Dr. Rafael Bejar is assistant professor of medicine in the division of hematology/oncology at the University of California, San Diego. Dr. Bejar speaks about clinical trials, (also known as clinical research studies), how patients can benefit, and why this can not only help the patient but also plays a major part in advancing the understanding of bone marrow failure diseases and pointing to new directions for treatment.
How You Can Be Involved in Clinical Trials
Should you consider participating in a research study? If you have a bone marrow failure disease, you may want to consider taking part in a clinical trial. You may get access to experimental drugs that may not become widely available for years. To find out where to look for clinical trials in your area, be sure to visit the Clinical Trials section on the Web site.
Can you briefly explain the four phases of a clinical trial and why these separate stages are needed?
Clinical trials in medicine are divided into to four phases. Phase 1 trials are designed to test new medications, or combinations of existing medications, for the first time in human subjects. The goal of phase 1 trials is not determine if a drug works against a particular disease, but to determine what doses are safe and tolerable to patients so that the best dose can be used in larger, more advanced trials.
Phase 2 trials involve more patients than phase 1 and can be more complicated. The goal in phase 2 trials is to determine whether a drug has efficacy. If it doesn’t seem to work, or if unexpected toxicity crops up, it is unlikely to be developed further.
Phase 3 trials are typically very large, multi-institution trials designed to better understand how well a drug works compared to existing treatments. Phase 3 trials are often randomized where patients are given either the experimental drug or an alternative such as an already approved therapy or placebo in its place. A placebo is a treatment that looks just like the experimental treatment but lacks the active ingredient. In double-blinded clinical trials, neither the patient nor the doctor knows whether the patient is getting the experimental therapy or the placebo. Phase 3 trials are designed to determine efficacy, and to look for signs of toxicity that might not have been evident in the smaller, earlier phase trials.
Medications are often approved based on the results of phase 3 trials, although occasionally based on results of phase 2 trials if they show a dramatic degree of efficacy or treat a life-threatening condition with few alternatives. After a drug has been approved by the FDA, they sometimes ask for what is unofficially called a “phase 4” trial. These are post-marketing studies that monitor a great number of patients receiving a treatment. The objective of these trials is to validate the results of earlier trials -- in particular, to confirm their results in a more real-world setting and looking for unanticipated toxicity. It’s rarely required, but in some cases, the FDA will approve a medication contingent on post-approval trials being done.
One person does not go through all phases of a trial. Each phase is a distinct study separated in time by quite a bit from earlier phases. In fact, if a later phase trial requires that a patient has never received this drug, or one like it, participants in the earlier trial would not even be eligible. There are some combined phase 1/2 trials where the first few participants help identify the ideal dose in the phase I portion and a larger group of participants receive that dose in the phase 2 portion.
Some clinical trials focus on a new drug, sometimes a combination of drugs, and sometimes a new use for an existing drug that was approved for another purpose. Can you explain how these different approaches are utilized, and can discoveries in one type influence another type?
Some trials focus on drugs never before tried in humans, some test combinations of approved drugs, while others are for an already approved drug used in a different setting. Here, the manufacturer wants proof that it works for another disease condition so that they can promote the product for this new indication. Keep in mind that physicians can prescribe an already approved medication for non-approved indications, which is referred to as “off-label prescribing,” but the FDA prohibits the manufacturer from advertising for the off-label use. Manufacturers may want to prove the drug works for a different purpose so they can actively promote it.
How do you advise patients who feel that clinical trials are just a ‘last resort’ to be avoided if possible, or others who feel that unless they are in the group getting the drug(s) being tested that participation isn’t worthwhile?
This is a very important point. There has been some resistance to, and misunderstanding of clinical trials. This results in fewer patients willing to consider participating in a clinical trial. Part of the misunderstanding is about the role of clinical trials. It’s true that there some are designed to enroll patients who have tried all other approved therapies and are left with few options. This is common in metastatic cancers, for example. But there are clinical trials in available for almost every stage for every disease. There are ones for patients who have never been treated before in order to come up with a better first line treatment for them. Other trials are designed to treat patients who have tried just one or two prior therapies, but still might have other options available. The hope is to always offer something that might be better than the current standard of care.
An institutional review board comprised of doctors, nurses, clergy, and laypeople will scrutinize all clinical trials in their approval process to protect the rights and welfare of potential participants. This is not only for patient safety, but to ensure that the question being asked by the trial is a fair one – for example, that patients who are randomized to the experimental drug are as likely to benefit as patients who are randomized to not get this treatment. These are drugs that we may not have much experience with, and it is possible that an experimental drug does not work or has more toxicity than expected, and thus, could be worse than getting the standard of care or a placebo. The reason many people sign up for a clinical trial is for the possibility of getting the new drug being tested. But even if someone is randomized to the arm of the study that doesn’t get the novel agent, they will still receive more scrutiny and interaction with physicians. In general, patients in clinical trials do better than similar patients who are not. One reason for this may be the added attention they receive – namely more frequent evaluation and follow-up,
Can related diseases be studied in the same clinical trial?
This often happens in phase 1, where trials may not be limited to one disease type. The goal is to find the safe dose. So a cancer drug might be tried in patients with different types of advanced cancers, for example. In subsequent phase 2 or 3 trials, the drugs will be used in a more limited way, for example, just lung cancer patients, whereas in phase 1, it might have been tried in colon cancer and breast cancer patients as well.
Have there been any unexpected failures or dead-ends that surprised you?
In general, the reality is that many new experimental drugs that look good in preclinical studies do not make it all the way to becoming an approved drug. They may seem promising in the beginning, but do either fail to work as well as we hoped or are found to have unexpected side-effects. For example, HDAC inhibitors as single agents have not had the effect in MDS that we had hoped for. So now, some HDAC inhibitors, like vorinostat, are being tried in combination trials like the one I mentioned earlier.
Is www.clinicaltrials.gov a patient friendly resource?
I find patients to be remarkably well informed and vested in finding out more about their disease, so I always recommend this site. It was not designed for patients primarily, but it is not difficult to use and has a robust search functionality. You can search for trials in a geographic area, or by disease at a particular stage, or you can look for trials of specific drugs you many have heard about. You can get very targeted results, so patients interested in clinical trials should explore this resource.
What should patients remember about clinical trials?
If we look to the past at what clinical trials have done for medicine, in retrospect, the standard of care has always been replaced by something that was proven to be better in clinical trials. Patients who have been on clinical trials have gotten these therapies sooner and have benefitted from hem before the general population does. Since we don’t have a cure for many bone marrow failure disease patients now and since we need better therapies, clinical trials are a very good way for getting access newer, and potentially better therapies before they become available to the general public.