Determinants of cancer drug pricing and how to overcome the cancer premium.

The high and increasing prices of cancer drugs are a public health challenge. To disrupt the cancer premium and improve patient access to cancer drugs, different action steps are indicated: more transparency on the price determination process and actual prices, value-based pricing, and "price with evidence development."

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Approval and therapeutic value of gene therapies in the US and Europe.

Gene therapies are a fast-growing area of innovation and hold promise for the treatment of many diseases currently with unmet medical need. To better understand the clinical importance of the current landscape of approved gene therapies, we conducted a systematic analysis of the approved gene therapies and their added therapeutic value. Through December 2022, 13 gene therapies have been approved in the US, 15 in the EU, and 9 in Switzerland. Nine gene therapies have been approved in all three jurisdictions, and 11 in both the US and EU. Among the 11 gene therapies approved in more than one jurisdiction, there were differences in the approved indications among the regulatory agencies, mostly the European drug agencies (EMA and Swissmedic) being more restrictive. Among the gene therapies with available therapeutic ratings, approximately two-thirds had high added therapeutic value, which is substantially higher than the average prevalence of high added therapeutic value ratings among new drugs and biologics (approximately one-third). However, therapies with high added therapeutic value will not be useful for patients if excessive prices limit access to them. Drug pricing reforms should address gene therapies to ensure access to new gene therapies that can offer important therapeutic value to patients.

Price changes and within-class competition of cancer drugs in the USA and Europe: a comparative analysis.

BACKGROUND: Cancer drugs are a major component of pharmaceutical spending in the USA and Europe. The number of approved cancer drugs continues to increase. More new drugs with overlapping mechanisms of action and similar approved indications might be expected to decrease prices within drug classes. We compared patterns of price changes for cancer drugs within the same class in the USA and in two European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. METHODS: For this comparative analysis, we identified cancer drugs approved for the treatment of solid cancers in the USA and Europe (Germany and Switzerland) between Jan 1, 2009, and Dec 31, 2020, using the US Food and Drug Administration's Drugs@FDA database and the European Medicines Agency's publicly available database. We considered cancer drugs as within-class competitors if they were approved for the same indication and had the same biological mechanism. We calculated monthly treatment prices for each drug, median price changes at launch and over time, and differences within and across drug classes. European price data were converted to US dollars by applying the exchange rates on Dec 1, 2020, and prices were adjusted for inflation. Median changes in the drugs' monthly treatment prices at 2 and 4 years after market entry across and within drug classes were also assessed. For the USA, correlations in relative price changes between all pairs of drugs within and across drug classes were calculated with Spearman's rank correlation. FINDINGS: Our study cohort comprised 12 drug classes covering nine indications. With the exception of one drug, increasing prices were observed within and across all drug classes in the USA (median 6·07% [range -3·60 to 33·83] 2 years after market entry, and 15·31% [-4·15 to 54·64] 4 years after market entry). By contrast, in Europe, prices generally decreased over time or did not increase more than inflation (2 years after market entry: -21·01% [range -50·72 to 12·71] in Germany and -1·48% [-26·81 to 1·69] in Switzerland; 4 years after market entry: -25·54% [-51·81 to 11·63] in Germany and -13·02% [-43·83 to 18·31] in Switzerland). In the USA, most prices changes within and across drug classes occurred at the end and beginning of the year (ie, from Dec 1 to Jan 31). In the USA, correlation for price changes was r=0·29 (SD 0·36) for within-class drugs and r=0·28 (0·36) for drugs across drug classes. INTERPRETATION: Competition within classes of cancer drugs generally did not constrain rising prices in the USA. Price negotiations, as practised in Germany or Switzerland, could help address the high prices of cancer drugs in the USA. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz), Swiss National Science Foundation, and Arnold Ventures.

Associations With Definitive Outcomes and Clinical Benefit of Cancer Drugs at the Time of Marketing Approval and in the Postmarketing Period.

BACKGROUND: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. METHODS: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. RESULTS: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. CONCLUSIONS: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

Prices and clinical benefit of cancer drugs in the USA and Europe: a cost-benefit analysis.

