Understanding Clinical Trials from
the Patient's Perspective
What is a "clinical trial?" Most Americans have never heard the term. But for one in three Americans who will be diagnosed with cancer understanding what a clinical trial is and how to find out about getting into one can have life saving or life extending implications.
In 1987, I was diagnosed with stage IV Hodgkin's disease , cancer of the lymph system. I had tumors in six sites including my liver. And yet, as grave as this sounded to me, the doctors were telling me that I had a 75 to 80 percent likelihood of being cured. I was 43-years-old and had lived long enough to know a few people with cancer. I had never met anyone who had survived with that much tumor involvement. How could there be a cure? I was told that for twenty years cancer researchers had been conducting Hodgkin's disease clinical trials which resulted in, not one, but two effective treatments for Hodgkin's disease. I resolved that if I was lucky enough to be cured, I would spend my time educating anyone who would listen to me about cancer clinical trials. Members of the medical scientific community refer to clinical trials in a variety of ways, such as clinical study, research protocol, or medical research. The definition of each will depend on the user's context. This, of course, leaves the general public very confused, which is the first problem with clinical trials and the cancer patient. When a cancer patient is told he has cancer and if the doctor discusses the patient's option to participate in a clinical trial, it is unlikely that the patient will be familiar with the implication of the doctor's suggestion. The terminology is alien and thus the patient, reeling from the shock of the diagnosis, is faced with another confusing decision.
The National Cancer Institute (NCI) defines a cancer clinical trial as "an organized study conducted in people with cancer to answer specific questions about a new treatment or a new way of using an old treatment."
In the following pages there are descriptions of the different types of clinical trials, including the three phases through which a drug must pass before it is judged to be safe and effective. The Food and Drug Administration (FDA) is the government agency with responsibility for overseeing the clinical trials process. Phase I and Phase II are the early stages of the drugs development, when the safety and the dosing level are tested in a small number of cancer patients. Once the safety and some evidence that the drug is effective in treatment of the cancer have been established, the drug's developer then proceeds to Phase III. In Phase III, many more cancer patients, usually several hundred, are given the new drug to see whether the early findings that demonstrated safety and effectiveness, will be borne out in a larger number of patients. Phase III is pivotal to learning hard statistical facts about a new drug. Larger numbers of patients reveal the percentage of patients in which the drug is effective, as well as give doctors a clearer understanding about the side effects which may occur.
At the time of enrollment in a cancer clinical trial, patients are usually assured that they will receive either the standard treatment known for their cancer or a treatment that is hoped will be an improvement. Most Phase III cancer clinical trials will compare the current, best treatment with the treatment being researched. Remember, the new treatment must have shown promise in earlier Phase I and Phase II studies in order for the trial to proceed.
Some patients considering a clinical trial fear they might receive a placebo, which is no treatment at all. It is true that in treating a few cancers, such as some types of non-Hodgkin's lymphoma, it is preferable to postpone treatment because immediate treatment is considered more harmful. In these cases, "no treatment" is the standard treatment.
Each treatment approach in a trial is referred to as an "arm" of the trial. For example, in my clinical trial there were two arms. The NCI was comparing, in arm one, the standard Hodgkin's treatment, known as MOPP (Mustargen-Oncovin-Prednisone-Procarbazine), with arm two, which was MOPP plus four additional anti-cancer drugs. Thus, in arm one, patients received four drugs and in arm two they received eight. The NCI scientists were hoping that adding four additional drugs to MOPP would improve the survival rate already achieved when MOPP therapy was used alone. The result of my clinical trial showed that there was no difference between the two arms. In other words, four drugs were just as effective as eight drugs in curing Hodgkin's disease. Because there was no difference and it is preferable to receive four drugs rather than eight, MOPP remained one of the standard treatments for Hodgkin's disease.
