The Medicines Repurposing Program - a critical perspective.

The Medicines Repurposing Program was launched on 1 March 2024. It provides a pathway for registering and subsidising off-label medicines of significant public health benefit but which sponsors have no financial incentive to pursue. This article provides a short overview and critical analysis of the program. One concern that emerges is that commercial sponsors still retain de facto veto power over which off-label uses are prioritised and so have the capacity to sway the process. Simple suggestions are proposed to help mitigate this risk.

Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.

ABSTRACT: Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 ( Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.

Barriers and facilitators to guideline for the management of pediatric off-label use of drugs in China: a qualitative descriptive study.

BACKGROUND: Despite being a global public health concern, there is a research gap in analyzing implementation strategies for managing off-label drug use in children. This study aims to understand professional health managers' perspectives on implementing the Guideline in hospitals and determine the Guideline's implementation facilitators and barriers. METHODS: Pediatric directors, pharmacy directors, and medical department directors from secondary and tertiary hospitals across the country were recruited for online interviews. The interviews were performed between June 27 and August 25, 2022. The Consolidated Framework for Implementation Research (CFIR) was adopted for data collection, data analysis, and findings interpretation to implement interventions across healthcare settings. RESULTS: Individual interviews were conducted with 28 healthcare professionals from all over the Chinese mainland. Key stakeholders in implementing the Guideline for the Management of Pediatric Off-Label Use of Drugs in China (2021) were interviewed to identify 57 influencing factors, including 27 facilitators, 29 barriers, and one neutral factor, based on the CFIR framework. The study revealed the complexity of the factors influencing managing children's off-label medication use. A lack of policy incentives was the key obstacle in external settings. The communication barrier between pharmacists and physicians was the most critical internal barrier. CONCLUSION: To our knowledge, this study significantly reduces the implementation gap in managing children's off-label drug use. We provided a reference for the standardized management of children's off-label use of drugs.

Agreement about Availability of Alternative Treatments for Innovative Drugs Assessed by the EMA and HTA Organizations.

The European Medicines Agency (EMA) and European national/regional health technology assessment (HTA) organizations consider the availability of existing treatments when evaluating a new drug. Since disagreement about the availability of alternative treatments may impact patient access to new drugs, this study aimed to investigate whether the EMA and HTA organizations agreed on the availability of alternative treatments and whether a lack of alternative treatments was associated with HTA organizations' added benefit assessment outcomes. For 97 innovative drugs authorized in 2019-2021 (excluding vaccines and diagnostic tools), assessments by the EMA and AEMPS (Spain), AIFA (Italy), HAS (France), IQWiG/G-BA (Germany), NICE (England and Wales), and ZIN (the Netherlands) were identified. Until 1 June 2022, 429 HTA drug-indication combinations were identified for these 97 drugs, of which 205 exactly matched the EMA's indication. For those, the overall agreement between the EMA and HTA organizations on whether alternative treatments were available was 87%. The agreement of HTA organizations with the EMA on whether available treatments were either pharmacological on-label, pharmacological off-label, or non-pharmacological was 87%, 21%, and 57%, respectively. For all 429 HTA drug-indication combinations, absence of alternative treatments as considered by HTA organizations was associated with a higher chance to provide added benefit: risk ratio 1.8 (95%-CI 1.4-2.3). In conclusion, although there was high overall agreement between the EMA and HTA organizations about whether alternative treatments exist, there were differences in the types of treatment considered. Parallel joint scientific consultations could inform drug developers about relevant alternative treatments to facilitate patient access to innovative drugs.

Real-World Healthcare Cost Savings and Reduced Relapse Rate with Off-Label Rituximab versus Disease-Modifying Treatments Approved for Relapsing-Remitting Multiple Sclerosis: A Nationwide Cost-Effectiveness Study.