BACKGROUND: Increasing cancer drug prices are a challenge for patients and health systems in the USA and Europe. By contrast with the USA, national authorities in European countries often directly negotiate drug prices with manufacturers. The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) developed frameworks to evaluate the clinical value of cancer therapies: the ASCO-Value Framework (ASCO-VF) and the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We aimed to assess the association between the clinical benefit of approved cancer drugs based on these frameworks and their drug prices in the USA and four European countries (England, Switzerland, Germany, and France). METHODS: For this cost-benefit analysis, we identified all new drugs with initial indications for adult cancers that were approved by the US Food and Drug Administration between Jan 1, 2009, and Dec 31, 2017, and by the European Medicines Agency up until Sept 1, 2019. For drugs indicated for solid tumours, we assessed clinical benefit using ASCO-VF and ESMO-MCBS. We compared monthly drug treatment costs between benefit levels using hierarchical linear regression models, and calculated Spearman's correlation coefficients between costs and benefit levels for individual countries. FINDINGS: Our cohort included 65 drugs: 47 (72%) drugs were approved for solid tumours and 18 (28%) were approved for haematological malignancies. The monthly drug treatment costs in the USA were a median of 2·31 times (IQR 1·79-3·17) as high as in the assessed European countries. There were no significant associations between monthly treatment costs for solid tumours and clinical benefit in all assessed countries, using the ESMO-MCBS (p=0·16 for the USA, p=0·98 for England, p=0·54 for Switzerland, p=0·52 for Germany, and p=0·40 for France), and for all assessed countries except France using ASCO-VF (p=0·56 for the USA, p=0·47 for England, p=0·26 for Switzerland, p=0·23 for Germany, and p=0·037 for France). INTERPRETATION: Cancer drugs with low or uncertain clinical benefit might be prioritised for price negotiations. Value frameworks could help identify therapies providing high clinical benefit that should be made rapidly available across countries. FUNDING: Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Vertebral body insufficiency fractures: detection of vertebrae at risk on standard CT images using texture analysis and machine learning.

PURPOSE: To evaluate the diagnostic performance of bone texture analysis (TA) combined with machine learning (ML) algorithms in standard CT scans to identify patients with vertebrae at risk for insufficiency fractures. MATERIALS AND METHODS: Standard CT scans of 58 patients with insufficiency fractures of the spine, performed between 2006 and 2013, were analyzed retrospectively. Every included patient had at least two CT scans. Intact vertebrae in a first scan that either fractured ("unstable") or remained intact ("stable") in the consecutive scan were manually segmented on mid-sagittal reformations. TA features for all vertebrae were extracted using open-source software (MaZda). In a paired control study, all vertebrae of the study cohort "cases" and matched controls were classified using ROC analysis of Hounsfield unit (HU) measurements and supervised ML techniques. In a within-subject vertebra comparison, vertebrae of the cases were classified into "unstable" and "stable" using identical techniques. RESULTS: One hundred twenty vertebrae were included. Classification of cases/controls using ROC analysis of HU measurements showed an AUC of 0.83 (95% confidence interval [CI], 0.77-0.88), and ML-based classification showed an AUC of 0.97 (CI, 0.97-0.98). Classification of unstable/stable vertebrae using ROC analysis showed an AUC of 0.52 (CI, 0.42-0.63), and ML-based classification showed an AUC of 0.64 (CI, 0.61-0.67). CONCLUSION: TA combined with ML allows to identifying patients who will suffer from vertebral insufficiency fractures in standard CT scans with high accuracy. However, identification of single vertebra at risk remains challenging. KEY POINTS: • Bone texture analysis combined with machine learning allows to identify patients at risk for vertebral body insufficiency fractures on standard CT scans with high accuracy. • Compared to mere Hounsfield unit measurements on CT scans, application of bone texture analysis combined with machine learning improve fracture risk prediction. • This analysis has the potential to identify vertebrae at risk for insufficiency fracture and may thus increase diagnostic value of standard CT scans.

Reforming the World Health Organization's Essential Medicines List: Essential but Unaffordable.

