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Summary 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).

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.

IMPORTANCE The high cost of cancer medicines is a public health challenge. Policy makers in the US and Europe are debating reforms to drug pricing that would cover both the prices of new medicines when entering the market and price increases after they are launched. OBJECTIVE To assess launch prices, postlaunch price changes, and clinical benefit of cancer drugs in the US compared with 3 European countries (England, Germany, and Switzerland). DESIGN, SETTING, AND PARTICIPANTS This economic evaluation identified all new drugs that were approved for use in the US, England, Germany, and Switzerland with initial indications for treatment of adult solid tumor and hematologic cancers. Analysis included drugs approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2019, and by the European Medicines Agency and Swissmedic until December 31, 2019. Prices were adjusted for currency and inflation. Clinical benefit of drugs indicated for solid tumors was assessed using the American Society of Clinical Oncology Value Framework and European Society for Medical OncologyMagnitude of Clinical Benefit Scale. Using Spearman rank correlation coefficients, correlations between clinical benefit and launch prices and postlaunch price changes for each country were evaluated. MAIN OUTCOMES AND MEASURES Launch prices, postlaunch price changes, and clinical benefit of cancer drugs. RESULTS The cohort included 65 drugs: 47 (72%) approved for solid tumors and 18 (28%) for hematologic cancers. In all countries, the lowest median monthly treatment costs at launch were greater in 2018-2019 vs 2009-2010: $14 580 vs $5790 in the US, $5888 vs $4289 in Germany, $6593 vs $5784 in Switzerland, and $6867 vs $3939 in England. Between 2009 and 2019, 48 of 65 (74%) cancer drugs had price increases in the US that were greater than inflation. Only 1 of 62 (2%) drugs in England, 0 of 60 drugs in Germany, and 7 of 56 drugs (13%) in Switzerland had a median price increase greater than inflation. There were no associations between launch prices or postlaunch price changes and clinical benefit in any assessed country. CONCLUSIONS AND RELEVANCE During this economic evaluation study period, launch prices of cancer drugs were substantially higher in the US than in the assessed similar high-income European countries, a gap that increased in the years after approval. Cancer drug prices frequently increased faster than inflation in the US but decreased on inflation-adjusted terms in Europe. Price changes were not associated with clinical benefit in any country.

Several sources of bias can affect the performance of machine learning systems used in medicine and potentially impact clinical care. Here, we discuss solutions to mitigate bias across the different development steps of machine learning-based systems for medical applications.

Background: Adequate patient selection is the key to successful lung volume reduction in patients with pulmonary emphysema. Computed tomography (CT) enables a reliable detection of pulmonary emphysema and allows an accurate quantification of the severity. Our goal was to investigate the usefulness and reliability of color-coded (CC) CT images in classification of emphysema and preoperative lung volume reduction planning. Methods: Fifty patients undergoing lung volume reduction surgery at our institution between September 2015 and February 2016 were retrospectively investigated. Three readers visually assessed the amount and distribution patterns of pulmonary emphysema on axial, multi-planar and CC CT images using the Goddard scoring system and a surgically oriented grading system (bilateral markedly heterogenous, bilateral intermediately heterogenous, bilateral homogenous and unilateral heterogenous emphysema). Observer dependency was investigated by using Fleiss’ kappa (κ) and the intraclass correlation coefficient (ICC). Results were compared to quantitative results from densitometry measurements and lung perfusion scintigraphy by using Spearman correlation. Recommendations for lung volume reduction sites based on emphysema amount and distribution of all readers were compared to removal sites from the surgical reports. Results: Inter-rater agreement for emphysema distribution rating was substantial for CC images (κ=0.70; 95% CI, 0.64–0.80) and significantly better compared to axial and multiplanar images (P≤0.001). The inter-rater agreement for recommended segment removal was moderate for CC images (κ=0.56; 95% CI, 0.49–0.63) and significantly better compared to axial and multiplanar images (P

