BACKGROUND:Terminally ill patients often have difficulty taking medications. Suitable, minimally invasive, fast-acting administration routes are particularly important. Trials on alternative drug administration routes in palliative care are essential to base therapy decisions on evidence rather than experience. AIM:To evaluate the effectiveness of intranasal compared with subcutaneous midazolam for the initial management of terminal agitation in palliative care patients. DESIGN:Randomized, investigator-initiated open-label phase-II trial, August 2022-July 2024. SETTING/PARTICIPANTS:Monocentric trial at the palliative care ward of a German University Hospital. 180 patients were assessed for suitability, 60 patients (median age, 68 years (SD 12.3), 26 female) were randomized 1:1 and analyzed. Patients with terminal agitation fulfilling all eligibility criteria were randomized to midazolam 5 mg administered either intranasal (n = 30) or subcutaneous (n = 30). PRIMARY OUTCOME:Improvement of terminal agitation by midazolam administration assessed by RASS-PAL-score. SECONDARY OUTCOME:Midazolam plasma concentrations after administration. RESULTS:Median RASS-PAL-scores decreased significantly in both groups. Intranasal group: 2 at baseline, to -1 at 5 min and -2 at 20 min. Subcutaneous group: 1,-0 and -1. Within-group reductions exceeded the clinically relevant threshold of ⩾ 1 point at 5 and 20 min (all p < 0.0001). Median midazolam plasma concentrations were significantly higher intranasal (5 min: 90 ng/ml, 20 min: 83 ng/ml) than subcutaneous (5 min: 15 ng/ml, 20 min: 24 ng/ml). No patients withdrawn due to adverse effects. CONCLUSION:Midazolam intranasal administration was effective in reducing terminal agitation and achieves higher plasma concentrations compared to subcutaneous administration. It is an alternative route of application to improve end-of-life care for terminally ill patients. TRIAL REGISTRATION:MinTU Study 173-01, Eudra CT No.: 2021-004789-36, DRKS ID: 00026775 (07.07.2022, https://drks.de/search/de/trial/DRKS00026775).

OBJECTIVES:This study aims to analyse the association between clinical trial design and treatment effects for cancer drugs with US Food and Drug Administration (FDA) approval. DESIGN:Cross-sectional study and meta-analysis. SETTING:Data from Drugs@FDA, FDA labels, ClincialTrials.gov and the Global Burden of Disease study. PARTICIPANTS:Pivotal trials for 170 drugs with FDA approval across 437 cancer indications between 2000 and 2022. MAIN OUTCOME MEASURES:Treatment effects were measured in HRs for overall survival (OS) and progression-free survival (PFS), and in relative risk for tumour response. Random-effects meta-analyses and meta-regressions explored the association between treatment effect estimates and clinical trial design for randomised controlled trials (RCTs) and single-arm trials. RESULTS:Across RCTs, greater effect estimates were observed in smaller trials for OS (ß=0.06, p<0.001), PFS (ß=0.15, p<0.001) and tumour response (ß=-3.61, p<0.001). Effect estimates were larger in shorter trials for OS (ß=0.08, p<0.001) and PFS (ß=0.09, p=0.002). OS (ß=0.04, p=0.006), PFS (ß=0.10, p<0.001) and tumour response (ß=-2.91, p=0.004) outcomes were greater in trials with fewer centres. HRs for PFS (0.54 vs 0.62, p=0.011) were lower in trials testing the new drug to an inactive (placebo/no treatment) rather than an active comparator. The analysed efficacy population (intention-to-treat, per-protocol, or as-treated) was not consistently associated with treatment effects. Results were consistent for single-arm trials and in multivariable analyses. CONCLUSIONS:Pivotal trial design is significantly associated with measured treatment effects. Particularly small, short, single-centre trials testing a new drug compared with an inactive rather than an active comparator could overstate treatment outcomes. Future studies should verify results in unsuccessful trials, adjust for further confounders and examine other therapeutic areas. The FDA, manufacturers and trialists must strive to conduct robust clinical trials with a low risk of bias.

