Compassionate drug uses and saving for the national health system: the case study of Fondazione Policlinico Gemelli.

OBJECTIVE: Compassionate Drug Use (CDU) allows patients with a specific disease and no further treatment option to access unauthorized treatments. In this study, we analyzed the requests of CDU approved by the Ethics Committee of Fondazione Policlinico Gemelli in the period January 1, 2018-June 30, 2021. We also estimated the economic impact of CUs. MATERIALS AND METHODS: CDU requests were analyzed by year, by frequency and by regulatory status of the medicines requested. If an ex-factory price was available at the cutoff date of June 30, 2021, we estimated what would have been the costs for the National Health System (NHS) if the price was already negotiated at the time of CDU request. RESULTS: In the study period, 463 CDU requests were processed by the Ethics Committee. The number of requests increase linearly from 45 in 2018 to an estimated number of 260 in 2021. The requests included 68 medicines or combinations of medicines; 16 products out of 68 accounted for 75% of all requests. For 7 of these 16 highly requested treatments, accounting for 110 requests out of 463, it was possible to estimate the costs of therapies according to their ex-factory prices. If these products were to be purchased by the NHS, the estimated cost was € 5.472.225. CONCLUSIONS: The access to unauthorized drugs through CDUs is undergoing a huge increase in the last few years. Such increase meets the ethical need to provide patients with the most recent, often innovative, therapeutic options.

Tocilizumab improves survival in severe COVID-19 pneumonia with persistent hypoxia: a retrospective cohort study with follow-up from Mumbai, India.

BACKGROUND: Cytokine storm triggered by Severe Coronavirus Disease 2019 (COVID-19) is associated with high mortality. With high Interleukin -6 (IL-6) levels reported in COVID-19 related deaths in China, IL-6 is considered to be the key player in COVID-19 cytokine storm. Tocilizumab, a monoclonal antibody against IL-6 receptor, is used on compassionate grounds for treatment of COVID-19 cytokine storm. The aim of this study was to assess effect of tocilizumab on mortality due to COVID-19 cytokine storm. METHOD: This retrospective, observational study included patients of severe COVID-19 pneumonia with persistent hypoxia (defined as saturation 94% or less on supplemental Oxygen of 15 L per minute through non-rebreathing mask or PaO2/FiO2 ratio of less than 200) who were admitted to a tertiary care center in Mumbai, India, between 31st March to 5th July 2020. In addition to standard care, single Inj. Tocilizumab 400 mg was given intravenously to 151 consecutive COVID-19 patients with persistent hypoxia, from 13th May to 5th July 2020. These 151 patients were retrospectively analysed and compared with historic controls, ie consecutive COVID-19 patients with persistent hypoxia, defined as stated above (N = 118, from our first COVID-19 admission on 31st March to 12th May 2020 i.e., till tocilizumab was available in hospital). Univariate and multivariate Cox regression analysis was performed for identifying predictors of survival. Statistical analysis was performed using IBM SPSS version 26. RESULTS: Out of 269 (151 in tocilizumab group and 118 historic controls) patients studied from 31st March to 5th July 2020, median survival in the tocilizumab group was significantly longer than in the control group; 18 days (95% CI, 11.3 to 24.7) versus 9 days (95% CI, 5.7 to 12.3); log rank p 0.007. On multivariate Cox regression analysis, independent predictors of survival were use of tocilizumab (HR 0.621, 95% CI 0.427-0.903, P 0.013) and higher oxygen saturation. CONCLUSION: Tocilizumab may improve survival in severe COVID-19 pneumonia with persistent hypoxia. Randomised controlled trials on use of tocilizumab as rescue therapy in patients of severe COVID-19 pneumonia with hypoxia (PaO2/FiO2 less than 200) due to hyperinflammatory state, are warranted.

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post-treatment hospitalisation status.

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged ≥18 years undergoing mechanical ventilation or with an oxygen saturation level of ≤94 % in air or a National Early Warning Score 2 of ≥4. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63 %) and discontinued by 13, of whom eight (22.8 %) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3 %) patients from IDW were discharged, two were still hospitalized and one died (5.9 %), whereas in ICU 6 (33.3 %) were discharged, 8 (44.4 %) patients died, three (16.7 %) were still mechanically ventilated and one (5.6 %) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8 % and 22.8 % of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when.

Characterizing expanded access and compassionate use programs for experimental drugs.

OBJECTIVE: We sought to determine the characteristics of "expanded access" and "compassionate use" programs registered in ClinicalTrials.gov and to determine the percentage of drugs provided through these programs that ultimately received FDA marketing approval. RESULTS: We identified 398 expanded access and compassionate use programs (hereafter referred to as expanded access programs) registered on ClinicalTrials.gov. Industry funded 61% (n = 241) of programs individually or collaboratively, while NIH and the US Federal Government rarely funded programs (3% [n = 11] and 2% [n = 6], respectively). Most programs provided access to drugs (71% [n = 282]), 11% to biologics (n = 43), and 10% to medical devices (n = 40). These programs covered 460 unique conditions, the most common being HIV (n = 26), leukemia (22), and multiple myeloma (n = 14). Only 2% of programs reported results in ClinicalTrials.gov. Most programs (82%) were open to enrolling adults and seniors (n = 326). These programs provided access to 210 unique experimental drugs, of which 76% have received FDA approval.

BRCA1 haplotype and clinical benefit of trabectedin in soft-tissue sarcoma patients.

BACKGROUND: This study aimed to determine whether the BRCA1 haplotype was associated with trabectedin efficacy in soft-tissue sarcoma (STS) patients. METHODS: We analysed BRCA1 single-nucleotide polymorphisms (SNPs) in tumour specimens from 135 advanced STS patients enrolled in published phase 2 trials or in a compassionate-use programme of trabectedin. Forty-four advanced STS patients treated with doxorubicin and 85 patients with localised STS served as controls. The 6-month nonprogression rate and overall survival (OS) were analysed according to BRCA1 haplotype using log-rank tests. RESULTS: A favourable BRCA1 haplotype (presence of at least one AAAG allele) was significantly associated with an improved 6-month nonprogression rate. It was the only variable significantly associated with OS. No correlations were found between outcomes for patients with localised or advanced STS treated with doxorubicin. CONCLUSIONS: The BRCA1 haplotype represents a potential DNA repair biomarker that can be used for the prediction of response to trabectedin in STS patients.

Dilemmas in the compassionate supply of investigational cancer drugs.

In Australia, patients who want to access medicines that are not yet approved have only two options: to enroll in a clinical trial if they are eligible, or obtain their medicine through 'compassionate supply', which is provided at the discretion of the manufacturer. In this article, we explore ethical issues associated with the provision of oncology medicines that are still in development, either prior to regulatory approval or government reimbursement.