Background Many European countries introduced (confidential) rebates in the past years. Authorities and manufacturers argue that this strategy allows reduction of spending on high-cost drugs, and quick access of innovative drugs. We evaluated these arguments using Switzerland as an example, one of the last countries with transparent rebates. Methods We identified all drugs granted rebates in Switzerland and all new drugs without rebates between January 2012 and October 2020. We assessed the amount of introduced drugs with and without rebates over time, clinical benefit of drugs with rebates, and duration between approval and price determination. Findings Our study cohort included 51 drugs with rebates, the majority were cancer drugs (32; 63%). 15/51 (29%) had high clinical benefit, 25/51 (49%) low benefit and for 11/51 (22%) benefit could not be assessed. The number of drugs with rebates increased in recent years. Time duration between approval and price determination was 302 days in median for drugs with and 106 days for drugs without rebates. Interpretation Drugs with rebates may hamper access to drugs and lead to overpayment. Improving transparency on actual drug prices and stronger cooperation between countries could help national authorities to make better informed pricing decisions, and improve access of innovative drugs to patients. Funding This study was partially funded by the Swiss Cancer Research Foundation (Krebsforschung Schweiz) and the Swiss National Foundation (SNF).

Legislators in the USA have been discussing reforms to reduce the high cost of brand-name drugs, which are much higher in the USA than in other industrialized countries. One solution is to actively negotiate prices based on drugs’ clinical benefits. We discuss two important complexities from such an approach: drugs that have been approved for multiple indications and as part of a combination regimen.

ObjectiveTo characterize the therapeutic value of new drugs approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) and the association between these ratings and regulatory approval through expedited programs.DesignRetrospective cohort study.SettingNew drugs approved by the FDA and EMA between 2007 and 2017, with follow-up through 1 April 2020.Data sourcesTherapeutic value was measured using ratings of new drugs by five independent organizations (Prescrire and health authorities of Canada, France, Germany, and Italy).Main outcome measuresProportion of new drugs rated as having high therapeutic value; association between high therapeutic value rating and expedited status.ResultsFrom 2007 through 2017, the FDA and EMA approved 320 and 268 new drugs, respectively, of which 181 (57%) and 39 (15%) qualified for least one expedited program. Among 267 new drugs with a therapeutic value rating, 84 (31%) were rated as having high therapeutic value by at least one organization. Compared with non-expedited drugs, a greater proportion of expedited drugs were rated as having high therapeutic value among both FDA approvals (45% (69/153) v 13% (15/114); Pv 27% (65/240); PConclusionsLess than a third of new drugs approved by the FDA and EMA over the past decade were rated as having high therapeutic value by at least one of five independent organizations. Although expedited drugs were more likely than non-expedited drugs to be highly rated, most expedited drugs approved by the FDA but not the EMA were rated as having low therapeutic value.

Background Approved drugs must be included on the so-called “special list” (SL) by the Federal Office for Public Health (FOPH) to be reimbursed by the social health insurance in Switzerland. The FOPH decides whether a drug may be included on SL and if so, negotiates the maximum price with the manufacturer. Time period between approval and inclusion on SL is important to evaluate accessibility of patients to drugs. Methods We identified all approved cancer drugs for first indication between 2009–2018 in Switzerland and determined whether they have been included on SL, and if so, how many days passed between approval and reimbursement, i.e., inclusion on SL. Descriptive statistical analysis was performed by using R. Results 70 cancer drugs have been approved between 2009 and 2018. Among this sample, 56 (80 %) are on SL. Average time from drug approval to inclusion date on SL increased from 234 days in 2009 to 463 days in 2018, with an average time of 352 days over the full analysis period. Conclusion Time period between approval and inclusion on SL has prolonged over the past years. This impedes patients’ access to cancer drugs. Prioritizing HTA and price negotiation of cancer drugs with high clinical benefit or implement a regulation that sets a maximum time period for HTA and price negotiation are possible policy implications.

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. 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. 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). 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. • 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.

