Clinical Trials for Oncology Drugs
Types of Clinical Trials
Clinical trials are experiments. Medical researcher and drug developer conduct clinical trials on real patients to find new and better treatments for cancer. Before the Food and Drug Administration (FDA) approves an oncology drug for market release and general use, the new medicine must go through a series of tests or clinical trials. The clinical trials process is well developed and follows established guidelines for patient safety and notification.
Cancer clinical trials investigate new surgical techniques, radiation therapy methods, and chemotherapy drugs. Combinations of treatment methods are also tested, sometimes for FDA approval and sometimes just to see if they work. Many chemotherapy trials are for extensions of the drug’s approval to a different form of cancer. For instance, a chemotherapy agent that is FDA-approved for kidney cancer might be tried in lung cancer patients to see if it has enough efficacy to merit FDA approval for widespread use in lung cancer.
It is expensive to carry out clinical trials. The bill is paid by a sponsor, who is usually the pharmaceutical company that developed the new drug. Sometimes more than one pharmaceutical company will team up or other investors will become part of sponsor syndicates if they reach an agreement about money splits following an FDA approval.
Do new drugs ever not pass the clinical trials process? Yes, all the time. Clinical trials are experiments, so there is no success or failure for the trial per se, but the medicine may prove ineffective or unsafe. Most cancer drugs that enter the clinical trials process are never approved by the FDA. Indeed, it is common for sponsors to cancel drug development following negative results in a trial.
New drugs not previously used for cancer treatment are referred to as investigational medicines in the clinical trail process. New oncology drugs are first tested in a laboratory (in vitro) and in animals (in vivo). This preclinical testing determines the toxicity of the drug at least in animals. Knowing the toxicity level of the oncology drug provides the sponsor with an upper limit to the amount of the drug that can safely be used in human subject clinical trials.
Once the oncology drug has passed the preclinical phase with an acceptable safety profile, the sponsor moves to human subject clinical trials. There are three phases (I-III) of human subject clinical trials prior to FDA approval for market release and one phase (IV) after market release.
Phase I Clinical Trials
Phase I clinical trials are known as safety trials. The sponsor submits documentation for an investigational new drug (IND) to the FDA and an investigational plan to institutional review board (IRB) to receive approval prior to starting a Phase I clinical trial. Phase I clinical trials usually have 20-80 healthy volunteers who sign an informed consent allowing a clinical investigator (typically a physician/scientist) to administer the new (investigational) oncology drug. These human subjects do not have cancer. The clinical investigator records data in a case report. The data collected includes side effects and anything that can be ascertained about how the investigational oncology drug is eliminated from the body. The goal of the Phase I clinical trial is to determine if the medicine is safe to use in subjects with a specific cancer by assuring that the data from the animal studies (level of toxicity) has not changed (i.e., harmed the subjects) during its use in the healthy volunteers.
Phase II Clinical Trials
Phase II clinical trials can begin if the Phase I clinical trial shows the drug is safe. A Phase II clinical trial typically has 30-300 subjects who have the type of cancer specifically to be treated by the new medicine. During a Phase II clinical trial, data are collected to show the investigational oncology drug’s safety as well as the effectiveness (change in illness/clinical benefit). Most often, Phase II clinical trials are controlled trials where the investigational oncology drug is compared to an existing, FDA-approved oncology drug or to a placebo. The subjects are randomized and given one of the drugs (or placebo) during the treatment period. Investigators keep an eye out for side effects that appear during the trial. If they are too bad and too prevalent, the trial is cancelled to protect the health of the patients enrolled.
The goals of Phase II clinical trials are usually to collect data on endpoints, such as time to tumor progression (TTP), progression free survival (PFS), and time to treatment failure (TTF). Analysis of data from these endpoints helps the sponsor and FDA determine if the investigational oncology drug is safe and effective for a larger population. At the completion of the Phase II clinical trial, FDA and the sponsor meet to determine if the investigational oncology drug has met the safety and effectiveness hypothesis in the investigational plan and how many subjects will be needed in a Phase III clinical trial.
Phase III Clinical Trials
Phase III clinical trials are also known as approval trials. These clinical trials typically have 300-3000 subjects. These clinical trials continue to review the investigational oncology drug for safety and effectiveness but in a larger population and with different dosages. Additionally, a Phase III clinical trial may compare one or more approved drugs (cocktail) to the investigational oncology drug.
What if the drug is shown to be effective (reduce mortality or extends survival period) and reasonably safe? Then the sponsor is free to file a new drug application (NDA) with FDA. This application includes data collected on preclinical and human subject clinical trials, manufacturing processes, and drug labeling. The application is reviewed by a team of FDA experts including chemists, statisticians, doctors, and pharmacologists. If the reviewers agree with the sponsor’s results and conclusion, the FDA approves the oncology drug for market release. If there is any question regarding the results or the conclusion, FDA a letter to the sponsor who responds as applicable and may change their application or continue trials.
Phase IV Clinical Trials
The FDA may require an oncology drug sponsor to have a post-approval or Phase IV clinical trial after the drug has been approved for market release. Phase IV clinical trials look at long-term safety (risks) and effectiveness (benefits) in the general population. Phase IV clinical trials typically have several thousand subjects.
Oncology vs. Other Drugs
A 2007 study published by the American Society of Clinical Oncology stated that 71% of first FDA approvals of oncology drugs have been “priority reviews”. Only 40% other drugs revised a FDA priority review in the period 1990 to 2005. One difference between oncology medicines and other new medicines is in which phase of the process the disapproved drugs struck out. Cancer drugs had higher rates of success getting through Phases 1 and 2 before striking out Phase 3. The extra time in clinical trials processes increases the cost of developing cancer drugs. The Pharmaceutical Research and Manufacturers of America estimates 8000 clinical trials are underway in the US for all branches of medicine.
Participating in Trials
Clinical trials are set up to answer specific questions and they therefore have to function along narrow criteria. The investigators – the people who design and run the trials – establish the rules before they ever recruit any patients. They define the treatment regimen they will test, the type and dosage and duration of treatment, the characteristics of the patients they want to test it in. Once these criteria are in place and trial recruitment is underway, there are no changes. Don’t take it personally if you are turned down for a clinical trial because you don’t meet the criteria.
Do I have to pay to be in a trial? No. There is no law that says the trial cannot charge you or your insurance company, but patients are rarely, if ever, asked to pay. As a patient, you are valuable to the experiment, so they should be glad to have you.
Some trials require regular check-in to the local treatment center and participants should live near the hospital or clinic. Others are not so restrictive and patients can be recruited from across the country.
The teams that run clinical trials include doctors, nurses, administrators, statisticians, and scientists. As a participant, you will probably get some diagnostic tests and free treatment. In return you agree to allow the trial investigators to collect information about you. Sometimes participants in completed trials are asked to take place in new trials.
You will probably never meet or learn the names of the other patients in the trial. Some trials go on for years, with early patients finishing the trial before later patients even start.
If you are interested and qualify and it is feasible for you to enroll in a study, your participation can help the medical community move forward with new treatments. Even if it turns out the treatment is ineffective, a well constructed clinical trial can be invaluable to science by pointing out that a given treatment doesn’t work or it can give clues on new research paths to pursue.
The federal government’s Center for Cancer Research keeps a clearinghouse list of trials in the US.