• Clinical trial phases
  
• Placebos: Misplaced worries
  
• Randomization
  
• Blinded and open-label trials
  

To determine whether a newly developed cancer treatment is any good, scientists must put it through a highly formalized series of experiments with human cancer patients. Only if a potential new treatment is proved to be safe and effective and better than current treatments will it be released to the public. This article describes the typical sequence of events involved in taking a new treatment from the laboratory to general use. When cancer patients participate in clinical trials, they generally participate in the kind of trials described here.

However, some clinical trials are different. These include trials of new medical devices, trials for the early detection of cancer, trials of methods for screening the population at large for certain types of cancer, or trials of treatments that may help prevent cancer.

Clinical trial phases

Once testing in people begins, in Phase I trials the safety of the new treatment first must be assessed. Of 100 potential new treatments, 70 pass Phase I testing.

Then, in Phase II trials, the treatment must be shown to be effective. Only 33 of the 70 treatments that enter Phase II are sufficiently effective to pass to the next stage.

Even an effective treatment will never come into common use unless Phase III trials show the new treatment to be better than the treatments that are already out there. A treatment might be judged to be better if more patients respond to it, or they respond for a longer period of time, or if the new treatment is less toxic and has fewer side effects than the old one. Just 25 of those 33 treatments successfully pass Phase III. Another way of putting that is, three out of four experimental cancer treatments are found to be unsafe, or ineffective, or no better than current treatments.

Finally, Phase IV trials keep track of the treatment once the US Food and Drug Administration allows it to be used in the population at large.

Placebos: Misplaced worries

You may be reluctant to consider clinical trials for fear that you may be given a placebo instead of active medication. But this fear is misplaced. People with cancer are unlikely to find themselves in placebo-controlled clinical trials.

You may have learned that for any scientific experiment to be valid, an experimental group must be compared to a control group. As you will see, this is not always the case in cancer clinical trials, but it's useful to understand the concept of controlled experiments just the same. To illustrate how a controlled experiment works with a simple example, suppose you wanted to figure out how well a new headache medication worked. You couldn't just give a single group of people a couple of the new pills and ask them if their heads still hurt. First of all, there's the possibility that simply taking a pill could cause psychological effects that would relieve headache pain. Second, since there are already several good headache medications out there, you'd want to prove that the new pill works better than the old ones.

For the experiment to have scientific validity, you have to make two kinds of comparisons. First you could compare people who took the new pill with people who took a phony pill. Something similar is done in many types of clinical trials: researchers compare a new medication to an inactive one, a placebo. If the people who took the headache pill had less severe headaches on average than the ones who took the placebo, you would have proved that the new medication had more than just a psychological effect. Experiments of this type are called "placebo controlled."

Placebos are necessary in many kinds of clinical trials because--for hotly debated reasons--doctors find that people receiving inactive medications often experience improvement in their conditions.¹ This is known as the placebo effect, and the classic paper on this phenomenon concluded that approximately 30 to 35 percent of the population respond to placebos, at least temporarily.² In order for an experimental treatment to be declared effective after a placebo-controlled clinical trial, the individuals receiving the active treatment must show significantly better results on average than those receiving the placebo.

To return to our example, in order to prove that your new medication was better at relieving headaches than aspirin or acetaminophen (Tylenol) or ibuprofen (Motrin), you'd have one group of people take the new stuff, and you'd have several other groups taking the established medications. Something similar is done in many kinds of clinical trials: researchers compare a new treatment to the standard treatments. If those taking the new medication had, on average, less severe headaches than those taking the established medications, and the difference between the groups was found to be statistically significant, then you might be able to say that the new pill was the best headache medication. Experiments of this type are said to have "active controls."

There are several reasons why it's unusual to find a placebo-controlled cancer trial. For one thing, Phase I and Phase II cancer trials hardly ever use any type of control, and typically all the participants in those trials receive the active treatment. And even in Phase III cancer trials, placebos are rarely used. One reason is that cancer treatments tend to have so many side effects that anyone receiving the placebo would figure it out in short order. A more important reason is that it would be unethical to deprive any person with such a serious illness of the best available treatment.