Social health insurance is mandatory in Switzerland and covers the costs of basic medical care. In general, with regard to medicines, the costs are only reimbursed if the drug is (1) approved by Swissmedic and (2) listed on the so-called Spezia­litätenliste (SL) by the Federal Office of Public Health (FOPH). However, the SL does not include all drugs. For non-SL drugs, cost coverage is only granted under exceptional circumstances. Absence of cost coverage by social health insurance is especially problematic for patients who need access to cancer drugs, since they are often costly. Even if such cancer drugs are approved by Swissmedic, patients may still lack access to them. Therefore, access to medicines includes two aspects: (1) the availability of a drug on the market (i.e., approval of a drug) and (2) inclusion on the SL (i.e., cost coverage by social health insurance). In this study, we aim to compare the current approval regulations for oncologic precision medicines in the USA, Europe, and Switzerland; to investigate cost coverage for these drugs in Switzerland; and to develop health policy implications about how access to these drugs could be improved in Switzerland.

Background: Successful first-generation drugs can be updated or copied with small alterations to make "second-generation drugs", which are less expensive to develop and carry less financial risk for manufacturers, since the mechanism of action has been validated and a well-defined consumer market exists. We compared the pivotal clinical trials and FDA approval pathways for first- and second-generation cancer drugs. Methods: Among cancer drugs approved in the US from 1994-2014, we found four classes of oncology drugs in which second-generation products followed many years after the first-generation agents: BCR-ABL tyrosine kinase inhibitors for treatment of chronic myelogenous leukemia, ALK tyrosine kinase inhibitors for non-small cell lung cancer, CD20 monoclonal antibodies for chronic lymphocytic leukemia and HER2 monoclonal antibodies for breast cancer. From information on these 13 drugs available in documents published by FDA at the time of approval, we extracted the following characteristics: approval pathway, pivotal trial design, number of participants, efficacy endpoints, and outcomes. Findings: The first-generation and 3 out of 4 second-generation BCR-ABL tyrosine kinase inhibitor drugs were granted expedited approval, while all 4 drugs were approved based on single-arm pivotal trials. Both ALK tyrosine kinase inhibitor drugs were based on single-arm trials and expedited regulatory review. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and 1 of the 2 second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All 3 HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways. Interpretation: Second-generation tyrosine kinase inhibitors and monoclonal antibodies used in cancer treatment were often approved through expedited approval pathways and studied in single-arm trials. Such pathways help facilitate the approval of these products for earlier use by patients, but are also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events. Funding Statement: Dr. Kesselheim's work is funded by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science and the Engelberg Foundation. Dr. Vokinger's work is funded by the Swiss National Foundation. Declaration of Interest: The authors have declared no conflicts of interest.

Zusammenfassung. Der Begriff «Klinische Leitlinien» (Clinical Practice Guidelines, CPG) wird in der Schweiz nicht einheitlich verwendet. Die FMH definierte «Guidelines» im Jahr 1999. In der Praxis werden Dokumente, die diese Definition nicht erfüllen, teilweise trotzdem als Leitlinien bezeichnet, und andererseits Empfehlungen, die die Definition erfüllen, nicht immer. Auch Umschreibungen wie etwa «(klinische) Richtlinien», «Empfehlungen» oder «Stellungnahmen» werden verwendet. Diese Heterogenität kann zu Unsicherheiten in der Medizin und zu potenziell unerwünschten (oder zumindest unerwarteten) rechtlichen Konsequenzen führen. So können «klinische Leitlinien» zur Konkretisierung des Sorgfaltspflichtmassstabes in einem strafrechtlichen, zivilrechtlichen oder öffentlich-rechtlichen Verfahren herangezogen werden. Eine einheitliche Verwendung des Begriffs «Klinische Leitlinien» könnte in der Schweiz zur Verbesserung von Qualität und Rechtssicherheit führen.

Historically, patient experience, including symptomatic toxicities, physical function, and disease-related symptoms during treatment or their perspectives on clinical trials, has played a secondary role in cancer drug development. Regulatory criteria for drug approval require that drugs are safe and effective, and almost all drug approvals have been based only on efficacy endpoints rather than on quality-of-life (QoL) assessments. In contrast to Europe, information regarding the impact of drugs on patients’ QoL is rarely included in oncology drug labeling in the United States. Until recently, patient input and preferences have not been incorporated into the design and conduct of clinical trials. In recent years, a more in-depth understanding of cancer biology, as well as regulatory changes focused on expediting cancer drug development and approval, has allowed earlier access to novel therapeutic agents. Understanding the implications of these expedited programs is important for oncologists and patients, given the rapid expansion of these programs. In this article, we provide an overview of the role of QoL in the regulatory drug–approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care.

