Clinical trial design and treatment effects: a meta-analysis of randomised controlled and single-arm trials supporting 437 FDA approvals of cancer drugs and indications.

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.

Breakthrough Therapy Cancer Drugs and Indications With FDA Approval: Development Time, Innovation, Trials, Clinical Benefit, Epidemiology, and Price.

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.

Partial Orphan Cancer Drugs: US Food and Drug Administration Approval, Clinical Benefit, Trials, Epidemiology, Price, Beneficiaries, and Spending.

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.

Launch and Post-Launch Prices of Injectable Cancer Drugs in the US: Clinical Benefit, Innovation, Epidemiology, and Competition.

BACKGROUND: Rising cancer drug prices adversely affect patients' adherence and survival. OBJECTIVE: 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. DATA AND METHODS: 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. RESULTS: Of 170 cancer drugs with FDA approval between 2000 and 2022, we identified 66 (39%) injectable cancer drugs with quarterly price data from 2005 to 2023. In 2023, mean prices amounted to $27,688 per month, with an average price increase of 94% from 2005 to 2023. Launch and post-launch price changes were significantly associated with the treated disease epidemiology. A 1% decline in disease incidence was associated with a 0.2511% (p = 0.008) increase in launch prices and a 0.0086% (p = 0.032) annual increase in post-launch prices. Accordingly, launch prices were 120% (p = 0.051) higher for orphan than non-orphan drugs, with 3% (p = 0.008) greater annual post-launch price increases. Post-launch prices declined by up to -2% annually as new supplemental indications were approved for the same drug. We found no consistent association between launch/post-launch prices and the drugs' clinical benefit in terms of overall survival, progression-free survival, and tumor response. The market entry of new competitors was not associated with price reductions. 28 of 33 drug pairs within the same class had positive correlation coefficients. Pearson correlation coefficients were high (>0.80) for PD-1/PD-L1 inhibitors, CD38 antibodies, CD20 antibodies, HER2 antibodies, and mTOR inhibitors. CONCLUSIONS: Cancer drug prices regularly increase faster than inflation; however, there is no evidence that launch prices and post-launch price changes are aligned with the clinical benefit a drug offers to patients. In particular, patients with rare diseases experience greater price increases for their orphan drugs. There is no evidence that brand-brand competition results in drug price reductions.

Clinical benefit, development, innovation, trials, epidemiology, and price for cancer drugs and indications with multiple special FDA designations.

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.

Special FDA designations for drug development: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

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.

Gene regulation for inflammation and inflammation resolution differs between umbilical arterial and venous endothelial cells.

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.

Cancer Drug Prices in the United States: Efficacy, Innovation, Clinical Trial Evidence, and Epidemiology.

OBJECTIVES: Rising cancer drug prices challenge patients and healthcare systems. Although prices are routinely assigned to original drug indications receiving US Food and Drug Administration (FDA) approval, the pricing of supplemental indication approvals remains uncertain. This study identifies and quantifies factors associated with cancer drug prices, distinctly analyzing original and supplemental indications. METHODS: Clinical trial evidence and epidemiologic data supporting new indications' FDA approval (2003-2022) were collected from the Drugs@FDA database, ClinicalTrials.gov, and Global Burden of Disease study. Indication-specific monthly treatment costs were calculated for Medicare patients. The association between log-prices and collected variables were assessed in regression analyses. RESULTS: We identified 145 drugs approved across 373 cancer indications. Drugs were priced at $24 444 per month on average (median = $16 013). For original indications, prices weakly correlated to improvements in overall survival (ß = 0.28, P = .037) and progression-free survival (ß = 0.16, P = .001). Original indications' prices were as follows: (1) negatively associated with disease incidence (ß = -0.21, P < .001) and prevalence; (2) positively correlated with first-in-class drugs (26%, P = .057), gene and cell therapies (176%, P < .001), hematologic cancers (62%, P < .001), and severe diseases with substantial unmet needs (6% per disability-adjusted life-year, P < .001); and (3) negatively correlated to indications with randomized-controlled phase 3 trials. Prices were poorly associated with supplemental indications' efficacy, clinical evidence, and epidemiology. CONCLUSIONS: Cancer drug prices are set based on the original indication's characteristics, thereby omitting the value of supplemental indications. Indication-specific pricing, coverage, and reimbursement policies considering each indication's safety, efficacy, innovativeness, and unmet needs are necessary to align a drug's value and price.