Instead, Phase III clinical trials for cancer typically compare the experimental treatment under study with the best available standard treatment. This is called an active-control clinical trial since even people assigned to the control group receive active treatment.

There are several exceptions to the rule that cancer clinical trials do not use placebos. Placebos may be used in trials involving those rare cancers for which no treatments are known to have any effect whatsoever, for which the best available treatment is no treatment. Fortunately, that's the case in a steadily diminishing percentage of cancers. In addition, placebos may be used in cancer prevention trials in which the participants are healthy to begin with.

Randomization

The fear of randomization is one of the most significant factors preventing cancer patients from considering clinical trials.³ Physicians also cite reluctance to permit randomization as a major reason they fail to refer their patients to clinical trials.⁴ If you're concerned about randomization, you should consider the following points:

• Randomization is typically an issue only in Phase III trials. Phase I trials are never randomized and Phase II trials are almost never randomized.

• Phase III trials are randomized because the investigators don't know whether the experimental treatment is better than the standard treatment. If the experimental treatment were known to be better, there'd be no need for a clinical trial.

• Anyone considering a clinical trial should examine the informed consent and protocol documents carefully for detailed information about randomization. For example, if a particular trial were designed to compare an experimental treatment with two different standard treatments, you might have only a one-third chance of receiving the experimental treatment.

• Phase III is the first time the experimental treatment is being given to large numbers of patients. There may well be serious side effects to the experimental treatment that had not shown up previously.

• If one treatment proves to be significantly superior to the others during the course of the study, the Data Safety and Monitoring Board will terminate the trial early and all patients will have the opportunity to receive the superior treatment.

You would have to decide if your conscience permits you to do this, but you could enter the trial and then quit if you didn't get what you wanted. But even if you think it would be ethical, you should only consider doing this if you knew for sure that you had some better option. I think it's dishonest, but that doesn't mean it's wrong.

Blinded and open-label trials

For that reason, the patients participating in some clinical trials are not told which treatment group they are in. In clinical-trial lingo this is called blinding. When it's just the patients who are kept in the dark about which treatment they're receiving, the study is referred to as a single-blind trial.

Patients in a clinical trial are often not the only ones who are kept in the dark. The investigators and the clinical staff may try to maintain scientific detachment, but they're human, and they too hope that the experimental treatment they're testing will be an improvement over the standard treatment. Bias can creep in if they communicate their hopes to the patients. With a wink or a nod a nurse or a technician might let a patient know which treatment group he's in. Even if staff members try mightily to keep the secret, they may unconsciously treat patients in the different groups differently, perhaps presenting a cheerier face to patients receiving the experimental treatment.

An investigator's bias may also appear when he records or interprets clinical data. Is that patient flushed, or does he have a naturally ruddy complexion? If the research nurse knows that the standard treatment tends to give patients a slight fever, perhaps he'll be more likely to note skin flushing for a patient in the standard group. For these reasons, sometimes the investigators are also kept in the dark about which patients are receiving which treatments. When both the patients and the clinical staff are blinded, the study is referred to as a double-blind trial.

How is it possible to keep the clinical staff--and the patients--in the dark about treatments? It's relatively simple if both the experimental and standard treatments involve simple medications that are administered at regular times during the day. Someone who's not directly involved in the care of patients in the study will prepare the medications, and they'll be designed to look alike. Additionally, instead of putting the names of the medications on the labels, she'll use a code. Neither the patients nor the clinical staff will know which medications they're receiving until the code is broken at the end of the study.

If the various experimental regimens being compared are complex and very different from one another-- as in many cancer trials--or if they have very different side effects, keeping the patients and the clinical staff blinded will be difficult or impossible. For example, suppose the study is comparing chemotherapy alone with chemotherapy plus radiation. It will be obvious to everyone which group each patient is in. For that reason, single-blind and double-blind studies are relatively rare in cancer clinical trials. Clinical trials that are not blinded are known as open-label trials.