2006 Background: Cancer drug costs are rising in the US and Europe. While drug manufacturers set prices without restriction in the US, European countries have regulations that allow national authorities to directly negotiate drug prices at launch and over time. We analyzed and compared the launch prices and price developments of cancer drugs in the US, Germany, Switzerland and England. Methods: We identified new drugs indicated to treat solid tumors in adults that were FDA-approved between 2009 and 2019 and had also been approved by the EMA and Swissmedic by 31 December 2019. Launch prices and post-launch price changes as of 1 January 2020 were extracted and adjusted to average sales prices for monthly treatment costs in the US and compared to comparable currency-adjusted ex-factory monthly treatment costs in Germany, Switzerland, and England. A cross-sectional analysis was conducted to infer yearly trends in launch prices and post-launch price changes across the countries. Results: The study cohort included 42 drugs for solid tumors, of which 40 (95%) drugs were first approved in the US compared to Germany and England, and 41 (98%) to Switzerland. Average launch prices for monthly treatment costs per patient were $15,178 in the US vs $7,049 in Germany, $7,421 in Switzerland and $8,176 in England, i.e., 215% (interquartile range [IQR] 263%-187%), 205% (IQR 202%-185%) and 186% (IQR 166%-189%) higher in the US compared to Germany, Switzerland and England respectively. Post-launch prices of 36 (86%), 40 (95%), and 38 (90%) drugs decreased over time with total savings of monthly treatment costs for all drugs in the study cohort of $86,744, $44,936, and $1744 in Germany, Switzerland, and England respectively. By contrast, prices of 8 (19%) drugs decreased, while 34 (81%) increased post-launch in the US with total additional expenses of $128,192 for monthly treatment costs. Conclusions: Launch prices for cancer drugs are far higher in the US than in Germany, Switzerland, or England. These price disparities continue to increase substantially after market entry since cancer drug prices, in general, decrease over time in Europe and increase in the US. Spending on cancer drugs could be reduced in the US if it adopted the principles used to more effectively negotiate drug prices in Europe.

7052 Background: Initial drug approval is often based on surrogate endpoints. Definitive outcomes like Overall Survival (OS) or Quality of life (QoL) may not be available. Here, we evaluate changes in the magnitude of clinical benefit using the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) comparing the time of approval to the most recent available data for cancer drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2015. Methods: We examined data on trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006 and December 2015. We performed a systematic search of Pubmed and ClinicalTrials.gov to identify updated OS and/or QoL data, with follow up through April 2019. For AA drugs we analysed initial and confirmatory trials as follow-up. ASCO-VF and ESMO-MCBS grades were applied for trials at approval and after marketing. We explored variables associated with improved clinical benefit scores using multivariable logistic regression. Results: We identified 102 trials supporting the approval of 59 drugs for 96 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (95%) were converted to RA. At time of approval, 38% of trials showed improved OS and 17% improved QoL. Substantial clinical benefit was observed in 26% of initial approval trials using ESMO-MCSB and in 34% using ASCO-VF. After a median post-marketing period of 3.3 years, updated results changed substantial clinical benefit in 20 trials with ESMO-MCBS (19 upgrades, 1 downgrade) and in 23 trials using ASCO-VF (19 upgrades, 4 downgrades). For 25% of trials no updated information was found. In the palliative setting, multivariable analysis showed association between improved ASCO-VF scores and initial approvals based on single-arm trials (OR 9.21, 95%CI 1.36-62.29, P=0.023), drugs with companion diagnostics (OR 4.95, 95%CI 1.01-24.22, P=0.049) and second or later lines (OR 7.80, 95%CI 1.35-45.02, P=0.022) while for ESMO-MCBS, drugs with companion diagnostics (OR 6.86, 95%CI 1.82-25.86, P=0.004) and immunotherapy drugs (OR 6.42, 95%CI 1.27-32.59, P=0.025) were associated with greater clinical benefit. Conclusions: Drugs with companion diagnostic tests, immunotherapy as well as approved based on single-arm trials were associated with increased clinical benefit after marketing approval. For a quarter of trials there were no updated data in the post-marketing period.