This Viewpoint proposes restructuring the WHO Essential Medicines List to remove consideration of cost and cost-effectiveness from the expert committee reviews of clinical effectiveness, safety, and public health value, and chartering a new framework for pooled global negotiation and procurement of costly medicines included in the list.

FDA-cleared artificial intelligence and machine learning-based medical devices and their 510(k) predicate networks.

The US Food and Drug Administration is clearing an increasing number of artificial intelligence and machine learning (AI/ML)-based medical devices through the 510(k) pathway. This pathway allows clearance if the device is substantially equivalent to a former cleared device (ie, predicate). We analysed the predicate networks of cleared AI/ML-based medical devices (cleared between 2019 and 2021), their underlying tasks, and recalls. More than a third of cleared AI/ML-based medical devices originated from non-AI/ML-based medical devices in the first generation. Devices with the longest time since the last predicate device with an AI/ML component were haematology (2001), radiology (2001), and cardiovascular devices (2008). Especially for devices in radiology, the AI/ML tasks changed frequently along the device's predicate network, raising safety concerns. To date, only a few recalls might have affected the AI/ML components. To improve patient care, a stronger focus should be placed on the distinctive characteristics of AI/ML when defining substantial equivalence between a new AI/ML-based medical device and predicate devices.

Defining 'therapeutic value' of medicines: a scoping review.

OBJECTIVES: In recent years, discussions on the importance and scope of therapeutic value of new medicines have intensified, stimulated by the increase of prices and number of medicines entering the market. This study aims to perform a scoping review identifying factors contributing to the definition of the therapeutic value of medicines. DESIGN: Scoping review. DATA SOURCES: We searched the MEDLINE, CINAHL, Embase, Business Source Premier, EconLit, Regional Business News, Cochrane, Web of Science, Scope and Pool databases through December 2020 in English, German, French, Italian and Spanish. ELIGIBILITY CRITERIA: Studies that included determinants for the definition of therapeutic value of medicines were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted using the mentioned data sources. Two reviewers independently screened and analysed the articles. Data were analysed from April 2021 to May 2022. RESULTS: Of the 1883 studies screened, 51 were selected and the identified factors contributing to the definition of therapeutic value of medicines were classified in three categories: patient perspective, public health perspective and socioeconomic perspective. More than three-quarters of the included studies were published after 2014, with the majority of the studies focusing on either cancer disorders (14 of 51, 27.5%) or rare diseases (11 of 51, 21.6%). Frequently mentioned determinants for value were quality of life, therapeutic alternatives and side effects (all patient perspective), prevalence/incidence and clinical endpoints (all public health perspective), and costs (socioeconomic perspective). CONCLUSIONS: Multiple determinants have been developed to define the therapeutic value of medicines, most of them focusing on cancer disorders and rare diseases. Considering the relevance of value of medicines to guide patients and physicians in decision-making as well as policymakers in resource allocation decisions, a development of evidence-based factors for the definition of therapeutic value of medicines is needed across all therapeutic areas.

The cancer premium - explaining differences in prices for cancer vs non-cancer drugs with efficacy and epidemiological endpoints in the US, Germany, and Switzerland: a cross sectional study.

