Non-commercial trials on medicines submitted to the Ethics Committee of the University Hospital of Bologna (Italy) along 8 years of activity: time to update rules and recommendations.

PURPOSE: In Italy, the non-commercial trials on medicines are regulated by the Ministry Decree 17 December, 2004. Its intent is of encouraging the independent research for the improvement of clinical practice. We aimed to analyze the main features of the proposals of non-commercial clinical trials on medicines submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2017. METHODS: Data were extracted from IEC registry and were organized with an ad hoc database. The relationships between the variables were examined using contingency tables. When appropriate, we applied the chi-square statistical test for the comparison of the categorical variables. RESULTS: Over the 8-year period, the IEC evaluated 2931 studies, of which 1156 (39.4%) related to clinical trials on medicines; 245 (21.2%) out of the latter were non-commercial ones. A percentage of 49.8 of the trials were of phase II; 137 trials (55.9%) were promoted by hospitals, medical schools or institutes for research, hospitalization and health care. Non-profit organizations and scientific societies were promoters of 88 trials (35.9%). Most phase I and phase II trials received additional support from pharmaceutical companies. CONCLUSIONS: Our results show a not negligible industrial influence on non-commercial trials through additional support, mostly to those of phase II. An update of the present legislation on this matter is desirable, adopting clearer rules on the relations sponsor-industry.

Six-year activity on approval of compassionate use of medicines by the Ethics Committee of the University Hospital of Bologna (Italy): time to update rules and recommendations.

PURPOSE: Compassionate use of forthcoming drugs has become an increasing pathway through which patients can take advantage of promising medicines. We aimed to analyse the main features of the requests of compassionate use submitted to the Independent Ethics Committee (IEC) of the University Hospital of Bologna in the period 2010-2015. METHODS: The present analysis concerns the requests of compassionate use received by the IEC in the period 2010-2015. For each requested drug, we paired the date of the first request to our IEC with the date(s) of (a) submission to EMA, (b) CHMP positive opinion, and (c) European marketing authorization (if issued). RESULTS: In the period 2010-2015, our IEC received compassionate use requests for 610 patients. Most of the requests concerned patients suffering from solid or haematological cancers not responsive to first or second line of treatment. Sixty-five couples of medicine/clinical condition (corresponding to 56 individual medicines) were submitted to our IEC, and 62 of them regarded products following the centralised procedure at the EMA. Twenty-one out of the latter (34%) had already obtained CHMP positive opinion. CONCLUSIONS: Our results indicate that compassionate use of forthcoming medicines represents a not negligible portion of the therapies utilized in hospital care. The observed large resort to medicines still on trial may suggest that doctors are more aware with the potential benefits of the new drugs. However, this trend may also indicate an increasing marketing activity of the pharmaceutical industry, addressing to get the clinicians used to the upcoming medicines.

Harmonization of the practice of independent ethics committees in Italy: project E-submission.

AIM: The high variability of "centre-specific" documentation required by Independent Ethics Committee (IEC) plays a role in the time required for activation of participating centres of multicentre clinical trials. This study (a) provides a picture of the different activities, structural requirements and resources dedicated to the operation of the local IEC in Italy; (b) defines a detailed list of "centre-specific" documents considered as essential by the IEC for issuing its opinion and (c) suggests a "single document" to reduce the variability of the "centre-specific" documents required by the IEC. METHODOLOGY: Two surveys were conducted through the portal of National Monitoring Centre of Clinical Trials (https://oss-sper-clin.agenziafarmaco.it/). The first survey focused on the local IEC resources and on the "centre-specific" documentation that local IEC required from the Sponsor and local Principal Investigator (PI). The second focused on "single document" required in the form of statements from the Sponsor and the PI. Answers were discussed and extended during regular scheduled teleconferences and plenary meeting. PRINCIPAL FINDINGS: From 22/07/2009 to 15/12/2009, and from 19/04/2010 to 14/05/2010, 131 and 125 IECs responded to the first and the second surveys, respectively. 67% and 51% of IECs consider the structural requirements and the staff dedicated to the activity of the IECs as sufficient, respectively. Most of the IECs consider the "centre-specific" documentation as necessary for issuing the opinion, and a high percentage of IECs consider the proposed documentation as acceptable in substitution to any other "centre-specific" documentation already in use. CONCLUSIONS: The harmonization of IECs practice in Italy is the first step to facilitate multicentre clinical trials. Similar efforts should be directed to reduce the total number of IECs and to standardize clinical trials approval procedures, focusing on administrative procedures as well.

Profile of atypical-antipsychotics use in patients affected by dementia in the University Hospital of Ferrara.

