Agenzia Italiana Del Farmaco Research Articles

Treatment Guidelines for Pompe Disease: A South European Perspective

Pompe disease is a rare lysosomal disorder of muscle glycogen metabolism due to -glucosidase (acid maltase) eficiency. The prevalence of the disease is estimated to be 1:40,000. The diagnosis is based on the identification of the specific biochemical defect and has to be confirmed by molecular genetic analysis. Since 2006, enzyme replacement therapy (ERT) for Pompe disease has been available in Southern Europe. Several countries in Southern Europe are allowed, once the diagnosis is confirmed, to perform ERT and its costs are fully supported by the Ministries of Health. For example, to our knowledge, either in Portugal or Italy, the drug reimbursement is based on a specific treatment programme which removes those costs from the hospital budget. Since 2006, AIFA (Agenzia Italiana del Farmaco) has approved alglucosidase(Myozyme) for the treatment of Pompe disease patients in Italy, either for infantile or late-onset patients. Authorisation to treat patients with ERT has to be given by a centre specialising in rare diseases. This centre must assess the diagnosis of Pompe disease with absolute certainty before starting treatment. In 2008, a group of leading Italian Pompe disease researchers reviewed, from a multidisciplinary point of view, the current practices in diagnosis, management and treatment of Pompe disease. The main criteria for starting ERT ncludes: (1) confirmed diagnosis; (2) symptoms and clinical signs of muscle weakness; (3) in cases of asymptomatic yperCKaemia, a 6-month follow up has been suggested in an attempt to monitor possible clinically relevant hanges suggesting treatment. In summary, our standard protocol mainly includes evaluation of muscle strength, respiratory assessment and keletal muscle MRI. We have studied over 80 patients treated with ERT coming from 18 different Italian centres ccording to this protocol. In a recent meeting on Pompe disease held in the Netherlands, researchers showed great interest in trying to ssess new criteria for early diagnosis of Pompe disease. In our opinion, there is an emerging role for neuroimaging based on new quantitative techniques (more precise valuation of muscle fat fraction), that should allow an earlier detection of muscle damage in Pompe patients and consequent early start of ERT.

Imatinib mesylate in thymic epithelial malignancies.

7091 Background: Study supported by Agenzia Italiana del Farmaco(AIFA code: FARM6HJ7CA). Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Histologic types, defined by the WHO (A, AB, B1, B2, B3 and Thymic carcinoma-TC), carry a variable prognosis, with TC being associated to the most aggressive clinical behavior. Anthracycline- and platinum-based chemotherapy is active in these tumors, but novel therapeutic options are still needed. Imatinib (Novartis Pharma) is a competitive inhibitor of BCR-ABL, KIT, PDGFRA, and PDGFRB tyrosine kinases. The rationale for its use in TETs lies in the high levels of expression of c-KIT reported in TC and for the reported efficacy of Imatinib in one case of TC (Stroebel, 2004). Methods: Phase II trial was initiated to deliver imatinib at 400 mg to a population of patients affected by TETs. Due to the low predicted accrual of patients with TC, patients with all histologic types of TETs were eligible for the trial. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the CTC of the NCI, version 3.0. 15 patients with advanced TETs (most of them B2 or B3 thymoma, some of them with a squamous component) , who had been pretreated with at least one chemotherapeutic agent, were enrolled at the Department of Molecular and Clinical Oncology and Endocrinology of University ‘Federico II of Naples’ from March, 2008 to July 2010. Results: One third of patients presented with thymic carcinomas. C-Kit was expressed only in some cases of TC, as revealed by immunohistochemistry. No mutations in the C-kit gene (exons 9-11-13 and 17) were found in the TC cases by mutational analysis. Imatinib was overall well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (range, 2.75-4). Median overall survival was not reached. Conclusions: The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. Imatinib seems to be not efficacy to treat TET.