2077 Background: A key clinical outcome for new cancer drugs is improvement in overall survival (OS), defined as time from the date of randomization to the death from any cause. However, many cancer drugs are approved by regulators based on changes to surrogate measures of OS, such as progression-free survival or overall response rate. When surrogate measures are not validated, they can provide misleading information about drug efficacy. We categorized pivotal trial endpoints for recently-approved cancer drugs in the US and Europe as showing improvements in OS vs non-OS surrogates, and evaluated the correlation with drug prices. Methods: We identified new drugs FDA-approved between 2009 and 2018 that were indicated to treat solid and hematologic tumors in adults and that had also been approved by the EMA and Swissmedic by December 2019. Launch prices were extracted and adjusted to average sales prices for monthly treatment costs in the US and compared to currency-adjusted ex-factory monthly treatment costs in Germany, Switzerland, and England. Pivotal clinical trial primary endpoints were collected from the drug labeling and FDA medical reviews for the US, and the EMA public assessment reports for Europe, and categorized as OS in any trial vs. not. Pearson’s correlation tests assessed the association between launch prices and OS vs non-OS endpoints in each country. Results: 54 drugs were approved by the FDA, EMA, and Swissmedic during the study period. In the US, 30 (56%) were approved based on OS by contrast to 35 (65%) in the EMA. The number of cancer drugs approved by the FDA based on OS decreased in the past years. By contrast, the number of approved cancer drugs by the EMA based on OS were stable. There was no association for the US (p = 0.05), Germany (p = 0.13) and England (p = 0.12), while Switzerland revealed an association (p = 0.03) between OS endpoint and price. Conclusions: Reductions in use of OS endpoints as the basis for cancer drug approval in the US is concerning. Drug pricing should be better aligned with the benefit that drugs provide to patients, as measured by clinical trial outcomes such as OS.

As COVID-19 spreads across the globe, crowdsourced digital technology harbours the potential to improve surveillance and epidemic control, primarily through increased information coverage, higher information speed, fast case tracking and improved proximity tracing. Targeting those aims, COVID-19-related smartphone and web-based health applications are continuously emerging, leading to a multitude of options, raising ethical and legal challenges and potentially overwhelming end users. Building on an existing trustworthiness checklist for digital health applications, we searched the literature and developed a framework to guide the assessment of smartphone and web-based applications that aim to contribute to controlling the current epidemic or mitigating its effects. It further integrates epidemiological subject knowledge and a legal analysis, outlining the mechanisms through which new applications can support the fight against COVID-19. The resulting framework includes 40 questions across 8 domains onldquo;purposerdquo;,ldquo;usabilityrdquo;,ldquo;information accuracyrdquo;,ldquo;organisational attributes / reputationrdquo;,ldquo;transparencyrdquo;,ldquo;privacyrdquo; andldquo;user control / self-determinationrdquo;. All questions should be primarily answerable from publicly available data, as provided by application manufacturers. The framework aims to guide end users in choosing a transparent, safe and valuable application and suggests a set of information items that developers ideally make available to allow a balanced judgement and facilitate the trustworthiness of their products.