OBJECTIVES:The Orphan Drug Act (ODA) incentivizes drug development for rare diseases with limited sales potential. Partial orphans-drugs used to treat rare and common diseases-frequently turn into multi-billion dollar blockbusters. This study analyzes partial orphan cancer drugs' development, approval, and economics. METHODS:170 drugs with US Food and Drug Administration approval for 455 cancer indications were identified (2000-2021). 110 full, 22 partial, and 38 non-orphan drugs were compared regarding their approval, benefits, trials, epidemiology, price, beneficiaries, and spending with data from regulatory documents, Global Burden of Disease study, and Medicare and Medicaid. RESULTS:Full orphans, relative to partial and non-orphans, were more frequently monotherapies for hematologic cancers supported by smaller single-arm trials treating diseases with a lower incidence and higher severity. The time from first to second indication approval was 1 year shorter for partial than full orphans. Full orphans offered a greater overall survival (median: 4.0 vs 2.8 vs 2.8 months, P < .001) and progression-free survival benefit (median: 5.1 vs 2.5 vs 3.6 months, P < .001). Monthly prices were higher for full and partial than non-orphan drugs (median: $17 177 vs $13 284 vs $12 457, P < .001). Beneficiaries (8790 vs 4390 vs 1730) and spending ($570 vs $305 vs $156 million) per drug were greater for partial than non-and full orphans. CONCLUSIONS:Although partial orphans' benefits, trials, and economics are more similar to non-than full orphans, they receive all of the ODA's benefits and are swiftly extended to new indications; resulting in greater spending. A maximum ODA revenue/patient threshold could limit expenditure on partial orphans.

This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response’s relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. The median development time for breast cancer drugs was 7.8 years (95

BACKGROUND:The breakthrough therapy designation (BTD) facilitates the development of drugs with a large preliminary benefit in treating serious or life-threatening diseases. This study analyzes the FDA approval, trials, benefits, unmet needs, and pricing of breakthrough and nonbreakthrough therapy cancer drugs and indications. PATIENTS AND METHODS:We analyzed 355 cancer indications with FDA approval (2012-2022). Breakthrough and nonbreakthrough indications were compared regarding their FDA approval, innovativeness, clinical trials, epidemiology, and price. Data were extracted from FDA labels, the Global Burden of Disease study, and the Centers for Medicare & Medicaid Services. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk (RR) of tumor response were meta-analyzed across randomized controlled trials. Objective response rates (ORRs) were meta-analyzed for single-arm trials. RESULTS:We identified 137 breakthrough and 218 nonbreakthrough cancer indications. The median clinical development time was 3.2 years shorter for breakthrough drugs than for nonbreakthrough drugs (5.6 vs 8.8 years; P=.002). The BTD was more frequently granted to biomarker-directed indications (46% vs 34%; P=.025) supported by smaller trials (median, 149 vs 326 patients; P<.001) of single-arm (53% vs 27%; P<.001) and phase I or II design (61% vs 31%; P<.001). Breakthrough indications offered a greater OS (HR, 0.69 vs 0.74; P=.031) and tumor response (RR, 1.48 vs 1.32; P=.006; ORR, 52% vs 40%; P=.004), but not a PFS benefit (HR, 0.53 vs 0.58; P=.212). Median improvements in OS (4.8 vs 3.2 months; P=.002) and PFS (5.4 vs 3.3 months; P=.005) but not duration of response (8.7 vs 4.7 months; P=.245) were higher for breakthrough than for nonbreakthrough indications. The BTD was more frequently granted to first-in-class drugs (42% vs 28%; P=.001) and first-in-indication treatments (43% vs 29%; P<.001). There were no differences in treatment and epidemiologic characteristics between breakthrough and nonbreakthrough drugs. Breakthrough drugs were more expensive than nonbreakthrough drugs (mean monthly price, $38,971 vs $22,591; P=.0592). CONCLUSIONS:The BTD expedites patient access to effective and innovative, but also expensive, new cancer drugs and indications.

