SMHS MethodsHeterogeneity CER

Methods for Studying Heterogeneity of Treatment Effects, Case-Studies of Comparative Effectiveness Research - Comparative Effectiveness Research (CER)

Observational Studies: Tips for the CER Practitioners

• Different study types can offer different understandings; neither should be discounted without closer examination.

• RCTs provide an accurate understanding of the effect of a particular intervention in a well-defined patient group under “controlled” circumstances.

• Observational studies provide an understanding of real-world care and its impact, but can be biased due to uncontrolled factors.

• Observational studies differ in the types of databases used. These databases may lack clinical detail and contain incomplete or inaccurate data.

• Before accepting the findings from an observational study, consider whether confounding factors may have influenced the results.

• In this scenario, subgroup analysis was vital in clarifying both study designs; what is true for the many (e.g., overall, estrogen appeared to be detrimental) may not be true for the few (e.g., that for the younger post-menopausal woman, the benefits were greater and the harms less frequent).

• Carefully examine the generalizability of the study. Do the study’s patients and intervention match those under consideration?

• Observational studies can identify associations but cannot prove cause-and-effect relationships.

Case-Study 1: The Cetuximab Study

What was done and what was found?

Cetuximab, an anti-epidermal growth factor receptor (EGFR) agent, has recently been added to the therapeutic armamentarium. Two important CRTs examined its impact in patients with mCRC (metastatic-stage Colorectal cancer). In the first one, 56 centers in 11 European countries investigated the outcomes associated with cetuximab therapy in 329 mCRC patients who experienced disease progression either on irinotecan therapy or within 3 months thereafter. The study reported that the group on a combination of irinotecan and cetuximab had a significantly higher rate of overall response to treatment (primary endpoint) than the group on cetuximab alone: 22.9% (95% CI, 17.5-29.1%) vs. 10.8% (95% CI, 5.7-18.1%) (P=0.007), respectively. Similarly, the median time to progression was significantly longer in the combination therapy group (4.1 vs. 1.5 months, P<0.001). As these patients had already progressed on irinotecan prior to the study, any response was viewed as positive. Safety between the two treatment arms was similar: approximately 80% of patients in each arm experienced a rash. Grade 3 or 4 (the more severe) toxic effects on the skin were slightly more frequent in the combination-therapy group compared to cetuximab monotherapy, observed in 9.4% and 5.2% of participants, respectively. Other side effects such as diarrhea and neutropenia observed in the combination-therapy arm were considered to be in the range expected for irinotecan alone. Data from this study demonstrated the efficacy and safety of cetuximab and were instrumental in the FDA’s 2004 approval.

A second CRT (2007) examined 572 patients and suggested efficacy of cetuximab in the treatment of mCRC. This study was a randomized, non-blinded, controlled trial that examined cetuximab monotherapy plus best supportive care compared to best supportive care alone in patients who had received and failed prior chemotherapy regimens. It reported that median overall survival (the primary endpoint) was significantly higher in patients receiving cetuximab plus best supportive care compared to best supportive care alone (6.1 vs. 4.6 months, respectively) (hazard ratio for death=0.77; 95% CI: 0.64- 0.92, P=0.005). This RCT described a greater incidence of adverse events in the cetuximab plus best supportive care group compared to best supportive care alone including (most significantly) rash, as well as edema, fatigue, nausea and vomiting.

Was this the right answer?

These RCTs had fairly broad enrollment criteria and the cetuximab benefits were modest. Emerging scientific theories raised the possibility that genetically defined population subsets might experience a greater-than-average treatment benefit. One such area of inquiry entailed examining “biomarkers,” or genetic indicators of a patient’s greater response to therapy. Even as the above RCTs were being conducted, data emerged showing the importance of the KRAS gene.

Emerging Data

Based on the emerging biochemical evidence that the epidermal growth factor receptor (EGFR) treatment mechanism (Cetuximab,) was even more finely detailed than previously understood, the study authors of the 2007 RCT undertook a retrospective subgroup analysis using tumor tissue samples preserved from their initial study. Following laboratory analysis, all viable tissue samples were classified as having a wild-type (non-mutated) or a mutated KRAS gene. Instead of the previous two study arms (cetuximab plus best supportive care vs. best supportive care alone), there were 4 for this new analysis: each of the two original study arms was further divided by wild-type vs. mutated KRAS status. Laboratory evaluation determined that 40.9% and 42.3% of all patients in the RCT had a KRAS mutation in the cetuximab plus best supportive care group compared to the best supportive care group alone, respectively. The efficacy of cetuximab was found to be significantly correlated with KRAS status: in patients with wild-type (non-mutated). KRAS genes, cetuximab plus best supportive care compared to best supportive care alone improved overall survival (median 9.5 vs. 4.8 months, respectively; hazard ratio for death=0.55; 95% CI, 0.41-0.74, P<0.001), and progression-free survival (median 3.7 vs. 1.9 months, respectively; hazard ratio for progression or death=0.40; 95% CI, 0.30-0.54, P<0.001). Meanwhile, in patients with mutated KRAS tumors, the authors found no significant difference in outcome between cetuximab plus best supportive care vs. best supportive care alone.