Importance The US Department of Health and Human Services (HHS) has proposed to reform drug pricing in Medicare Part B, which primarily covers physician-administered drugs and biologic agents. One HHS proposal would shift coverage of certain drugs from Medicare Part B to Part D, which is administered by private prescription drug plans. Objective To estimate the association of changes of a shift in Medicare Part B to Part D with total drug spending and patient cost-sharing. Design, Setting, and Participants Retrospective drug cohort study of the 75 brand-name drugs associated with the highest Part B expenditures among fee-for-service Medicare beneficiaries in 2016. Main Outcomes and Measures Estimated total Medicare spending in Part B and Part D; annual out-of-pocket costs in Part B and under the standard 2018 Part D benefit; and proportion of drugs in Part D’s protected drug classes (immunosuppressants for prophylaxis of organ transplant rejection, antidepressants, antipsychotics, anticonvulsants, antiretrovirals, and antineoplastics). Results At 2018 prices, total Medicare Part B spending for the 75 brand-name drugs with the highest Part B expenditures was estimated to be $21.6 billion annually. Under the proposed policy, total Part D drug spending for these drugs was estimated to range between $17.6 billion and $20.1 billion after rebates, corresponding to a 6.9% to 18.3% decrease in drug spending in Part D compared with Part B. Of the 75 drugs studied, 33 (44.0%) drugs, accounting for $9.5 billion (43.9%) in Part B spending, were in protected Part D classes where plans must cover essentially all drugs. For 67 drugs with available information, the prices for 65 (97.0%) were a median of 45.8% to 59.7% lower in comparator high-income countries than Part B drug prices. Median patient cost-sharing in Part B for all 75 brand-name drugs was $4683 (interquartile range [IQR], $1069-$9282) per year. Shifting Part B drugs to the 2018 standard Part D benefit was projected to decrease out-of-pocket costs by a median of $860 (IQR, −$3884 to $496) among Medicare beneficiaries without Medicaid or Part B supplemental insurance (Medigap). For beneficiaries who would qualify for the low-income subsidy program in Part D, cost-sharing would be lower in Part D than in Part B for all drugs. For beneficiaries with Medigap insurance, estimated Part D out-of-pocket costs exceeded average Medigap premium costs by a median of $1460 for those with Part D coverage and by a median of $1952 for those without Part D coverage. Conclusions and Relevance Although the HHS proposal to shift certain drugs from Medicare Part B to Part D may reduce total drug spending, it may increase out-of-pocket costs for some Medicare beneficiaries, including those with Medicare supplement insurance. The Department of Health and Human Services should ensure that the proposed reforms benefit both patients and payers.

BACKGROUND Successful first-generation drugs can be converted with small alterations to "second-generation drugs," which are cheaper to develop and may pose less financial risk for manufacturers due to already validated action mechanism and a well-defined consumer market. METHODS We found four classes of cancer drugs for first- and second generation products approved in the US: BCR-ABL tyrosine kinase inhibitors (TKI) for treatment of CML, ALK + TKI for NSCLC, CD20 monoclonal antibodies for CLL, and HER2 monoclonal antibodies for breast cancer. We analyzed the characteristics of the clinical trials and the approval pathways for these 14 drugs. RESULTS First-generation and 4 out of 5 s-generation BCR-ABL TKI drugs were granted expedited approval, while all drugs were approved based on single-arm trials. Both ALK + TKI drugs were based on single-arm trials and expedited approval. The first-generation CD20 monoclonal antibody drug was approved based on single-arm trials, and one of the second-generation drugs had pivotal trials that were randomized. All benefited from expedited approval. All HER2 monoclonal antibodies in the sample were based on randomized trials and expedited pathways. CONCLUSION Second-generation TKI and monoclonal antibodies were often approved through expedited regulatory pathways and studied in single-arm trials. This helps to facilitate the approval for earlier use by patients, but is also associated with greater risk of post-approval safety-related labeling changes or unanticipated adverse events.

Accurate attenuation correction (AC) is an inherent problem of positron emission tomography magnetic resonance imaging (PET/MRI) systems. Simulation studies showed that time-of-flight (TOF) detectors can reduce PET quantification errors in MRI-based AC. However, its impact on lesion detection in a clinical setting withNon-TOF SUV was significantly lower compared to TOF in all osseous structures, except the skull, in primary lesions of the prostate, and in pelvic nodal and osseous metastasis. Concerning lymph node metastases, both experienced readers detected 16/19 (84%) on TOF PET, whereas on non-TOF PET readers 1 and 2 detected 11 (58%), and 14 (73%), respectively. With TOF PET readers 1 and 2 detected 14/15 (93%) and 11/15 (73%) bone metastases, respectively, whereas detection rate with non-TOF PET was 73% (11/15) for reader 1 and 53% (8/15) for reader 2. The interreader agreement was good for osseous metastasis detection on TOF (kappa 0.636, 95% confidence interval [CI] 0.453-0.810) and moderate on non-TOF (kappa = 0.600, CI 0.438-0.780).TOF reconstruction for

