December 6, 2013 - Like all doctors, I've often wrestled with the question of what’s the best course of treatment for my patients. While each patient is unique, one fundamental issue is always the same: Which treatment will likely help the most and pose the least risk for harm?
Unfortunately, the answer is often elusive because hard evidence that one treatment is better than another is lacking. That comparison can only come from well-designed clinical studies.
Trial design 101
Designing clinical trials can get incredibly complicated. But the core of comparative trials is actually quite simple.
Such trials are designed to evaluate an investigational medicine compared to existing treatments. One option is an additive study, in which an investigational medicine is added to a standard of care and compared to the standard alone. This is often the case for cancer medicines, where targeted treatments are frequently added to established chemotherapies, and using a true placebo (i.e., no active treatment) may be unethical.
The other main option is a head-to-head trial, where an investigational medicine is directly compared to an existing standard of care.
Why head to head?
More and better options for patients are unequivocally a good thing, and we’ve advanced the care of many diseases using additive trials. However, head-to-head trials are the only way that we can definitively say one medicine is more effective or less harmful than another. For the doctor and patient discussing their treatment options, that’s incredibly powerful information.
So the question is, why wouldn’t we always use head-to-head trials to evaluate new investigational medicines?
In a perfect world, we would know the efficacy of every medicine compared to every other medicine for every possible use. But in the real world, clinical trials require the involvement of thousands of patients, tens of thousands of hours, and millions of dollars. It’s impractical to test every medicine against every other medicine. What’s more, it would be unethical to keep sick patients waiting while we conduct numerous lengthy studies. So we have to focus on designing the best, most informative studies from the very beginning.
Putting our heads together
In many disease settings, there is a clear-cut, well-established standard of care. In these cases, head-to-head trials are straightforward but can be risky. However, in an effort to follow the science and advance care for patients, the possibility of beating the standard of care is a risk worth taking.
In other cases, we face the challenge of a rapidly changing treatment landscape. On the one hand, that means great positive progress. But on the other hand, it’s very difficult to design a good head-to-head study if you can’t say definitively which medicine is currently the best available. Factors like recent or anticipated FDA approvals and rapid medical progress can put the standard of care in a state of flux. We’re witnessing this now in chronic lymphocytic leukemia (CLL), for example.
CLL AT ASH 2013
The best way to deal with a situation in flux is to adapt quickly. Historically, clinical trials have been massive, sluggish undertakings. However, as we continue to develop new investigational medicines, we need to be more nimble. We need to adapt to change.
One key to becoming more nimble is to advance and adopt early or surrogate endpoints [link to MRD article]. These can be simple laboratory measurements, physical signs, or tissue-based measurements that can “stand in” for clinically meaningful – but often slow-to-manifest – outcomes. For example, lower cholesterol levels are considered a surrogate for lowered risk of a heart attack. And tumor shrinkage can be an early endpoint that correlates with disease-free or progression-free survival rates in some cancers.
The FDA grants accelerated approvals based on early endpoints that are likely to predict clinical benefit, and this pathway could certainly be utilized in more head-to-head trials. With endpoints that are used earlier or are easier and faster to measure, we can make timely comparisons that are relevant for the current landscape and quickly make comparisons when the landscape shifts.
Small but mighty
Late-stage “Phase III” trials historically require hundreds of participants, and enrolling enough people can be challenging and require long periods of time, especially in disease areas where there are smaller patient populations. By designing trials that are smaller but equally powerful, enrollment can be completed much more quickly and results can be collected sooner. There are multiple ways to enhance the power of small trials, including adaptive design and biomarker-based selection of patients using companion diagnostics.
Breaking the mold
No one ever said that clinical trials have to follow the simple model of two arms, one comparison. Trials can be designed with multiple arms and multiple stages that allow several comparisons to be built in – for example, the comparison of an investigational medicine to a placebo, an additive model, and a head-to-head comparison against the current standard of care. Varying the duration of each stage can provide different points of data to compare the medicines in the study.
This kind of “compound trial” addresses the conundrum I mentioned earlier. While it’s not realistic to test every possible comparison in endless clinical trials, we should do our best to gain as much information as possible from each trial.
These are big challenges, to be sure, but this is a time for great optimism. As a physician, I’m thrilled that cancer medicine has advanced to a point where people often have multiple treatment options, and the pace of progress has accelerated so much that what may be considered the standard of care for many diseases today is likely to be improved upon in the near future.
We must adapt to keep head-to-head trials relevant and powerful. However, for doctors like me and patients everywhere, the valuable information we get from head-to-head trials is worth the effort.