Background: High treatment prices of new cancer drugs are a global public health challenge to patients and healthcare systems. Policymakers in the US and Europe are debating reforms to drug pricing. The objective of this study was to assess whether drug efficacy or epidemiological characteristics (prevalence, incidence, mortality) explain the gap in treatment prices between cancer and non-cancer drugs in the US, Germany, and Switzerland. Methods: This cross-sectional study identified all new drugs approved in the US, Germany, and Switzerland between 2011 and 2020. Drug efficacy was extracted from pivotal trials, drug prices from public and commercial databases, and epidemiological characteristics from the Global Burden of Disease (GBD) 2019 study. We used regression models to explain drug prices with drug efficacy and epidemiological characteristics (prevalence, incidence, mortality). Findings: The cohort included 181 drugs, including 68 (37.5%) drugs approved for treatment of cancer. A significant negative correlation was found between incidence/prevalence and treatment prices, and a significant positive correlation was observed between mortality and treatment prices for both, cancer and non-cancer drugs. A significant association between relative drug efficacy and treatment prices of drugs was observed, however, less pronounced for cancer drugs. Our regression estimates indicated that after adjusting for efficacy and epidemiological characteristics, cancer drugs were on average approximately three times more expensive compared to non-cancer drugs in all three countries, indicating a cancer premium; i.e., treatment prices of cancer drugs were on average USD 74,412 (95% CI [62,810; 86,015]) more expensive in the US compared to non-cancer drugs, USD 37,770 (95% CI [26,175; 49,367]) more expensive in Germany, and USD 32,801 (95% CI [27,048; 38,555]) more expensive in Switzerland. Our model explained 72% of the variance in observed prices (R2). Interpretation: Drug pricing reforms should target the cancer premium to improve access of patients to cancer drugs as well as to achieve equity across the different therapeutic areas and sustainability in the health care systems. Funding: This study was funded by the Swiss National Science Foundation (SNSF, grant number PCEGP1_194607) and the Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study.

OBJECTIVE: To analyze the therapeutic value of supplemental indications compared with first indications for drugs approved in the US and Europe. DESIGN: Retrospective cohort study. SETTING: New and supplemental indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2011 and 2020. MAIN OUTCOME MEASURES: Proportion of first and supplemental indications rated as having high therapeutic value using ratings from the French and German national, independent health authorities. RESULTS: The cohort study included 124 first and 335 supplemental indications approved by the FDA and 88 first and 215 supplemental indications approved by the EMA between 2011 and 2020; the largest subset was for cancer disorders. Therapeutic ratings were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe. Among FDA approved indications with available ratings, 41% (44/107) had high therapeutic value ratings for first indications compared with 34% (61/179) for supplemental indications. In Europe, 47% (41/87) of first and 36% (67/184) of supplemental indications had high therapeutic value ratings. Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating (relative ratio 0.64, 95% confidence interval 0.43 to 0.96) and third indication approvals were 45% less likely (0.55, 0.29 to 1.01) compared with the first indication approval. Similar findings were observed for Europe and when weighting by the inverse number of indications for each drug. CONCLUSIONS: The proportion of supplemental indications rated as having high therapeutic value was substantially lower than for first indications. When first or supplemental indications do not offer added therapeutic value over other available treatments, that information should be clearly communicated to patients and physicians and reflected in the price of the drugs.

Clinical Benefit and Expedited Approval of Cancer Drugs in the United States, European Union, Switzerland, Japan, Canada, and Australia.

PURPOSE: Regulatory agencies have sought to speed up the review of new cancer medicines and reduce delays in approval between countries. We examined trends in regulatory review times and association with clinical benefit for new cancer medicines in six jurisdictions: United States (Food and Drug Administration [FDA]), European Union (European Medicines Agency [EMA]), Switzerland (Swissmedic), Japan (Pharmaceuticals and Medical Devices Agency [PMDA]), Canada (Health Canada), and Australia (Therapeutic Goods Administration). METHODS: We studied all new cancer drugs approved in the six aforementioned jurisdictions from 2007 to 2020. We extracted all applicable expedited programs, total regulatory review times, and, for drugs first approved by the FDA, times to subsequent regulatory approval. Clinical benefit was assessed using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale value framework and ASCO-Cancer Research Committee's targets. Nonparametric Kruskal-Wallis test was used to compare total review times for high versus low clinical benefit drugs. RESULTS: One hundred and twenty eight drugs received initial approval in at least one of the six included jurisdictions. Most drugs approved by the FDA (91%) and Health Canada (59%) qualified for at least one expedited program within those jurisdictions, compared with 46% of EMA approvals and 18% of PMDA approvals. The FDA was the first regulator to approve 102 (80%) drugs. Delays in submission accounted for a median of 20.2% (EMA) to 83.8% (PMDA) of the time to subsequent approval. There was no association between high clinical benefit and shorter total review times. CONCLUSION: Most new cancer therapies were approved first by the FDA, and delays in submission of regulatory applications accounted for substantial delays in approving cancer drugs in other countries. Regulators should prioritize faster review for drugs with high clinical benefit.

