Steve’s Strategic Guide to the Clinical Trial System

What Are Clinical Trials?

This article is the beginning of an in depth exploration of the clinical trial system. If you're new to clinical trials, please read my brief introduction, "What are Clinical Trials and Why Investigate Them?" first.

Clinical trials are conducted within a complex system with fairly well defined rules. A good understanding of the system gives you a framework for making good decisions. It also gives you an essential framework for understanding clinical trial results reported in the medical literature. There are can find brief superficial explanations of the sytem in many sites. My approach is to give you a detailed and intensely patient oriented tour specifically designed to help you find the best treatment.

Understanding the details will help you:

  • Ask the best questions about trials you’re considering
  • Know which kind of trial is likely to be appropriate and more quickly weed out inappropriate trials
  • Recognize promising trials
  • Recognize unpromising trials
  • Give you other options if eligiblity or randomization is making it hard to get the treatment you want
  • Maximize your odds through strategic thinking

In this article I set the stage with a brief introduction to the system, and then link you to CancerGuide’s detailed Phase by Phase Guides. If you’re already somewhat familiar with clinical trial phases you may want to skip directly to the detailed guides.

A Few Important Principles

As you go through CancerGuide's clinical trial articles, there are a few general principles which you'll want to keep in mind which will help you put it all together.

Promise and Uncertainty

I talk much about things being more or less promising based on the data, but often you just can't tell. When considering previous results of new treatments there is almost always great uncertainty. Often the data simply do not exist to suggest a new approach is truly promising and you may be unable to determine whether a particular trial is promising or not. Don't expect to be able to come to a definite conclusion about each and every trial - or even most of them. But when there are data suggesting there is real promise, and when you find that data, understand it, and act upon what you find, you may change your odds by getting the best treatment!

Each Option Must Be Compared to All Others

Although I describe strategies for investigating and thinking about each phase of trial, in reality, to find the best, any treatment option must be evaluated in the context of all other options. The alternative to a Phase I trial is not just another Phase I trial, but any other trials you are qualified for as well as any standard treatments which might be of value. It is impossible to know if something is promising unless you know what results can be expected with standard therapies.

Variations on a Theme

Trials can vary from the standard or classic model, and a surprisingly large number of trials are non-standard in one way or another. I describe the standard and some of the variations for each phase of trial, but I can't hope to cover all of the possiblities. But understanding the standard cases will help you figure out how to understand and evaluate trials even when they don't quite fit the classic mold.

Phase I Trials

In a Phase I Trial, the first phase of testing, a new drug or treatment is tried in humans for the first time ever. The goal of the Phase I trial is not to see how well a new treatment works but rather just to discover how much of the drug can be given safely, and to understand its side effects and chemistry in the body. These trials most closely fit the stereotype of a truly experimental treatment. Phase I trials are for patients with advanced cancer who have no effective standard treatment.

Steve's Advice In a Nutshell

The limited experience with the treatment normally makes it extremely difficult to evaluate the promise of the treatment, and there is a significant risk of getting an inadequate dose, even if the treatment is effective. Phase I trials are open to some patients who don't qualify for Phase II trials, and very carefully selected Phase I trials can be promising, but most patients who qualify for other trials would be well advised to avoid Phase I trials.

Phase II Trials

In a Phase II Trial, the new treatment is tested to see if it can shrink tumors in patients with a particular type of cancer using the dose and schedule set during the prior Phase I trial. This is the first test of efficacy. Like Phase I trials, Phase II trials are for patients with advanced cancer, but Phase II trials also have some additional entry requirements.

Steve's Advice In a Nutshell

Phase II trials offer the opportunity to get a new treatment at the correct dose, and without the uncertainties of randomization. The amount of prior evidence for a treatment in Phase II is highly variable, but can be enough to suggest the trial is promising. In my judgement if you have advanced cancer, your greatest chance to benefit from a new treatment through a clinical trial is probably a Phase II trial, but the trial must be carefully selected.

Phase III Trials

In a Phase III Trial, the new treatment is compared to the standard treatment to see which produces better survival. Phase III trials are normally randomized - half the patients are randomly selected to get the new treatment, and half the standard treatment. The survival of the two groups is then compared to determine which treatment was best. In some cases, Phase III trials compare two standard treatments or two new treatments. Phase III trials are not limited to patients with advanced cancer, but may be a consideration at any stage.

Steve's Advice In a Nutshell

Phase III trials are randomized, which means you don't know what treatment you will get until after you enter and you are randomly assigned to an arm of the trial. This complicates the decision making! In an ethical Phase III trial, the evidence shouldn't favor one treatment to the degree that the outcome is a forgone conclusion, but it is still quite possible that a rational analysis of the trial in light of your values would conclude that one arm is more desirable. Phase III trials involve better established treatments than earlier phase trials and there should be more available evidence on the treatments involved than is the case for earlier phase trials. Phase III trials can offer the chance for an improved treatment, but require very careful strategic thinking.

Adjuvant Trials

Adjuvant Trials are tests of additional treatment intended to reduce the risk of recurrence after initial treatment (usually surgery) for apparently localized disease. Most adjuvant trials are basically a special type of Phase III trial, and are randomized, but the considerations in choosing one are different enough that they deserve a separate discussion.

Steve's Advice In a Nutshell

You only get one crack at adjuvant therapy, so you need to investigate adjuvant trials before starting any standard adjuvant therapy! You also have to enter the trial within a limited time after completing the primary treatment and sometimes even before starting the primary treatment, so you must investigate these trials promptly. Your decision must take into account your risk of recurrence, the side effects of treatment, whether there is any standard adjuvant treatment, and the specific evidence for the treatments used in any particular trial.

Regulatory and Institutional Aspects in Brief

Human Subject Protection

Clinical trials are governed by a complex bureaucracy and process designed to protect people from unethical research. CancerGuide does not dwell on regulatory protections because I believe that your best protection is to become deeply informed! But you should know that all reputable clinical trials are approved by a local Institutional Review Board to ensure that they meet minimum nationally established ethical standards. This includes ensuring that trials do not seriously harm patients solely for the purpose of gathering research data, that the risks are appropriate considering the situation, and that patients who participate in a trial give their informed consent through a process which culminates in signing an informed consent document. For advice on how to get the most out of informed consent, see my article, A Guide to Informed Consent for The Active Patient

Regulation of Experimental Drugs and Devices

In the US, to use any drug or device that is not approved for general marketing (e.g. "experimental") researchers must obtain a permit called an IND. An IND is approval to use an experimental drug usually in a clinical trial, but it does not mean the FDA has approved the treatment for general use or even that it thinks the treatment has merit. Occasionally I see drugs or nutritional supplements touted as "FDA approved" when the only approval is an IND for use in clinical trials.

Eligiblity Criteria

A notable and important feature of the clinical trial system is the strict and complex set of eligiblity criteria for each trial. Understanding this aspect of the system will make it much easier to figure out which trials you qualify for. The eligiblity criteria are include relatively standard requirements for all trials as a whole, some requirements which are typical of each phase trial, as well as many requirements which are specific to a particular trial. I cover the standard phase specific requirements in my detailed article on each phase of trial.

Next Steps

Steve’s Strategic Clinical Trial Guides: Phase by Phase

This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: March 3, 2002, Last Updated: August 7, 2004