Clinical trial findings are often simplified into a binary conclusion, focusing on a P value of less than 0.05 for a treatment difference. However, a more nuanced interpretation requires examining the total evidence, including secondary end points, safety issues, and trial size and quality.
This article aims to facilitate a more sophisticated and balanced interpretation of trial evidence, using examples from cardiovascular disease trials.
The primary outcome is positive, and there are several key questions to consider when evaluating the outcome.
- Statistical significance is a prerequisite for therapy adoption, but it’s not enough.
- Trial results are scrutinized by stakeholders like regulators, payers, and clinicians.
- To determine if findings are sufficient to modify medical practice, in-depth interpretation of trial data and related results is needed.
- Positive trials may advance clinical practice, while studies revealing harm may inform practice, but validity must be closely examined.
Is a P value of less than 0.05 sufficient?
- A P value of 0.05 can lead to false positive results, so a smaller P value is needed for proof of a genuine treatment difference.
- For example, the PARADIGM-HF trial showed significant benefits for heart failure patients, justifying regulatory approval.
- However, the SAINT I trial for acute ischemic stroke showed no significant effect, indicating NXY-059 is ineffective.
What Is the Magnitude of Treatment Benefit?
- To determine clinical significance, a treatment difference must be clinically meaningful, requiring examination on both relative and absolute scales.
- The 95% confidence interval should be considered, considering the uncertainty in the estimated effect, which can range from almost no effect to a larger upper boundary.
- The IMPROVE-IT trial compared ezetimibe and placebo in patients with acute coronary syndromes. The hazard ratio for composite primary outcomes was 0.94, with 32.7% with ezetimibe compared to 34.7% with placebo. However, the FDA advisory panel recommended against expanding the ezetimibe label to include an indication for a reduction in cardiovascular events.
Is the Primary Outcome Clinically Important (and Internally Consistent)?
Surrogate Outcomes
Phase 3 trials often use surrogate primary outcome measures for certain diseases, such as glycated hemoglobin levels. However, large-scale trials have raised questions about the wisdom of such markers. For example, the ACCORD trial showed lower glycated hemoglobin levels but higher cardiovascular events and mortality. The LIDO trial showed greater hemodynamic improvement but no treatment benefit and FDA approval.
Composite Outcomes
Positive composite primary outcomes must be carefully inspected to determine which components are driving the result.
Are Secondary Outcomes Supportive?
- Confidence in a trial’s positivity is increased when secondary outcomes show treatment benefit.
- Conversely, if no benefit is found, doubts arise.
- For example, the SAINT I trial of NXY-059 in acute ischemic stroke raised suspicion about the positive primary outcome.
Are Findings Consistent across Important Subgroups?
- Treatment effects vary based on patient characteristics, with high-risk subgroups benefiting more.
- For example, long-term statin use is typically limited to patients with high baseline risk.
- Subgroup analyses in positive trials can identify patients who don’t benefit from new treatments, requiring caution due to spurious findings.
- Protecting these patients from ineffective or harmful treatments depends on statistical interaction strength.
Is the Trial Large Enough to Be Convincing?
Small clinical trials with statistical significance need cautious interpretation due to potential exaggeration of positive treatment effects and potential false positives.
Was the Trial Stopped Early?
- Trials often stop early due to strong interim results of treatment superiority, which can exaggerate treatment efficacy and truncate evidence for important secondary and safety outcomes.
- This practice often crosses statistical stopping boundaries and convinces data and safety monitoring boards of overwhelming benefit.
Do Concerns about Safety Counterbalance Positive Efficacy?
- New treatments with superior efficacy must address safety concerns to balance benefits.
- A balanced account should present absolute benefits and risks, considering percentage differences and net clinical benefit.
Is the Balance of Efficacy and Safety Patient-Specific?
The net clinical benefit of a new treatment may be patient-specific, with trade-offs between efficacy and safety challenging to calculate, requiring statistical modeling techniques.
Are There Flaws in Trial Design or Conduct?
Significant primary outcome results prove findings cannot be attributed to chance, but biases in trial design and conduct must be ruled out for genuine benefits.
Do the Findings Apply to My Patients?
- Trial findings are specific to the patients and therapies used, and the question of generalizability must be considered.
- The generalizability of a trial’s results can be influenced by its geographic representation, as many major trials are multinational, providing global significance.
- Single-center trials should be viewed cautiously due to center-specific effects and lack of quality-control measures. Results should not be used to change guidelines without validation in multicenter trials.
- The relevance of long-term findings from randomized trials may decrease as advances in care become more prevalent in contemporary practice.
Conclusions
- A 5% significance level is required for a trial to be declared positive, prompting deeper examination of study processes and outcomes. A comprehensive approach to all available evidence is necessary.
- The trial’s efficacy and safety are confirmed, followed by evaluating its quality and internal validity. The findings are tested for treatment effectiveness and net clinical benefit in real-world patients, but caution is needed when using nonrandomized registries. Cost-effectiveness determines reimbursement levels.
- The approval of a new drug depends on the total evidence from the pivotal trial and related studies, often requiring further evidence to clarify its safety profile, and may require additional safety studies.
- Societal guideline committees synthesize knowledge and evidence for new treatments, influencing practice. Physicians interpret clinical trial results and integrate regulatory and guideline recommendations for optimal patient care.
Reference
Pocock SJ, Stone GW. The Primary Outcome Is Positive – Is That Good Enough? N Engl J Med. 2016 Sep 8;375(10):971-9. doi: 10.1056/NEJMra1601511. PMID: 27602669.