness of a treatment. They usually take place after the treatment has been approved for standard use and involve up to several thousand people.

From Trial Results to Clinical Practice

After a clinical trial is completed, researchers analyze the data before making decisions about the meaning of the findings and further testing. They will determine whether to move on to the next phase or, especially after a Phase III trial, whether the results have medical importance.

Results are often published in scientific journals that are reviewed by experts to ensure the analysis and conclusions are solid. The results may be featured by the media and discussed by patient advocacy groups before they are published.

Once clinical trials indicate that a new approach is safe and effective, it may become a standard practice—widely accepted and used by medical practitioners and part of guidelines offered by health organizations.

Screening Trials

Screening trials evaluate new tests for detecting cancer and other health conditions in people before symptoms are present. The goal is to determine whether or not the screening test saves lives and at what cost.

The methods of detecting disease, often called screening tests, can include:

• Imaging tests - that produce pictures of areas inside the body.
• Laboratory tests - that check blood, urine, and other body fluids and tissues.
• Genetic tests - that look for inherited genetic markers linked to disease. A genetic marker is a specific gene or other identifiable portion of DNA that can be used to identify an individual disease or trait.

Reducing Mortality: The Ultimate Screening Goal

Before a screening program is widely accepted and recommended by medical practitioners, it must do more than detect disease at an early stage. The accepted measure of screening effectiveness is a reduction in the number of deaths from the given disease.

Following early detection, there need to be diagnostic and treatment services available that will result in better outcomes for those patients compared to those who do not have the benefit of early detection. Successful screening programs must produce greater benefit than harm and do so at a cost that society can afford.

Screening trials are instrumental in determining to what extent screening methods actually reduce mortality (death rate)—and at what cost.

Examples of screening tests that have become standard medical practice, based on research findings that demonstrated reduced death rates, are Pap tests for cervical cancer and mammography for breast cancer.

Imaging Tests in Screening

Imaging Screening Trials American College of Radiology Imaging Network (ACRIN) maintains a current list of screening trials using imaging at www.acrin.org/Default.aspx?tabid=76.

There is a great deal of attention being focused today on screening by imaging. Imaging tests such as computed tomography (CT), magnetic resonance imaging (MRI) and a developing field called molecular imaging are increasingly capable of detecting critical illnesses at their earliest stages. Imaging screening trials currently underway or recently completed include screening for breast cancer with digital mammography, with MRI and with ultrasound, for colon cancer with CT and for lung cancer with CT.

The life-saving potential of imaging technologies to detect cancer should be weighed against the other health and socioeconomic costs incurred by using these technologies.

Although today's highly sensitive imaging tests can detect some cancers at their most curable stage, they can also produce a high rate of false-positives (test results that indicate cancer is present when it is not). Imaging screening may also detect small tumors that would never become life threatening, a phenomenon called "over-diagnosis" that can put individuals at risk for unnecessary biopsies, surgeries and other treatments.

Example: Lung Cancer Screening with CT

This dilemma is illustrated in the current National Lung Screening Trial (NLST), a lung cancer screening trial sponsored by the National Cancer Institute (NCI). Launched in 2002, NLST is comparing two ways of detecting lung cancer: spiral computed tomography (CT) and standard chest x-ray.

At present, when lung cancer is detected the disease has already spread outside the lung in 15 percent to 30 percent of cases. Spiral CT detects smaller abnormalities than chest x-ray. Conventional wisdom suggests that the smaller the tumor, the more likely the chance of survival. However, smaller cancers are not always "early" cancers, and it is not known whether detecting these small abnormalities and treating them will save lives.

Moreover, recent studies indicate that up to 60 percent or more of screening CT scans of smokers and former smokers will show abnormalities, most of which are not lung cancer. However, these abnormalities—including scars from smoking, areas of inflammation, or other non-cancerous conditions—can mimic lung cancer on CT scans and may require additional testing. These tests cause anxiety for the patient and may lead to unnecessary biopsy or surgery.

As a large randomized, controlled trial, the NLST is designed to determine whether spiral CT scans are better than chest x-rays at reducing a person's chances of dying from lung cancer. This trial addresses other important questions related to screening including:

• What are all of the causes of death in people being screened for lung cancer?
• How cost effective is lung cancer screening?
• How does lung cancer screening affect quality of life between the time of a positive test to definitive diagnosis?
• Can other tests, e.g. laboratory tests on blood, urine, or sputum (phlegm), predict lung cancer in high risk groups?

A Final Word on Interpreting Clinical Trial Results

Healthcare stories garner an increasingly large share of news headlines. Knowing the basics of clinical research—and where to turn for additional guidance—can help when it comes to interpreting new research results.

A resource designed to help consumers understand scientific studies and research results is a publication titled Understanding Risk: What Do Those Headlines Really Mean offered by the National Institute of Health's National Institute on Aging (NIA).

When evaluating a new medical finding, the NIA encourages consumers to ask a series of questions, including:

• Was the study conducted in the laboratory, in animals or in people? The results of research in people are more likely to be meaningful.
• Does the study include people like you? Check to see if the people in the study are of the same age, sex, education level, income group, ethnic background and with the same health concerns.
• Was the study a randomized, controlled clinical trial involving thousands of people? Such studies are the most expensive and time consuming but, provided that the technology used in the trial is up to date, they give scientists the most reliable results.
• The bottom line: talk to your doctor or healthcare provider for help on understanding research results and what they can mean for your health.