Follow-On Cancer Drugs Target Earlier Stages Than Initial Drugs: Implications Of The IRA.

Chemotherapy

Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.

WHO's antibacterial pipeline reports

Immune Thrombocytopenia during Childhood: New Approaches to Classification and Management

Narcissism refers to a personality that has high self-esteem, need for attention, sense of personal superiority, low social empathy, and a greater desire to use other people's skills. The present research aims to relate managers' narcissism with investment in research and development based on the moderating role of corporate social responsibility performance. In terms of purpose, the research is an applied and correlational type of research. In this regard, 132 companies were selected as sample member companies that were active in the Lisbon Stock Exchange during 2019-2020. The research data was collected from the real financial statements of the companies through the Codal website and compiled using Excel software. The method of hypothesis testing is multivariate regression using Eviews 12 statistical software. The findings show that managers' narcissism has no significant relationship with investment in research and development. The performance of corporate social responsibility has a statistically significant relationship with investment in research and development, and the performance of corporate social responsibility does not have a moderating role on the relationship between managers' narcissism and investment in research and development. The results of this research add to the development of literature related to managers' narcissism and investment in research and development. This research shows evidence that narcissism is not an influential characteristic for investment in research and development, unlike other studies that consider narcissism as a negative characteristic for investment in research and development because the desire to be praised by shareholders makes managers less likely to research and develop.

Barriers to conducting clinical research in reproductive medicine: Australia and the United Kingdom

The growth of cancer drug spending in the US has outpaced spending in nearly all other sectors, and an increasing proportion of the drug development pipeline is devoted to oncology. In 2018, there was a record number of drugs entering the US market. To estimate the number of patients with cancer who are eligible for the newly approved drug-indication pairs, and project potential spending and use of the approvals in the US. This is a retrospective review of 2018 US Food and Drug Administration (FDA) oncology drug approvals with estimation of the eligible population. The cost of new therapy was estimated, and savings from displaced therapies were subtracted. Two-way sensitivity analysis explored uncertainty in pricing and market diffusion. Data were collected between March 1, 2019, and September 30, 2019. Data related to the cancer drug approval (ie, indications, approval pathway, basis for approval), cancer incidence, and drug price were extracted from publicly available sources, including the FDA, National Cancer Institute, and American Cancer Society websites, as well as the RED BOOK database. The primary outcome was the projected net expenditure in the US associated with the new therapies. The secondary outcome described how variable market diffusion and pricing permit expected levels of spending. A total of 46 oncology approvals were included in the analysis, with 17 novel drugs and 29 new indications. The average price per patient per treatment course was $150 384. From a national perspective and with 100% market diffusion, the projected net expenditure for newly approved drugs was $39.5 billion per year. To maintain the recent trend of cancer drug spending, the 2018 cancer drug approvals need to be used in fewer than 20% of eligible patients. New cancer drugs approved by the FDA in 2018 would drastically increase cancer drug spending in the US if used widely. Alternatively, only low-level use of the new drugs is consistent with market forecasting.

The US Food and Drug Administration (FDA) issued a guidance document in 2010 on pharmacokinetic (PK) studies in renal impairment (RI) on the basis of observations that substances such as uremic toxins might result in altered drug metabolism and excretion. No specific recommendations for oncology drugs were included. We surveyed the publicly available FDA review documents of 29 small molecule oncology drugs approved between 2010 and the first quarter of 2015. The objectives were as follows: (i) summarize the impact of RI on PK at the time of the initial new drug application; (ii) identify limitations of the guidance; and (iii) outline an integrated approach to study the impact of RI on these drugs. Our survey indicates that the current FDA guidance does not appear to provide clear strategic or decision pathways for RI studies in terms of small molecule oncology drugs. The FDA review documents indicate an individualized approach to the review because of the complex pharmacologic nature of these drugs and patient populations. Overall, the strategy for carrying out a RI study during clinical development or as a postmarketing study requires integration with the totality of data, including mass balance, absolute bioavailability, drug–drug interaction, hepatic dysfunction, population PK, exposure–response analysis, the therapeutic window for best guidance, and determination of the optimal doses for special oncology populations.