OBJECTIVE: Although off-label use of rituximab is a common alternative to disease-modifying therapies (DMTs) approved for multiple sclerosis (MS) in several countries, the impact of this on treatment cost-effectiveness is not well known. METHODS: We evaluated the relative cost-effectiveness of rituximab and MS-approved DMTs in a register-based cohort study of Swedish residents with relapsing-remitting MS, aged 18-65 years, starting treatment with rituximab, natalizumab, fingolimod, or dimethyl fumarate between January 2010 and July 2016, and followed through July 2021 (n = 5,924). By linking the population-based Swedish MS register to several Swedish health care and demographic registers, we estimated health care costs in relation to number of relapses, over 5 years from treatment start. Differences between treatments were estimated in inverse probability of treatment-weighted regression models, adjusting for a broad range of potential confounders covering demographics, medical history, and MS-related clinical characteristics. RESULTS: Off-label rituximab was associated with both lower total health care costs (mean cost savings ranged $35,000-$66,000 vs. each approved DMT), and fewer relapses (mean number of prevented relapses ranged 0.12-0.22), per started therapy over 5 years. Results were robust to variations in discounting and pricing of health care visits, with the main driver of cost-savings being the price of the index drug itself. INTERPRETATION: The cost-effectiveness of rituximab dominated the MS-approved alternatives. Off-label, low-dose rituximab should be considered for persons with MS and could reduce barriers to treatment, especially in resource-limited settings. ANN NEUROL 2024;95:1099-1111.

Reforming Paediatric Drug Regulations in Canada: A Clinical and an Access Imperative.

Children deserve the same high standards for drug safety, efficacy and access as adults. Unfortunately, Canada lags behind leading international regulators in implementing reforms to ensure access to paediatric medications. Paediatric regulations, also known as paediatric rules in the US, include a mandate to submit paediatric data in all new drug applications when paediatric use can be anticipated. Absent paediatric regulations, many medications with paediatric-specific indications in other countries remain "off-label" for Canadian children. In addition to concerns related to off-label drug safety, the absence of paediatric indications prohibits appropriate paediatric-specific health technology assessments and limits the evidence-based listing of paediatric medications on public and private formularies.

Longitudinal Patterns in Testosterone Prescribing After US FDA Safety Communication in 2014.

BACKGROUND: The objective of this study was to describe changes in testosterone prescribing following a 2014 US Food and Drug Administration (FDA) safety communication and how changes varied by physician characteristics. METHODS: Data were extracted from a 20% random sample of Medicare fee-for-service administrative claims data from 2011 through 2019. The sample included 1,544,604 unique male beneficiaries who received evaluation and management (E&M) services from 58,819 unique physicians that prescribed testosterone between 2011 and 2013. Patients were categorized based on presence of coronary artery disease (CAD) and non-age-related hypogonadism. Physician characteristics were identified in the OneKey database and included specialty and affiliations with teaching hospitals, for-profit hospitals, hospitals in integrated delivery networks, and hospitals in the top decile of case mix index. Linear segmented models described how testosterone prescriptions changed following a 2014 FDA safety communication and how changes were associated with physician and organizational characteristics. RESULTS: Among 65,089,560 physician-patient-quarter-year observations, mean (standard deviation) age ranged from 72.16 (5.84) years for observations without CAD or non-age-related hypogonadism to 75.73 (6.92) years with CAD and without non-age-related hypogonadism. Following the safety communication, immediate changes in off-label testosterone prescription levels fell by 0.22 percentage points (pp) (95% confidence interval [CI] -0.33 to -0.11) for patients with CAD and by -0.16 pp (95% CI -0.19 to -0.16) for patients without CAD. A similar change was noticed in on-label prescribing levels. Off-label testosterone prescription quarterly trend, however, increased for patients with CAD and without CAD; on-label testosterone prescription trends declined for both groups. Declines in off-label prescribing were larger when treated by primary care physicians vs. non-primary care physicians, and physicians affiliated with teaching compared to nonteaching hospitals. Physician and organizational characteristics were not associated with changes in on-label prescribing. CONCLUSION: On-label and off-label testosterone therapy declined following the FDA safety communication. Certain physician characteristics were associated with changes in off-label, but not on-label, prescribing.

Optimizing therapeutic decision-making for off-label medicines use: A scoping review and consensus recommendations for improving practice and research.

