Non-inferiority Approach Research Articles

Methods for Equivalence and Noninferiority Testing

Classical hypothesis testing focuses on testing whether treatments have differential effects on outcome. However, sometimes clinicians may be more interested in determining whether treatments are equivalent or whether one has noninferior outcomes. We review the hypotheses for these noninferiority and equivalence research questions, consider power and sample size issues, and discuss how to perform such a test for both binary and survival outcomes. The methods are illustrated on 2 recent studies in hematopoietic cell transplantation.

The reproducibility of adenosine monophosphate bronchial challenges in mild, steroid-naive asthmatics

Repeated adenosine monophosphate (AMP) challenges are used to assess drug efficacy in clinical trials of mild, steroid-naive asthmatics. Refractoriness has been reported after repeated challenges over short intervals. This study evaluated possible tachyphylaxis after repeated AMP challenges at 12 and 24 h in mild, steroid-naive asthmatics. This was an open, three-way crossover study. Twenty-six steroid-naive asthmatic subjects were randomized to the following AMP challenge regimens separated by 7-14 days: (A) challenge at 08.00 h, repeated 24 h later; (B) challenge at 08.00 h, repeated 12 and 24 h later; (C) challenge at 20.00 h, repeated 12 h later. Comparisons within day were assessed using 90% confidence intervals (CIs). Non-inferiority approach taken with 1 doubling concentration (DC) as a clinically relevant difference. Regimen A: Significant increase in AMP reactivity at 24 h. Mean DC difference was 0.6 (90% CI 0.24, 0.96). Regimen B: No evidence of difference between AMP reactivity at 08.00 h and a repeated challenge 12 h later. Repeated challenge at 24 h caused a significant increase in provocation concentration (PC)(20) compared with 12 h (mean DC difference 0.48, 90% CI 0.02, 0.95) and 0 h (mean DC difference 0.82, 90% CI 0.49, 1.14 - the upper CI exceeds the criteria of 1 DC). Challenge regimen C: No difference between challenges; mean DC difference of 0.28 (90% CI -0.2, 0.76). The small decline in AMP reactivity during repeated challenges was not consistently observed, and was small compared with the known effects of inhaled drugs.

Use of a novel biomarker HE4 for monitoring patients with epithelial ovarian cancer

5535 Background: The serum biomarker CA125 is effectively used for monitoring response to therapy and monitoring for recurrent disease in patients with epithelial ovarian cancer (EOC). However, CA 125 is not elevated in approximately 20% of patients. The novel tumor marker HE4 has been shown to be elevated in the majority of EOC patients as well as in patients that do not express CA125. The object of this study was to determine the concordance between HE4 and CA125 in patients being followed with EOC. Methods: This was a retrospective study utilizing serum samples obtained from an IRB approved serum bank. Serial samples from patients either undergoing treatment for EOC or being monitored for recurrence were obtained. Clinical status of the patients was assessed through serial CA125 and CT imaging with documentation of regression or progression of disease or absence of disease over time. Serum CA125 and HE4 levels were measured using the Architect CA 125II assay and the HE4 EIA assay. Serial changes in the serum CA125 and HE4 levels were compared to the documented clinical status using a cutoff of 25%. Concordance between HE4 and CA125 was determined and the performance of CA125 and HE4 was compared directly using a non-inferiority approach. Results: A total of 434 serial samples from 80 patients either undergoing treatment for EOC or being monitored for recurrence were obtained. Longitudinal analysis of the serum sample sets showed that changes in HE4 values were not inferior to changes in CA125 values in accordance with clinical status (p=0.039). CA125 correlated with clinical status in 78.8% (63/80) and HE4 correlated in 76.2% (61/80). In patients where CA125 did not correlate with clinical status, HE4 correlated in 23.5% (4/17). In patients where HE4 did not correlate with clinical status, CA125 correlated in 31.6% (6/19). In consideration of all cases either CA125 or HE4 correlated with clinical status for 83.8% (67/80). Conclusions: HE4 is a valuable biomarker for the majority of patients with EOC and behaves in concordance with CA125 in patients with EOC. As well, HE4 is a valuable marker for the management of some patients where CA125 is not of clincal utility. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Fujirebio Diagnostics, Inc Fujirebio Diagnostics, Inc, Thiel Statistical Consultants Fujirebio Diagnostics, Inc Fujirebio Diagnostics, Inc

