Primary endpoint
The primary endpoint, called the primary variable in regulatory guidance and sometimes the primary outcome measure, is the single measurement a trial is designed and powered to answer, fixed in the protocol before anyone is unblinded.
Why it matters here
Met its primary endpoint is a binary, and in our view it is the most misleading true sentence in drug development. It says a difference reached statistical significance. It says nothing about how large the difference was, what it was measured against, or whether a patient would notice. A trial can meet its primary endpoint with an effect a clinician would call modest, and miss it with an effect that would have mattered. The three questions worth asking of any met or missed headline are which endpoint, at what timepoint, and against which comparator. All three are in the protocol, and all three were fixed before the result existed, which is exactly what makes the answer trustworthy.
The international guidance defines it and explains why it is fixed in advance. ICH E9, Statistical Principles for Clinical Trials, says: "The primary variable ('target' variable, primary endpoint) should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial. There should generally be only one primary variable."
On pre-specification, the same guideline is blunt: "The primary variable should be specified in the protocol, along with the rationale for its selection. Redefinition of the primary variable after unblinding will almost always be unacceptable, since the biases this introduces are difficult to assess." (ICH E9, CPMP/ICH/363/96.)
Our coverage has turned on this repeatedly. Issue 2 reported Germany's EPIsoDE trial in three words, "Primary endpoint not met", and then held the line: "the access programmes are producing encouraging real-world signals, and a missed primary endpoint in a blinded trial is still a missed primary endpoint."
Issue 3 showed the other half of the problem, that meeting an endpoint and mattering are different: Compass's trials "have hit their primary endpoints" with an effect we described as "statistically clear but clinically modest".
And Issue 6 shows why the comparator belongs in the sentence: the 3.8-point advantage "that cleared the primary endpoint is 25mg over this 1mg dose of the same drug", not over placebo.