PURPOSE: Off-label medicines use is a common and sometimes necessary practice in many populations, with important clinical, ethical and financial consequences, including potential unintended harm or lack of effectiveness. No internationally recognized guidelines exist to aid decision-makers in applying research evidence to inform off-label medicines use. We aimed to critically evaluate current evidence informing decision-making for off-label use and to develop consensus recommendations to improve future practice and research. METHODS: We conducted a scoping review to summarize the literature on available off-label use guidance, including types, extent and scientific rigor of evidence incorporated. Findings informed the development of consensus recommendations by an international multidisciplinary Expert Panel using a modified Delphi process. Our target audience includes clinicians, patients and caregivers, researchers, regulators, sponsors, health technology assessment bodies, payers and policy makers. RESULTS: We found 31 published guidance documents on therapeutic decision-making for off-label use. Of 20 guidances with general recommendations, only 35% detailed the types and quality of evidence needed and the processes for its evaluation to reach sound, ethical decisions about appropriate use. There was no globally recognized guidance. To optimize future therapeutic decision-making, we recommend: (1) seeking rigorous scientific evidence; (2) utilizing diverse expertise in evidence evaluation and synthesis; (3) using rigorous processes to formulate recommendations for appropriate use; (4) linking off-label use with timely conduct of clinically meaningful research (including real-world evidence) to address knowledge gaps quickly; and (5) fostering partnerships between clinical decision-makers, researchers, regulators, policy makers, and sponsors to facilitate cohesive implementation and evaluation of these recommendations. CONCLUSIONS: We provide comprehensive consensus recommendations to optimize therapeutic decision-making for off-label medicines use and concurrently drive clinically relevant research. Successful implementation requires appropriate funding and infrastructure support to engage necessary stakeholders and foster relevant partnerships, representing significant challenges that policy makers must urgently address.

Superiority of ceftazidime off-label high-dose regimen in PK/PD target attainment during treatment of extensively drug-resistant Pseudomonas aeruginosa infections in cancer patients.

AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

Cost-Effectiveness and Budget Impact of Future Developments With Whole-Genome Sequencing for Patients With Lung Cancer.

OBJECTIVES: This study aimed to investigate the cost-effectiveness, budget impact (BI), and impact of uncertainty of future developments concerning whole-genome sequencing (WGS) as a clinical diagnostic test compared with standard of care (SoC) in patients with locally advanced and metastatic non-small cell lung cancer. METHODS: A total of 3 likely scenarios to take place within 5 years (according to experts) were simulated using a previously developed, peer reviewed, and published decision model. The scenarios concerned "WGS results used for treatment selection" (scenario 1), "WGS-based biomarker for immunotherapy" (scenario 2), and "off-label drug approval for WGS results" (scenario 3). Two diagnostic strategies of the original model, "SoC" and "WGS as a diagnostic test" (base model), were used to compare our scenarios with. Outcomes were reported for the base model, all scenarios separately, combined (combined unweighted), and weighted by likelihood (combined weighted). Cost-effectiveness, BI, and value of information analyses were performed for WGS compared with SoC. RESULTS: Total costs and quality-adjusted life-years for SoC in metastatic non-small cell lung cancer were €149 698 and 1.235. Incremental outcomes of WGS were €1529/0.002(base model), -€222/0.020(scenario 1), -€2576/0.023(scenario 2), €388/0.024(scenario 3), -€5041/0.060(combined unweighted), and -€1715/0.029(combined weighted). The annual BI for adopting WGS for this population in The Netherlands ranged between €682 million (combined unweighted) and €714 million (base model). The consequences of uncertainty amounted to €3.4 million for all scenarios (combined weighted) and to €699 000 for the diagnostic yield of WGS alone (combined weighted). CONCLUSIONS: Our findings suggest that it is likely for WGS to become cost-effective within the near future if it identifies more patients with actionable targets and show the impact of uncertainty regarding its diagnostic yield. Modeling future scenarios can be useful to consider early adoption of WGS while timely anticipating on unforeseen developments before final conclusions are reached.

Cost-effectiveness of molecularly matched off-label therapies for end-stage cancer - the MetAction precision medicine study.

BACKGROUND: Precision cancer medicine (PCM), frequently used for the expensive and often modestly efficacious off-label treatment with medications matched to the tumour genome of end-stage cancer, challenges healthcare resources. We compared the health effects, costs and cost-effectiveness of our MetAction PCM study with corresponding data from comparator populations given best supportive care (BSC) in two external randomised controlled trials. METHODS: We designed three partitioned survival models to evaluate the healthcare costs and quality-adjusted life years (QALYs) as the main outcomes. Cost-effectiveness was calculated as the incremental cost-effectiveness ratio (ICER) of PCM relative to BSC with an annual willingness-to-pay (WTP) threshold of EUR 56,384 (NOK 605,000). One-way and probabilistic sensitivity analyses addressed uncertainty. RESULTS: We estimated total healthcare costs (relating to next-generation sequencing (NGS) equipment and personnel wages, molecularly matched medications to the patients with an actionable tumour target and follow-up of the responding patients) and the health outcomes for the MetAction patients versus costs (relating to estimated hospital admission) and outcomes for the BSC cases. The ICERs for incremental QALYs were twice or more as high as the WTP threshold and relatively insensitive to cost decrease of the NGS procedures, while reduction of medication prices would contribute significantly towards a cost-effective PCM strategy. CONCLUSIONS: The models suggested that the high ICERs of PCM were driven by costs of the NGS diagnostics and molecularly matched medications, with a likelihood for the strategy to be cost-effective defying WTP constraints. Reducing drug expenses to half the list price would likely result in an ICER at the WTP threshold. This can be an incentive for a public-private partnership for sharing drug costs in PCM, exemplified by ongoing European initiatives. CLINICALTRIALS.GOV, IDENTIFIER: NCT02142036.

