New Methods for New Medicines
Biostatistical methods—such as power calculations, hazard ratios, and hypothesis tests—are a scientific compass of evidence-based medicine. We depend on them to deliver objective evidence of how well medicines work and have served us well over the past decades to deliver many new treatments for cancer, including chemotherapies and targeted therapies.
It’s an exciting time in cancer research. Today we have cancer immunotherapies that harness the body’s immune system to attack tumors, better diagnostic tests to choose medicines and monitor how they work, and a dizzying number of combination treatments in clinical trials. We are seeing reductions in tumor size (responses) that can last for years and are working to extend this benefit across the spectrum of cancer types.
These advances are leading us to rethink our approach to clinical trials so we can deliver on them as quickly as possible. We need different ways of looking at clinical measures (called endpoints), and smarter trial designs that seamlessly adapt to emerging data and deliver better evidence.
The Measure of a Medicine
One of the central questions of most clinical studies is, how well does the medicine work? In cancer trials, we often answer this by assessing whether survival is longer, whether it takes longer for the disease to get worse, or whether tumors get smaller (you can read more about endpoints here). With novel biology, better patient selection, and many combination treatments to choose from, reductions in tumor size observed in Phase I trials become more important than ever
Cancer immunotherapies that harness the immune system against the tumor work in a fundamentally different way than chemotherapies and targeted therapies. That difference becomes important for clinical trial design. For example, early on tumors can appear to get bigger instead of smaller. Therefore we’re gathering and exploring evidence to develop novel measurements of benefit designed specifically for this class of medicine, like biomarkers and immune-related response criteria.
A Biostatistician’s Tools of the Trade
It’s not enough to simply rethink the endpoints we’re using—we need to evolve our entire approach to clinical trials. The truth is, standard cancer trials simply aren’t built to assess cancer immunotherapies in a timely way. With cancer immunotherapies, the efficacy of a medicine may improve with longer follow-up, yet we have to act quickly to deliver these promising medicines to patients.
To address this tension, we are being creative with study design. For example, flexible clinical trials such as those using adaptive designs allow us to adjust ongoing studies based on new scientific data. Seamless designs combine the typical clinical trial phases into a single study that can be evaluated and adapted at multiple points. This allows us to avoid the lengthy step-wise process of stopping and starting new trials as we progress from Phase I to Phase III. The FDA is also taking an active role in how we practically implement this progressive thinking, while protecting the rigor of the studies and the safety of patients.
Statistics Isn’t Static
The job of biostatisticians in cancer research today goes far beyond our “bread-and-butter” activities of designing studies, analyzing data, and communicating results. We’re partnering with our scientific and medical colleagues to design flexible studies with novel endpoints, balancing the need to fill holes in our scientific knowledge with the opportunity to adapt to emerging data.
But no matter how creative we get, some hard trade-offs are fundamental in clinical development. How to get new medicines to patients quickly while collecting rigorous long-term evidence? How do we handle crossover between arms in trials? Do we stop a trial because of a lack of improvement (or conversely, especially strong improvement) in an early surrogate endpoint? How to discover novel biomarkers while not over-reacting to small signals that could be due to chance?
There are no simple answers to these questions—cancer is too complicated and the number of scientific issues is too diverse. But one thing is certain: if we aren’t collectively creative, adaptable, and holistic in how we approach oncology clinical trials, then we will miss out on our best opportunity to take advantage of this new era in cancer treatment.