Orphan Drug Prices and Epidemiology of Rare Diseases: A Cross-Sectional Study in Italy in the Years 2014-2019.

INTRODUCTION: It is well acknowledged that the price of orphan drugs is normally higher than that resulting from the value-based pricing. A correlation between the cost of therapy for orphan drugs and the epidemiology (prevalence and incidence) of the related rare disease can be hypothesized. METHODS: This analysis includes all approved orphan drugs by European Medicines Agency whose reimbursement was granted for the first therapeutic indication in the years 2014-2019 in Italy. Regression and correlation analyses were performed to analyze the possible correlations between the logarithm of the annual therapy cost and the epidemiology of the rare diseases, between orphan drugs consumption and epidemiology of related rare disease and between therapy cost and the consumption. RESULTS: The regression analysis between the annual cost of therapy estimated on the published ex-factory price and the prevalence showed a slightly decreasing, not statistically significant, trend (coefficient: -0.10, p-value: 0.41). The results were similar when using the price resulting from the application of Managed Entry Agreements (coefficient: -0.11, p-value: 0.40). The regression analysis between sales volume and prevalence showed a positive slope without an acceptable level of significance (p-value: 0.04). The correlation analysis between the therapy cost and the sales volume highlighted again an absence of significant association, similarly if considering only ATC L orphan drugs, or the incidence. DISCUSSION: The definition of the price of an orphan drug seems not to depend on the rarity of the disease, and sales volumes do not correlate with the epidemiology of the rare disease and with the annual cost of therapy.

Access and pricing of medicines for patients with rare diseases in the European Union: an industry perspective.

INTRODUCTION: The EU Orphan Regulation has successfully stimulated R&D of medicines for rare diseases, resulting in a substantial increase of orphan designations and authorized orphan medicinal products in the EU during last decade. Despite such advances, access to treatment across the 27 EU Member States is still highly variable. AREAS COVERED: We provide an overview of the current situation of patient access to orphan drugs in the EU. We discuss the EU policy landscape regarding joint assessment and pricing & reimbursement negotiations of medicinal products, price and sustainability of orphan drugs for health care systems, and the importance of Real-World Data and registry infrastructures for rare diseases. Additionally, we provide recommendations for areas of improvement throughout the lifecycle of orphan drugs, aiming to preserve a positive R&D climate for rare diseases in the EU and accelerate patient access. EXPERT OPINION: The EU needs to maintain a patient-centric pharmaceutical ecosystem that encourages long-term investments and rewards innovation in areas of high unmet medical need. Areas of potential improvement range from enhanced alignment of regulatory and HTA evidence requirements and use of specific value frameworks for the assessment of orphan drugs to the development of registry infrastructures and innovative performance-based pricing agreements.

Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations.

To maintain orphan drug status at the time of market authorization, orphan medicinal products (OMPs) need to be assessed for all criteria, including significant benefit, by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). Subsequently, health technology assessment (HTA) organizations evaluate the same OMPs in their relative effectiveness assessments (REAs). This review investigates the similarities and differences between the two frameworks for six HTA organizations, including the European Network for HTA. We discuss differences between both assessment frameworks within five domains (clinical evidence used, patient population, intervention, comparators, and outcome measures) for all drugs. Five illustrative cases studies were selected for a qualitative review.

The fourth edition of the European Network for Health Technology Assessment Forum: highlights and outcomes.

The European Network for Health Technology Assessment (EUnetHTA) organizes an annual Forum with stakeholders to receive feedback on its activities, processes, and outputs produced. The fourth edition of the EUnetHTA Forum brought together representatives of HTA bodies, patient organizations, healthcare professionals (HCPs), academia, payers, regulators, and industry. The aim of this paper is to provide an overview of the highlights presented at the 2019 EUnetHTA Forum, reporting the main items and themes discussed in the plenary panel and breakout sessions. The leading topic was the concept of unmet medical need seen from different stakeholders' perspectives. Breakout sessions covered the joint production of assessment reports and engagement with payers, patients, and HCPs. Synergies, pragmatism, and inclusiveness across Member States and stakeholders were emphasized as leading factors to put in place a collaboration that serves the interest of patients and public health in a truly European spirit.

[Establishing the value of new drugs in Italy.] / Quanto vale la negoziazione del prezzo di un nuovo farmaco in Italia?

