Researchers have identified regional differences in outcomes of clinical trials supporting the regulatory approval of cancer drugs in the United States. 

The researchers noted, however, that it isn’t always clear if these regional variations are clinically meaningful or statistical anomalies, so the group devised a series of questions that may provide insight.

The group’s findings and questions were recently published in the Journal of the National Comprehensive Cancer Network.

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“Regional differences in treatment efficacy can generate doubt about the generalizability of results,” the researchers noted. “Although clinical trials strive to standardize on-study treatment to minimize the effects of practice variation on outcome, they cannot control for differences in practice that precede study enrollment or treatments that follow study discontinuation, both of which could influence overall survival.” 

For this study, the researchers analyzed data from 147 trials supporting drug approvals between January 2010 and December 2020. The trials included a total of 93,226 patients with solid tumor malignancies. 

These trials became more multinational over time (P =.04). Most participating countries were high-income countries (median, 81.2%). There were no low-income countries participating in the trials. 

There was a significant increase in the proportion of studies with regional analyses over time (P =.03). About half (53%) of the studies reported regional subgroup analyses. Of these 78 studies, 68% had a protocol that specified a regional analysis. 

Regional heterogeneity was found in 17.8% of the trials with an overall survival endpoint and 18% of the trials with a progression-free survival endpoint. 

The researchers noted that regional subgroup analyses should be interpreted with caution. 

“With any subgroup analysis, false-positives may occur due to multiple comparisons and false-negatives due to inadequate power,” the researchers explained. “When subgroups are analyzed without being defined a priori … statistically significant results may be identified by chance.”

“Even within single-country studies, population-level heterogeneity in outcomes may be detected due to environmental, social, economic, racial, and cultural differences,” the researchers continued. “However, the degree of population-level heterogeneity is likely to be even greater between countries where populations do not share common regulatory and health systems.”

With this in mind, the researchers suggested that clinicians should ask 5 questions to determine if regional differences are genuine: 

  1. How have the regions or countries been grouped, were they prespecified, and does the grouping make sense from a biological and clinical standpoint?
  2. Are the regional differences in effects on a relative or absolute scale?
  3. Are the regional differences statistically significant using a test for heterogeneity, and how large are the subgroups?
  4. What is the plausibility, consistency, and strength of the observed regional difference; are there potential genetic or pharmacogenetic differences; and are regional differences consistent with similar studies in the same tumor type?
  5. Is there a clinical explanation for the observed regional difference; are there differences in socioeconomic factors, pretreatment therapy, or subsequent treatment options; and do treatment compliance rates differ by region?

“As studies become more international, the oncology community needs to develop a strategy for reporting and interpreting regional variation,” the researchers wrote. “The question guide… may help clinicians interpret regional variations in trials and determine whether they are likely to be clinically meaningful.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Wilson BE, Pearson S-A, Barton MB, Amir E. Regional variations in clinical trial outcomes in oncology. J Natl Compr Canc Netw. 2022;20(8):879-886.e2. doi:10.6004/jnccn.2022.7029

This article originally appeared on Cancer Therapy Advisor