Background This study analyzes the development, US Food and Drug Administration (FDA) approval, benefits, innovation, trials, epidemiology, and price of cancer drugs with multiple special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. Methods In total, 355 FDA-approved cancer drug indications with 841 special designations were identified (2012-2022). Trial, epidemiology, and price data were collected from FDA labels, the Global Burden of Disease study, and Medicare and Medicaid. The association between efficacy outcomes and indications’ number of special designations were compared in meta-analyses. Results Median development times were 7.3, 7.8, and 5.4 months (P = .027) for drugs with 0 to 1, 2 to 3, and 4 to 5 special designations, respectively. Multiple special designations were associated with higher biotechnological and clinical innovation. Median patient enrollment in trials were 615, 471, 398, 168, 104, and 120 (P < .001) for indications with 0 to 5 special designations. Drugs for rare diseases supported by open-label phase 1/2 trials of single-arm design were granted more special designations. Hazard ratios for overall survival (0.80 vs 0.73 vs 0.73 vs 0.69 vs 0.56 vs 0.52; P = .003) and progression-free survival (0.70 vs 0.61 vs 0.59 vs 0.44 vs 0.37 vs 0.67; P < .001) substantially declined while tumor response increased with more special designations. Mean monthly prices increased for drugs with 0 to 4 but not 5 special designations ($21 596 vs $14 753 vs $32 410 vs $41 240 vs $38 703 vs $19 184). Conclusions Multiple special designations are associated with faster clinical development and greater benefits for patients with unmet needs but also with nonrobust trial evidence and a tendency toward higher drug prices.

The healthcare sector is ubiquitously plagued by workforce shortages in economies around the globe. The fragility of this structural shortage becomes apparent when external shocks, such as the COVID-19 pandemic, exacerbate the lack of workers in clinical practice. In this article, we summarize current trends in healthcare workforce development across the globe, review theoretical concepts of workforce shortages, and discuss policies to address them. In practice, developed countries often address workforce shortages with targeted migration policies. However, targeted workforce migration policies only intensify workforce shortages in low-and middle-income countries. Theoretical macroeconomic models suggest that supply shortages may result from too low wages, supply lagging behind demand, and social perception. Changes in the wage rate cannot sufficiently increase the supply of health professionals as scholars find inelastic wages for physicians and nurses. Nonpecuniary factors such as working conditions, job satisfaction, and intrinsic motivation are at least equally important as financial incentives. In conclusion, increased wages can only be part of a heterogeneous policy plan to address shortages. Migration and retirement levels of health professionals can temporarily mitigate workforce shortages but rarely change the underlying systemic issues. Increasing the number of places available in medical and nursing schools while also improving, both, financial and nonfinancial incentives for employees are long-term structural policy options.