When I arrived at NCI, the staff carefully explained the clinical trial to me and then gave the explanation to me in writing. This document is known as the Informed Consent Form. I was told that if I entered this trial, the therapy I received would either be arm one or arm two, but that the computer would choose so that the selection was unbiased. This process is known as "randomization." Randomization assures patients that their treatment selection will be free of any treatment preference a physician might have. Since it is not known whether the new treatment is an improvement, the two treatments are considered equal. In other words, neither treatment is considered superior. If it were known that one was superior to the other, the clinical trial would not be necessary. If during the course of a clinical trial it is discovered that the treatment in one arm is superior to the other arm or arms, the trial is stopped and patients in each are given the superior treatment. The computer chose MOPP for me.
But why should cancer patients learn about this complex subject of clinical trials? The answer is simple. Clinical trials are the only road to progress in improving cancer treatment. When cancer researchers come up with a new treatment, they must prove to their colleagues and to cancer patients that the new treatment is better or at least equal to existing treatments. The only way to prove it is to run a clinical trial to demonstrate how the new treatment fares when compared to the standard treatment.
This road to progress in treating cancer is not a superhighway. It a rough, gravelly road filled with holes and barriers. I would like to outline some of the barriers.
NCI reports that less than five percent of cancer patients participate in clinical trials. Dr. Vincent DeVita, former director of the National Cancer Institute, has said that if only 10 percent of cancer patients participated in clinical trials we would know the answers about the effectiveness of new therapies in one year instead of the three to five years it currently takes to complete a clinical trial. Some physicians are worried about referring patients to clinical trials because they will not control their care or their treatment selection. And the growth of managed care as a health care financing mechanism has seriously limited the availability of clinical trials for some patients.
Patients are usually dependent upon their physician to tell them which clinical trial might be appropriate for them. However, this need no longer be the case. Cancer patients can directly investigate their own eligibility for a clinical trial by calling the Cancer Information Service (CIS) at 1-800-4-CANCER. This is a comprehensive information service sponsored by the NCI which helps patients search for appropriate clinical trials along with a wealth of helpful information about their diagnosis and treatment. There are more than 1,500 clinical trials in this data base. A live information specialist works directly with each caller and sends information to them within three days of the call. The same information is available on the Internet and is accessible through NCI's Cancernet. In addition, pharmaceutical companies developing cancer therapies also have clinical trials underway. While these are not always listed in the NCI's computer data base, the drug companies can be contacted directly regarding cancer clinical trials. Drug company phone numbers can be found in the Physicians' Desk Reference book which is available in most public libraries.
Last year marked the 25th anniversary of President Nixon's announcement of a war on cancer. There is no doubt in my mind that without this war I would absolutely not be alive today. I am deeply grateful for that, but as I look around the battlefield I still see far too many of us dying and wounded. Patients, survivors, family members and cancer scientists must regroup and rearm ourselves to wage a stronger assault on this enemy, cancer. Cancer clinical trials are one of the toughest weapons we have.
Most clinical trials are carried out in steps called phases. Each phase is designed to find different information. Patients may be eligible for studies in different phases, depending on their general condition, the type and stage of their cancer, and what therapy, if any, they have already had. Survivors are seen regularly to determine the effect of the treatment, and treatment is always stopped if side effects become too severe.
Phase I Clinical Trials
The purpose of a Phase I clinical trial is to find the best way to give a new treatment and how much of it can be given safely. In a Phase I study a new treatment is given to a small number of patients. For a new drug, the study start by giving a very low dose of the drug, then the dose is slowly increased as new patients enter the trial. The dose can be increased by giving more at one time or by giving the same dose more often. Physicians watch patients carefully for any harmful side effects. Although the research treatment has been well tested in laboratory and animal studies, the side effects in patients cannot be completely known ahead of time. Phase I studies effects may involve significant risks for this reason. They are offered only to patients whose cancer cannot be helped by other known treatments. Phase I treatments may or may not produce anti-cancer effects, but some patients have been helped by these treatments. Once the best dose is chosen, the drug is studied for its ability to shrink tumors in Phase II trials.
