Q&A: What does it mean when a clinical trial is delayed? More than you think

Frank David was just starting an independent research program on cell signaling in cancer and kidney development at a lab in Boston when he realized he’d rather be doing something else.

“I figured out I was more interested in how science turned into medicine than I was in actually making and discovering new science,” he recalled.

The problem was, he wasn’t sure what to do instead. He had wanted to be a doctor from a young age — he remembers reading an article in elementary school about Barney Clark, the pioneering recipient of an artificial heart transplant — and that aspiration carried him through medical school and a Ph.D. program in pathology at Columbia University.

Now, though, he wanted more variety. He began talking to people who had left basic science to do other things, and the advice he got convinced him that consulting might be a good fit.

Sixteen years later, David is the founder and managing director of Pharmagellan, a firm that consults with biotech and pharma companies on R&D strategy. He’s the author of “The Pharmagellan Guide to Analyzing Biotech Clinical Trials,” and a popular newsletter on interpreting clinical trials.

He’s also the author of three new STAT Reports on clinical trials — practical guides designed to help people be more confident, methodical, and thoughtful in evaluating trials. The reports include proprietary data from STAT Trials Pulse, AppliedXL’s machine-learning platform that analyzes real-time news flow, and many recent examples.

The first report in this series, “Clinical trial delays: what they mean and why you should care,” published Monday.

STAT sat down with David recently to talk about why he thinks trial delays are important, how clinical trials have changed over the years, and whether he would volunteer for a clinical trial himself. Here’s an excerpt of that conversation.

Frank, you’ve been closely tracking clinical trials for 15 years or more, both as a consultant and for your books. What, if anything, has changed in the way clinical trials are conducted?

Today’s trials are much more likely to focus on patients who have been selected to have the greatest odds of responding to the new therapy. That may seem obvious now, but it’s important to appreciate what a big change that is from the early 2000s, when the EGFR inhibitor Tarceva got its first approval in “all comers” lung cancer, regardless of whether patients’ tumors were driven by the drug’s target or not. Since then, the idea of bringing the “right drug to the right patients” has been embedded in how companies think about developing new therapies.

Another big change is that today’s trials are much more complicated, especially in early stages. Sponsors are trying to get a ton of data in Phase 1 and Phase 2 to help them de-risk the program and plan future studies. That means earlier trials have a lot more endpoints, assays, and patient visits than they did a decade or so ago, which can make them longer, more expensive, and harder to execute successfully.

What is the most common mistake that people make when they look at clinical trial data?

Many people jump straight to the results without first being clear in their own minds about what the study’s goal was and how it was designed. For example, how you interpret the results of a Phase 2 trial depends on whether it was mainly intended to quantify the effect size, figure out the best way to design the upcoming pivotal trial, establish how the drug looks versus its competitors, pave the way for accelerated approval, or drive interest from investors or a big pharma partner. Once you understand the goal, then you can look at the design and see if the study was set up appropriately to achieve it — and only then does it finally make sense to look at the results.

In your STAT Report, which launches Monday, you’ve written about the significance of clinical trial delays. Why should biotech executives or investors care about pushbacks in a trial’s expected completion date?

Trial delays are very common, but it can be hard to figure out exactly what they mean. On the one hand, a timing pushback is never good news because it can reduce the value of a program, cause it to fall behind its competitors, or be a sign of worse things to come. But on the other hand, sometimes it’s just a temporary blip, and things get back on track later. That means the delay is an important signal, but it then takes a lot more context about why it happened to understand its implications.

Does a delay in a trial necessarily mean that a product will ultimately fail? 

Absolutely not! There are no data linking trial delays to the probability of success. And if you think about it, you wouldn’t expect that link to be very strong. For example, delays that are due to overly optimistic estimates of how quickly sites would open or patients would enroll may not have much impact on the chance the trial will be successful. And even when a delay is due to a worrisome safety signal, a trial often gets back on track and yields a positive readout.

That said, as the cumulative delay increases, that could be a sign that a trial might flame out before completion for operational reasons, independent of whether or not the drug works. Sometimes that means there were issues finding enough of the right patients due to the study’s inclusion and exclusion criteria, competition with other trials, or other factors.

Can you give an example of a delay that had an impact on a developing drug’s future?

The clearest and usually most significant negative impacts of trial delays are the ones that happen due to serious safety issues. For example, Magenta Therapeutics put its lead program on hold earlier this year due to a patient’s death. By itself that might not necessarily have been the end of the road for the program, but in the context of Magenta’s battered stock price and the poor economic environment overall, there just wasn’t enough time or money for the biotech to recover. Now Magenta appears to be winding down not just that program, but the entire company.

Would you ever consider volunteering to be a subject in a clinical trial yourself?

This industry survives because the people who volunteer for clinical trials are extremely altruistic. At the end of the day, there is no sure thing in a clinical trial from a patient’s point of view. There are certainly diseases that are life-threatening, and those patients are sometimes willing to try anything. But even in that context, there’s a risk that the new therapy won’t work and at worst, it could actually cause harm.

Not everybody wants to do that or is emotionally set up for that. In my own personal life, just thinking about this, I’m not sure that I would enter a clinical trial, that I have that level of altruism. But I’m grateful for all the people who do.