Clinical Trials for Oncology Drugs

Types of Clinical Trials

Clinical trials are experiments. Medical researchers and drug developers 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.  An article in Nature stated that “clinical trials in oncology have the highest failure rate compared with other therapeutic areas.”  The authors speculated that the reason was the high number of new therapies submitted for trial lowers the bar for sponsors to submit.

New drugs not previously used for cancer treatment are referred to as investigational medicines in the clinical trial process.  New oncology drugs are first tested in a laboratory (in vitro) and in animals (in vivo). This preclinical testing determines 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) aftermarket 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 the 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 I trials typically have fewer than 50 participants.  The small size lowers the financial risk and the risk of very serious detrimental effects.  The main information desired at this point relates to safety/toxicity. If the drug appears to work, great, but the sample size is too small at this point to prove efficacy and safety at this point.  The idea is that is the drug is strongly unsafe or toxic, it will show in even a small number of users and not too many people are put at risk to find out this information. Researchers may also learn about the medicine’s efficacy and side effects in Phase I, and that may help them to design protocols for Phase II.

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.  These trials are explicitly intended to determine efficacy and the best dosage that strikes a balance between side effects and curative action.  Phase II trials more often include people who do not have the disease the researchers are targeting. Phase I trials may also include non-patients, but the inclusion of these participants tends to increase in later stages of trials.  Why might non-patients be recruited? For one thing, the researchers may want to find out if the drug has negative effects on healthy people. Also, the non-patients may have a related disease or one with a common etiology and the scientists might want to see what the medicine does in those people.

Phase II clinical trial data is intended to demonstrate 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 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 drug.

Phase III trials typically have thousands of patients and protocols are established only after the sponsor has a firm idea of what they are going to claim in their application.  So things like dosages (or range of dosages) and method and timing of administration are close to what is eventually approved. The large number of people taking the medicine in Phase III helps generate high quality data.  A higher number of people and more data allow researchers to get statistically significant results. Phase III trials are trying to prove efficacy, of course, but also to establish the best dose, the nature, prevalence, and severity of side effects, and also to find interactions with other common medicines.

You might sometimes see the term “pivotal study” or “pivotal trial” to refer to large Phase III trials with participants of the target population for the drug under consideration.  The researchers go out of their way to keep tight protocols and do detailed statistical analysis. The regulators likewise scrutinize these studies closely. The pivotal studies ideally provide strong evidence of efficacy and safety and are important in gaining approval for NMEs.

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, the FDA sends 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.

Protocols and Experiment Design

Double-arm or multiple-arm studies organize patients into cohorts in which everyone in the cohort receives that same treatment.  The differences between the treatments on the arms are what drives the experiments. One arm is the experimental one, where patients gets the drug under investigation.  The regimens used in other arms are called comparators. At least one arm has a placebo comparator (an inactive therapy). (Some researchers designate the placebo as a “sham competitor”, meaning the inactive therapy is made to look like an active therapy.)  Some clinical trials include one or more arms with an active comparator – another treatment, perhaps one widely used for the illness the new drug targets.

A non-randomized trial is one in which all participants receive the therapy under investigation.  There is no control group. These also called single-arm trials. These happen frequently in Phase I and Phase II trials, in which less precise and convincing data on safety and efficacy is sought. The endpoint in these trials is often the response rate – what percentage of patients show an improvement in disease status.

Phase III trials, which are done to prove to the regulatory agency the drug should be approved, include a control arm.  The patients are assigned randomly to arms so as to maintain clean unbiased data.

Almost always, the patients do not know which arm they are in, in order to control for placebo or psychological effects.  This is called a blind study. Phase III trials are always blind. Often the researchers who personally interact with the patients also are kept in the dark about which patients are getting which treatment.  This is an even tighter control because it eliminates the possibility that human researchers will treat patients differently based on what kind of treatment (or placebo) they are receiving. This is called a double-blind study.  A randomized double-blind study is the gold standard of drug testing.

 

The number of patients in the study (in all arms) is called the sample size in statistical parlance.  Generally speaking, a bigger sample size means the scientists (and their regulatory reviewers) will have more confidence in the results of the experiment.  But it is expensive to run bigger clinical trials with more patients. And the protocols that the researchers set (e.g. age, sex, general health, presence of disease of interest) often limits the percentage of the population that is eligible to participate.  So getting a high enough number of participants to get reliable data within a budget it often tough.

Data and Proof of Efficacy

Data for clinical trials comes from all over the world.  The patients do not live in the United States, for the most part.  A report issued by the FDA stated 105,808 people were involved in pivotal clinical trials worldwide in 2015, with 29,775 of those people in the United States.

The globalization of clinical trials makes sense.  Data gathered from trials may be used in support of drug approval applications to agencies in different countries and regions.  And the large pharmaceutical companies are global in scope – the intended to sell or license medicines in many countries.

When clinical trials are planned, their designers designate “endpoints” they will look for.  This is how good experiments are made: decide in advance what hypothesis you are testing and what constitutes confirmation of your hypothesis.  Along the way you might find interesting things (good, bad, or otherwise) by serendipity. But you still have planned endpoints.

Pharmaceutical clinical trials use either a clinical endpoint or a surrogate endpoint.  When a the experimenters look for a positive development that is evident to an unaided human observer, that is terms a clinical endpoint.  Increased survival rate and less pain are clinical endpoints. Surrogate endpoints are ones for which the doctor must use some technology to evaluate, and they are not a direct clinical benefit.  A surrogate endpoint is more likely to predict a clinical benefit. The decrease in biomarker levels and shrinkage of tumors are surrogate endpoints. Clinical endpoints are better, but sometimes surrogate endpoints are more practical for experimenters to get ahold of.

Disease Free Survival (DFS) is an endpoint you often see in cancer research.  It is the average length of time (or distribution of times) that patients experience from the end of treatment until the cancer relapses.  This metric is more common when discussing treatment by surgery than by chemotherapy. Progression Free Survival (PFS) is more often seen in chemotherapy studies.  It is the length of time from the end of treatment until the disease becomes measurably worse. Overall Survival is a clinical endpoint that is the length of time between the end of treatment and death of the patient (from any cause).

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, and the characteristics of the patients in whom they want to test it. 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.  In fact there is currently in the US a shortage of cancer patients willing to be in trials.

Some trials require regular check-ins 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.  The National Institutes of Health has a good webpage answering common questions.

Helping out medical science

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 as to new research paths to pursue.

The federal government’s Center for Cancer Research keeps a clearinghouse list of trials in the US.

https://ccr.cancer.gov/clinical-trials

Access to Clinical Trial Results

If the results have been published in a journal, you can usually find the abstract, and sometimes more, on the internet.  Google’s academic search engine scholar.google.com is useful.

Trialtrove is an online service that sells clinical trial data.  We have no experience with it so cannot say how useful or cost-effective it is.