Human growth hormone (GH) immunoassay: standardization and clinical implications

The poor comparability of growth hormone (GH) results obtained using commercially available methods, is partly due to standard preparations used in calibration. The system relies on the use of the International Reference Preparation (IRP) international standard (IS) 80/505, of human pituitary origin, containing all GH isoforms. Recently, a 22K recombinant GH isoform IRP IS 98/574 was commercialized. Our aim was to evaluate the influence of both calibrators on GH results. GH concentration in 97 serum samples from children undergoing a growth hormone releasing hormone+arginine stimulation test was measured using Siemens IMMULITE electro-chemiluminescence method, calibrated with both IS 80/505 and IS 98/574 (GRH Growth hormone-Recombinant 98/574-kit). Comparison of our results obtained with the two sets of calibrators showed good correlation, although we found higher percentage variation (var%) than that stated by Siemens. The mean var% value was confirmed when all results were sub-divided into subgroups based on both high and low GH concentrations. Since the GH assay is influenced by a variety of binding proteins, isoforms and conversion factors, standardization of the assay is strongly required. In Italy, the Agenzia Italiana del Farmaco 39 note provides GH laboratory values which are useful for therapy. On the basis of our results, we therefore propose to adjourn these GH values in order to ensure better management of patients with GH-related disorders.

Abstract P5-12-05: 9 Weeks vs 1 Year Adjuvant Trastuzumab in Combination with Chemotherapy: Preliminary Cardiac Safety Data of the Phase III Multicentric Italian Study Short-HER

Abstract Introduction: Several large randomized trials have shown the superiority of combining trastuzumab with chemotherapy versus chemotherapy alone as adjuvant treatment for HER2+ breast cancer patients. We are running a large phase III trial comparing two different trastuzumab durations (Short-HER study). We are reporting the preliminary cardiac safety data. Methods: The Short-HER study is a phase III, multicentric, Italian trial where 2500 HER2+ breast cancer patients will be randomized to: Arm A (Long) 4 courses of anthracycline based chemotherapy (AC or EC) followed by 4 courses of docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab followed by FEC x3. this is a non-inferiority trial with DFS and OS as primary end points, and 2-yr failure rate and incidence of cardiac events as secondary end points. Left ventricular ejection fraction (LVEF) is measured at baseline, at the end of each sequence of chemotherapy in both arms, and after 9 and 12 months since randomization thereafter. A cardiac event (CE) was defined as the occurrence of any of the followings: 1) LVEF decrease of more than 15 percentage points from baseline ; 2) LVEF decrease of more than 10 percentage points with absolute value below 50%; 3) symptomatic cardiac failure; 4) other cardiac side effects of grade 2 or more. Results: 510 patients from 69 Italian centers have been randomized so far, 251 in arm A (long) and 259 in Arm B (Short). 146 patients enrolled in arm A and 150 patients enrolled in arm B have received at least 3 months of therapy, and are eligible for the present analysis. In arm A (long), 20 patients (13.7%) experienced a CE: 12 patients experienced a LVEF decline of > 15 percentage points (5 patients with LVEF below 50%, one patient with concomitant atrial fibrillation); 3 patients had a LVEF decline of >10 percentage points with an absolute value below 50%. One patient had symptomatic cardiac failure. Two patients developed Grade 2 hypertension. Two patients developed Grade 2 arrhythmia. In arm B (short), 11 patients (7.3%) experienced a CE: 7 patients had a LVEF decline of > 15 percentage points; one patient had a LVEF decline of > 10 percentage points with an absolute value below 50%. Three patients developed Grade 2 arrhythmia Conclusions: This is a non-inferiority study designed on the assumption that a shorter treatment duration is associated with a significantly lower incidence of cardiac events. With 9 clinically relevant CEs (symptomatic cardiac failure or LVEF below 50%) in arm A (Long) and 1 in arm B (Short), these preliminary data support the assumption, and recruitment is ongoing. Supported by Agenzia Italiana del FArmaco (AIFA). Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-12-05.