What next?

Based on these and similar results from other studies, the FDA narrowed its product labeling in July 2009 to indicate that cetuximab is not recommended for mCRC patients with mutated KRAS tumors. This distinction reduces the relevant population by approximately 40%. Similarly, the American society of Clinical oncology released a provisional clinical recommendation that all mCRC patients have their tumors tested for KRAS status before receiving anti-EGFR therapy. The benefits of targeted treatment are many. Patients who previously underwent cetuximab therapy without knowing their genetic predisposition would no longer have to be exposed to the drug’s toxic effects if unnecessary, as the efficacy of cetuximab is markedly higher in the genetically defined appropriate patients. In a less-uncertain environment, clinicians can be more confident in advocating a course of action in their care of patients. And finally, knowledge that targeted therapy is possible suggests the potential for further innovation in treatment options. In fact, research continues to demonstrate options for targeted cetuximab treatment of mCRC at an even finer scale than seen with KRAS; and similar genetic targeting is being investigated, and advocated, in other cancer types.

Lessons Learned From this case Study

Although RCTs are generally viewed as the gold standard, results of one or even a series of trials may not accurately reflect the benefits experienced by an individual patient. This case-study suggests that cetuximab initially appeared to have rather modest clinical benefits. Albeit, new information that became available and subsequent genetic subgroup assessments led to very different conclusions. Clinicians should be aware that the current knowledge is likely to evolve and any decisions about patient care should be carefully considered with that sense of uncertainty in mind. As in this case study, subgroup analyses (e.g., genetic subtypes) need a theoretical rationale. Ideally, the analyses should be determined at the time of original RCT design and should not just occur as explorations of the subsequent data. When improperly employed, post hoc analyses may lead to incorrect patient care conclusions.

RCTs Tips for the CER Practitioners

o RCTs can determine whether an intervention can provide benefit in a very controlled environment.

o The controlled nature of an RCT may limit its generalizability to a broader population.

o No results are permanent; advances in scientific knowledge and understanding can influence how we view the effectiveness (or safety) of a therapeutic intervention.

o Targeted therapy illuminated by carefully thought out subgroup analyses can improve the efficacious and safe use of an intervention.

Case-Study 2: The Rosiglitazone Study

Meta-analysis

Often the results for the same intervention differ across clinical trials and it may not be clear whether one therapy provides more benefit than another. As CER increases and more studies are conducted, clinicians and policymakers are more likely to encounter this scenario. In a systematic review, a researcher identifies similar studies and displays their results in a table, enabling qualitative comparisons across the studies. With a meta-analysis, the data from included studies are statistically combined into a single “result.” Merging the data from a number of studies increases the effective sample size of the investigation, providing a statistically stronger conclusion about the body of research. By so doing, investigators may detect low frequency events and demonstrate more subtle distinctions between therapeutic alternatives.

When studies have been properly identified and combined, the meta-analysis produces a summary estimate of the findings and a confidence interval that can serve as a benchmark in medical opinion and practice. However, when done incorrectly, the quantitative and statistical analysis can create impressive “numbers” but biased results. The following are important criteria for properly conducted meta-analyses:

1. Carefully defining unbiased inclusion or exclusion criteria for study selection

2. Including only those studies that have similar design elements, such as patient population, drug regimen, outcomes being assessed, and time-frame

3. Applying correct statistical methods to combine and analyze the data

Reporting this information is essential for the reader to determine whether the data were suitable to combine, and if the meta-analysis draws unbiased conclusions. Meta-analyses of randomized clinical trials are considered to be the highest level of medical evidence as they are based upon a synthesis of rigorously controlled trials that systematically reduce bias and confounding. This technique is useful in summarizing available evidence and will likely become more common in the era of publicly funded comparative effectiveness research. The following case study will examine several key principles that will be useful as the reader encounters these publications.

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