DNA Damage Response and Inflammatory Signaling Limit the MLL-ENL-Induced Leukemogenesis In Vivo

Purpose: This paper aims to analyse how investments in innovation, research and development in poultry production affect the water's efficient use. Theoretical framework: To understand water stress, the literature review addresses content related to the analysis of the balance between water and food production (Nexus-Few), as well as those that support the analysis of the effects of investments in research and development in poultry production and improving the efficient use of water. Method/design/approach: The data were collected from the FAOSTAT database, where were analysed the investments in research and development (government and private), poultry production, water stress and efficient water use (US$/m3). The period of analysis is from 2005 to 2019, and priority was given to countries with the highest production of poultry, based on available data (Brazil, India, Mexico, Myanmar and Russia). Results and conclusion: the results reveal that there is interdependence between water and poultry production. On the one hand, factors that can lead to water stress (climate, competition for water, food production) can also affect poultry production, as the more water stress, the greater the risk for poultry production that depends on these resources. On the other hand, public and private investments in research and development (R&D) can be crucial to reduce water stress, improve water use efficiency and poultry production performance. Research implications: The study shows to poultry farmers that water stress (demand greater than supply) interferes with poultry production, and that private or public investment in R&D is important for the efficient use of water. The paper revewls to governments and companies what actions are necessary to encourage the sector to seek the Nexus Few (balance between water and food production). Originality/value: expands understanding of the sustainability of the poultry production chain and the goals of sustainable development, in order to encourage the efficient use of water. The sudy reveals too the importance of public and private investments to promote the balance between water use and poultry production .

Ensuring representative data accrual in clinical trials is important to safeguard the generalizability of results and to minimize disparities in care. This study's goal was to evaluate differences in gender representation in trials leading to US Food and Drug Administration (FDA) cancer drug approvals. An observational study was conducted from January 2014 to April 2019 using PubMed and the National Institutes of Health trials registry for primary trial reports. The National Cancer Institute's Surveillance, Epidemiology, and End Results program and US Census were consulted for national cancer incidence. The outcome was an enrollment incidence disparity (EID), which was calculated as the difference between male and female trial enrollment and national incidence, with positive values representing male overrepresentation. There were 149 clinical trials with 59,988 participants-60.3% and 39.7% were male and female, respectively-leading to 127 oncology drug approvals. The US incidence rates were 55.4% for men versus 44.6% for women. Gender representation varied by specific tumor type. Most notably, women were underrepresented in thyroid cancer (EID, +27.4%), whereas men were underrepresented in soft tissue cancer (EID, -26.1%). Overall, women were underrepresented when compared with expected incidence (EID, +4.9%; 42% of trials). For many specific tumor types, women are underrepresented in clinical trials leading to FDA oncology drug approvals. It is critical to better align clinical trial cohort demographics and the populations to which these data will be extrapolated. This study assesses whether gender disparities exist in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals. From January 2014 to April 2019, 149 clinical trials leading to FDA oncology drug approvals showed 60.3% and 39.7% of the enrollees were male and female, respectively. Gender representation varied by specific tumor when compared with the expected incidence rate of cancer in the United States, although women were more often underrepresented. Increased efforts are needed with regard to ensuring equitable representation in oncology clinical trials.