Established and Emerging Lipid-Lowering Drugs for Primary and Secondary Cardiovascular Prevention.

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.

FDA approval, clinical trial evidence, efficacy, epidemiology, and price for non-orphan and ultra-rare, rare, and common orphan cancer drug indications: cross sectional analysis.

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.

Cost-Effectiveness of Lipid-Lowering Therapies for Cardiovascular Prevention in Germany.

PURPOSE: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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% probability of cost-effectiveness was surpassed at €20,000 for icosapent ethyl (primary and secondary prevention), €119,000 for alirocumab, and €149,000 for evolocumab. CONCLUSIONS: For primary cardiovascular prevention, a combination therapy of icosapent ethyl plus statin is a cost-effective use of resources compared to statin monotherapy. For secondary prevention, icosapent ethyl, ezetimibe, evolocumab, and alirocumab increase patient benefit at different economic costs.

Overall Survival, Progression-Free Survival, and Tumor Response Benefit Supporting Initial US Food and Drug Administration Approval and Indication Extension of New Cancer Drugs, 2003-2021.

PURPOSE: Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval. PATIENTS AND METHODS: Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed. RESULTS: Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% CI, 0.72 to 0.75; I2 = 29.6%) for OS and 0.57 (95% CI, 0.54 to 0.60; I2 = 90.6%) for PFS, whereas tumor response was 1.38 (95% CI, 1.33 to 1.42; I2 = 80.7%). Novel pharmaceuticals increased patient survival by a median of 2.80 months (IQR, 1.97-4.60 months) for OS and 3.30 months (IQR, 1.50-5.58 months) for PFS. Initial indications more frequently received accelerated approval, supported by single-arm trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 v 0.58; P = .002) and tumor response (relative risk, 1.76 v 1.36; P < .001). CONCLUSION: New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an indication-specific level.

Cost-Effectiveness of Icosapent Ethyl, Evolocumab, Alirocumab, Ezetimibe, or Fenofibrate in Combination with Statins Compared to Statin Monotherapy.

BACKGROUND: Despite treatment with statins, dyslipidaemia patients with elevated cholesterol- and triglyceride-levels remain at high residual risk for major adverse cardiovascular events (MACE). New lipid-lowering drugs must prevent the occurrence of MACE and exhibit cost-effectiveness for their successful adoption to clinical practice. OBJECTIVE: To assess the cost effectiveness of icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab in combination with statins compared to statin monotherapy for cardiovascular prevention from the perspective of UK's National Health Service. METHODS: A Markov model simulated the progression of cardiovascular disease and MACE, including myocardial infarction, stroke, angina pectoris, and coronary revascularisation, in dyslipidaemia patients. The model was populated with cardiovascular outcome trial data for each drug. Cost and utility data were extracted from peer-reviewed literature. The incremental cost-effectiveness ratio (ICER) is reported per quality-adjusted life years (QALY) gained in 2021 Great Britain Pounds (£). RESULTS: For primary cardiovascular prevention, icosapent ethyl increased QALYs by 0.79 and costs by £15,421 compared to statin monotherapy (ICER = £19,485/QALY). Fenofibrate yielded 0.62 additional QALYs at cost-savings of - £6127 (ICER = - £9932/QALY). For secondary prevention, the omega-3 fatty acid icosapent ethyl extended QALYs by 0.98 at costs of £12,981 compared to statin monotherapy (ICER = £13,285/QALY). Fenofibrate added 0.85 QALYs whilst saving - £637 (ICER = - £7472/QALY). Ezetimibe increased QALYs by 0.60 at cost reductions of - £2529 (ICER = - £4231/QALY). PCSK9 inhibitors provided QALYs of 0.53 and 0.86 at costs of £45,279 and £46,375 for evolocumab (ICER = £85,193/QALY) and alirocumab (ICER = £54,211/QALY), respectively. At a willingness-to-pay threshold of £25,000/QALY, there is a probability of 100% for icosapent ethyl (98% in primary prevention) and 0% for PCSK9 inhibitors to be cost effective in secondary prevention. CONCLUSIONS: Icosapent ethyl is cost effective for primary and secondary cardiovascular prevention at an annual price of £2064 in the UK. For PCSK9 inhibitors, price discounts or prescription restrictions are necessary to achieve cost effectiveness.

