Increasing transparency in indirect treatment comparisons: is selecting effect modifiers the missing part of the puzzle? A review of methodological approaches and critical considerations.

Failure to adjust for effect modifiers (EMs) in indirect treatment comparisons (ITCs) can produce biased and uncertain effect estimates. This is particularly important for health technology assessments (HTAs), where the availability of new treatments is based on comparative effectiveness results. Much emphasis has been placed on advancing ITC methods to adjust for EMs, yet whether EMs are appropriately identified for the conduct of ITCs in the first place is unclear. To understand the extent of guidance and requirements for the selection of EMs for ITCs currently available and if and how this guidance is applied in practice, a series of pragmatic reviews of guidance documents from HTA and non-payer organizations, primary published ITC analyses, and prior HTA submissions in two indications (non-small cell lung cancer and psoriasis) was conducted. The reviews showed that current ITC guidance mainly focused on developing analytical methods to adjust for EMs. Some organizations, such as HTA bodies in the UK, France and Germany, recommended the use of literature reviews, expert opinion and statistical methods to identify EMs. No detailed guidance on the selection process or the appropriate literature review approach was found. Similar trends were identified through the database search and review of prior HTA submissions; only few published ITCs and submissions included information on the EM selection process which was either based on findings from the literature, trial subgroup analyses, or clinical input. No reference to a systematic selection approach was found. There is an urgent need to fill the guidance gap identified across the reviews by including a step in ITC guidelines on how EMs should be identified through systematic reviews, formal expert elicitation, and a quantitative assessment of the EM distribution. Researchers and manufacturers are also encouraged to improve transparent reporting and justification of their selection of EMs to allow for an independent review of the set of factors being considered for adjustment. Both will contribute toward reducing bias in the ITC results and ultimately increase confidence in decision-making.

Assessing the prognostic utility of hematologic response for overall survival in patients with newly diagnosed AL amyloidosis: results of a meta-analysis.

OBJECTIVES: Amyloid light-chain (AL) amyloidosis is a rare disease characterized by amyloid fibril deposits made up of toxic light chains causing progressive organ dysfunction and death. Recent studies suggest that hematologic response may be an important prognostic indicator of overall survival (OS) in AL amyloidosis. The aim of this study was to evaluate the trial-level association between hematologic complete response (CR) or very good partial response or better (≥ VGPR) and OS in newly diagnosed patients. METHODS: Studies were identified via systematic literature review. Pooled effect estimates were generated by a random-effects model. RESULTS: Nine observational studies reporting hematologic CR or ≥VGPR and OS hazard ratios (HRs) were included in the meta-analysis. Achieving hematologic CR was associated with improved OS (HR, 0.21; 95% confidence interval [CI] 0.13-0.34). Achieving ≥ VGPR was also associated with improved OS (HR 0.21; 95% CI 0.17-0.26). Results of a sensitivity analysis excluding one outlier study revealed no heterogeneity and a better overall HR estimate. Potential limitations of this meta-analysis include the small number of eligible studies (consistent with the rarity of the disease) and inconsistencies in reporting of results. CONCLUSIONS: Overall, our findings support the use of deep hematologic response (CR or ≥VGPR) as a clinical trial endpoint in newly diagnosed AL amyloidosis. This study provides evidence that early hematologic response is a strong patient-level surrogate for long-term OS in patients with AL amyloidosis receiving frontline therapy. Structured data collection of depth of response in future trials will further strengthen these observations.

Efficacy of non-intensive therapies approved for relapsed/refractory acute myeloid leukemia: a systematic literature review.

Aim: De novo relapsed and/or refractory acute myeloid leukemia (rrAML) has limited treatment options for patients not eligible ('unfit') to receive intensive chemotherapy-based interventions. The authors aimed to summarize outcomes for licensed therapies in this setting. Materials & methods: A systematic literature review identified licensed therapies in this setting. A feasibility assessment was made to conduct a network meta-analysis to evaluate comparative efficacy. Results: Seven unique trials were identified. Median survival months were 13.8 for gemtuzumab ozogamicin (GO), 9.3 for gilteritinib (FLT3 mutated rrAML), 5.6 for low-dose cytarabine and 3.2 for best supportive care; transplant rates with gilteritinib and GO were 25.5 and 19%, respectively. A network meta-analysis was not feasible. Conclusion: There remains a high unmet need in de novo rrAML patients not eligible for intensive therapy, with GO and gilteritinib (only FLT3-mutated AML) providing the best current options.

Some patients with acute myeloid leukemia (AML) have no response to initial treatment or have a response that is subsequently lost. Follow-on treatment options after that initial stage are limited, especially for patients who are not able to have intensive therapy, such as chemotherapy, due to age, physical or cognitive function, existing comorbidities or symptoms. This study aimed to review the published literature to identify data associated with treatments that are licensed for use in patients ineligible for intensive therapy who do not maintain a response from their initial therapy. The study found that the drug gilteritinib was an option for the subgroup of AML patients with FLT3-mutated disease with an average life expectancy just under 1 year, while gemtuzumab ozogamicin was an option for a wider group of AML patients with a life expectancy just over 1 year. Between a fifth and a quarter of patients went on to receive a stem-cell transplant after treatment with one of these. With limited options, this patient group needs further attention; however, the availability of the previously mentioned treatments is promising.