BACKGROUND: The use of off-label atypical antipsychotic drugs (AA) has been noted for the treatment of behavior disorders in older patients affected by Alzheimer's or by other forms of dementia, even though effectiveness data are limited and use seems to be associated with severe cerebrovascular risks. The data concerning such risks caused the Italian Ministry of Health to release a statement discouraging doctors from prescribing olanzapine and risperidone outside of the registered indications, in May 2004. This study aimed to analyze the prescriptive profile of AAs in patients with dementia, in terms of the choice of active substance and of the clinical characteristics of the patients. METHODS: Patients with a diagnosis of dementia and in treatment with AA (risperidone, olanzapine, and quetiapine) were selected from three main Alzheimer Evaluation Centers (Geriatrics, Neurology, Internal Medicine) of the University Hospital in Ferrara, in the period 05/2003-04/2006. For each subject, the following information was collected: the frequency of prescriptions, the drug received, and the amount of AAs in the considered period. In the third year of observation, the intensity of treatment was evaluated (intense treatment: >300 tablets of any AA; weak treatment: <300 tablets of any AA or up to three packages of risperidone drops). Such data were analyzed in terms of the type of dementia, the behavioral disturbance, and the possible presence of psychomotor agitation. In addition, the adverse reactions that occurred during the treatment were gathered. Lastly, the use of acetylcholinesterase inhibitors among the selected subjects was described. RESULTS: Among the 392 subjects (63% female), Alzheimer's (49%) was the most frequent form of dementia, hallucinations were present in 50% of the cases and aggression in 53%.The statement by the Ministry of Health resulted in a foreseeable increase in the consumption of quetiapine and a parallel decrease in risperidone and olanzapine; subsequently, the distribution among the drugs stabilized to similar percentages. The doses used for the control of behavioral disturbances during dementia were on average much lower than those for treating more severe psychoses. Among the patients followed in the third year of observation (n = 159), the number of subjects in intense treatment was greater than those in weak treatment (60 vs 40%). Olanzapine was the AA most frequently used in intense dosages. Among the patients in weak treatment, about 50% used risperidone, available as oral droplets. In the patients at the Geriatric Center (n = 174), in the initial period of analysis 10 adverse events were observed and out of these 10 subjects, all of whom were under intense treatment , 8 out of 10 took quetiapine. The most frequently observed adverse events were tremors, a typical extrapyramidal symptom. CONCLUSIONS: As physicians await next studies helping to identify specific classes of drugs for specific symptoms or subpopulations, they should turn to pharmacological treatment only after a careful risk-benefit evaluation. They should consider both the important role of the relationship between patient and carers and the adverse effects of antipsychotics, which are particularly dangerous in the elderly.

Initial treatment of hypertension and adherence to therapy in general practice in Italy.

BACKGROUND: Antihypertensive agents are among the most used therapeutic classes. The approach to the pharmacological treatment of hypertension is guided by international recommendations and adherence to treatment is known to result in effective prevention of cardiovascular risk. AIM: The aim of this study was to evaluate the pattern of use of antihypertensive agents in general practice in terms of drug choice for the initial treatment of hypertension and adherence to treatments among newly recruited patients. METHODS: We collected the data of all antihypertensive drugs prescribed by general practitioners (GPs) and reimbursed between January 1998 and December 2002 by a Local Health Authority of Emilia Romagna (Ravenna district, 350,000 inhabitants). We selected subjects aged 40 years and older, permanently living in the area during the whole period of the study, who received their first prescription of antihypertensives between January and December 1999, with no prescription of antihypertensive agents in the previous year. For each patient, we documented the starting regimen and evaluated adherence to treatment in terms of persistence during the years (patients were defined persistent if they received at least one prescription per year) and in terms of daily coverage (patients were defined covered if they received an amount of drugs consistent with a daily treatment). Finally, switches or addition of other therapeutic classes during the 3-year period were identified. RESULTS: A cohort of 6,043 subjects receiving their first antihypertensive treatment in 1999 was obtained. Regarding the starting regimen, monotherapies with angiotensin converting enzyme inhibitors (n = 1,597; 26%) or calcium channel blockers (n = 1126; 19%) were the most frequently prescribed. Of the patients, 21% started with a drug combination regimen. Regarding adherence to treatment, 18% of the cohort received only one prescription throughout the 3 years, 13% received more than one prescription but stopped the therapy during the first year, 69% were persistent during the second year and 60% also during the third year. Only 34% were covered during the first year and 24% also during the second year, whereas only 20% of the patients resulted covered throughout the 3 years. Among persistent patients, 41% maintained the same antihypertensive regimen throughout the 3 years, 25% added other drugs to the initial treatment and 34% switched to completely different regimens. CONCLUSIONS: Our findings reflect the lack of convergence among guidelines on the drug class(es) to be considered as first choice in the initial treatment of hypertension. Although an intervention in this field may have important implications in terms of cost savings, the ongoing debate does not allow us to draw definite conclusions on whether measures should be taken by the National Health Authority. However, the lack of adherence to antihypertensive treatment is undoubtedly a matter of concern for public health and should be addressed with appropriate interventions.