Italy was used as a case study to investigate the determinants of the difference between the price proposal for medicines submitted by the industry and the final negotiated price (∆P). Data was gathered through the information system used by Italian Medicines Agency (AIFA) and the time-frame for this analysis is 2013-2017. Factors influencing the delta price were analyzed through a regression analysis. Forty four orphan drugs and 89 new other molecular entities obtained reimbursement in the period considered. Following the negotiation process, prices proposed by Marketing Authorization Holders (MAH) were lowered during the negotiation process by 25.1% and 28.6% on average for orphan drugs and other molecules respectively. The price reduction was higher for innovative drugs (-32.2%). Statistically significant determinants associated to higher price reduction were: i) the implementation of a product specific monitoring registry, ii) the negotiation of a financial-based (FB) Managed Entry Agreement, iii) a target population larger than 20,000 patients, iv) an expected National Health Service expenditure larger than € 200 million. The impact of some variables on the delta price was predictable (e.g. for drugs with an expected higher budget impact and a larger target population), others were more surprising (e.g. a significant price reduction for "innovative" drugs). The implementation of FB agreements, which often rely on confidential arrangements, was one of the determinants with higher impact on price reduction.

How Do Drug Regulatory Bodies Deal With Potential Innovative Therapies?

Given the extensive development of new molecules over the last 10 years, regulatory authorities (RAs) have been intensively working on evaluating how to identify and manage "innovative" drugs. The purpose of this article is to analyze whether RAs have procedures capable of ensuring access to innovative drug therapies and to understand what criteria RAs around the world (Europe, USA, Canada, Australia, and Japan) use to identify innovative drugs, comparing the different strategies and tools used to prioritize the assessment of the most promising drugs. All the RAs under review consistently use two elements to speed up drug access: (1) the handling (shortening) of approval times and the (2) management of the (limited) evidence available. No international RA utilizes any state-of-the-art method to evaluate the innovativeness of medicinal products. Harmonizing a definition and the criteria used to define pharmaceutical innovation would allow faster access to patients.

Using GRADE methodology to assess innovation of new medicinal products in Italy.

AIM: In April 2017 the Italian Medicine Agency (AIFA) developed new criteria to grant any new medicinal product with an innovative designation. The aim of this study is to describe this new model and how it works. METHODS: A retrospective descriptive analysis was performed on the results of the assessment process of innovativeness of new medicinal products (or therapeutic indications) based on the AIFA's new innovation criteria (therapeutic need, added therapeutic value and quality of clinical evidence through GRADE methodology) carried out between April 2017 and February 2019 and made publicly available on the AIFA website starting from January 2018. RESULTS: A total of 37 full reports (22 for oncological indications) explaining the rationale for the AIFA's decision is made publicly available on the agency's website. A total of 12 therapeutic indications (5 oncological) were evaluated as fully innovative, 13 indications (11 oncological) were evaluated as conditionally innovative, while 12 indications (6 oncological) as non-innovative. CONCLUSION: The new AIFA innovation criteria resulted in a much more flexible and transparent model to define and assess what constitutes a therapeutic innovation. In particular, the choice of AIFA to use the GRADE methodology to evaluate the quality of clinical evidence within a process of drug innovativeness assessment is essential for the early identification of the discrepancy between the need for patients of a rapid access to innovative therapies and the available clinical data needed to make decisions on drug innovativeness.

Determinants of price negotiations for new drugs. The experience of the Italian Medicines Agency.

OBJECTIVES: The aim of this paper is to investigate the determinants of the difference between the price proposal submitted by the industry and the final negotiated price. We used Italy as a case-study. METHODS: Data were gathered through the information system used by Italian Medicines Agency. The time-frame for this analysis is 2013-2017. Factors influencing the delta price were analyzed through a regression analysis. RESULTS: 44 orphan drugs and 89 new other molecular entities obtained reimbursement in the last five years. Following the negotiation process, prices were lowered by 25.1% and 28.6% on average for orphan drugs and other molecules respectively. The price reduction was higher for innovative drugs (-32.2%). Statistically significant determinants associated to higher price reduction were: i) the implementation of a product specific monitoring registry, ii) the negotiation of a financial-based Managed Entry Agreement, iii) a target population larger than 20,000 patients, iv) an expected National Health Service expenditure larger than €200 million. DISCUSSION: The impact of some variables on the delta price was predictable (e.g. for drugs with an expected higher budget impact and a larger population target), others were more surprising (e.g. a significant price reduction for "innovative" drugs). The implementation of financial-based agreements, which often rely on confidential arrangements, was one of the determinants with higher impact on price reduction.

Information needs on precision medicine: a survey of Italian health care professionals.