Background Insufficient patient enrollment per month (=accrual) is the leading cause of cancer trial termination. Objective To identify and quantify factors associated with patient accrual in trials leading to the US Food and Drug Administration (FDA) approval of new cancer drugs. DataAll anti-cancer drugs with FDA approval were identified in the Drugs@FDA database (2000-2022). Data on drug indication's background-, treatment-, disease-, and trial-related factors were collected from FDA labels, clinicaltrials.gov, and the Global Burden of Disease study. The association between patient accrual and collected variables was assessed in Poisson regression models reporting adjusted rate ratios (aRR). Results We identified 170 drugs with approval in 455 cancer indications on the basis of 292 randomized and 163 single-arm trials. Among randomized trials, median enrollment per month was 38 patients (interquartile range [IQR]: 26-54) for non-orphan, 21 (IQR: 15-38, aRR 0.88, p = 0.361) for common orphan, 20 (IQR: 10-35, aRR 0.73, p <0.001) for rare orphan, and 8 (IQR 6-12, aRR 0.30, p < 0.001) for ultra-rare orphan indications. Patient enrollment was positively associated with disease burden [aRR: 1.0003 per disability-adjusted life year (DALY), p < 0.001), trial sites (aRR: 1.001 per site, p < 0.001), participating countries (aRR: 1.02 per country, p < 0.001), and phase 3 vs. 1/2 trials (aRR: 1.64, p = 0.037). Enrollment was negatively associated with advanced-line vs. first-line treatments (aRR: 0.81, p = 0.010) and monotherapy vs. combination treatments (aRR: 0.80, p = 0.007). Patient enrollment per month was similar between indications with and without a biomarker (median: 27 vs. 32, aRR 0.80, p = 0.117). Patient enrollment per month was substantially lower in government-sponsored than industry-sponsored trials (median: 14 vs. 32, aRR 0.80, p = 0.209). Enrollment was not associated with randomization ratios, crossover, and study blinding. Conclusions Disease incidence and disease burden alongside the number of study sites and participating countries are the main drivers of patient enrollment in clinical trials. For rare disease trials, greater financial incentives could help expedite patient enrollment. Novel trial design features, including skewed randomization, crossover, or open-label masking, did not entice patient enrollment.

ObjectivesFor US Medicare and Medicaid, single drug prices do not reflect the value of supplemental indications. Value-based indication-specific and weighted-average pricing has been suggested for drugs with multiple indications. Under indication-specific pricing, a distinct price is assigned to the differential value a drug offers in each indication. Under weighted-average pricing, a single drug price is calculated that reflects the value and/or volume of each indication. This study estimates price reductions and cost savings for cancer drugs under value-based indication-specific pricing and weighted-average pricing.MethodsWe collected data on US Food and Drug Administration (FDA)-approved cancer drugs and indications (2003-2020) from FDA labels, the Global Burden of Disease study, clinicaltrials.gov, and Medicare and Medicaid. A multivariable regression analysis, informed by characteristics of original indications, was used to predict value-based indication-specific prices for supplemental indications. These indication-specific prices were combined with each indication's prevalence data to estimate value-based weighted-average prices and potential cost savings under each policy.ResultsWe identified 123 cancer drugs with 308 indications. Medicare and Medicaid spent a total of $28.2 billion on these drugs in 2020. Adopting value-based indication-specific pricing would increase drug prices by an average of 3.9%, with cost savings of $3.0 billion (10.6%). However, 43.7% higher prices for ultra-rare diseases would increase spending by 16.8% ($44 million). Adopting value-based weighted-average pricing would reduce prices by an average of 4.6% and spending by $3.0 billion (10.6%). Under weighted-average pricing, prices for and spending on ultra-rare diseases would be reduced by 22.6% and $55 million, respectively.ConclusionsValue-based indication-specific and weighted-average pricing could help to align the value and price of new indications, thereby reducing expenditure on drugs with multiple indications.