Need for Redesigning Pharmacologic Research in Older Individuals. A Position Statement of the Geriatric Working Group of the Agenzia Italiana del Farmaco (AIFA)

66 Discussions about the most appropriate methods for testing the effectiveness and safety of pharmacological intervention for older patients crowded the literature of the past decade, but little action has followed from such a wide discussion. The number of patients aged 65 years and older included in randomized controlled trials raised. However, epidemiological studies have generally demonstrated that the phenotypic emergence of the negative consequences of aging occur much later in life, in the eighth and ninth decade. Interestingly, this is the section of the population that is experiencing a steep demographic expansion, is often affected by severe comorbidity and disability, is the most eager consumer of drugs, and also the most likely to suffer from the iatrogenic consequences of chronic treatment and polypharmacy (1). In the United States, nearly 90% of patients over 75 years of age receive one or more medications, and the probability of having multiple prescription increases geometrically with age, severity of illness, and poor physical and cognitive function (2). There are many reasons why frail older persons that assume multiple drugs are prone to develop iatrogenesis, including drug–drug interactions, reduced physiological reserve, changes in pharmacokinetics, and poor compliance (3). The management of comorbid conditions with multiple medications is indeed one of the greatest challenges in geriatrics. The Hippocratic oath “primum non nocere” is translated into the “unchallenged principle” in geriatric medicine: The number of medications should be kept as low as possible. However, when facing the “brown bag full of pills” brought by your patient, deciding which treatment can stay and which one should go is challenging. Of course, only drugs with proven efficacy should stay, but this is also not an easy decision. Elderly patients with comorbidity, disability, and polypharmacy are systematically excluded from clinical trials, even those trials that test drugs mostly used in those same elderly patients with comorbidity, disability, and polypharmacy. Due to those exclusion criteria, the findings of these trials cannot be extended to our typical patients: Therefore, we are left with an “unchallenged principle” and impossible decisions (4,5). We are certainly not the first to denounce this difficult situation. Eminent geriatricians have voiced that the current practice produces an evidence-biased rather and evidencebased medicine and have called for the conduction of appropriately designed trials involving real geriatric patients (6,7). Letter to the Editor

"Poker" association of weekly alternating 5-fluorouracil, irinotecan, bevacizumab and oxaliplatin (FIr-B/FOx) in first line treatment of metastatic colorectal cancer: a phase II study

BackgroundThis phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC).MethodsSimon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks.ResultsFifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%.ConclusionPoker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered.Trial registrationOsservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34

Time to market and patient access to new oncology products in Italy: a multistep pathway from European context to regional health care providers

Aim: The main purpose of this study was to identify each sequential phase followed by an oncology product, from European assessment until to patient access in each Italian region (IR).Methods: A panel of oncology products approved by the European Medicines Agency (EMA) in the period 2006–2008 was considered. The explored sequential phases included the times to market for: the EMA; pharmaceutical companies; the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA); and IRs as final providers of health care. The IR’s time to market was also analyzed by a Cox regression model.Results: The overall mean time required before patients access was 2.3 years. EMA accounted for the greater proportion of time (31.8%), followed by AIFA (28.2%). However, the duration for both pharmaceutical companies and IRs was associated with the highest variability. An oncology product authorized with a risk-sharing agreement showed an early access in the IRs. On the contrary, the introduction in IRs having a compulsory formulary was delayed. Both a high forecast of economic impact and a high oncology product price can also delay the patient access.Conclusion: The process before patient access to an oncology product is time and cost consuming. This study identifies the main predictors that affect the missing overlap between market and patient access in Italy.

Hepatitis B immune memory in children primed with hexavalent vaccines and given monovalent booster vaccines: an open-label, randomised, controlled, multicentre study

