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Background: Although expanded access is an increasingly used pathway for patients to access investigational medicine, little is known on the magnitude and content of published scientific research collected via expanded access. Methods: We performed a review of all peer-reviewed expanded access publications between January 1, 2000 and January 1, 2022. We analyzed the publications for drugs, diseases, disease area, patient numbers, time, geographical location, subject, and research methodology (single center/multicenter, international/national, prospective/retrospective). We additionally analyzed endpoints reported in all COVID-19-related expanded access publications. Results: We screened 3810 articles and included 1231, describing 523 drugs for 354 diseases for 507,481 patients. The number of publications significantly increased over time (p< 0.001). Large geographical disparities existed as Europe and the Americas accounted for 87.4% of all publications, whereas Africa only accounted for 0.6%. Oncology and hematology accounted for 53% of all publications. Twenty-nine percent of all expanded access patients (N = 197,187) reported on in 2020 and 2021 were treated in the context of COVID-19. Conclusions: By summarizing characteristics of patients, diseases, and research methods described in all scientific literature published on expanded access, we provide a unique dataset for future research. We show that published scientific research on expanded access has surged over the past decades, partly due to COVID-19. However, international collaboration and equity in geographic access remain an issue of concern. Lastly, we stress the need for harmonization of research legislation and guidance on the value of expanded access data within real-world data frameworks to improve equity in patient access and streamline future expanded access research.

ObjectivesTo evaluate the incremental value of new drugs across disease areas receiving favourable coverage decisions by the UK’s National Institute for Health and Care Excellence (NICE) over the past decade.Design, setting, and participantsThis cross-sectional study assessed favourable appraisal decisions of drugs between 1 January 2010 and 31 December 2020. Estimates of incremental benefit were extracted from NICE’s evidence review groups reports.Primary outcome measureIncremental benefit of novel drugs relative to the best alternative therapeutic option, expressed in quality-adjusted life-years (QALYs).Results184 appraisals of 129 drugs provided QALYs. The median incremental value was 0.27 QALY (IQR: 0.07–0.73). Benefits varied across drug-indication pairs (range: −0.49 to 5.22 QALY). The highest median benefits were found in haematology (0.70, IQR: 0.55–1.22) and oncology (0.46, IQR: 0.20–0.88), the lowest in ophthalmology (0.09, IQR: 0.04–0.22) and endocrinology (0.02, IQR: 0.01–0.06). Eight appraisals (4.3%) found contributions of more than two QALYs, but one in four (50/184) drug-indication pairs provided less than the equivalent of 1 month in perfect health compared to existing treatments.ConclusionsIn our review period, the median incremental value of novel drugs approved for use within the English National Health System, relative to the best alternative therapeutic option, was equivalent to 3–4 months of life in perfect health, but data were heterogeneous. Objective evaluations of therapeutic value helps patients and physicians to develop reasonable expectations of drugs and delivers insights into disease areas where medicinal therapeutic progress has had the most and least impact.

Precision medicine is gaining importance in the treatment of acute myeloid leukemia (AML). Objectively reviewing past and current knowledge aids guiding future research. Therefore, we provide a complete overview of all phase II and phase III trials investigating targeted therapies in AML and their primary endpoints over the past two decades in perspective of their clinical benefit. We assessed whether drugs were primarily designed to treat AML or were repurposed and how successful they were based on progression of distinct drugs from phase II to phase III to FDA-approval. Between January 2000 and September 2020, 167 agents with 96 targets were investigated in 397 phase II trials. Twenty-eight agents were steered towards phase III, after three phase II trials on average. Repurposed drugs less often advanced in clinical development than drugs primarily developed for AML. Composite responses were the most prevalent primary endpoints in phase II. Of the eight FDA-approved drugs, none investigated quality of life at time of approval, and three out of eight have yet to show benefit in overall survival. Returns on targeted therapy research remain lean for AML patients. Future trials should not overlook non-targeted agents and foremost study endpoints proven to predict patient well-being.

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.

Expanded access is a pathway to access unregistered medicines if there are no registered treatments available and patients cannot enroll in clinical trials. Expanded access may serve as a last resort for patients who are in dire need of treatment options and cannot await the completion of drug development and for patients who may benefit from treatments that are not (or not anymore) registered in their jurisdiction. Unregistered medicine can be acquired via named-patient pathways ('Leveren op Artsenverklaring') or via group programs ('Compassionate Use Programma's). We describe the origins of expanded access and its daily practice in the Netherlands. We observe an increasing trend in expanded access requests. The potential risks these treatments provide, the possibility of ceasing further treatment and the preferences of individual patients should all inform the decision whether or not to pursue expanded access.