e13655 Background: Over the past decades, US congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. It remains unclear whether multiple designations per indication are redundant. This study analyzes cancer drugs with multiple special designations regarding their FDA approval timelines, evidence, benefit, epidemiology and price. Methods: All anti-cancer drugs and their supplemental indication approvals were identified in the Drugs@FDA database from 2000 to 2022. For each indication, clinical trial characteristics, epidemiologic, and price data were collected from FDA labels, the Global Burden of Disease Study, and Medicare & Medicaid Part B and D, respectively. The association between overall survival (OS) and progression-free survival (PFS) hazard ratios (HR) and drug indications’ number of special designations were compared in meta-analyses and meta-regressions. Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. The median time to first FDA approval was 13.8 years for drugs with zero, 7.3 years with one, 7.1 years with two, 7.8 with three, 5.8 with four, and 5.3 with five special designations (HR per additional designation: 1.27, 95%CI: 1.09-1.48, p=.002). Drug indications with more special designations were more frequently granted to rare diseases with fewer treatment options supported by smaller and shorter open-label phase 1/2 trials. OS HRs were 0.79 for indications with zero, 0.74 with one, 0.73 with two, 0.69 with three, 0.59 with four, and 0.52 with five special designations (p=.024). On average, each additional special designation was associated with lower HRs for OS (ß=-0.03, p=.002) and PFS (ß=-0.07, p<.001). Each additional special designation was associated with a 19.05% (95%CI: 4.56-35.55, p=.013) higher drug price. Conclusions: The FDA’s special designations are non-redundant. Multiple special designations are associated with faster approval times and a greater efficacy for patients with high unmet needs, while multiple special designations are associated with less robust trial evidence and higher drug prices. This study supports the strategy of special FDA designations for unmet clinical needs.

BACKGROUND:Over the past decades, US Congress enabled the US Food and Drug Administration (FDA) to facilitate and expedite drug development for serious conditions filling unmet medical needs with five special designations and review pathways: orphan, fast track, accelerated approval, priority review, and breakthrough therapy. OBJECTIVES:This study reviews the FDA's five special designations for drug development regarding their safety, efficacy/clinical benefit, clinical trials, innovation, economic incentives, development timelines, and price. METHODS:We conducted a keyword search to identify studies analyzing the impact of the FDA's special designations (orphan, fast track, accelerated approval, priority review, and breakthrough therapy) on the safety, efficacy/clinical benefit, trials, innovativeness, economic incentives, development times, and pricing of new drugs. Results were summarized in a narrative overview. RESULTS:Expedited approval reduces new drugs' time to market. However, faster drug development and regulatory review are associated with more unrecognized adverse events and post-marketing safety revisions. Clinical trials supporting special FDA approvals frequently use small, non-randomized, open-label designs. Required post-approval trials to monitor unknown adverse events are often delayed or not even initiated. Evidence suggests that drugs approved under special review pathways, marketed as "breakthroughs", are more innovative and deliver a higher clinical benefit than those receiving standard FDA approval. Special designations are an economically viable strategy for investors and pharmaceutical companies to develop drugs for rare diseases with unmet medical needs, due to financial incentives, expedited development timelines, higher clinical trial success rates, alongside greater prices. Nonetheless, patients, physicians, and insurers are concerned about spending money on drugs without a proven benefit or even on drugs that turn out to be ineffective. While European countries established performance- and financial-based managed entry agreements to account for this uncertainty in clinical trial evidence and cost-effectiveness, the pricing and reimbursement of these drugs remain largely unregulated in the US. CONCLUSION:Special FDA designations shorten clinical development and FDA approval times for new drugs treating rare and severe diseases with unmet medical needs. Special-designated drugs offer a greater clinical benefit to patients. However, physicians, patients, and insurers must be aware that special-designated drugs are often approved based on non-robust trials, associated with more unrecognized side effects, and sold for higher prices.

Novel pharmaceutical treatments reducing cardiovascular events in dyslipidaemia patients must demonstrate clinical efficacy and cost-effectiveness to promote long-term adoption by patients, physicians, and insurers. To assess the cost-effectiveness of statin monotherapy compared to additive lipid-lowering therapies for primary and secondary cardiovascular prevention from the perspective of Germany’s healthcare system. Transition probabilities and hazard ratios were derived from cardiovascular outcome trials for statin combinations with icosapent ethyl (REDUCE-IT), evolocumab (FOURIER), alirocumab (ODYSSEY), ezetimibe (IMPROVE-IT), and fibrate (ACCORD). Costs and utilities were retrieved from previous literature. The incidence of major adverse cardiovascular events was simulated with a Markov cohort model. The main outcomes were the incremental cost-effectiveness ratios (ICER) per quality adjusted life year (QALY) gained. For primary prevention, the addition of icosapent ethyl to statin generated 0.81 QALY and €14,732 costs (ICER: 18,133), whereas fibrates yielded 0.63 QALY and € − 10,516 costs (ICER: − 16,632). For secondary prevention, the addition of ezetimibe to statin provided 0.61 QALY at savings of € − 5,796 (ICER: − 9,555) and icosapent ethyl yielded 0.99 QALY and €14,333 costs (ICER: 14,485). PCSK9 inhibitors offered 0.55 and 0.87 QALY at costs of €62,722 and €87,002 for evolocumab (ICER: 114,639) and alirocumab (ICER: 100,532), respectively. A 95

