Costs and causes of oncology drug attrition with the example of insulin-like growth factor-1 receptor inhibitors

Importance: The development of oncology drugs is expensive and beset by a high attrition rate. Analysis of the costs and causes of translational failure may help to reduce attrition and permit the more appropriate use of resources to reduce mortality from cancer. Objective: To analyze the causes of failure and expenses incurred in clinical trials of novel oncology drugs, with the example of insulin-like growth factor-1 receptor (IGF-1R) inhibitors, none of which was approved for use in oncology practice. Design, Setting, and Participants: In this cross-sectional study, inhibitors of the IGF-1R and their clinical trials for use in oncology practice between January 1, 2000, and July 31, 2021, were identified by searching PubMed and ClinicalTrials.gov. A proprietary commercial database was interrogated to provide expenses incurred in these trials. If data were not available, estimates were made of expenses using mean values from the proprietary database. A search revealed studies of the effects of IGF-1R inhibitors in preclinical in vivo assays, permitting calculation of the percentage of tumor growth inhibition. Archival data on the clinical trials of IGF-1R inhibitors and proprietary estimates of their expenses were examined, together with an analysis of preclinical data on IGF-1R inhibitors obtained from the published literature. Main Outcomes and Measures: Expenses associated with research and development of IGF-1R inhibitors. Results: Sixteen inhibitors of IGF-1R studied in 183 clinical trials were found. None of the trials, in a wide range of tumor types, showed efficacy permitting drug approval. More than 12000 patients entered trials of IGF-1R inhibitors in oncology indications in 2003 to 2021. These trials incurred aggregate research and development expenses estimated at between $1.6 billion and$2.3 billion. Analysis of the results of preclinical in vivo assays of IGF-1R inhibitors that supported subsequent clinical investigations showed mixed activity and protocols that poorly reflected the treatment of advanced metastatic tumors in humans. Conclusions and Relevance: Failed drug development in oncology incurs substantial expense. At an industry level, an estimated $50 billion to$60 billion is spent annually on failed oncology trials. Improved target validation and more appropriate preclinical models are required to reduce attrition, with more attention to decision-making before launching clinical trials. A more appropriate use of resources may better reduce cancer mortality.

The contribution of unstable housing to HIV and hepatitis C virus transmission among people who inject drugs globally, regionally, and at country level:a modelling study

BACKGROUND: A considerable proportion of people who inject drugs are unstably housed. Although unstable housing is associated with HIV and HCV infection among people who inject drugs, its contribution to transmission is unknown. We estimated the global and national proportions of incident HIV and HCV infections among people who inject drugs attributed to housing instability from 2020 to 2029. METHODS: In this modelling study, we developed country-level models of unstable housing and HIV and HCV transmission among people who inject drugs in 58 countries globally, calibrated to country-specific data on the prevalences of HIV and HCV and unstable housing. Based on a recently published systematic review, unstably housed people who inject drugs were assumed to have a 39% (95% CI 6–84) increased risk of HIV transmission and a 64% (95% CI 43–89%) increased risk of HCV transmission. We used pooled country-level estimates from systematic reviews on HCV and HIV prevalence in people who inject drugs. Our models estimated the transmission population attributable fraction (tPAF) of unstable housing to HIV and HCV transmission among people who inject drugs, defined as the percentage of infections prevented from 2020 to 2029 if the additional risk due to unstable housing was removed. FINDINGS: Our models were produced for 58 countries with sufficient data (accounting for >66% of the global people who inject drugs population). Globally, we project unstable housing contributes 7·9% (95% credibility interval [CrI] 2·3–15·7) of new HIV infections and 11·2% (7·7–15·5) of new HCV infections among people who inject drugs from 2020 to 2029. Country-level tPAFs were strongly associated with the prevalence of unstable housing. tPAFs were greater in high-income countries (HIV 17·2% [95% CrI 5·1–30·0]; HCV 19·4% [95% CrI 13·8–26·0]) than in low-income or middle-income countries (HIV 6·6% [95% CrI 1·8–13·1]; HCV 8·3% [95% CrI 5·5–11·7]). tPAFs for HIV and HCV were highest in Afghanistan, Czech Republic, India, USA, England, and Wales where unstable housing contributed more than 20% of new HIV and HCV infections. INTERPRETATION: Unstable housing is an important modifiable risk factor for HIV and HCV transmission among people who inject drugs in many countries. The study emphasises the importance of implementing initiatives to mitigate these risks and reduce housing instability. FUNDING: National Institute for Health Research and National Institute of Allergy and Infectious Diseases and National Institute for Drug Abuse

The Potential Impact of a Hepatitis C Vaccine for People Who Inject Drugs:Is a Vaccine Needed in the Age of Direct-Acting Antivirals?

