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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).

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.

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.

The Lancet Digital Health, 3 (6), ISSN:2589-7500

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.

Federal Supreme Court Decisions in Medical Law (2000-2017) - Overview and Selected Case Reports Abstract. Within the framework of an empirical and casuistic analysis of Federal Court decisions in medical law between 2000 and 2017, the goal was to describe tendencies and patterns of Federal Court decisions in medical law. Among other things, our results show that specialists in internal medicine, psychiatry, gynecology, obstetrics and surgery are more frequently involved in federal court proceedings. By contrast, pathologists, forensic specialists or (diagnostic) radiologists are rarely represented. This may be explained by the fact that the first group consists of more physicians than the other specialties. Furthermore, in the first group, either stronger action may be taken against the will of the patient (e.g. in the context of compulsory medication in psychiatry) or a possible breach of the duty of care is more obvious for the patient or his relatives or at least recognizable even without medical knowledge.Zusammenfassung. Im Rahmen einer empirischen und kasuistischen Analyse arztrechtlicher Bundesgerichtsurteile zwischen 2000 und 2017 war das Ziel, Tendenzen und Muster der bundesgerichtlichen Rechtsprechung zum Arztrecht zu beschreiben. Unter anderem zeigte das Ergebnis, dass Fachärzte der Inneren Medizin, Psychiatrie, Gynäkologie und Geburtshilfe sowie Chirurgie verhältnismässig häufig involviert sind in bundesgerichtliche Verfahren. Demgegenüber sind Pathologen, Rechtsmediziner oder (diagnostische) Radiologen selten vertreten. Dies kann möglicherweise damit erklärt werden, dass der ersten Gruppe im Verhältnis zu den anderen Facharztrichtungen mehr Ärzte angehören. Des Weiteren wird in der ersten Gruppe entweder stärker gegen den Patientenwillen (z.B. im Rahmen der Zwangsmedikation in der Psychiatrie) vorgegangen oder eine eventuelle Sorgfaltspflichtverletzung ist für den Patienten bzw. seine Angehörigen offensichtlicher bzw. auch ohne medizinische Kenntnisse zumindest erkennbar.

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.

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.

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.