Therapeutic Value of Drugs Granted Accelerated Approval or Conditional Marketing Authorization in the US and Europe From 2007 to 2021.

Importance: The number of drugs approved through the accelerated approval or conditional marketing authorization pathways has increased with unclear evidence of their therapeutic value. Objectives: To assess the therapeutic value of drug indications granted accelerated approval in the US or conditional marketing authorization in the European Union (EU) overall and for cancer indications. Design, Setting, and Participants: This cohort study used the public databases of the US Food and Drug Administration and the European Medicines Agency to identify all drugs (initial and supplemental indications) granted accelerated approval in the US or conditional marketing authorization (initial indications only) in the EU between January 1, 2007, and December 31, 2021. Therapeutic value ratings were obtained from national health authorities in Germany, France, and Canada. Main Outcomes and Measures: Descriptive statistics were used to assess the proportion of accelerated approvals and conditional marketing authorizations overall and for cancer vs noncancer indications rated as having high added therapeutic value. Results: The cohort included 146 drug indications (94 first indications, 52 supplemental indications) in the US and 58 (all first indications) in the EU. Most drugs were approved for cancer (122 [83.6%] in the US; 40 [69.0%] in the EU). Therapeutic value ratings were available for 90 drug indications (61.6%) in the US and 56 (96.6%) in the EU. Overall, 35 drug indications granted accelerated approval (38.9%) and 21 granted conditional marketing authorization (37.5%) had high added therapeutic value in the US and EU, respectively, at the time of approval. The proportions of indications rated as having high added therapeutic value were 36.0% (27 of 75) for cancer vs 53.3% (8 of 15) for noncancer indications in the US and 30.8% (12 of 39) for cancer vs 52.9% (9 of 17) for noncancer indications in the EU. Conclusions and Relevance: In this cohort study, among new drug indications approved through the accelerated approval or conditional marketing authorization pathways in the US and Europe from 2007 to 2021, 38.9% and 37.5%, respectively, demonstrated high therapeutic value. A substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value. Policy makers and regulators should increase enforcement of timely postapproval study completion for drugs qualifying for these pathways.

Comparison of Uptake and Prices of Biosimilars in the US, Germany, and Switzerland.

Importance: Biologics account for a substantial proportion of health care expenditures. Their costs have been projected to reach US $452 billion in global spending by 2022. Given recent expiration of patent protection of biologics, a shift toward greater follow-on competition among biosimilars would be expected that would allow greater uptake and lower drug costs. Objective: To assess uptake and prices of biosimilars in the US compared with 2 European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. Design, Setting, and Participants: In this cohort study, biologics and biosimilars that were approved in the US, Germany, and Switzerland until August 2020 were identified. Prices and sales data were extracted from public and commercial databases for the years 2011 to 2020. Data were analyzed from August 1, 2021, to February 28, 2022. Main Outcomes and Measures: Descriptive statistics were used to show temporal trends in the uptake of biosimilars and relative prices compared with those of reference products (ie, biologic agents) for each country. Descriptive analysis was also performed to compare the uptake of biosimilars between the 3 countries limited to biologics that have biosimilars on the market in all countries. To test if biosimilar awareness in each country increased over the last decade, a linear least squares regression was applied. Results: The study cohort included 15 biosimilars and 6 biologics for the US, 52 biosimilars and 15 biologics for Germany, and 28 biosimilars and 13 biologics for Switzerland. Uptake of biosimilars increased over time in all countries. On average, the biosimilar market share at launch was highest in Germany; however, it increased at the fastest rate in the US. Monthly treatment costs of biosimilars in the US were a median of 1.94 (IQR, 1.78-2.44) and 2.74 (IQR, 1.91-3.46) higher than corresponding costs in Germany and Switzerland, respectively. Conclusions and Relevance: The findings of this cohort study suggest that more biosimilars have been marketed in Germany and Switzerland than in the US. Policies that counter anticompetitive practices in the US could allow biosimilars to enter the market sooner and could also lower health care costs with improved access. Awareness of biosimilars should be promoted to increase uptake of biosimilars globally.