Background and Aims: The advent of highly effective hepatitis C (HCV) treatments has questioned the need for a vaccine to control HCV amongst people who inject drugs (PWID). However, high treatment costs and ongoing reinfection risk suggest it could still play a role. We compared the impact of HCV vaccination amongst PWID against providing HCV treatment.\ud \ud Methods: Dynamic HCV vaccination and treatment models among PWID were used to determine the vaccination and treatment rates required to reduce chronic HCV prevalence or incidence in the UK over 20 or 40 years. Projections considered a low (50% protection for 5 years), moderate (70% protection for 10 years) or high (90% protection for 20 years) efficacy vaccine. Sensitivities to various parameters were examined.\ud \ud Results: To halve chronic HCV prevalence over 40 years, the low, moderate and high efficacy vaccines required annual vaccination rates (coverage after 20 years) of 162 (72%), 77 (56%) and 44 (38%) per 1000 PWID, respectively. These vaccination rates were 16, 7.6 and 4.4 times greater than corresponding treatment rates. To halve prevalence over 20 years nearly doubled these vaccination rates (moderate and high efficacy vaccines only) and the vaccination-to-treatment ratio increased by 20%. For all scenarios considered, required annual vaccination rates and vaccination-to-treatment ratios were at least a third lower to reduce incidence than prevalence. Baseline HCV prevalence had little effect on the vaccine's impact on prevalence or incidence, but substantially affected the vaccination-to-treatment ratios. Behavioural risk heterogeneity only had an effect if we assumed no transitions between high and low risk states and vaccinations were targeted or if PWID were high risk for their first year.\ud \ud Conclusions: Achievable coverage levels of a low efficacy prophylactic HCV vaccine could greatly reduce HCV transmission amongst PWID. Current high treatment costs ensure vaccination could still be an important intervention option

Socio-demographic and ecological factors associated with anti-HCV prevalence in people who inject drugs:a systematic review

Background: The World Health Organization (WHO) aim to eliminate hepatitis C virus (HCV) as a public health threat by 2030. People who inject drugs (PWID) are a key risk group for HCV transmission globally. We explored socio-demographic and ecological variables associated with HCV antibody (anti-HCV) prevalence among samples of PWID. Methods: We systematically searched for and screened journal articles and online reports published between January 2011 and June 2017. Serologically confirmed anti-HCV prevalence among PWID and other study-level socio-demographic variables were extracted. Country-level ecological indicators were sourced from online databases. We used generalized linear models to investigate associations between anti-HCV prevalence estimates and other study-level and country-level variables. Results: There were 223 studies from 84 countries contributing 569 estimates of anti-HCV prevalence among PWID. Among study-level indicators, higher levels of anti-HCV prevalence were associated with higher HIV prevalence (B = 0.20; 95 % Confidence Interval [95 %CI] = 0.12, 0.29, p < 0.001) and year of data collection (B=−0.08; 95 %CI=−0.15, −0.02; p = 0.011). At a national level, higher Human Development Index scores (B=4.37; 95 %CI=0.12, 8.63, p = 0.044) were associated with higher levels of anti-HCV in samples. Implications: Serological surveillance data are increasingly available globally; however, there are still geographical gaps in quantification of HCV prevalence among PWID that must be addressed to inform efforts to achieve HCV elimination. Anti-HCV prevalence was lower in samples of PWID from countries with lower Human Development Index scores, which points to an opportunity to provide targeted intervention and potentially control transmission rates of infection in countries characterized by poor population health, education, and income

A quasi-experimental evaluation of dried blood spot testing through community pharmacies in the Tayside region of Scotland

Objective Comparison of uptake of dried blood spot testing (DBST) for hepatitis C virus (HCV) infection between community pharmacies and established services.&nbsp; Design Quantitative evaluation of a service development with qualitative process evaluation undertaken in parallel.&nbsp; Setting Six pharmacies from 36 community pharmacies within Dundee City, a large urban settlement with high levels of socioeconomic deprivation.&nbsp; Participants Patients in receipt of opioid substitution therapy (OST) not tested for HCV within 12 months. The 6 pharmacies provided OST for approximately 363 patients from a cohort of 1385 patients within Dundee City.&nbsp; Intervention Provision of DBST by pharmacists.&nbsp; Main outcome measure Receipt of DBST between January and December 2014.&nbsp; Results 43 of 143 service users with no record of testing from the 6 community pharmacies accepted DBST. Of 561 from the remaining 1022 service users with no record of testing, 75 were tested for HCV (30% vs 13%). The OR for increased uptake of testing within the 6 pharmacies was 2.25 (95% CI 1.48 to 3.41, Z statistic=3.81, p=&lt;0.0001) compared with other services. The DBST taken by the pharmacies provided 12 patients with a reactive test. The process evaluation identified key themes important to staff and recipients of the service. A logic model was constructed.&nbsp; Limitations Non-experimental service evaluation performed in community pharmacies records service activity in one location across a single time period.&nbsp; Interpretation Some evidence that DBST from community pharmacies may be feasible. Service users received the service positively. Staff reported that DBST was straightforward and achievable

