The wider perspective: twenty years of clinical trials in myelodysplastic syndromes

Abstract

Summary Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS‐specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.

Incremental benefits of novel pharmaceuticals in the UK: a cross-sectional analysis of NICE technology appraisals from 2010 to 2020

“…QALYs are a useful tool for comparison, but the measure omits important health-related variables, such as the extent to which a patient remains unable to live out a ‘normal’ life expectancy or achieve complete health. Other factors, such as lack of fundamental understanding of disease pathologies,20 21 or the abundance or absence of sufficient research funding may also limit health gains 22. Our figures evaluate the net present health-related benefits of drugs that are considered cost-effective by NICE over the past decade.…”

The predictive value of a positive phase 2 ASH abstract for peer-reviewed publication and progression to phase 3

“…Although further investigation is needed into why therapeutics in positive phase 2 trials do not progress to phase 3 trials, it is encouraging that nearly one-half of the regimens presented in positive ASH abstracts are steered toward phase 3, considering the resources needed for randomized studies. 2 Further improving research practice and ethics, combined with trial designs that smartly test multiple "promising" agents, 2,6 as well as synthesizing evidence from additional resources such as registries or expanded access programs, 7 will further advance the development and implementation of novel therapeutic options across hematological malignancies.…”

‘We cannot paint them all with the same brush’: the need for a better definition of patients with myelodysplastic syndromes for clinical trial design

“…When compared to acute myeloid leukaemia (AML), an inherently related disorder, the United States Food and Drug Administration (FDA)‐approved drug list adds up to almost 10 new agents or formulations 5 . Along with such considerations, Duetz et al 6 . explored the history of the last 20 years of clinical trials in MDS, pinpointing the pitfalls of conducting clinical research in this field.…”

“…Indeed, human cell lines and patient‐derived xenografts are much better established for AML and HR MDS, whereas human LR MDS cells have lower rates of engraftment, undermining the difficulties of in vitro drug discovery and development 7 . The hindrances in drug designing are reflected by the analysis of Duetz et al ., 6 which identified that most MDS phase II studies did not have an MDS‐only phase I but rather re‐purposed agents explored in other malignancies with the aim of both identifying subgroups of responding patients and avoiding the extensive length from testing to final FDA approval of novel agents. However, such an approach is less likely to be fruitful in a biologically heterogeneous disorder such as MDS, especially for LR patients who represent around two‐thirds of the MDS population 8 .…”

“…4 When compared to acute myeloid leukaemia (AML), an inherently related disorder, the United States Food and Drug Administration (FDA)-approved drug list adds up to almost 10 new agents or formulations. 5 Along with such considerations, Duetz et al 6 explored the history of the last 20 years of clinical trials in MDS, pinpointing the pitfalls of conducting clinical research in this field. In a retrospective analysis interrogating clinicaltrials.gov and clinicaltrialsregister.eu, the Authors identified 384 unique drugs in 426 phase I, 430 phase II and 48 phase III trials between 2000 and 2020.…”