Socio-economic burden of disease: Survivorship costs for bladder cancer.

BACKGROUND: In this cost-of-illness study, we analysed the socio-economic burden of bladder cancer survivorship for the ten years after initial treatment in Germany during 2000, 2010 and 2020. METHODS: Bladder cancer follow-up guidelines were extracted from the European Association of Urology. Per patient costs were estimated with a micro-costing approach considering direct and indirect medical expenses derived from literature and official scales of tariffs. Three perspectives covering costs for patients, providers, and insurers were included to estimate societal costs. RESULTS: Mean 10-year follow-up costs per patient amounted to EUR 2214 for low-risk, EUR 4758 for medium-risk, and EUR 11,325 for high-risk non-muscle invasive bladder cancer (NMIBC) in 2020. The mean economic burden of muscle-invasive and metastatic bladder cancer (MIBC) was EUR 8994 per patient. Overall expenditure rose by 65% from 2000 to 2020 across all cancer stages (p < 0.001). While insurers covered 38% of costs in 2000, only 31% of costs were reimbursed in 2020 (p < 0.001). 58% of high-risk NMIBC follow-up resources were consumed by physician-patient visits and 17% by medical imaging (x-ray, CT-IVU, ultrasound). Spending was unevenly distributed across follow-up years (years 1-2: 43%, years 3-5: 29%, years 5-10: 28%). CONCLUSIONS: The rising socio-economic burden of follow-ups signifies the relevance of cancer survivorship for the healthcare system and society. This burden must be evenly distributed across stakeholders and considered in cost-effectiveness evaluations of novel anti-cancer drugs. Policy summary Personalized, equitable, and effective follow-up schedules covered by insurance funds are necessary to care for cancer survivors.

Initial and supplementary indication approval of new targeted cancer drugs by the FDA, EMA, Health Canada, and TGA.

BACKGROUND: Previous research focused on the clinical evidence supporting new cancer drugs' initial US Food and Drug Administration (FDA) approval. However, targeted drugs are increasingly approved for supplementary indications of unknown evidence and benefit. OBJECTIVES: To examine the clinical trial evidence supporting new targeted cancer drugs' initial and supplementary indication approval in the US, EU, Canada, and Australia. DATA AND METHODS: 25 cancer drugs across 100 indications were identified with FDA approval between 2009-2019. Data on regulatory approval and clinical trials were extracted from the FDA, European Medicines Agency (EMA), Health Canada (HC), Australian Therapeutic Goods Administration (TGA), and clinicaltrials.gov. Regional variations were compared with χ2-tests. Multivariate logistic regressions compared characteristics of initial and supplementary indication approvals, reporting adjusted odds ratios (AOR) with 95% confidence intervals (CI). RESULTS: Out of 100 considered cancer indications, the FDA approved 96, the EMA 92, HC 86, and the TGA 83 (83%, p < 0.05). The FDA more frequently granted priority review, conditional approval, and orphan designations than other agencies. Initial approvals were more likely to receive conditional / accelerated approval (AOR: 2.69, 95%CI [1.07-6.77], p < 0.05), an orphan designation (AOR: 3.32, 95%CI [1.38-8.00], p < 0.01), be under priority review (AOR: 2.60, 95%CI [1.17-5.78], p < 0.05), and be monotherapies (AOR: 5.91, 95%CI [1.14-30.65], p < 0.05) than supplementary indications. Initial indications' pivotal trials tended to be shorter (AOR per month: 0.96, 95%CI [0.93-0.99], p < 0.05), of lower phase design (AOR per clinical phase: 0.28, 95%CI [0.09-0.85], p < 0.05), and enroll more patients (AOR per 100 patients: 1.19, 95%CI [1.01-1.39], p < 0.05). CONCLUSIONS: Targeted cancer drugs are increasingly approved for multiple indications of varying clinical benefit. Drugs are first approved as monotherapies in rare diseases with a high unmet need. Whilst expedited regulatory review incentivizes this prioritization, indication-specific safety, efficacy, and pricing policies are necessary to reflect each indication's differential clinical and economic value.