In 2000, hexavac and infanrix hexa were licensed in Europe for primary immunisation of children against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive infections caused by Haemophilus influenzae b. In 2005, hexavac was suspended because of concerns about the long-term immunogenicity of its hepatitis B component. We aimed to assess the duration of immunity and need for booster injections in children primed with these vaccines. In an open-label, randomised, controlled, multicentre study in six local health units and at the Bambino Gesù Paediatric Research Hospital in Italy, antibody concentrations were measured 5 years after immunisation of infants with hexavac or infanrix hexa. Children with concentrations of antibodies to hepatitis B surface antigen (anti-HBs) lower than 10 mIU/mL were randomly assigned by simple randomisation to receive a booster of HBVaxPro or engerix B monovalent hepatitis B vaccine and tested 2 weeks later. Primary endpoints were the proportion of children with anti-HBs concentrations of at least 10 mIU/mL, geometric mean concentrations (GMCs) of antibody 5 years after vaccination, and the proportion of children with anti-HBs concentrations lower than 10 mIU/mL who had anamnestic response to booster. The study is registered with Agenzia Italiana del Farmaco, code FARM67NFPN. 1543 children were enrolled, 833 had received hexavac and 710 infanrix hexa. 831 children who received hexavac and 709 who received infanrix hexa were included in the analysis. 319 children who received hexavac (38.4%, 95% CI 35.1-41.7) had anti-HBs concentrations of at least 10 mIU/mL compared with 590 who received infanrix hexa (83.2%, 80.5-86.0; p<0.0001). GMCs before booster were 4.5 mIU/mL in the hexavac group compared with 61.3 mIU/mL in the infanrix hexa group (p<0.0001). After booster 409 (92.1%, 89.6-94.6) of 444 children primed with hexavac and 99 (94.3%, 89.8-98.7) of 105 primed with infanrix hexa had anti-HBs concentrations of at least 10 mIU/mL (p=0.4); GMCs were 448.7 mIU/mL and 484.9 mIU/mL (p=0·6). The two booster vaccine groups did not differ in number of side-effects; no serious adverse events were reported. 5 years after immunisation with hexavalent vaccines, immunological memory seems to persist in children with anti-HBs concentrations lower than 10 mIU/mL, suggesting that booster doses are not needed. Additional follow-up is needed. Agenzia Italiana del Farmaco.

Farmaco equivalente, sicurezza del paziente e profili di responsabilità

A diabetic patient under oral therapy with a generic drug had a sudden indisposition and hyperglycaemia due to the consumption of a tablet of another equivalent drug product – same active principle – with evident lack of therapeutic effect. The patient herself solved the problem by interrupting the new generic drugs and taking the one normally used. The general practitioner signalled the event to the Pharmacovigilance Centre that, in turns, signalled it to the Agenzia Italiana del Farmaco (AIFA), appointed to execute the controls. The case described is paradigmatic to discuss the responsibilities of the different actors involved (general practitioner, pharmacist, AIFA, and pharmaceutical industry).

Aspetti del principio di costituzionalità in ambito sanitario regionale e direttive AIFA

Italian Constitution stipulates citizens’ social rights and underlines the need of equity and efficiency in the provision of health care services. In recent years a trend towards federalism is emerging, leading to the risk of differences in patients’ treatment among Italian Regions. AIFA’s role (Agenzia Italiana del Farmaco) is to regulate and coordinate drugs prescription in order to avoid not only inequality in patients’ care, but also inadequate consumption of economic resources. The article examines the so called LEA (Livelli Essenziali di Assistenza), that are basic health parameters established to assure equity also at a regional level.

Intra-articular clodronate for the treatment of knee osteoarthritis: dose ranging study vs hyaluronic acid

Bisphosphonates may have a chondroprotective effect in patients with knee OA (KOA), but the results of clinical trials with oral bisphosphonates have been contradictory. In this Phase 2 randomized, partially blind clinical trial, we tested the efficacy of IA clodronate vs HA in patients with primary KOA. One hundred and fifty men or women aged 50-75 years suffering from KOA were randomized to one of five IA therapies: (i) clodronate 0.5 mg one IA injection/week for 4 weeks; (ii) clodronate 1 mg one IA injection/week for 4 weeks; (iii) clodronate 2 mg one IA injection/week for 4 weeks; (iv) clodronate 1 mg two IA injections/week for 2 weeks (clodronate 1 + 1 mg); and (v) HA 20 mg one IA injection/week for 4 weeks. Visual analogue scores (VASs) for different types of pain and the Lequesne index significantly improved in all treatment groups after the first injection and continued to improve even 2-4 weeks after the last injection without significant difference among the groups. A significant (P = 0.03) linear trend for a dose-response (0.5-2 mg clodronate) relationship was found for active movement VAS pain. Both joint extension and mobility scores improved significantly at all time points in all treatment groups without statistical differences among them. This study indicates that IA clodronate provides symptomatic and functional improvements at least as good as those obtained with HA. Trial Registration. Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali - Agenzia Italiana del Farmaco. Comitato Etico Azienda Ospedaliera Universitaria Senese number CLIO 22/02 http://oss-sper-clin.agenziafarmaco.it.