5232 AGING Cancer is among the leading causes of death worldwide, with the Global Burden of Disease study estimating a total of 10 million people die of cancer yearly. Age is a major risk factor for cancer given that most cases occur in patients over the age of 65. As the global population ages, the burden of cancer on society increases. The World Health Organization forecasts that there will be 19.3 million new cases and 9.6 million deaths by 2025.

Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients’ risk of adverse cardiovascular events. Apart from statins, data on new drugs’ use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.

Background: The design of clinical trials may influence measured treatment effect estimates. However, the Food and Drug Administration (FDA) approval of new cancer drugs ought to be supported by unbiased and robust clinical trials.Objective: To analyze the association between clinical trial design characteristics and treatment effect estimates for FDA-approved cancer drugs.Data and methods: Clinical trial evidence supporting the FDA approval of new anti-cancer drugs were collected from Drugs@FDA and clincialtrials.gov between 2000-2022. Treatment effects were measured in hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS), and in relative risk (RR) for tumor response. Meta-analyses and meta-regressions explored the association between treatment effect estimates and clinical trial design characteristics.Results: We identified 170 anti-cancer drugs with FDA approval in 455 indications. Across these indications, greater effect estimates were observed in smaller trials for OS (ß=0.06, 95%CI [0.04,0.09], p<0.001), PFS (ß=0.15, 95%CI [0.11,0.20], p<0.001), and tumor response (ß=-3.61, 95%CI [-5.54,-1.68], p<0.001). Effect estimates were greater in shorter trials for OS (ß=0.08, 95%CI [0.04,0.11], p<0.001) and PFS (ß=0.09, 95%CI [0.03,0.14], p=0.002), yet not tumor response (ß=-2.42, 95%CI [-5.24,0.41], p=0.093). Treatment effects were greater in trials comparing the new drug to an inactive (placebo/no treatment) rather than an active comparator for PFS (HR: 0.54 vs. 0.62, p=0.011), yet not OS (HR: 0.74 vs. 0.73, p=0.590). Effect estimates were greater for trials testing the new drug with only supportive care relative to those with a backbone anti-cancer treatment for OS (HR: 0.72 vs. 0.75, p=0.038) and tumor response (RR: 1.56 vs. 1.28, p<0.001), yet not PFS (HR: 0.55 vs. 0.59, p=0.213). Greater effect estimates were observed in phase 1/2 compared to phase 3 trials for OS (HR: 0.61 vs. 0.74, p=0.002) and tumor response (RR: 1.78 vs. 1.38, p=0.032), yet not PFS (HR: 0.47 vs. 0.57, p=0.065). Results were consistent for single-arm trials.Conclusions: The design of FDA approval trials significantly influences measured treatment effect estimates. Particularly small, short, phase 1/2 trials testing a new drug compared to an inactive rather than an active comparator could overstate treatment outcomes. The FDA, pharmaceutical companies, and clinicians must strive to conduct robust and unbiased clinical trials.

