[BioNOW] Failure to Secure Statistical Significance... Clinical Success or Failure?

To Achieve Clinical Success, 'Primary Endpoint' Must Be Met
Not Only Achieving Set Endpoints but Also 'Statistical Significance'

Statistical Significance Distinguishes Whether Efficacy Differences Are 'By Chance' or Real
"If Statistical Significance Is Not Secured, the Clinical Trial Is a Failure Anyway"

[Asia Economy Reporter Lee Chun-hee] Recently, clinical results for new drug development by domestic pharmaceutical and bio companies have been emerging one after another. However, some of these results have sparked increasing controversy over whether the clinical trials were truly successful. How can the success of a clinical trial be accurately determined?

The indicators for clinical success are predetermined and submitted together when filing an Investigational New Drug (IND) application to relevant regulatory agencies such as the Ministry of Food and Drug Safety (MFDS) in Korea or the U.S. Food and Drug Administration (FDA), and must be approved by these authorities.

The most important goal set at this stage is the 'primary endpoint.' In Phase 1, which focuses on confirming drug safety, safety-related indicators are used, while from Phase 2 onwards, the primary endpoint mainly assesses efficacy achievement. Additional goals set to be achieved afterward are called secondary endpoints.

The success of a clinical trial hinges primarily on the primary endpoint. If the primary endpoint is not met, even if the secondary endpoints are achieved, it is difficult to consider the trial a complete success. For anticancer drugs, overall survival (OS) is commonly used. If OS is not reached, even if progression-free survival (PFS) or objective response rate (ORR)?usually set as secondary endpoints?show overwhelming results compared to placebo or existing drugs, the trial is considered a failure.

Statistical Significance Not Achieved but Clinical Trial Declared Successful? ... "It’s Still a Failure"

However, recent announcements of clinical trial results by domestic bio companies often raise some doubts. Many companies release promotional materials claiming to have confirmed safety and efficacy through clinical trials, but upon closer inspection, they often fail to prove the primary endpoint.

The main issue lies in whether the 'statistical significance' of the primary endpoint has been achieved. The primary endpoint and its statistical value, the 'P-value (probability of significance),' serve as indicators of statistical significance. The P-value represents the probability that the observed difference in efficacy between the treatment and control groups is due to chance, even though there is actually no difference. Therefore, if the P-value, typically set at 5% (0.05), is 5% or higher, it is difficult to prove whether the drug truly has efficacy or if the observed effect is just a 'coincidence.' For the drug to be considered effective, the P-value must be less than 5%.

Nonetheless, many biotech companies recently have claimed clinical success despite the P-value for the primary endpoint being higher than 5%. Their rationale is that although statistical significance was not achieved, there was a clear difference in drug efficacy between the clinical and control groups, or that secondary endpoints were met.

However, the industry consensus is that if the primary endpoint is not met, the trial cannot be considered 'successful.' There is concern that using such misleading terminology confuses the public and investors, potentially undermining the credibility of the entire industry. An industry insider pointed out, "The success indicator set at the start of the trial is the achievement of the primary endpoint. If statistical significance was not secured but efficacy was claimed, the trial should be redone with more participants to achieve success. Simply promoting the trial as successful is nothing but denial."

Of course, failing to meet the primary endpoint does not necessarily mean the drug itself is a complete failure. There are cases where drugs that did not achieve statistical significance for the primary endpoint in clinical trials later prove efficacy by modifying the trial design. If the trial is at a lower phase than the final Phase 3, it is not impossible to proceed to the next phase if some degree of effect is observed despite not meeting the primary endpoint. Additionally, for rare disease treatments, regulatory authorities may grant approval recognizing urgency if some level of drug efficacy is observed, even without achieving statistical significance.