The prevalence of non-fatal overdose among people who inject drugs:a multi-stage systematic review and meta-analysis

People who inject drugs (PWID) are at an elevated risk of fatal overdose in the first year after experiencing a non-fatal event. Such non-fatal events may also result in overdose-related sequelae, ranging from physical injury to paralysis. Given variation in drug markets and treatment availability across countries and regions, we may see similar variations in non-fatal overdose prevalence. Monitoring non-fatal overdose prevalence among PWID is essential for informing treatment intervention efforts, and thus our review aims to estimate the global, regional, and national prevalence of non-fatal overdose, and determine characteristics associated with experiencing such an event.We conducted a systematic review and meta-analyses to estimate country, regional, and global estimates of recent and lifetime non-fatal overdose prevalence among PWID. Using meta-regression analyses we also determined associations between sample characteristics and non-fatal overdose prevalence.An estimated 3.2 (1.8-5.2) million PWID have experienced at least one overdose in the previous year. Among PWID, 20.5% (15.0-26.1%) and 41.5% (34.6-48.4%) had experienced a non-fatal event in the previous 12 months and lifetime respectively. Frequent injecting was strongly associated with PWID reporting recent and lifetime non-fatal overdose. Estimates of recent non-fatal overdose were particularly high in Asia and North America.Around one in five PWID are at an elevated risk of fatally overdosing every year, however there is substantial geographical variation. In countries with higher rates of non-fatal overdose there is need to introduce or mainstream overdose prevention strategies such as opioid agonist treatment and naloxone administration training programs

Co-production of an educational package for the universal human papillomavirus (HPV) vaccination programme tailored for schools with low uptake:A participatory study protocol

AIM: To co-produce with young people an educational package about the human papillomavirus (HPV) vaccine that is tailored to increase vaccine uptake in schools and populations with lower uptake. INTRODUCTION: Persistent infection with HPV can result in cancers affecting men and especially women. From September 2019, the English-schools-based HPV vaccination programme was expanded to include young men (in addition to young women) aged 12-13 years. Some young people attending schools with lower uptake of the vaccine have unmet information needs. We hypothesise that mechanisms to address information needs and increase young people's autonomy in consent procedures will result in higher uptake. METHODS AND ANALYSIS: The Medical Research Council's framework for development and evaluation of complex interventions will inform intervention development. Recruitment of young people aged 12-15 years and key stakeholders (National Health Service commissioners, school staff, immunisation nurses and youth workers/practitioners) will be facilitated through existing links with healthcare organisations, schools and youth organisations in areas with lower uptake of the HPV vaccination programme. The proposed research will comprise three phases: (1) a rapid review of adolescent immunisation materials and preliminary qualitative interviews with young people and key stakeholders, (2) theory development and co-production of HPV vaccine communication materials through an iterative process with young people and (iii) testing delivery mechanisms and acceptability of the educational package in four schools with lower uptake. ETHICS AND DISSEMINATION: The University of Bristol's Faculty of Health Sciences and London School of Hygiene and Tropical Medicine's Research Ethics Committees provided approvals for the study. A dissemination event for young people and key stakeholders and webinar with the National Immunisation Network will be organised. The study findings will be published in peer-reviewed journals and presented at conferences. Recommendations for a future larger scale study will be made

Impact of HCV testing and treatment on HCV transmission among men who have sex with men and who inject drugs in San Francisco: A modelling analysis

BACKGROUND: Men who have sex with men who ever injected drugs (ever MSM-IDU) carry a high hepatitis C virus (HCV) burden. We estimated whether current HCV testing and treatment in San Francisco can achieve the 2030 World Health Organization (WHO) HCV elimination target on HCV incidence among ever MSM-IDU. METHODS: A dynamic HCV/HIV transmission model among MSM was calibrated to San Francisco data, including HCV antibody (15.5%, 2011) and HIV prevalence (32.8%, 2017) among ever MSM-IDU. MSM had high HCV testing (79%-86% ever tested, 2011-2019) and diagnosed MSM had high HCV treatment (65% ever treated, 2018). Following coronavirus disease 2019 (COVID-19)-related lockdowns, HCV testing and treatment decreased by 59%. RESULTS: Among all MSM, 43% of incident HCV infections in 2022 were IDU-related. Among ever MSM-IDU in 2015, HCV incidence was 1.2/100 person-years (95% credibility interval [CrI], 0.8-1.6). Assuming COVID-19-related declines in HCV testing/treatment persist until 2030, HCV incidence among ever MSM-IDU will decrease by 84.9% (95% CrI, 72.3%-90.8%) over 2015-2030. This decline is largely attributed to HCV testing and treatment (75.8%; 95% CrI, 66.7%-89.5%). Slightly greater decreases in HCV incidence (94%-95%) are projected if COVID-19 disruptions recover by 2025 or 2022. CONCLUSIONS: We estimate that HCV incidence will decline by &gt;80% over 2015-2030 among ever MSM-IDU in San Francisco, achieving the WHO target