OBJECTIVE:To analyze the US Food and Drug Administration (FDA) approval, trials, unmet needs, benefit, and pricing of ultra-rare (<6600 affected US citizens), rare (6600-200 000 citizens), and common (>200 000 citizens) orphan cancer drug indications and non-orphan cancer drug indications. DESIGN:Cross sectional analysis. SETTING:Data from Drugs@FDA, FDA labels, Global Burden of Disease study, and Medicare and Medicaid. POPULATION:170 FDA approved drugs across 455 cancer indications between 2000 and 2022. MAIN OUTCOME MEASURES:Comparison of non-orphan and ultra-rare, rare, and common orphan indications regarding regulatory approval, trials, epidemiology, and price. Hazard ratios for overall survival and progression-free survival were meta-analyzed. RESULTS:161 non-orphan and 294 orphan cancer drug indications were identified, of which 25 were approved for ultra-rare diseases, 205 for rare diseases, and 64 for common diseases. Drugs for ultra-rare orphan indications were more frequently first in class (76% v 48% v 38% v 42%; P<0.001), monotherapies (88% v 69% v 72% v 55%; P=0.001), for hematologic cancers (76% v 66% v 0% v 0%; P<0.001), and supported by smaller trials (median 85 v 199 v 286 v 521 patients; P<0.001), of single arm (84% v 44% v 28% v 21%; P<0.001) phase 1/2 design (88% v 45% v 45% v 27%; P<0.001) compared with rare and common orphan indications and non-orphan indications. Drugs for common orphan indications were more often biomarker directed (69% v 26% v 12%; P<0.001), first line (77% v 39% v 20%; P<0.001), small molecules (80% v 62% v 48%; P<0.001) benefiting from quicker time to first FDA approval (median 5.7 v 7.1 v 8.9 years; P=0.02) than those for rare and ultra-rare orphan indications. Drugs for ultra-rare, rare, and common orphan indications offered a significantly greater progression-free survival benefit (hazard ratio 0.53 v 0.51 v 0.49 v 0.64; P<0.001), but not overall survival benefit (0.50 v 0.73 v 0.71 v 0.74; P=0.06), than non-orphans. In single arm trials, tumor response rates were greater for drugs for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications (objective response rate 57% v 48% v 55% v 33%; P<0.001). Disease incidence/prevalence, five year survival, and the number of available treatments were lower, whereas disability adjusted life years per patient were higher, for ultra-rare orphan indications compared with rare or common indications and non-orphan indications. For 147 on-patent drugs with available data in 2023, monthly prices were higher for ultra-rare orphan indications than for rare or common orphan indications and non-orphan indications ($70 128 (£55 971; €63 370) v $33 313 v $16 484 v $14 508; P<0.001). For 48 on-patent drugs with available longitudinal data from 2005 to 2023, prices increased by 94% for drugs for orphan indications and 50% for drugs for non-orphan indications on average. CONCLUSIONS:The Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases. These orphan indications fill significant unmet needs, yet their approval is based on small, non-robust trials that could overestimate efficacy outcomes. A distinct ultra-orphan designation with greater financial incentives could encourage and expedite drug development for ultra-rare diseases.

Systemic inflammation affects the whole vasculature, yet whether arterial and venous endothelial cells differ in their abilities to mediate inflammation and to return to homeostasis after an inflammatory stimulus has not been addressed thoroughly. We assessed gene-expression profiles in isolated endothelial cells from human umbilical arteries (HUAEC) or veins (HUVEC) under basal conditions, after TNF-α stimulation and various time points after TNF-α removal to allow reinstatement of homeostasis. TNF-α regulates the expression of different sets of transcripts that are significantly changed only in HUAEC, only in HUVEC or changed in both. We identified three types of gene regulation, i.e. genes that were significantly regulated after 24 h of TNF-α stimulation but no longer when TNF-α was removed (homeostatic regulation), genes that maintained significantly regulated after TNF-α removal (not homeostatic regulation) and genes that were only significantly regulated when TNF-α was removed (post-regulation). HUAEC and HUVEC quantitatively differed in these types of gene regulation, with relatively more genes being post-regulated in HUAEC. In conclusion our data demonstrate that HUAEC and HUVEC respond intrinsically different to an inflammatory insult. Whether this holds true for all endothelial cells and its relevance for inflammatory insults in different organs during systemic inflammation warrants further studies.