Phase II Clinical Trials
Phase II studies are designed to find out if the treatment actually controls cancer cells in people. Usually groups of 20 to 50 patients with one type of cancer receive a Phase II treatment. For example, patients with breast cancer who no longer respond to standard therapy may choose to be treated in a Phase II study. Patients are closely observed for anti-cancer effect by repeated measurement of tumor size to see if it has shrunk since the beginning of the trial. When the tumor gets a lot smaller and stays smaller for at least a month, the patient is said to have " responded" to the treatment. If a significant portion (usually at least one-fifth) of the patients in the Phase II study respond to the treatment, the treatment is judged active against their tumor type. In addition to monitoring patients for response, any side effects of the treatment are carefully recorded and assessed. Since larger numbers of patients receive the treatment in Phase II studies than in Phase I studies, there is more chance to observe unusual side effects. Each new phase of a clinical trial depends on and builds on information from an earlier phase. If a treatment has shown activity against cancer in a Phase II trial, it becomes part of a Phase III trial.
Phase III Studies
Phase III studies usually compare standard treatments (the treatment most accepted) with treatments that appeared to be good in the small Phase II studies. Phase III trials require large numbers of patients; some trials use thousands of patients. Patients are usually randomized, which means they are assigned by chance to one of the treatments being studied. The group that receives the standard treatment is called the "control" group. The researchers know that a certain number of these patients will be helped by the treatment. Another patient group receives the newer therapy to see if it will help the patients more. Phase III studies look for longer life, better quality of life, fewer side effects, and fewer cases of the cancer returning.
Adjuvant therapy trials are conducted to determine if additional therapy will improve the chance for cure in patients at risk for the cancer coming back after surgical removal of the visible disease. An example is study for patients with large bowel cancer. The standard therapy for large bowel cancer is surgery. An adjuvant study could be run in which one group of patients with large bowel cancer received surgery and the other group received surgery and chemotherapy. If the study shows that surgery plus chemotherapy is better than surgery alone, surgery plus chemotherapy will become the new standard therapy. Adjuvant studies progress through Phase I, II, and III trials like other treatment studies.
Treatment is given first to reduce the cancer to a size where standard therapy is effective. For example, the standard therapy for head and neck cancer is radiotherapy and/or surgery. Sometimes the cancer is too large to safely treat with either of these methods. The chemotherapy may make the tumor shrink to a size that can be treated with radiotherapy or that can be removed surgically. Neoadjuvant studies progress through Phase I, II, and III trials like other treatment studies.
Supportive Care Studies
Clinical trials also try to find better ways of caring for the side effects caused by cancer treatment (such as nausea and vomiting) and the side effects of the cancer itself (such as pain or sleeplessness). Some supportive care studies use drugs to treat side effects, and such studies will have phases (Phases I, II, III) like cancer therapy clinical trials. Other studies look at whether support groups help ease the discomfort of the survivor. Supportive care studies sometimes try to find better ways to help the families of survivors of cancer cope with the illness of a loved one.
Prevention and Early Detection Studies
Often people in prevention studies are considered likely to develop cancer (high risk) because several family members have related cancers. Prevention studies usually compare a group of people that receive no special treatment to a group that is given a drug or a change in diet to try to prevent cancer from developing. People in both groups are contacted for many years to see if there is a difference in how many of them get cancer. Early detection studies assess methods of screening people of cancer to try to find the cancer when it is still very small. If the cancer can be found when it is small., the cancer may be more easily treated, increasing the chance of survival. These methods may use x-rays, blood tests or touch (among others) to find cancer. Early detection studies may or may not run over many years.
Group C and Treatment Referral Studies
These types of studies make drugs available to some cancer doctors. These drugs have been through clinical trials, have been shown to work for some tumors, and may soon be approved by the Food and Drug Administration for sale. Group C drugs can be used by a wider groups of doctors than drugs used in either modified Group C or Treatment Referral Center studies. Survivors who receive drugs by any of these means are checked regularly by their doctors as if they were on a clinical trial.
This article originally appeared in Coping, May/June 1997. At that time Patty Delaney was a 10-year survivor of Hodgkin's disease and a member of the FDA's Cancer Liaison Program in the Office of Special Health Issues.
This article was posted on July 25, 2005.