BACKGROUND: Despite advances in technology development for precision medicine, obstacles remain as barriers to progress and change. In this context simple questions arise: what is the level of understanding of precision medicine among healthcare professionals? We tried to address this question with a survey whose objective was to explore the perception and understanding of precision medicine. METHODS: A questionnaire was administered to a sample made of oncologists, clinical and hospital pharmacists, pharmacologists and infectiologists in the context of five different Italian national congresses. Participation in the survey was voluntary and anonymous. RESULTS: The questionnaire was filled-in by a total number of 1113 professionals out of 3670 registered participants in the congresses. About half of respondents stated they were not sufficiently informed about precision medicine, and infectiologists were the ones who felt less informed. Most respondents agreed with the basic principles and definitions of precision medicine and believed this new approach is going to require deep changes in healthcare. CONCLUSIONS: Our findings show that healthcare professionals have partial knowledge on this topic and that there is a significant association between respondents' knowledge and their clinical specialty. However, despite some misconceptions about precision medicine, a genuine interest and familiarity with its basic principles seems to emerge.

[Innovative medicinal products: the new criteria of the Italian Medicines Agency.] / Farmaci innovativi: i nuovi criteri dell'Agenzia Italiana del Farmaco.

The Italian Medicines Agency (AIFA), which has the dual function of a regulatory and a reimbursement authority, has recently established new criteria to define innovative medicinal products. Indeed, the decision making process to grant the innovative status is based on the evaluation of the unmet medical need, the added therapeutic value compared to existing therapeutic options and the overall quality of clinical evidence, which is assessed based on the GRADE system. Following this evaluation, if a medicinal product is granted the status of "full innovativeness" for a specific therapeutic indication, its manufacturer can access dedicated yearly funds amounting to 500 million Euros each, depending on the type of medicine (one fund for oncology, the other for all other innovative medicinal products). Alternatively, the product can be granted the status of "conditional innovativeness" which allows immediate access to all Regional formularies, with no additional re-assessments at the local level. The third possible outcome is that no innovativeness is recognized. Starting from January 2018, a full report explaining the rationale for the Agency Committee's decision is made publicly available on the AIFA's website.

The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations.

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.

Comparing safety information of biosimilars with their originators: a cross-sectional analysis of European risk management plans.

BACKGROUND AND AIMS: Biosimilars have been available in the European Union (EU) since 2006. However, their uptake in routine care is heterogeneous across countries. The aim of the present study was to compare the safety information of biosimilars and their originators based on the information in the European risk management plan (RMP). METHODS: A cross-sectional analysis on publicly available regulatory documents (RMPs and Summaries of Product Characteristics) of biosimilars and corresponding originators up to 1 November 2015 was performed. The safety concerns were extracted and merged into general safety concerns, and clinical relevance was assessed. The frequency of safety concerns and the representation of these safety concerns per general safety concern were assessed by either comparing RMPs of biosimilars and originators (if available for both) or comparing RMPs with the Summary of Product Characteristics of the originator. RESULTS: Nineteen biosimilars and six originators were included. Overall, 55 general safety concerns (12 low, 21 medium and 22 highly clinically relevant) were identified. For all active substances, except for infliximab, no or only one difference was found in the listed general safety concerns. Comparison of regulatory documents for infliximab identified three medium clinically relevant general safety concerns more for infliximab biosimilars and two general safety concerns more for its originator. CONCLUSION: Based on publicly available information filed for regulatory purposes, no substantial differences were observed in the reporting of safety information for biosimilars and related originators. A direct comparison between biosimilars and related originators through formal postmarketing studies is needed to evaluate specific safety issues emerging during the products' life cycle.

How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice.

BACKGROUND: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. AIMS: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. METHODS: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. RESULTS: The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. CONCLUSIONS: There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice.

Evaluation of oncology drugs at the European Medicines Agency and US Food and Drug Administration: when differences have an impact on clinical practice.

PURPOSE: The aims of this study were to compare the approaches of the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in the evaluation and approval of new anticancer indications and to identify possible clinical implications associated with these differences. METHODS: Information on the European Union therapeutic indications for the cohort of anticancer drugs was extracted from the European Public Assessment Reports and from the FDA review reports. RESULTS: Overall, 42 anticancer drugs were approved by EMA between 1995 and 2008, corresponding to a total of 100 indications. In 47 of 100 indications, a difference was found. For 19 of these 47 indications, the difference was that one agency approved an indication, whereas the other agency did not. For the remaining 28 indications, the same indication was approved by both of the agencies and differences were evaluated through an algorithm; in 10 cases, discrepancies in therapeutic indications between EMA and FDA were considered clinically relevant. We found an overall trend that the agency that was second to give a positive approval was usually more restrictive in terms of wording of the indication compared with the agency that provided approval first. Regarding the use and robustness of available clinical data for evaluation, no clear associations could be found. CONCLUSION: Clinically relevant differences in the outcome of the EMA and FDA approval process of oncology products were found. Neither of the agencies seems to have a prevailing restrictive behavior over the other. Further efforts on harmonizing decision making between regulatory systems are needed.