Noninferiority Testing Beyond Simple Two-Sample Comparison*

In order to fulfill the requirement of a new drug application, a sponsor often need to conduct multiple clinical trials. Often these trials are of designs more complicated than a randomized two-sample single-factor study. For example, these trials could be designed with multiple centers, multiple factors, covariates, group sequential and/or adaptive scheme, etc. When an active standard treatment used as the control treatment in a two-arm clinical trial, the efficacy of the test treatment is often established by performing a noninferiority test through comparison of the test treatment and the active standard treatment. Typically, the noninferiority trials are designed with either a generalized historical control approach (i.e., noninferiority margin approach or δ-margin approach) or a cross-trial comparison approach (i.e., synthesis approach or λ-margin approach). Many of the statistical properties of the approaches discussed in the literature were focused on testing in a simple two sample comparison form. We studied the limitations of the two approaches for the consideration of switching between superiority and noninferiority testing, feasibility to be applied with group sequential design, constancy assumption requirements, test dependency in multiple trials, analysis of homogeneity of efficacy among centers in a multi-center trial, data transformation and changing analysis method from the historical studies. Our evaluation shows that the cross-trial comparison approach is more restricted to simple two sample comparison with normal approximation test because of its poor properties with more complicated design and analysis. On the other hand, the generalized historical control comparison approach may have more flexible properties when the variability of the margin δ is indeed negligibly small.

Clinical evaluation of imidapril in congestive heart failure in dogs: results of the EFFIC study

The clinical efficacy and safety of imidapril were evaluated in dogs that presented with mild to severe congestive heart failure (New York Heart Association stage II to IV) by comparing the success rate of imidapril with a positive control by a non-inferiority approach. This good, clinical practice compliant, multicentre study (EFFIC study) enrolled 142 client-owned dogs and was conducted in 20 locations in France, Belgium and Germany. Dogs of various breed, age and weight were included in the study. These dogs were randomised into two groups that were treated for 84 days with either the test product, imidapril, or the positive control, benazepril, and followed up in parallel over this period. Both treatments were administered at a dose of 0.25 mg/kg once a day with the possibility of doubling this dose to 0.5 mg/kg if considered necessary from a clinical point of view. In addition, concomitant treatment was given to dogs presenting with pulmonary oedema and/or ascites, supraventricular tachyarrhythmia and/or dilated cardiomyopathy. The evolution of the New York Heart Association stage and the "functional signs" score were evaluated as primary efficacy criteria. The success rate in the imidapril group was 66 compared with 68 per cent in the benazepril group. Regarding safety, 35 dogs in each group experienced at least one adverse event. Nine dogs in each group experienced at least one serious adverse event. The difference between these results was not statistically significant. Imidapril is as efficacious and safe as the reference product, benazepril.

Rethinking Statistical Approaches to Evaluating Drug Safety

PurposeThe current methods used to evaluate the efficacy of drug products are inadequate. We propose a non-inferiority approach to prove the safety of drugs.Materials and MethodsTraditional hypotheses for the evaluation of the safety of drugs are based on proof of hazard, which have proven to be inadequate. Therefore, based on the concept of proof of safety, the non-inferiority hypothesis is employed to prove that the risk of new drugs does not exceed a pre-specified allowable safety margin, hence proving that a drug has no excessive risk. The results from papers published on Vioxx® and Avandia® are used to illustrate the difference between the traditional approach for proof of hazard and the non-inferiority approach for proof of safety.ResultsThe p-values from traditional hypotheses were greater than 0.05, and failed to demonstrate that Vioxx® and Avandia® are of cardiovascular hazard. However, these results cannot prove that both Vioxx® and Avandia® are of no cardiovascular risk. On the other hand, the non-inferiority approach can prove that they are of excessive cardiovascular risk.ConclusionThe non-inferiority approach is appropriate to prove the safety of drugs.