e18835 Background: Longitudinal data assessing seroconversion after different doses of SARS-CoV-2 vaccines and the role of personal protective measures to prevent COVID-19 infections remain scarce. This is the first study to evaluate the association between SARS-CoV-2 vaccination, tumor subgroups, cancer treatment, and personal protective measures with antibody titers as well as COVID-19 infections in a real-world cohort of cancer patients. Methods: This retrospective cohort study enrolled 633 adult patients all treated at a large oncology clinic in Hamburg (Germany) from January 2020 to July 2022. Data about demographics, cancer treatment, vaccinations, SARS-CoV-2-IgG antibody titers, personal protective measures, COVID-19 infections and infection-associated symptoms were reported in the patients’ health records. Primary outcomes were: (i) patients’ SARS-CoV-2-IgG antibody concentrations and (ii) COVID-19 infections. A multivariate regression model, reporting adjusted odds ratios (AOR), evaluated the association between collected variables and seroconversion rates after SARS-CoV-2 vaccination. A time-varying Kaplan-Meier survival analysis explored the association between the collected variables and the risk of infection. Results: Of 633 cancer patients, 52% had solid tumors and 48 % hematologic malignancies. Seroconversion was significantly associated with the number of vaccine doses, prior infections (AOR: 1.91, 95%CI: 1.01-3.60, p = .045), hematologic cancers (AOR: 0.58, 95%CI: 0.40-0.85, p = .005), and treatment with CD20/38 inhibitors or immune checkpoint inhibitors (ICI) (AOR: 0.58, 95%CI: 0.35-0.95, p = .030). 120 patients (19%) had a COVID-19 infection with 77% experiencing exhaustion, 67% fever, 62% rhinitis, 62% headache, 56% sore throat, and 48% a non-productive cough. Patients on anti-cancer treatments had a 63% (HR: 1.63, 95%CI: 1.04-2.57, p = .034) higher risk of infection. The risk of infection was 43% (AOR: 0.57, 95%CI: 0.38-0.85, p = .006) and 87% (AOR: 0.23, 95%CI: 0.11-0.47, p < .001) lower among patients with 2 and ≥3 vaccine doses, respectively. Wearing FFP2 masks (AOR: 0.74, 95%CI: 0.56-0.99, p = .046) and reducing social contacts (AOR: 0.81, 95%CI: 0.65-0.99, p = .042) were associated with a lower risk of infection, but this was not the case for wearing surgical masks or using a “Corona warning” app. Conclusions: In this study, SARS-CoV-2 vaccination was associated with lower infection rates in cancer patients. However, certain subgroups remained at an increased risk of infection despite vaccination, e.g. patients receiving CD20/38 or ICI anti-cancer therapy with hematologic cancers. More than two vaccine doses, FFP2 masks, and social distancing led to lower infection rates. These findings are instrumental in guiding recommendations for preventing COVID-19 infections in cancer patients.

Rising cancer drug prices adversely affect patients’ adherence and survival. We aimed to identify and quantify factors associated with launch prices and post-launch price changes of injectable cancer drugs in the US from 2005 to 2023. All anticancer drugs with US FDA approval between 2000 and 2022 were identified in the Drugs@FDA database. The sample was then restricted to cancer drugs covered under Medicare Part B (injectable drugs). Data characterizing each drug’s clinical benefits, disease epidemiology, approved indications, competition, and price were obtained from FDA labels, the Global Burden of Disease study, and the Centers for Medicare and Medicaid Services. The association between launch/post-launch prices and collected variables was assessed in random-effects regressions. Of 170 cancer drugs with FDA approval between 2000 and 2022, we identified 66 (39