Socio-economic burden of disease: Survivorship costs for renal cell carcinoma.

OBJECTIVE: The objective of this study is to assess the risk-stratified 10-year socio-economic burden of renal cell carcinoma (RCC) follow-up costs after initial treatment in Germany from 2000 to 2020. METHODS: A micro-costing method considering direct and indirect medical expenditure associated with follow-up procedures was employed to calculate survivorship costs per patient. The frequencies of physician-patient visits, examinations and diagnostic tests were extracted from guidelines, whilst expenses were sourced from literature and official scales of tariffs. Societal costs were calculated based on three perspectives: patients, providers and insurers. RESULTS: Mean societal 10-year follow-up costs per patient amounted to EUR 3,377 (95%CI: 2,969-3,791) for low-risk, EUR 3,367 (95%CI: 3,003-3,692) for medium-risk and EUR 4,299 (95%CI: 3,807-4,755) for high-risk RCC in 2020. Spending increased by +32% from 2000 to 2020 for low-risk RCC, whilst medium-and high-risk RCC expenditure was cut by -39% and -22%, respectively. Patients shouldered 27%, providers 43% and insurers 35% of costs in 2020. Resources were consumed by medical imaging (52%), physician-patient consultations (31%), travel expenses (17%) and blood tests (1%). CONCLUSION: Results highlight the economic burden cancer survivorship poses for society. Cancer survivors require individualised, evidence-based and insurance-covered follow-up schedules to permit the early detection of side-effects, metastasis and secondary malignancies.

Cost-Effectiveness of Bivalent, Quadrivalent, and Nonavalent HPV Vaccination in South Africa.

BACKGROUND AND OBJECTIVES: In South Africa, the prevalence of human papillomavirus (HPV) and associated diseases, such as cervical cancer and genital warts, is among the highest in the world. This study evaluates the cost-effectiveness of bivalent, quadrivalent, and nonavalent HPV vaccination for 9- to 14-year-old girls from the South African healthcare system perspective. METHODS: A Markov model portraying the natural HPV disease progression from high-risk infection to cervical intraepithelial neoplasia (CIN) I, CIN II/III, or cervical cancer and from low-risk infection to genital warts was built. Transition probability, utility, and efficacy data were sourced from peer-reviewed literature. Vaccination costs were calculated based on the World Health Organization (WHO) guidelines. The model was populated with a cohort of 520,000 9-year-old girls to calculate incremental cost-effectiveness ratios (ICER) in South African Rand (R) per quality-adjusted life-years (QALYs) gained for each vaccination strategy. RESULTS: All HPV vaccination strategies dominate the no vaccine strategy. Compared with the bivalent vaccine, the nonavalent strategy increases QALYs by 0.14 and costs by R1793 (ICER: R13,013 per QALY) per person, while the quadrivalent vaccination provides -0.02 incremental QALYs and R1748 costs (ICER: -R116,397 per QALY). Consequently, at the South African willingness-to-pay threshold of R23,630 per QALY, nonavalent vaccination is the preferred strategy, with a probability of 90.2%. Scenario analysis demonstrated that results are influenced by vaccine coverage, efficacy, and duration of efficacy. CONCLUSIONS: The introduction of nonavalent for bivalent HPV vaccination is a cost-effective intervention in South Africa. HPV vaccination should be part of a multifaceted public health strategy entailing screening, condoms, and education of all stakeholders to reduce the significant burden of sexual transmitted diseases in South Africa. Sex-neutral and catch-up vaccinations are subjects for further research.

