One Arena Where You Can Bend the Rules to Your Advantage: Clinical Trials

Why changing the primary endpoint "target" of a trial is considered a questionable research practice.

Picture a grand tennis match. The game begins with clear rules, yet as it progresses, the organisers notice their favourite player struggling to keep up. In an effort to boost their favourite player's chances, they change the rules of the game.... Unless you're watching a dark comedy, such as one where a character such as the Dictator, played by Sacha Baron Cohen, is meant to win the match, such a scenario would be unimaginable… Changing the rules mid-match would undermine the legitimacy of any competition, wouldn’t it?

But what if I told you this happens often in clinical trials? And, surprisingly, everyone seems fine with it.

Moving the primary endpoint “target”: one example

The QUANTUM-First trial is a notable example of a clinical trial where the primary endpoint was modified, not just once, but twice. Had the trial adhered to its original endpoint, it would have been considered a negative trial.

In this trial, between September 27, 2016, and August 14, 2019, 539 newly diagnosed patients with acute myeloid leukaemia (FLT3-ITD positive) were enrolled and randomised into two groups to receive either quizartinib or placebo. The primary endpoint was event-free survival (EFS), with overall survival (OS) as one of the secondary endpoints. This meant that OS data would only be analysed if EFS was positive.

The final change occured 1 year after the enrolment of the last patient

On April 7, 2020, the primary endpoint of the study was suddenly changed to dual primary endpoints: EFS and OS.

The rationale given was: "Changing to two primary endpoints of EFS and OS ensured that OS would be analysed regardless of EFS results."

This can be seen as a risk mitigation strategy: if one endpoint failed to show a significant effect, the other might still demonstrate the treatment's benefit, providing a backup measure of success.

After discussing these changes, the FDA indicated that the agency’s definition of EFS was different and stricter. As a result, on October 28, 2020, more than one year after the enrolment of the last patient in the trial, the primary endpoint was changed for a second time—this time to OS as the sole primary endpoint. Remarkably, OS became the only positive endpoint of the study.

Unanswered Questions and Regulatory Approval

In its assessment report, the EMA raises concerns regarding the uncertainties in this study:

“The key secondary endpoint EFS per FDA definition was not statistically significant different between the quizartinib and placebo arms (p = 0.24).” Furthermore, “The difference in overall survival of quizartinib compared to placebo is not supported by other secondary endpoints; rates of CR, CR with FLT3-ITD MRD negativity, and CRc with FLT3-ITD MRD negativity were similar between treatment arms.”

At first glance, you might think, "Does that really matter? Isn’t overall survival the ultimate goal?" And you’re right—OS is indeed the gold standard endpoint. But these other endpoints provide crucial insight into the biological activity of the compound and its ability to control the disease at a deeper, molecular level. The negative results of these secondary endpoints raise questions about how the drug is actually improving survival, as it does not seem to be eradicating the disease more effectively than the placebo.

Several questions remain unanswered,* yet quizartinib has been authorised by both the EMA and FDA since 2023. This approval follows the rejection of the drug earlier in 2019 for the same indication, but as monotherapy in the relapsed or refractory setting, based on a randomised trial comparing it to chemotherapy (EMA, FDA).

Changing primary endpoints happens all too often

The quizartinib case is not unique. A cross-sectional analysis of 755 phase 3 cancer studies found that the primary endpoints were changed in 19% of trials after initiation. Less than a third discussed the changes in the published articles. Not surprisingly, the changes to primary endpoints appeared to be independently associated with trial positivity. Another study by Richters et al., which examined 38 randomised trials involving immunotherapies, found that 63% of the trials changed at least one aspect of their primary endpoint. In 6 out of 38 trials, the assessment of protocols was hindered due to redacted sections related to primary endpoints or the absence of original protocols.

Florez et al. suggest that journals should require the publication of protocols and amendments, as well as mandate the disclosure of any changes to endpoints along with the reasons for those changes, to ensure fairness to trial participants, the public and the competitors who conduct a fair trial.

Just as organisers of a sports match wouldn’t change the rules mid-game, trialists should stick to a validated primary endpoint to ensure fair play and scientifically valid results.

Footnotes:

* Several questions remain unanswered regarding the QUANTUM-First trial. For instance, could the imbalances between the two study arms (e.g., higher rates of discontinuation due to adverse events in the quizartinib group) and/or the differences in other treatments received by patients lead to a survival advantage? These are important questions, especially considering the limited statistical strength of the evidence for overall survival (p=0.03). The EMA notes that “not all subsequent (non-protocol) therapies were recorded for all patients” and that “during follow-up for OS, in addition to receiving already approved AML therapies (Note: Midostaurin received US approval 7 months after the start of QuANTUM-First and EU approval 12 months after) and Hematopoietic Stem Cell Transplantation as subsequent treatment options, patients in the study also moved to a new clinical trial for another investigational drug or received treatments that may not be available to all patients in Europe.”