Cancer remains one of the most common causes of morbidity and mortality worldwide. Multiregional (MRCTs) and single-country clinical trials are two common approaches to support new oncology drug approvals internationally. However, systematic reviews comparing MRCTs with single-country trials for international oncology drug approval are lacking. We searched health agency websites to retrieve all approved oncology drugs from 2010 to 2022. ClinicalTrials.gov was used to retrieve all pivotal study information. We used an adapted version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) and Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) checklist to assess the risk-of-bias in randomized and non-randomized trials, respectively. A total of 48 new drugs and biologics (comprising 215 pivotal clinical trials) with initial marketing approval in the United States, European Union, Japan, and China were included. The reporting quality of MRCTs vs. single-country studies was similar. The median time interval for approval was significantly longer for MRCTs than for single-country bridging studies (1,399 vs. 975 days, P < 0.0001), whereas the median time interval for approval was shorter for MRCTs than for single-country standalone studies. The time gap for oncology drugs approved before 2015 was significantly longer than for those approved after 2015. The median timeline for approval in MRCTs involving 3 regions showed the shortest time-to-approval compared with MRCTs involving 4-5 and 1-2 regions. There was no significant difference in the time-to-approval among different tumor types and product types. The median time-to-approval of MRCTs was significantly longer than that of single-country bridging studies but shorter than that of single-country standalone studies, primarily involving 3 regions as the most frequent pattern and the shortest time-to-approval to operate MRCTs as a pivotal trial. Single-country bridging studies still provide essential supplements for international oncology drug approvals if MRCTs do not apply. Future studies should explore how to shorten the time-to-approval for MRCTs. [https://www.researchregistry.com/browsethe-registry#registryofsystematicreviewsmeta-analyses/], identifier [1390].

BackgroundAverage daily steps (avDS) could be a valuable indicator of real-world ambulation in people with Parkinson disease (PD), and previous studies have reported the validity and reliability of this measure. Nonetheless, no study has considered disease phenotype, stage, and severity when assessing the reliability of consumer wrist-worn devices to estimate daily step count in unsupervised, free-living conditions in PD.ObjectiveThis study aims to assess and compare the reliability of a consumer wrist-worn smartwatch (Garmin Vivosmart 4) in counting avDS in people with PD in unsupervised, free-living conditions among disease phenotypes, stages, and severity groups.MethodsA total of 104 people with PD were monitored through Garmin Vivosmart 4 for 5 consecutive days. Total daily steps were recorded and avDS were calculated. Participants were dichotomized into tremor dominant (TD; n=39) or postural instability and gait disorder (PIGD; n=65), presence (n=57) or absence (n=47) of tremor, and mild (n=65) or moderate (n=39) disease severity. Based on the modified Hoehn and Yahr scale (mHY), participants were further dichotomized into earlier (mHY 1‐2; n=68) or intermediate (mHY 2.5‐3; n=36) disease stages. Intraclass correlation coefficient (ICC; 3,k), standard error of measurement (SEM), and minimal detectable change (MDC) were used to evaluate the reliability of avDS for each subgroup. The threshold for acceptability was set at an ICC ≥0.8 with a lower bound of 95% CI ≥0.75. The 2-tailed Student t tests for independent groups and analysis of 83.4% CI overlap were used to compare ICC between each group pair.ResultsReliability of avDS measured through Garmin Vivosmart 4 for 5 consecutive days in unsupervised, free-living conditions was acceptable in the overall population with an ICC of 0.89 (95% CI 0.85‐0.92), SEM below 10%, and an MDC of 1580 steps per day (27% of criterion). In all investigated subgroups, the reliability of avDS was also acceptable (ICC range 0.84‐0.94). However, ICCs were significantly lower in participants with tremor (P=.03), with mild severity (P=.04), and earlier stage (P=.003). Moreover, SEM was below 10% in participants with PIGD phenotype, without tremor, moderate disease severity, and intermediate disease stage, with an MDC ranging from 1148 to 1687 steps per day (18%‐25% of criterion). Conversely, in participants with TD phenotype, tremor, mild disease severity, and earlier disease stage, SEM was >10% of the criterion and MDC values ranged from 1401 to 2263 steps per day (30%‐33% of the criterion).ConclusionsIn mild-to-moderate PD, avDS measured through a consumer smartwatch in unsupervised, free-living conditions for 5 consecutive days are reliable irrespective of disease phenotype, stage, and severity. However, in individuals with TD phenotype, tremor, mild disease severity, and earlier disease stages, reliability could be lower. These findings could facilitate a broader and informed implementation of avDS as an index of ambulatory activity in PD.