Medical education and mental health during COVID-19: a survey across 9 countries.

OBJECTIVES: To investigate students' experience with medical education alongside their mental and physical health since the onset of the COVID-19 pandemic across nine countries. METHODS: A cross-sectional online survey was distributed by local collaborators to 2,280 medical students across 148 medical schools in Brazil, Chile, Colombia, Germany, Italy, Japan, Mexico, Spain, and Venezuela using non-probability convenience sampling from June 22 to July 24, 2020. Students answered questions regarding teaching, internet use, COVID-19, physical and mental well-being. A multivariate logistic regression examined factors associated with depressed mood, insomnia, and headache. RESULTS: Academic teaching shifted to a virtual (67%, n=1,534) or hybrid environment (23%, n=531), whilst bedside teaching was suspended or cancelled (93%, n=2,120). Across all countries students were equally satisfied with the teaching modality, quantity, quality, and the evaluation system of in-person, hybrid, and online curricula. Negative changes in mental (40% (n=912) insomnia, 57% (n=1,300) emotional irritability, 47% (n=1,072) emotional instability, 41% (n=935) anhedonia, 40% (n=912) depressed mood) and physical (36% (n=821) headache, 57% (n=1,299) ocular tiredness, 49% (n=1,117) backache) health symptoms were frequently observed. Positive associations between the number of daily screen hours and depressed mood (adjusted odds ratio (AOR)=1.09, 95%CI: 1.05-1.12, p<.001), insomnia (AOR=1.08, 95%CI: 1.05-1.11, p<.001), and headache (AOR=1.11, 95%CI: 1.07-1.14, p<.001) were identified. CONCLUSIONS: Students' experience with digital and hybrid medical curricula was diverse during the pandemic. Education modality, quantity, and quality were positively evaluated. However, students' mental and physical health worsened. Besides bedside teaching, faculties ought to digitalize and strengthen social communities and extend support services for students.

Value drivers of development stage biopharma companies.

OBJECTIVE: Scholars previously estimated research and development (R&D) costs of the internal drug development process. However, little is known about the costs and value arising from externally acquired therapeutics. This study identifies and estimates the magnitude of factors associated with Biopharma acquisition value. METHODS: SDC Thomson Reuter and S&P Capital IQ were screened for majority acquisitions of US and EU Biopharma companies developing new molecular entities for prescription use (SIC code: 2834) from 2005 to 2020. Financial acquisition data were complemented with variables characterizing the target's product portfolio extracted from clinicaltrials.gov, Drugs@FDA database, US SEC filings, and transaction announcements. A multivariate regression assesses the association of firm value with extracted variables. RESULTS: 311 acquisitions of companies developing prescription drugs were identified over the study period. Acquirers paid 37% (p < 0.05) more for companies with biologics and gene therapeutics than small-molecule lead drugs. Multi-indication products were acquired for a 12% premium per additional indication (p < 0.01). No significant valuation difference between companies developing orphan and non-orphan designated lead products was observed (18%, p = 0.223). Acquisition value positively correlated with the total number of further products, headquarter location in the US, underlying market conditions, and acquirer market capitalization (p < 0.05). CONCLUSIONS: Internal and external drug development consumes many financial and human resources, yet it is important for entrepreneurs, regulators, and payers to understand their precise magnitude and value drivers. This information permits the design of targeted pricing and industrial policies that incentivize the development of novel drugs in areas with high unmet needs.