La politica farmaceutica in Italia nell’ultimo decennio: instabilità o consolidamento?

Pharmaceutical policy in Italy has been reshaped as a result of the 1993–4 crisis, in which it was revealed that pharmaceutical companies, policy makers and top Department of Health (DOH) officers had constructed an illegal system to set prices. Following this crisis, the rise of technical competency and leadership in the Italian Department of Health and, since 2004, in the Drug Regulatory Agency (AIFA, Agenzia Italiana del Farmaco) has achieved major improvements in many aspects of pharmaceutical policy. These improvements have included increased transparency of decision making, the use of evidence-based medicine principles for reimbursement and pricing, and the use of generic drugs to lower prices.

The Last Decade of Italian Pharmaceutical Policy

Pharmaceutical policy in Italy has been reshaped as a result of the 1993-4 crisis in which it was revealed that pharmaceutical companies, policy makers and top Department of Health officers had constructed an illegal system to set prices. Following this crisis, the rise of technical competency and leadership in the Italian Department of Health and, since 2000, in the Drug Regulatory Agency (Agenzia Italiana del Farmaco; AIFA) has achieved major improvements in many aspects of Italian pharmaceutical policy. These improvements have included increased transparency of decision making, the use of evidence-based medicine principles for reimbursement and pricing, and the use of generic drugs to lower prices.As a result of these changes, pharmaceutical expenditure has been controlled and equity has improved, mainly because co-payments have been reduced, thus reducing private expenditure on reimbursable drugs. However, a short-term approach to cost containment has prevailed, and Italian pharmaceutical policy has neglected industrial parameters. Hence, the trend in pharmaceutical expenditure has been erratic, and Italy has not favoured localization of research and development and production in its territory. The dominant issue of Italian health policy in recent years has been devolution of powers to regions, the intermediate tier of the Italian State. Overall, devolution has increased regional accountability on healthcare spending. However, regions react to enhanced freedom in different ways, reflecting their institutional capacity and competencies. This process has also affected pharmaceutical policy, more than in other decentralized healthcare systems (such as Germany and Spain). Such a situation is causing increasing regional variations and geographical equity concerns. In addition, the regional level appears rather inadequate to promote an industrial perspective unless it is supported by national initiatives.

Farmacoeconomia e outcomes research

Pharmaceutical products are relevant for their contribution to the medicine progress and in health peoples improvement, altough this evidence goes back to the forthy years with the reduction in mortality, morbidity and hospitalisation rates. The ambivalence of drugs, both remedy and poison, needs a careful assessment of risks and benefits. Primitive estimates of health treatments evaluation occurred in the human history but the modern concept of evaluation in health care derived from cost-benefit analysis (welfare economics) and technology assessment. Then a new discipline, pharmacoeconomics and outcomes research, developed with the contribution of health economics, clinical medicine, pharmacology, statistics and epidemiology. Pharmaceutical products are also relevant because of their responsability of health expenditure growth. From 1992, in Italy, several legislative actions were made to face up the pharmaceutical expenditure. The most important one (L. 537/1993) achieved the maximum decrease of 16,8%, in 1994, and modified radically the pharmaceutical policy. Nevertheless, in the following six years the pharmaceutical expenditure grew more than 93%. New actions were made fixing the pharmaceutical expenditure to 13% of health expenditure, any excess being charged to Regions. In the new version for the current year, the excesses will be paid-back by pharmaceutical companies (60%) and Regions (40%). Furtherly, the creation of Agenzia Italiana del Farmaco increases the relevance of cost-effectiveness analyses for drugs reimbursement. However, pharmacoeconomic evaluations have still many methodological problems. Economic variables should be treated in the same manner of biomedical or epidemiological data, that is, by confidence intervals and sample sizes. There would be an “economic significance” besides to clinical and statistical ones. In this way, pharmacoeconomics and outcomes research would be able to add rationality to health care expenditure.