Background Given rising cancer drug costs, US Medicare recently proposed to tie some drug prices to average prices paid by comparable countries. To understand the potential scope of this policy, we assessed differences in cancer drug prices in the US and European countries. We also evaluated the correlation between drug prices and their clinical benefit, as measured by two value frameworks: the American Society of Clinical Oncology Value Framework v2 (ASCO VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale v1.1 (ESMO-MCBS). Methods We identified all new drugs for adult solid and hematologic cancers, approved by the FDA from 2009-2017 and that have also been approved by the EMA by December 31, 2018. US average sales prices (and if not available, wholesale acquisition costs) were extracted as of February 1, 2019, and compared to comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland. ASCO VF and ESMO-MCBS scores were assessed for pivotal trials supporting solid tumor drugs; in case of multiple trials, we focused on the highest score. Consistent with the developers of the rating scales, “high benefit” was defined as scores of A-B (neo/adjuvant setting) and 4-5 (palliative setting) on the ESMO-MCBS scale and scores ≥45 on the ASCO VF. Linear regression models and non-parametric Kruskal-Wallis test and were used to assess the association between drug prices and benefit scores. Results The study cohort included 63 drugs approved by the FDA and the EMA during the study period. 46 (73%) were approved for solid tumors, and 17 (27%) were approved for hematologic malignancies. Overall, median cancer drug prices in Europe were 52% (interquartile range: 37-72%) lower than US prices. There was no association between monthly treatment cost and ASCO-VF or ESMO-MCBS scores in any country. There was also no association between price differential between US and median European drug prices and either ASCO-VF (P = 0.599) or ESMO-MBCS (P = 0.321) scores. Conclusions Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries. Cancer drug prices in the US were significantly higher than in the compared European countries. Legal entity responsible for the study University of Zurich. Funding Swiss Cancer League. Disclosure All authors have declared no conflicts of interest.

ObjectiveTo determine differences in the characteristics of cancer drugs designated as orphan drugs by the Food and Drug Administration (FDA) and European Medicines Agency (EMA).Design and settingIdentification of all cancer drugs (initial or supplementary indication) with orphan status approved by the FDA between 2008–2017 based on publicly accessible reports. The European public assessment reports (EPAR) was searched to determine whether these FDA-approved drugs were also approved by the EMA.Main outcome measuresExtraction of active ingredient, trade name, approval date and approved indication from two FDA data sources (Orphan Drug Product Designation Database, Drugs@FDA) and comparison with the same data from EPAR.ResultsThe FDA approved 135 cancer drugs with orphan indications that met our inclusion criteria, of which 101 (75%) were also approved by the EMA. 80/101 (79%) were first approved in the USA. Only 41/101 (41%) also received orphan designation by the EMA. 33/101 (33%) were approved for biomarker-based indications in the USA, however, only nine approved cancer drug indications by the EMA were biomarker-derived drugs. 78% (47/60) of approved cancer drugs that were only approved in the USA with orphan status were indicated for solid tumours, 22% (13/60) had indications for non-solid tumours. By contrast, out of those approved cancer drugs that received orphan designation by both agencies, 20% (8/41) were indicated for solid, and 80% (33/41) for non-solid tumours.ConclusionsOrphan designation was intended to encourage drug development for rare conditions. This study shows that the FDA approves more cancer drugs with such designations compared with the EMA, especially for subgroups of more prevalent cancers. One reason for the difference could be that the European Union requires demonstration of significant benefit for drugs that target the same indication as a drug already on the market to earn the orphan designation.