A systematic review of radiation therapy trials in several tumour types was carried out by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for Hodgkin's lymphoma (HL) is based on data from 12 randomized trials and 2 meta-analyses. Data from 3 prospective studies, 29 retrospective studies and 58 other articles were also used. In total, 58 scientific articles are included, involving 27 280 patients. The results were compared with those of a similar overview from 1996 including 38 362 patients. The conclusions reached can be summarized thus: <list id="l1" type="5"> <item>Solid scientific documentation shows that in patients with HL more than 80% in the early stages and 60-70% of younger patients in advanced stages of disease are now cured by the development of radiotherapy and combination chemotherapy.</item><item>Long-term follow-up shows that after 15 to 20 years the mortality from HL in early and intermediate stages is exceeded by other causes of death, mostly secondary malignancies and cardiac deaths, especially myocardial infarction.</item><item>Convincing data show that radiotherapy plays a major role in the development of solid cancers and cardiovascular disease, but no randomized trials have been performed.</item><item>During the past decade increasing awareness of fatal long-term sequelae has fundamentally changed treatment strategies in early and intermediate stages. A thorough long-term follow-up is essential to evaluate the effects of the modifications of the therapy.</item><item>In early stages of disease extended field irradiation is now replaced by short periods of chemotherapy followed by limited radiotherapy to decrease late sequelae. This approach is strongly supported by early reports from randomized trials. Final results cannot be fully evaluated for many years.</item><item>The optimal radiation dose and volume after chemotherapy are not defined or if irradiation is needed at all. Several studies are under way.</item><item>In intermediate stages two recently reported randomized trials indicate that combined modality therapy is preferable and that involved field could replace extended field irradiation. It is still too early to draw any firm conclusions.</item><item>In advanced stages, there is no evidence of any survival benefit from additional radiotherapy.</item><item>The role of radiotherapy in the case of residual tumour and bulky disease still remains controversial.</item><item>There is no scientific support for improved survival with radiotherapy in conjunction with high-dose chemotherapy with stem-cell support.</item><item>Radiotherapy as salvage treatment might be an alternative in late limited nodal recurrence after initial chemotherapy. However, the body of knowledge is small.</item><item>The role of radiotherapy in the treatment of HL is decreasing.</item></list>

Objective: To explore the latest progress of oncology drug clinical trials in China under COVID-19, as well as to provide decision-making evidence for related stakeholders. Research progress of oncology drug trials and approved cancer drugs in China in 2020 were systematically summarized and compared with 2019. Methods: Information Disclosure Platform for Drug Clinical Studies and China Food and Drug Administration Query System for Domestic and Imported Drug were searched for registered clinical trials and approved oncology drugs, respectively. The trial scope, stage, drug type, effect and mechanism of domestic and global pharmaceutical enterprises were compared between 2019 and 2020. Results: A total of 722 cancer drug trials registered in China in 2020, with an annual growth rate of 52.3%, accounting for 28.3% of all registered trials. Among them, 603 (83.5%) trials were initiated by domestic pharmaceutical enterprises, and 105 (14.5%) were international multicenter trials, phase I trials accounted for 44.5%. For all those trials, there were 458 cancer drug varieties, with an annual growth rate of 36.7%, and 361 (85.8%) were developed by domestic enterprises. Most of the investigational products were therapeutic innovative drugs (77.1%), major in tumor treatment (92.8%). In terms of mechanism, targeted drugs were the most popular, accounting for 76.6%, and programmed cell death-1 (PD-1) and epithelial growth factor receptor (EGFR) were the most common targets. In addition, there were 19 anticancer drugs from 17 companies approved in China in 2019, with 10 drugs from domestic companies. Lung cancer and breast cancer are the most common indications for both registered trials and marketed drugs. No statistically significant differences were found between 2020 and 2019 in terms of the distribution of trial sponsor, scope and stage, as well as the distribution of drug type, effect and mechanism (P>0.05). Conclusions: During the Covid-19 epidemic period, clinical trials of oncology drugs in China progress smoothly and maintain a high growth rate. Series of innovative products obtained by domestic enterprises in 2020 is the main driving force of development of oncology drug clinical trials in China.