A comparison of buprenorphine and lofexidine for community opiate detoxification: results from a randomized controlled trial

To investigate whether a buprenorphine opiate detoxification regimen can be considered to be at least as clinically effective as a lofexidine regimen. An open-label randomized controlled trial (RCT) using a non-inferiority approach. Non-inferiority is demonstrated if, within a 95% confidence interval, buprenorphine performs within a preset tolerance limit of clinically acceptable difference in outcomes and completion rates between the two treatments. Individuals ready for heroin detoxification were given information about the trial and invited to participate. Consenting participants (n = 210) were then randomized to one of the two treatments. Detoxification was undertaken in a specialist out-patient clinic according to predefined protocols. The primary outcome was whether or not an individual completed the detoxification. Abstinence at 1-month follow-up was used as a secondary outcome measure. Additional secondary outcome measures were substance use, dependence, psychological health, social satisfaction, and treatment satisfaction. Data were also collected for individuals who declined randomization and instead chose their treatment (n = 271). A total of 46% of those on lofexidine and 65% of those on buprenorphine completed detoxification. Of these, 35.7% of the lofexidine and 45.9% of the buprenorphine groups reported abstinence at 1 month. Of those not completing detoxification abstinence was reported at 27.5% and 29.0%, respectively; 271 individuals who opted not to be allocated randomly and instead chose one of the two treatments produced similar results Buprenorphine is at least as effective as lofexidine detoxification treatment. Whether or not individuals were randomized to, or chose, a treatment appeared not to affect the study's outcome.

Final results of a randomized, double-blind, active-controlled trial of darbepoetin alfa administered once every 3 weeks (Q3W) for the treatment of anemia in patients receiving multicycle chemotherapy

LBA8284 Background: Chemotherapy-induced anemia (CIA) often results in debilitating fatigue that can be alleviated with erythropoietic agents, epoetin alfa and darbepoetin alfa (DA). The ability to administer DA on a Q3W schedule to synchronize with the majority of chemotherapy regimens is of particular interest to clinicians and patients. The objective of this study is to evaluate and compare the efficacy and safety of Q3W with once-weekly (QW) DA using a non-inferiority approach. This is the largest study to date to examine efficacy of DA in the treatment of CIA using a fixed dose with extended dosing. Methods: This is a randomized, double-blind, active-controlled, phase 3 trial in 160 centers across Europe. Eligibility include age ≥18 years, anemia (hemoglobin [Hb] <11g/dL), and nonmyeloid malignancy with ≥12 weeks (wks) of planned chemotherapy. Patients (pts) were randomized 1:1 to either 2.25mcg/kg QW or 500mcg Q3W DA, stratified by tumor type, screening Hb (<10 or ≥10g/dL) and region. Pts in the Q3W treatment arm received QW placebo to maintain the double-blind nature and to avoid bias in treatment decisions. Pts were treated up to 16 wks. The primary endpoint is the incidence of transfusions from wk 5 to end of treatment period (EOTP). Other clinically meaningful endpoints include change in Hb, change in FACT-Fatigue scores and achievement of Hb ≥11g/dL from wk 5 to EOTP in the absence of transfusions. Analyses will be based on data from pts who received ≥1 dose of study medication. Kaplan-Meier estimates, adjusted for stratification factors, for each treatment arm will be compared using log-rank test. For the primary endpoint, a two-sided 95% confidence interval (CI) for the difference (Q3W-QW) in transfusion rates will be calculated. If the upper limit of the CI is ≤12.5% (based on previous studies of DA 2.25mcg/kg), then non-inferiority of the Q3W regimen to the QW regimen will be concluded. Two-sided 95% CI will also be calculated for the difference in mean Hb change of the treatment groups adjusting for stratification and baseline factors. Results: Final transfusion incidence rates on 705 pts will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly Amgen Amgen, Eli Lilly

A Bayesian Noninferiority Approach to Evaluation of Bridging Studies#

A bridging study defined by The International Conference on Harmonization E5 is usually conducted in the new region only after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. In this paper, we address the issue of analysis of clinical data generated by the bridging study conducted in the new region to evaluate the similarity for extrapolation of the foreign clinical data to the population of the new region. Information on efficacy, safety, dosage, and dose regimen of the original region cannot be concurrently obtained from the local bridging studies but are available in the trials conducted in the original region. A Bayesian noninferiority approach is therefore proposed to incorporate the data generated in the original region to evaluate bridging evidence by the local bridging studies and assess similarity between the new and original regions. Methods for sample size determination for the bridging study are also proposed.