In their open peer commentary: “Making It Count: Extracting Real World Data from Compassionate Use and Expanded Access Programs” (Rozenberg and Greenbaum 2020), Rozenberg and Greenbaum discuss impo...

Precision medicine is gaining importance in the treatment of acute myeloid leukemia (AML). Objectively reviewing past and current knowledge aids guiding future research. Therefore, we provide a complete overview of all phase II and phase III trials investigating targeted therapies in AML and their primary endpoints over the past two decades in perspective of their clinical benefit. We assessed whether drugs were primarily designed to treat AML or were repurposed and how successful they were based on progression of distinct drugs from phase II to phase III to FDA-approval. Between January 2000 and September 2020, 167 agents with 96 targets were investigated in 397 phase II trials. Twenty-eight agents were steered towards phase III, after three phase II trials on average. Repurposed drugs less often advanced in clinical development than drugs primarily developed for AML. Composite responses were the most prevalent primary endpoints in phase II. Of the eight FDA-approved drugs, none investigated quality of life at time of approval, and three out of eight have yet to show benefit in overall survival. Returns on targeted therapy research remain lean for AML patients. Future trials should not overlook non-targeted agents and foremost study endpoints proven to predict patient well-being.

Reports of "positive" results in early phase trials as presented at ASH presumably herald therapeutic advances, or at a minimum, a larger, potentially confirmatory, randomized trial. However, the predictive value of an ASH abstract reporting positive results in AML for subsequent clinical utility seems low (Estey 2006, ASH). Furthermore, not all results presented at ASH are published in peer-reviewed journals, and selectively publishing positive results leads to publication bias. Moreover, truly negative studies may be scientifically more rigorous and accurate than positive studies given the unequivocal findings. The extent of publication bias is unknown as is the frequency with which positive or negative abstracts lead to subsequent investigation in phase III and the reasons why positive phase II studies might not progress to phase III. We downloaded all 2013 - 2015 ASH abstracts (N = 17,251) and evaluated all abstracts reporting phase II clinical trials (N = 371) of novel drugs and therapeutic regimens presented at ASH in these years, covering investigational treatments of MM, CLL, AML, DLBCL, MDS, NHL, ALL, CML, MCL, SLL, other lymphomas and POEMS. We first scored abstracts "positive", "negative" or "inconclusive". Criteria for a positive abstract were words/phrases such as "encouraging", "promising", "could represent a novel therapeutic option" and "warrants investigation in a randomized trial". Negative abstracts included terms such as "does not support further research" and "demonstrates no clinical activity". The remainder were scored as inconclusive. Using this approach, we scored 296/371 (80%) abstracts as positive, 37/371 (10%) as negative, and 38/371 (10%) as inconclusive. 292/371 abstracts (79%) were published in peer-reviewed journals. The abstract conclusion (positive, negative or inconclusive) was not associated with publication in a peer-reviewed journal. Most frequently, studies were published in Blood (34/292 [11.6%]) and British Journal of Haematology (39/292 [13.4%]) . In Blood, 91% (31/34) of the studies were positive. British Journal of Haematology published significantly more negative studies than Blood (26%, Fisher Exact p = 0.02). Abstracts reporting studies with larger sample sizes tended to be published more often (p = 0.066). Differences exist between the abstract conclusion and later peer-reviewed publications. Of positive ASH abstracts, 6% changed to a negative conclusion in the peer-reviewed publication. Similarly, 6.5% of the initial negative abstract later reversed to a positive conclusion. 53% of positive abstracts did not lead to phase III studies, as registered on clinicaltrials.gov. Subsequently, regimens described in positive peer-reviewed publications did not proceed to phase III research in 48%. To explore why, we sent questionnaires to the first and/or last authors of positive studies not prompting phase III trials. 52% responded. Failure of positive phase II trials to proceed to phase III was due to the decision by the pharmaceutical company to halt clinical investigation (44%), lack of any intent to study the drug in phase III in the first place (40%), insufficient funding (35%), insufficient efficacy (despite the "positive" abstract; 33%) and safety concerns (4%) (Figure). Additional reasons for not proceeding to phase III were the availability of newer regimens, the rarity of the disease, or when regulatory approval had already been obtained after phase II. In conclusion, "positive" and "negative" ASH abstracts are published as full papers equally often, although the positive ones may be published more often in journals with higher "impact factors". More than half of the regimens presented in positive ASH abstracts remain unevaluated in randomized phase III trials. A separate problem is the likely tendency to disproportionately submit (and/or accept) positive, rather than negative, studies to ASH in the first place. We believe our findings raise issues in clinical research that may not be in the best interest of patients. This demands more consideration than it currently receives. Figure 1 Figure 1. Disclosures Ossenkoppele: Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Rowe: Biosight Inc.: Consultancy.