6638 Background: Given rising cancer drug costs, Medicare recently proposed to tie some US drug prices to average prices paid by comparable countries. To understand the potential scope of this policy, we assessed differences in cancer drug prices in the US and selected European countries. We also evaluated the correlation between drug prices and their clinical benefit, as measured by two value frameworks: the American Society of Clinical Oncology Value Framework v2 (ASCO VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale v1.1 (ESMO-MCBS). Methods: We identified all new drugs for adult solid and hematologic cancers, approved by the FDA from 2009-2017 and that have also been approved by the EMA by December 31, 2018. US average sales prices (and if not available, wholesale acquisition costs) were extracted as of February 1, 2019, and compared to comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland. ASCO VF and ESMO-MCBS scores were assessed for pivotal trials supporting solid tumor drugs; in case of multiple trials, we focused on the highest score. Consistent with the developers of the rating scales, “high benefit” was defined as scores of A-B (neo/adjuvant setting) and 4-5 (palliative setting) on the ESMO-MCBS scale and scores≥45 on the ASCO VF. Linear regression models and non-parametric Kruskal-Wallis test and were used to assess the association between drug prices and benefit scores. Results: The study cohort included 63 drugs approved by the FDA and the EMA during the study period. 46 (73%) were approved for solid tumors, and 17 (27%) were approved for hematologic malignancies. Overall, median cancer drug prices in included European countries were 52% (interquartile range: 37-72%) lower than US prices. There was no statistically significant association between monthly treatment cost and ASCO-VF or ESMO-MCBS scores in any country. There was also no association between price differential between US and median European drug prices and either ASCO-VF (P = 0.599) or ESMO-MBCS (P = 0.321) scores. Conclusions: Cancer drug prices in the US were significantly higher than in the compared European countries. Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries.

Increasing prescription drug expenditures in the United States are primarily driven by high brand-name drug prices. Although generic competition helps lower drug prices, manufacturers of brand-name drugs often work to delay the availability of generic versions of their products. Strategies to forestall generic competition include patenting peripheral aspects of a drug or modified formulations that do not add clinical value, paying generic manufacturers to settle lawsuits challenging the validity of patents on brand-name drugs ("reverse payment" settlements), denying generic manufacturers access to drug samples necessary for bioequivalence testing, misusing risk evaluation and mitigation strategies, and filing citizen petitions with the US Food and Drug Administration (FDA). To address such tactics, the federal government can interpret existing patenting standards more strictly and promote certain types of patent challenges to ensure that patents are granted or upheld only for true innovations. Congress can enact pending legislation that would help discourage reverse payment settlements and compel brand-name manufacturers to share drug samples for bioequivalence testing. Finally, the FDA can provide earlier guidance on bioequivalence determinations for complex generic products and adopt the presumption that late-filed citizen petitions should be summarily rejected.

Background: Tamoxifen is frequently used for the treatment of hormone receptor positive breast cancer (BC). Mainly CYP2D6 is responsible for the transformation to therapeutically active metabolites, but CYP2C19, CYP2C9 and CYP2B6 also are involved. We investigated the impact of polymorphisms within the genes encoding these CYP enzymes on the relapse-free time (RFT) in patients with BC. Methods: Ninety-nine patients with hormone receptor positive BC, who had undergone adjuvant tamoxifen therapy, were genotyped for seventeen common variants within the genes encoding CYP2D6, CYP2C9, CYP2C19 and CYP2B6 using TaqMan and PCR-RFLP technology. Kaplan-Meier and Cox regression analyses were performed to elucidate the impact of genetic variants on RFT. Furthermore, CYP2D6 metabolic activity was determined in a subset of 50 patients by assessing dextromethorphan/dextrorphan urinary excretion ratios. CYP2D6 activity was compared to the CYP2D6 allelic combinations to evaluate the predictive value of the CYP2D6 genotyping results on phenotype. Results: Although a trend toward longer RFTs in carriers of CYP2D6 allele combinations encoding for extensive and ultrafast metabolizer phenotypes was observed, none of the investigated genetic variants had a statistically significant impact on RFT. The combined analysis of five major CYP2D6 variants was useful for the discrimination between poor and non-poor metabolizers. Conclusions: Comprehensive CYP2D6 genotyping has a good predictive value for CYP2D6 activity. Common variants in CYP2C9, CYP2C19, CYP2D6, and CYP2B6 did not have a significant impact on the RFT in this cohort of patients with BC.