The economic impact of compassionate use of medicines.

BACKGROUND: Compassionate use programs (CUP) for medicines respond to the ethical imperative of providing access to medicines before marketing approval to patients not recruited in trials. The economic impact of clinical trials has previously been investigated. No evidence on the net economic benefit of CUP exists. This research aims to address this information gap by estimating the economic consequences of 11 CUP in Italy conducted between March 2015 and December 2020 from the perspective of public health care system in Italy (National Health Service). Eight programs concern cancer treatments, two refer to spinal muscular atrophy, and one is indicated for multiple sclerosis. METHODS: Since CUP medicines are covered by the industry, the net economic benefit includes: (i) avoided costs of the Standard of Care (SoC) the patients would have received had they not joined the CUP, (ii) costs not covered by the pharmaceutical industry sponsor, but instead sustained by payers, such as those associated with adverse events (only severe side effects resulting in hospitalisation and attributable to CUP medicines), and (iii) costs for combination therapies and diagnostic procedures not used with the SoC. The SoC costing relied on publicly available data. Information on adverse events and diagnostic procedures was retrieved from the CUP and monetized using the relevant fee for episode or service. One CUP was excluded since a SoC was not identified. RESULTS: 2,713 patients were treated in the 11 CUP where a SoC was identified. The SoC mean cost per patient ranged from €11,415 to €20,299. The total cost of the SoC ranged between €31.0 and €55.1 million. The mean cost per patient covered by hospitals hosting CUP was equal to €1,646, with a total cost of €4.5 million. The net economic benefit ranged €26.5 million - €50.6 million. CONCLUSIONS: Despite research limitations, this paper illustrates for the first time the net economic impact of CUP from a public payer perspective. It is important to integrate these estimates with the prospective effects of CUP implementation, i.e., the economic value of the comparative benefit profile of medicines used in CUP versus the SoC, including effects from a societal perspective.

Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study.

BACKGROUND: In the USA, about 30 200 well-differentiated thyroid carcinomas were diagnosed in 2007, but the prevalence of thyroid nodules is much higher (about 5% of the adult population). Unfortunately, the preoperative characterisation of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology are referred to surgery. About 85% of these thyroid nodules are classified as benign at final histology. We aimed to assess the diagnostic effect of galectin-3 expression analysis in distinguishing preoperatively benign from malignant follicular thyroid nodules when FNA findings were indeterminate. METHODS: 544 patients were enrolled between June 1, 2003, and Aug 30, 2006. We used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively on 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with the final histology. FINDINGS: 31 patients were excluded because they had small galectin-3-negative thyroid nodules; we did not have data for 47 patients; and one patient with an oncocytic nodule was excluded. 331 (71%) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. 280 (85%) of these galectin-3-negative lesions were classified as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29%) thyroid proliferations, 101 (75%) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78% (95% CI 74-82) and specificity was 93% (90-95). Estimated positive predictive value was 82% (79-86) and negative predictive value was 91% (88-93). 381 (88%) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy were correctly classified preoperatively by use of the galectin-3 test. However, 29 (22%) of 130 cancers were missed by the galectin-3 method. INTERPRETATION: Our findings show that if the option of surgery was based theoretically on galectin-3 expression alone, only 134 thyroid operations would have been done in 465 patients; therefore a large proportion (71%) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers could be potentially missed. The galectin-3 test proposed here does not replace conventional FNA cytology, but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.

Poly(ADP-ribose)polymerase activity is reduced in circulating mononuclear cells from type 2 diabetic patients.

Poly(ADP-ribose)polymerase (PARP-1), a nuclear enzyme activated by DNA strand breaks, is involved in DNA repair, aging, inflammation, and neoplastic transformation. In diabetes, reactive oxygen and nitrogen species occurring in response to hyperglycemia cause DNA damages and PARP-1 activation. Because circulating mononuclear cells (MNCs) are involved in inflammation mechanisms, these cells were chosen as the experimental model to evaluate PARP-1 levels and activity in patients with type 2 diabetes. MNCs were isolated from 25 diabetic patients (18 M, 7 F, age, 63.5 +/- 10.2 years, disease duration 17.7 +/- 8.2 years) and 11 age and sex matched healthy controls. PARP-1 expression and activity were analyzed by semi-quantitative PCR, Western and activity blot, and immunofluorescence microscopy. PARP-1-mRNA expression was increased in MNCs from all diabetic patients versus controls (P < 0.01), whereas PARP-1 content and activity were significantly lower in diabetic patients (P < 0.0001). To verify whether low PARP-1 levels and activity were due to a proteolytic effect of caspase-3 like, the latter activation was measured by a fluorimetric assay. Caspase-3 activity in MNCs was significantly higher in diabetic patients versus control subjects (P < 0.0001). The different PARP-1 behavior in MNCs from patients with type 2 diabetes could therefore be responsible for the abnormal inflammation and infection responses in diabetes.