This week I was asked to be a guest “expert” on a wonderful website called “Talk About Health” to answer questions from participants on a few subjects related to cancer research funding, peer review, clinical trials research and so on.
I was encouraged to cross-post my answers here and am enthusiastically doing so in case anyone interested missed it over there (here is my TalkAboutHealth page and the original posts).
Yesterday I posed about research funding and dollar allocation. Today’s post is an amalgam of a few more questions about clinical trials.
Question: At what point in the research process is a clinical trial started? What milestones need to be reached?
Any time that some fundamental piece of knowledge is ready to be “translated” into possible clinical activity, the most reliable route is a clinical trial or clinical study of some sort. Whether the new piece of information is a lead compound determined in a laboratory to kill cancer cells that we want to see if it can be taken from the so-called “bench to beside” or whether the new piece of knowledge is a study that seems to suggest that patients fare better in their cancer journeys when that are part of a support group, any intervention can be (and should be!) tested under controlled conditions to see if it really is effective or not, or just wishful thinking.
The milestones, or end points will be as varied as the trials, and are determined on a case by case basis. In the case of a new drug for example, the milestone may be that the new drug has to be statistically proven to work better than the existing best-accepted treatment and have no additional/worse side effects. In some cases the milestone may be a very quantitative one – overall survival is longer with “X” than with “Y” . Or the endpoint may be more qualitative (and harder to measure) – patients doing “A” feel better than patients doing “B”. In some cases the endpoint is in fact to show no difference at all – there may be a new treatment that is easier to administer, or is cheaper or is more acceptable to patients etc, but first it has to be proven that it is at least as good as, even if not better, for patients before it can be adopted as a new standard of treatment or care.
Question: What are the differences between phase 1, 2, and 3 clinical trials?
Phase I trials are the first stage of testing in humans, usually involving healthy volunteers and usually between 20-80 or so people. The main purpose of a Phase I trial is asses safety and side effects and to determine what looks to be a safe and tolerable dose in the case of a drug or treatment. Under normal circumstances (there are exceptions) the purpose of Phase I is not to actually see outcome improvements – after all the subjects are healthy to begin with – but to determine what regimen and dosage and administration will be safe to use in Phase II and beyond.
Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups of people, usually patients. Numbers vary but 100-300 subjects would not be uncommon. Now that a safe dose has been established in Phase I it is time to see if the new drug, treatment or intervention actually makes a DIFFERNCE to people with the disease being treated. Sometimes new toxic effects not found in the more limited Phase I trial emerge and the trial is stopped, and sometimes even if side effects are not an issue, it may now seem under further testing in real patients that the new regimen just does not work as hoped for, the trial may also be stopped as it becomes pointless to continue. However, if no new safety/toxicity concerns emerge, AND if there truly is data to support the belief that the new treatment MAY have the desired effect, it is time to begin the really rigorous part of the trial, the Phase III.
Phase III studies are (usually) what are called randomized controlled trials, most often needing several hundred to as many as several thousand patients to be enrolled. That means that they are also usually conducted in multiple centres (according to a strict and consistent protocol from centre to centre) to be able to accrue the number of patients needed to make a statistically reliable decision at the end. Phase III trials are all about answering, is drug “A” better than drug “B”; is diagnostic “X” better than diagnostic “Y”; is prevention intervention “P” better than intervention “Q” and so on. Biostatisticians set very rigorous models in place to make sure that the answer will be meaningful and reliable and that any differences between trial arms can be attributed to the treatments being tested, and not to stray chance factors.
For that reason, Phase III trials in oncology often take several years to complete because the numbers of patients that have to be enrolled is high, especially since most often we are looking for small incremental advances over what is an accepted treatment protocol. There is also a lot of regulatory work that goes on (some say we have swung the pendulum too far and that the bureaucracy is now impeding the conduct of trials) since patient safety is of utmost concern above all else. This makes trials frustratingly slow to start up even after approval, makes them inevitably long, and of course increasingly expensive.
But since clinical trials are a critical part of the research landscape it is essential that we improve the way we do trials or the system will soon implode under its own weight. I recently had the privilege to play a leadership role on an important Task Force to study the threats to the systematic conduct of clinical trials in Canada. You can read more about that here – http://www.ccra-acrc.ca/PDF%20Files/CT%20report%20Oct%202011.pdf.
Question: Why would I want to be a guinea pig in a clinical trial?
First and foremost it needs to be understood that participation (and even continuing after you start) in a clinical trial, is at all times strictly voluntary. Many people choose not to participate in clinical trials because they have heard or believe horror stories and/or they don’t see why they should volunteer to be a “guinea pig” so that some big pharmaceutical company can rake in the big bucks on their backs.
The first important point to understand is that not all trials are treatment trials, and in fact not even all treatment trials are drug trials. Clinical trials may test new drugs or other kinds of treatments, but they may also test new interventions for prevention, for early diagnosis, for screening or even for quality of life and survivorship interventions. So even if you did not want to be in a drug trial, there may be other options for you to consider.
To be sure, there are risks in being involved in a clinical trial. First and foremost, a trial is RESEARCH and the outcomes, even when there are good supportive and promising data, is unknown and uncertain. You may not feel well and your condition may worsen. Adhering to a rigorous clinical trial protocol involves a commitment that you may not feel you can make. And at the end of the day, you may not even benefit in terms of your own cancer outcomes.
But there are significant advantages of being on a clinical trial that, in my mind, outweigh the downsides. Leave aside the feeling of just knowing that you are helping to move the frontiers of knowledge forward. Even if you don’t benefit directly, knowing that others who follow will have better options because of you, is often enough in itself.
Speaking personally, I would always prefer to be treated at a centre where research is actively being carried out as opposed to a centre where it is not, if at all possible. Why? Because that means that I might have access to those who understand and appreciate the state-of-the art thinking of my disease, and be treated by health care professionals who are at the leading edge of treating my disease. After all, these are experimental treatments so that means that they are available to trial participants long before they are available to everyone else.
But what about this idea of being a guinea pig? To answer that you must understand that in oncology, it is very rare to have what you would call a “placebo trial”. In other words, the idea that you might randomly be assigned to the control group that gets no treatment at all except a sugar pill, while another group gets the experimental drug, is almost never true. As long as there is an accepted standard of care and treatment for your cancer, you will NEVER be denied that, at a minimum.
To deny someone standard care as a reward for participating in a trial is unethical and would never pass the scrutiny of the independent Ethics Review Boards that must authorize every single trial involving human subjects.
This is why the most common cancer trials do not test “A” against “nothing” but instead test “A” against “B”, where “B” is already the standard of care.
But wouldn’t you get that standard of care anyway? In principle, yes, but in practice it is well understood that the rigour with which trials are done means that you will get, at a minimum, the very best standard of care delivered to the nth degree. And fully documented. No corners cut, no stones left un-turned. Indeed, there is some evidence that people who participate in clinical trials have overall better outcomes than non-participants, even if they are in the control group.
Bottom line – it is not an easy decision to participate in a clinical trial, but one must at least approach it knowing the facts and not the myths.