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Clinical Trials Part I


by Steven Hirschfeld MD Source: Fall 2002 CCCF Newsletter

Drug development is a highly regulated process designed to minimize the risk of a new treatment for patients, while at the same time determine the benefit to treating a disease. Clinical trials are controlled research studies that test new drugs and other therapies being developed by biotechnology, pharmaceutical and medical device companies, for both safety and “efficacy.” Efficacy means the benefit seen in a clinical study which is used to predict effectiveness in a general population.

Before any cancer therapy is tested in humans, it must be identified, characterized for its chemical ingredients in the laboratory, and then tested in animal studies. Scientists (often including organic chemists, molecular biologists and toxicologists) work in the laboratory to identify compounds that potentially show activity against a cancer cell type or a specific target in a cancer cell. Only a small percentage of the chemical compounds studied by scientists show promise. Drugs that appear to have activity are then studied further through animal studies. This stage allows researchers to learn how the drug interacts with a living being – how it is absorbed in the blood for example, as well as to identify side effects that are likely to occur in humans.

Once these initial studies are completed, companies must obtain permission from the Federal Government to test a therapy in humans. This is done through the filing of an Investigational New Drug (IND) application with the Food and Drug Administration (FDA). A necessary component of the filing is the design and inclusion of a “study protocol.” The protocol is a detailed written description of how the clinical study is intended to be done. Once submitted, the FDA has 30 days to review it for safety by a multidisciplinary team of clinical, chemistry and pharmacologytoxicology experts. Additional review is done by local authorities that constitute an Institutional Review Board (IRB). Clinical studies generally proceed in defined phases.

Phase I trials involve a small number of patients and are designed to determine the treatment dosage, and preliminary safety information of a drug. Historically, less than 10% of cancer therapies tested in Phase I trials show any positive anticancer results. Phase I trials therefore are not likely to result in a remission or cure. Nevertheless, there is a strong rationale for participating in a Phase I study because patients are given access to new treatments before they are available to others; patients receive exceptional attention and care; all of the information learned will contribute to medical research to help future patients; and there is always the possibility that the patient will receive some benefit from a new and effective therapy.

Phase II trials are larger studies with more focused evaluation of the efficacy of the treatment; e.g. “Does it have activity against a particular disease?” Historically, between a quarter and a third of Phase II trials show positive results, and in many cases, studies in children may have a higher percentage because therapies are often screened in adults prior to being tested in pediatric patients. All Phase II studies require a patient protocol and review by an Institutional Review Board (IRB), where the patient is being treated. The FDA may also review the protocol if investigational or unapproved drugs are being tested.

If a new therapy shows promise during Phase II, then Phase III studies may follow. Phase III studies are designed to directly compare a new therapy with currently available standard therapy. Direct comparison is the best and most unbiased way to determine which therapy is preferred. Cancer therapies are most commonly used in combination, so Phase III studies usually compare combinations of drugs where a new drug may be substituted for a currently used one or a new drug may be added to a currently used combination.

Phase IV trials are conducted after the FDA has agreed that the drug shows safety and efficacy, and has approved a claim about the use of the product. This phase continues to evaluate the effectiveness of the treatment after it has been made available to the general patient population, while collecting valuable information on any side effects associated with its use. Not every product undergoes Phase IV testing.

The ultimate goal of any clinical study is to evaluate an outcome, one in which there is clinical benefit to the patient. In the case of cancer, the outcome or ‘endpoint’ would be a change in either the patient or the tumor, that leads to cure, prolonging of survival or improvement in patient symptoms either from the disease or from other therapy.

Any study that has a design that would not allow evaluation of an outcome is considered unethical. It is not ethical to expose people to unknown or unapproved therapies without the ability to evaluate the effects. It is therefore important that anyone participating in a study be made aware of what the outcome being measured is. This should be stated in the consent form and if it is not absolutely clear, study participants should ask.

In addition to patients being protected through Federal authorities including the FDA, the Office of Human Research Protection (OHRP), the National Institute of Health (NIH), and local authorities including Institutional Review Boards (IRB), it is important that anyone participating in a clinical trial be made aware of what the outcome being measured actually is. To assist a patient in this understanding, clinical trials must include an ‘informed consent’ document. The informed consent includes the goals of the trial, a brief explanation about why it is being done, information about the actual treatment, the known risks and benefits of the treatment as well as information about other possible treatments that are currently available (standard care). Contact information for the principle investigators (PI’s) of the study are also included in the consent form. Participation in a clinical trial is voluntary. There are no obligations to participate in a trial of an experimental therapy and if a patient does enroll, they are entitled to change their mind and withdraw from the study at any time.

Clinical trials in childhood cancer are among the most organized and extensive in the world, with 60% of all children under 15 years of age entered into clinical trials. There is no question that this has led to a tremendous increase in the survival and cure of children with some types of leukemia as well as some other childhood cancers. This collaboration between the child, their family, physicians, and scientists has served as an example for other childhood and adult diseases. This said, many types of pediatric cancer still show poor prognosis, and many treatments can have very serious long-term side effects. Thus, the collaboration must continue if the overall survival of all children with cancer is to improve.

It is important to understand the clinical trial process, as well as available optional treatments for your child before entering into a study. In order to assist families with this search, the ACCO has added a clinical trial search engine to their website at: Additional information can be found at: