Medicines and Healthcare products Regulatory Agency

PURPOSEThere is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs.METHODSUsing the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion.RESULTSConsensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies.CONCLUSIONThis foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation-ultimately contributing to the development of safer, more effective therapies.

The estimand framework is increasingly established to pose research questions in confirmatory clinical trials. In evidence synthesis, the uptake of estimands has been modest, and the population, intervention, comparator, and outcome (PICO) framework is more often applied. While PICOs and estimands have overlapping elements, the estimand framework explicitly considers different strategies for intercurrent events. We propose a pragmatic framework for the use of estimands in meta-analyses of clinical trials, highlighting the value of estimands to systematically identify and mitigate key sources of quantitative heterogeneity, and to enhance the applicability or external validity of pooled estimates. Focus is placed on the role of strategies for intercurrent events, within the specific context of meta-analyses for health technology assessment. We apply the estimand framework to a network meta-analysis of clinical trials, comparing the efficacy of semaglutide versus dulaglutide in type 2 diabetes. We explore the impact of a treatment policy strategy for treatment discontinuation or initiation of rescue medication versus a hypothetical strategy for the corresponding intercurrent events. The specification of different target estimands at the meta-analytical level allows us to be explicit about the source of heterogeneity, the intercurrent event strategy, driving any potential differences in results. We advocate for the integration of estimands into the planning of meta-analyses, while acknowledging that potential challenges exist in the absence of subject-level data. Estimands can complement PICOs to strengthen communication between stakeholders about what evidence syntheses seek to demonstrate, and to ensure that the generated evidence is maximally relevant to healthcare decision-makers.

Lassa fever is a zoonotic disease endemic to several West African countries, with seasonal outbreaks and potential to cause future epidemics. Vaccines and other medical countermeasures are in development, requiring reliable assays for evaluation. A WHO International Standard (IS) for anti-Lassa virus (LASV) antibodies can support harmonization of serological assay results, aiding vaccine and therapeutic assessment, surrogates of protection identification, and improving epidemiological understanding. In this study, a pooled plasma sample from Lassa fever survivors was evaluated in a multi-centre collaborative study involving 17 laboratories for its suitability as a reference material for detecting anti-LASV antibodies. Additionally, two well-characterized monoclonal antibody (mAb) cocktails were assessed as potential alternatives to convalescent plasma. Expressing the antibody titre of the collaborative study panel samples relative to the convalescent plasma pool (NIBSC 20/202) or the mAb cocktails harmonized the results from the participants reducing the inter-laboratory variation. However, while the candidate IS 20/202 performed consistently across all assays, the mAb cocktails were not detected by a few binding antibody methods. These findings support the use of mAb cocktails as reference material for evaluating humoral responses within a laboratory or network using common assays; however, for an IS, applicable globally across methods, convalescent serum or plasma remains the most suitable material.

In the 2025 novel drug mini-review, one can take a full measure of the ingenuity that underlies current drug design and development, despite the year's smaller harvest (46 novel drugs) compared to 2024 (53) and 2023 (70). 54% of the novel drugs are first-in-class (FIC). The emphasis on proteins/antibodies is maintained (~25% novel drugs in 2025), an industry trend that does not seem to abate. Fewer than half of the novel medicines address major or common disorders. Among the FIC drugs, it is worth mentioning the Nav1.8 channel inhibitor suzetrigine, the first non-opioid approved to palliate acute pain; the first positive allosteric modulator of transient receptor potential melastatin 8 (TRPM8), acoltremon, that increases basal tear production in dry eye disease, a globally common disorder; lerodalcibep, a 'third generation' adnectin inhibitor of the protease Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) to treat elevated LDL-c; and zoliflodacin and gepotidacin, both innovatively targeting bacterial topoisomerases to treat uncomplicated urinary tract infections. Most of the approved medicines target unmet medical need areas and/or orphan indications (the latter alone accounting for 41% of the 2025 novel drugs) by applying imaginative approaches. These approaches include: the combination of two FIC drugs, the RAF/MEK clamp avutometinib paired with the FAK/Pyk2 inhibitor defactinib, to block more efficiently the RAS-RAF-MEK-ERK/FAK oncogenic pathway in low-grade serous ovarian cancer; fitusiran, the first RNAi therapy for haemophilia, targeting for the first time the production of the natural anticoagulant anti-thrombin in the liver; and brensocatib, which attenuates the activation of downstream neutrophil proteases by inhibiting the protease DPP1, thereby preventing lung tissue destruction in bronchiectasis. The landscape of novel drugs approved in 2025 reveals that pharmaceutical innovation continues to advance through FIC mechanisms, sophisticated therapeutic approaches, and a strong focus on unmet medical need.

Background & Aims Human pluripotent stem cell (PSC) derived cell therapy products (CTP) hold significant promise for the treatment of a wide range of chronic diseases. Indeed, with more than 115 clinical trials having received regulatory approval to date, this therapeutic potential is beginning to be realized. Nonetheless, the translation of PSC derived cell therapies has been slowed by both technological and regulatory hurdles. Foremost among these are safety considerations, particularly the risk posed by residual undifferentiated PSCs in PSC derived CTPs, as these cells retain the ability to form teratomas. To mitigate this risk and detect residual PSCs, current quality control (QC) assays typically employ digital droplet PCR to detect genes highly expressed in PSCs relative to their differentiated progeny.Here, we aim to develop a well characterised biological reference material that can serve as a standard in QC assays to detect residual PSCs in PSC derived CTPs. Thus, ensuring assay accuracy, reliability and comparability. Methodology To evaluate analytical sensitivity, we performed spike-in experiments in which defined numbers of PSCs were introduced into PSC-derived MSCs across four independent cell lines at ratios of 1:10,000, 1:33,333, 1:100,000, 1:333,333 and 1:1,000,000. Results ESRG and LIN28 were identified as the most sensitive markers, capable of 1:33,333 and 1:100,000 sensitivity respectively, although some variability in marker performance was observed across lines. To convert the assay into a usable biological reference material, spiked populations from the most representative cell line were prepared and lyophilised as a cell-based standard or following RNA extraction as an RNA-based standard. Importantly, lyophilisation did not affect assay sensitivity in either the cell-based or RNA-based formats. Conclusion Ongoing work will evaluate the cell-based and RNA-based reference material formats, including assessments of stability and consistency through accelerated degradation studies, as well as broader utility via a collaborative study. In parallel, we will also assess the suitability of a synthetic oligo-based standard as an alternative approach.