Impact of off-label use regulations on patient care in dermatology - a prospective study of cost-coverage applications filed by tertiary dermatology clinics throughout Germany.

BACKGROUND: In dermatology, a medical speciality with a relatively high number of rare diseases, physicians often have to resort to off-label treatment options. To avoid claims, physicians in Germany can file a cost-coverage request (off-label application, OL-A). OBJECTIVES: Our aim was to investigate the extent to which the current regulations affect patient care. MATERIAL AND METHODS: Prospective cohort study among tertiary dermatology clinics throughout Germany, consecutively including OL-As (05/2019-09/2020) and assessing the follow-up correspondence. We modelled regressions to assess factors associated with cost-coverage decisions and the time needed by health insurers to process the OL-As. RESULTS: Thirteen clinics provided data on 121 OL-As, two of which applied for on-label treatments. Of the remaining 119 OL-As, 70 (58.8%) were immediately approved and 44 (37.0%) rejected. Including cases with one or more appeals, 87 of 119 OL-As (73.1%) were finally approved and 26 (21.9%) rejected. There was an association of the final approval rate with (1) the class of medication/treatment, with approval rates being significantly lower for JAK inhibitors than for biologics (OR 0.16, 95%-CI: 0.03-0.82); (2) German state, with approval rates being lower in eastern than in western states (OR 0.30, 95%-CI 0.12-0.76); and (3) cost of the intervention (no linear trend). However, none of these predictors was significant in our multiple logistic regression models. The median health insurer's processing time (first response) was 29 days (IQR 22-38). Our analyses showed no evidence of an association with the predictors we assessed. In cases approved, the median time from the decision to file an OL-A to the actual initiation of the treatment was 65.5 days (IQR 51-92). CONCLUSIONS: Our study points to substantial delays and inequalities in the provision of timely health care for dermatological patients with rare diseases, often involving treatments for which there is no adequate approved therapy.

Assessment of Knowledge, Attitude, and Practice of Obstetricians and Gynecologists Toward Off-Label Medicine Use in Female Reproductive Health Issues.

Background: Off-label medication usage (OLMU) is prevalent in the treatment of various diseases, including female reproductive health issues (FRHIs). However, there is a paucity of literature on the perspective of health professionals on this subject. The purpose of the current study was to assess gynecologists/obstetricians' knowledge, attitude and practice toward OLMU in the treatment of FRHIs. Methods: The current cross-sectional study was conducted in September and October 2021, at five tertiary care hospitals (two public and three private sector), different clinics and maternity homes in a metropolitan city of Karachi, Pakistan. The target population was gynecologists, obstetricians and physicians/residents working in the ob/gyn department in various hospitals and clinical settings of Karachi. Results: The overall response rate was 77.1%. The mean age of the study respondents was 36.1 ± 7.7 years; n = 85 (55.9%) respondents were working in primary patient care. The majorly reported OLMU by the respondents were clomiphene citrate in unexplained infertility (n = 66; 43.4%), metformin to improve cycle regularity in females with polycystic ovary syndrome (PCOS) (n = 59; 38.8%) and letrozole to induce ovulation (n = 31; 20.4%). The majorly stated categories of OLMU were at a different dose (n = 95; 62.5%) and at different indications than approved to treat (n = 89; 58.5%). It was reported by the majority of the respondents (n = 95; 62.5%) that they do not follow any guidelines or regulations for OLMU in their work setting; however, the response was statistically varied with the working organization (CI 2.14-2.93; p = 0.037) and practice area (CI 2.85-4.32; p = 0.0001) of respondents. Conclusions: The present study revealed that the respondents were well-familiar with the practice of OLMU in the treatment of FRHIs. They expressed their concerns about decreasing such practices by being involved in collective decision-making procedures, and they were inclined to accept initiatives aimed at ensuring drug safety in patients.

