On Biostatistics and Clinical Trials: Subgroup Analyses for Clinical Trial Data

Subgroup analyses have been used in the clinical trials for many years and when the sample size is adequate, subgroup analyses can assess the qualitative consistency of treatment effect across different subgroups and can provide the information for identifying a sub-population that may have greater benefit from the treatment. Recently, the purpose of subgroup analyses has been expanded. As mentioned in the “Concept paper on the need for a Guideline on the use of Subgroup Analyses in Randomised Controlled Trials”, the subgroup analyses can be used to:

- Assess internal consistency,

- Try to rescue trials that ‘fail’ based on the full analysis set

- try to identify patient groups with the most favourable benefit-risk profile

The subgroup analyses may:

- be pre-specified in the trial protocol, based on demographic, genomic or disease characteristics (e.g. sub-entities of a disease that are widely recognised within the medical community)

- materialise based on a need or desire to further explore study results.

Sub-group analyses may be especially useful in personalized medicine. Through sub-group analyses, certain biomarkers/subgroups may be identified so that we can develop the tailored therapeutics.

If the sub-group analyses are not pre-specified and are post-hoc after the data dredging / mining, the interpretation of the findings from the sub-group analyese needs to be cautioned. If we introduce the ‘learning/confirming’ concept, the post-hoc sub-group analyses is a learning process and the results of interest need to be confirmed in further prospectively designed trials.

There are many examples of clinical trials where the statistically significant treatment effect in a specific sub-group identified from a study can not be subsequently verified / confirmed in prospectively designed trials.

In PRASE (THE PROSPECTIVE RANDOMIZED AMLODIPINE SURVIVAL EVALUATION) study, the study was powered to detect the treatment difference in death from any cause and hospitalization for major cardiovascular events between Amlodipine and Placebo in overall population. The study result was not statistically significant. Sub-group analyses were then performed to compare the treatment difference in the patients with ischemic heart disease and in the patients with nonischemic cardiomyopathy.The statistically significant difference between the Amlodipine and Placebo Groups was obtained among Patients with Nonischemic Dilated Cardiomyopathy. The author concluded “Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study”

A subsequent PRAISE-2 trial was conducted to confirm the finding from the sub-group analyses of the PRAISE study. Unfortunately, the results are negative. The study results were not published in peer-reviewed paper (since it is negative), but was presented in the scientific meeting by American Heart Association

“The Trial: PRAISE-2
Presenter: Milton Packer, Columbia University College of Physicians and Surgeons, New York, NY.
The study: A randomized, double-blind, placebo-controlled trial of amlodipine in patients with nonischemic cardiomyopathy on maximal medical therapy. A total of 1652 patients were randomized to receive either amlodipine (initially 5 mg/d, then increased to 10 mg/d after 2 weeks) or placebo. The primary end point of the study was all-cause mortality. The study was powered at 90% to detect a 25% difference in mortality between the treatment arms.
The results: No significant differences existed in all-cause mortality between the 2 arms (placebo, 31.7%; amlodipine, 33.7%; hazard ratio, 1.09; log-rank P=0.32). A pooled analysis of the PRAISE-1 and PRAISE-2 trials showed no significant affect of amlodipine on mortality (placebo, 34%; amlodipine, 33.4%; hazard ratio, 0.98; log-rank P=0.81).
Summary: Despite the fact that in PRAISE-1 a survival benefit was noted with amlodipine in patients with nonischemic cardiomyopathy, no such difference was noted in PRAISE-2 or when PRAISE-1 and PRAISE-2 were combined. Long-term treatment with amlodipine does not seem to be of benefit in patients with severe, chronic heart failure. “

In Sepsis indication, the Kybersept study compared the 28-day all cause mortality between High-Dose Antithrombin III and Placebo treatment groups. The results indicated “High-dose antithrombin III therapy had no effect on 28-day all-cause mortality in adult patients with severe sepsis and septic shock when administered within 6 hours after the onset. High-dose antithrombin III was associated with an increased risk of hemorrhage when administered with heparin. There was some evidence to suggest a treatment benefit of antithrombin III in the subgroup of patients not receiving concomitant heparin.”

Subsequently, a paper based on the post-hoc sub-group analyses were published and concluded “High-dose AT without concomitant heparin in septic patients with DIC may result in a significant mortality reduction. The adapted ISTHDIC score may identify patients with severe sepsis who potentially benefit from high dose AT treatment.”

Unfortunately, there was no formal randomized clinical trial to study this specific sub-group. Had a prospectively designed study been conducted to study the subjects without concomitant heparin, the results might not be significant as anticipated.

If the results from the sub-group analyses are used for supporting the drug approval or claim in the product label, it is obvious that the multiplicity issue will arise. A good paper about this is “A flexible strategy for testing subgroups and overall population” by Alosh and Huque.

For statistical issues arising from the clinical trial practice, European Medicines Agency (EMA) seems to be always ahead of the US. For the sub-group analysis, EMA organized an expert workshop on subgroup analysis in November, 2011. Various topics related to sub-group analyses were discussed during the workshop. The presentation materials and the workshop summary can all be found at EMA’s website.