Clinical trial succussed in phase 2, but failed in phase 3

Clinical trials are the backbone of drug developments, acting as the gateway between laboratory research and practical, commercial, real-world treatments. These trials typically progress through several phases, with Phase 2 and Phase 3 being crucial stages in the journey of a new treatment or drug. However, it is not uncommon for a treatment to show promise in Phase 2, only to stumble and fail in Phase 3. Understanding why these failures occur is key to improving future trials and ultimately enhancing patient care.

Several years ago, FDA published a report called "22 CASE STUDIES WHERE PHASE 2 AND PHASE 3 TRIALS HAD DIVERGENT RESULTS ". Raps.org had an article to discuss this report "22 Case Studies Where Phase 2 and 3 Results Diverge: New FDA Report". There are a lot of examples that the early phase (phase 2) clinical trial was successful, but the late phase (confirmatory, phase 3) study failed. As a matter of fact, when the drug development program moved to the phase 3 study stage, there was usually successful results from the early phase clinical trials and there was an expectation that the phase 3 study would reproduce the success observed from the phase 2 studies. However, we often see that the promising results from phase 2 can not be reproduced in the large scale phase 3 studies. 

Fiercebiotech.com tracks these trial flops (clinical trials succussed in phase 2, but failed in phase 3). 

• 2020’s top 10 clinical trial flops
• 2021's top 10 clinical trial flops
• 2022's 10 top clinical trial flops
• 2023's top 10 clinical trial flops
• 3 big recent trial flops
• 10 clinical trials to watch in the second half of 2024

The Reality Check of Phase 3

Phase 3 trials are more extensive, involving several hundred to several thousand participants. These trials are designed to confirm the efficacy and safety of the treatment on a larger scale, comparing it directly to existing standard treatments or placebos. Phase 3 trials are pivotal because they provide the comprehensive data needed for regulatory approval- so called 'licensure trial'.

Despite the promise shown in Phase 2 study, many treatments fail in Phase 3 study. The reasons for these failures are multifaceted and can be broadly categorized into four main areas:

1. Differences in Population and Scale:

   • Population Diversity: Phase 2 trials often involve more homogeneous patient groups, while Phase 3 trials encompass a broader and more diverse population. This diversity can introduce variables that were not accounted for in the smaller, more controlled Phase 2 trials. For example, genetic differences, comorbidities, and concurrent medications can all influence treatment outcomes.
   • Sample Size: The larger sample size in Phase 3 trials can reveal less common side effects or variations in treatment efficacy that were not apparent in Phase 2. What appeared as a clear benefit in a smaller group may not hold up when tested on a larger scale. The large sample size requires more clinical trial sites for patient enrollment and the study needs to be designed as the multi-regional clinical trial.

2. Study Design and Execution:

   • Study Rigidity: Phase 3 trials often have more rigid protocols and endpoints compared to Phase 2. The stringent criteria and predefined outcomes might not fully capture the treatment’s potential benefits, leading to negative results. Phase 3 trials are usually more statistically rigor. More stringent statistical analysis approaches are used in the analyses of the phase 3 study data including controlling type-1 error, adjustment for multiplicity, missing data handling, estimands and strategies for handling the intercurrent events...
   • Execution Challenges: The complexity of conducting large-scale trials can introduce logistical issues, variations in study conduct across different sites, and difficulties in maintaining consistent treatment administration. Execution challenges may also include the difficulties in patient retention, treatment compliance, and maintaining the treatment blinding,...

3. Efficacy and Endpoint Discrepancies:

   • Efficacy Overestimation: Positive results in Phase 2 might be due to smaller sample sizes, shorter follow-up periods, or more lenient statistical thresholds. When scaled up, the actual efficacy might be less impressive.
   • Endpoints and Metrics: The primary and secondary endpoints in Phase 3 trials may differ from those in Phase 2. A treatment might show improvement in a specific metric in Phase 2 but fail to meet the broader, more comprehensive endpoints required in Phase 3. Phase 2 study may be based on surrogate endpoints and biomarkers while phase 3 study needs to use the endpoints that measure patients' feel, function, and survival to meet the regulatory requirements. Phase 2 study is usually shorter in duration while phase 3 study is usually longer.

4. Unanticipated Safety Concerns:

   • Rare Adverse Events: Larger trials can uncover rare but serious adverse events that were not evident in the smaller Phase 2 trials. These safety concerns can overshadow the benefits observed, leading to a failed trial.
   • Long-Term Effects: Phase 3 trials typically have longer follow-up periods, which can reveal long-term side effects or diminishing efficacy over time.

In a paper by Fogel (2018) "Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review", the following reasons were given:

"There are many reasons that potentially efficacious drugs can still fail to demonstrate efficacy, including a flawed study design, an inappropriate statistical endpoint, or simply having an underpowered clinical trial (i.e., sample size too small to reject the null hypothesis), which may result from patient dropouts and insufficient enrollment."

Here are two new examples with promising phase 2 study results, but failed phase 3 study: 

The StarScape study is a Phase 3 trial designed to evaluate the efficacy and safety of Zinpentraxin Alfa in patients with Idiopathic Pulmonary Fibrosis (IPF). It was based on a Phase 2 trial that showed promising results over a 28-week period. However, the StarScape study failed significantly, as it did not meet the primary efficacy endpoint of change from baseline to week 52 in forced vital capacity (FVC), nor did it succeed in any of the secondary efficacy endpoints. A companion editorial suggested that the failure of the StarScape study might have been due to outliers in the FVC measurements of two patients in the placebo group, that resulted in false positive results in Phase 2 study. 

"...Prompted by these negative results, a post hoc reevaluation of the phase II trial revealed that the apparent benefit of zinpentraxin alfa was primarily driven by two outliers in the placebo group who had an FVC decrease of more than 2,000ml/yr."

The biotech company Amylyx conducted a Phase 2 trial, known as the CENTAUR trial, to evaluate the safety and efficacy of AMX0035 for the treatment of Amyotrophic Lateral Sclerosis (ALS). Despite the relatively small sample size, the CENTAUR study demonstrated statistically significant results in the primary efficacy endpoint, which was the ALS Functional Rating Scale-Revised (ALSFRS-R) slope change. As a result, Amylyx received regulatory approval from both Health Canada and the US FDA. However, as a condition of approval, the FDA required the completion of an ongoing Phase 3 study called the PHOENIX trial. When the results of the PHOENIX study were released, none of the primary, secondary, or subgroup analyses showed statistical significance, marking the study as a total failure.

The likely reason for the failure of the Phase 3 study is the difference in geographic regions and patient populations. The Phase 2 CENTAUR study was conducted entirely in the United States, with 25 sites across the country. In contrast, the Phase 3 PHOENIX study was a multinational trial conducted at 69 sites across 12 countries in the US and Europe. Unfortunately, due to the failure of the Phase 3 study, the already approved and marketed drug had to be withdrawn from the market.