Adverse Outcomes Associated With Off-Label Agents Used to Treat Dementia Patients With Psychosis: A Case-Control Medicare Database Study.

INTRODUCTION: Currently, there are no Food and Drug Administration-approved therapies to treat dementia-related psychosis (DRP). This study investigated the association between using antipsychotics and the anticonvulsant divalproex (sodium valproate) to manage DRP and adverse outcomes. METHODS: A retrospective case/control matching study evaluated the risk of mortality, extrapyramidal symptoms (EPS), ischemic stroke, and cardiac arrest/ventricular arrhythmia (CA/VA) with ever-use of antipsychotics/divalproex in patients with DRP vs never-use. RESULTS: 49 509 patients were included; 76.8% used an antipsychotic/divalproex. Treatment ever-use was associated with an increased risk of all-cause mortality (odds ratio, 1.14; 95% CI, 1.10-1.18) and a smaller increase in the risk of EPS (1.10; 1.00-1.19) relative to never-use (adjusted for matching demographic variables, comorbid conditions, and disability). CONCLUSIONS: Current agents used for DRP were associated with increased risk of death and adverse outcomes. An increased risk of death was evident within 3 months of antipsychotic/divalproex initiation and persisted with long-term use.

Testing fractional doses of COVID-19 vaccines.

Due to the enormous economic, health, and social costs of the COVID-19 pandemic, there are high expected social returns to investing in parallel in multiple approaches to accelerating vaccination. We argue there are high expected social returns to investigating the scope for lowering the dosage of some COVID-19 vaccines. While existing evidence is not dispositive, available clinical data on the immunogenicity of lower doses combined with evidence of a high correlation between neutralizing antibody response and vaccine efficacy suggests that half or even quarter doses of some vaccines could generate high levels of protection, particularly against severe disease and death, while potentially expanding supply by 450 million to 1.55 billion doses per month, based on supply projections for 2021. An epidemiological model suggests that, even if fractional doses are less effective than standard doses, vaccinating more people faster could substantially reduce total infections and deaths. The costs of further testing alternative doses are much lower than the expected public health and economic benefits. However, commercial incentives to generate evidence on fractional dosing are weak, suggesting that testing may not occur without public investment. Governments could support either experimental or observational evaluations of fractional dosing, for either primary or booster shots. Discussions with researchers and government officials in multiple countries where vaccines are scarce suggests strong interest in these approaches.

Tamsulosin and risk of priapism: A causality assessment using Austin Bradford Hill Criteria.

Tamsulosin hydrochloride, a selective alpha-adrenergic blocking agent has been previously associated with priapism. Priapism is a medically serious condition that, if not intervened, can cause permanent erectile dysfunction. This study was conducted to investigate whether the association of tamsulosin and priapism is causal. All currently available evidence such as experimental, biological, toxicological, published studies, and safety data mined from the WHO global pharmacovigilance database was systematically organized into the Austin Bradford Hill causality assessment framework. In the international pharmacovigilance database, a strong association between tamsulosin and priapism (IC025  = 4.1; PRR025  = 19.9; ROR025  = 20) was observed. There were 122 cases of priapism associated with tamsulosin submitted to the database from 23 countries. In 87.7% of the cases, tamsulosin was reported as a 'sole suspect,' and in 50.8%, it was the only drug administered. In several patients, priapism resolved following discontinuation of tamsulosin and recurred after its reintroduction. Both in the published and unpublished data, for majority of the cases, the time to onset of priapism was within few days following the first intake of tamsulosin. Cases of priapism, particularly those published, were consistent in their clinical features with patients experiencing prolonged painful erection that required aspiration of cavernosal blood, irrigation of the corpora cavernosa, and treatment with vasopressors. Other alpha-adrenergic blocking agents that are structurally analogous with tamsulosin have also been associated with priapism. In several cases, tamsulosin was used off-label, for the treatment of ureteral calculi expulsion. Eight patients experienced priapism that ended up with serious complications such as ejaculation disorders and erectile dysfunction. The currently available totality of evidence suggests that the association of tamsulosin and priapism is causal. Healthcare professionals are therefore recommended to cautiously prescribe tamsulosin and ensure that consumers are aware of the potential risk of priapism.