Therapeutic indications in oncology: emerging features and regulatory dynamics.

The regulatory route leading to the definition of therapeutic indications of new compounds as well as extensions of indication (EoI) of already approved ones is a challenging process. If new anticancer drugs reach the market with a lack of complete evidence, this usually leads regulators to request additional data, post approval commitments or restrictions in therapeutic indications. This study aims at quantifying the time needed for anticancer drugs approved by the EMEA to get an extension, the rates and characteristics of extensions approved, and at exploring the regulatory process leading to the definition of new indications. A total of 103 therapeutic oncological indications, related to a cohort of 43 anticancer drugs, were retrieved between 1995 and 2008. The median time occurring between different indications for the same compound (defined as Time to New Extension, TtNE) significantly decrease from about 81 months in 1996 to 6 months in 2006. Twenty-four out of 43 approved anticancer medicines (about 56%) have only a single therapeutic indication, 12 of which were approved before 2005. When considering two different cohorts of drugs in relation to the time of approval (1995-2004 versus 2005-2008), although not statistically significant, the older cohort tended to have a decreased probability of having EoI when compared to the new cohort (OR=0.27; 95% confidence interval (CI): 0.07-1.04). With regard to the type of EoI (n=60), our findings showed that in 48% of cases the initially approved indication was extended to treat a different tumour, in 37% of cases the extension consisted in a switch of line within the same therapeutic indication. The other two types of indication broadening refer to a different tumour stage (8%) and to the inclusion of a new patient population (7%). The analysis of indication restrictions showed that in 20 cases out of 50 (40%) therapeutic indications were restricted by the Committee for Medicinal Products for Human Use (CHMP) during the assessment, with 60% of the restrictions occurring in 2006-2007. This study adds three main pieces of information: (i) the majority of anticancer drugs still have a single indication regardless of the year of approval; (ii) the time needed to obtain an extension of indication has decreased significantly over the last decade and (iii) a highest rate of regulatory restrictions is matched to shorter clinical developments.

Off-label use of medicines in children: can available evidence avoid useless paediatric trials? The case of proton pump inhibitors for the treatment of gastroesophageal reflux disease.

PURPOSE: In some cases of drug therapy, the available evidence might be sufficient to extend the indications to children without further clinical studies. METHODS: We reviewed the available evidence for one of the categories of drugs most frequently used off-label in children: proton pump inhibitors (PPIs) used for the treatment of gastroesophageal reflux disease (GERD). A classification of the appropriateness of off-label use of PPIs in children with GERD was also performed. RESULTS: Of the five PPIs evaluated, only omeprazole has a paediatric indication in Europe. Overall, 19 clinical trials were retrieved and evaluated on the basis of pharmacokinetics, efficacy and safety data. The off-label use of omeprazole, esomeprazole and lansoprazole in children was evaluated as appropriate given the consistent available evidence retrieved in literature. CONCLUSION: This study demonstrates the existence of a large body of clinical evidence on the use of PPIs in children. Regulatory agencies and ethical committees should cope with this issue for ethical reasons to avoid unnecessary trial replication.

Haematological anticancer drugs in Europe: any added value at the time of approval?

OBJECTIVE: Current European regulations only require drugs to be safe and effective, although there is heavy demand for comparative efficacy data to demonstrate the added value of new drugs. The objective of the analysis reported here was to assess the added value of new anticancer drugs for haematological malignancies that have been approved by the European Medicines Agency (EMEA) based on the clinical data provided at the time of submission. METHODS: Information on the evidence supporting the approval was extracted from the European Public Assessment Reports (EPARs). Documents were surveyed for new applications and for subsequent extensions between January 1995, when the EMEA was set up, and May 2006. The added value of newly approved drugs was assessed by an algorithm that evaluates the strength of evidence based on methodological appropriateness (randomised comparison) and the importance of clinical advantage (in terms of the magnitude of benefit, hardness of outcome measures, adequacy of comparator). RESULTS: Eleven anticancer drugs were analysed. Of 17 indications, nine (53%) were approved on the basis of single-arm trials (SATs), and eight (47%) were approved on the basis of randomised controlled (clinical) trials (RCTs). The most frequently used endpoint was response rate (12 of 17 indications, 70%). On the basis of our criteria, only four of the 11 drugs show a consistent added value. CONCLUSION: We were unable to establish an added value for about two thirds of the drugs evaluated in this study, primarily due to methodological aspects related to study design and endpoint robustness.

Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders.

Epidemiological and experimental studies have indicated that consumption of more n-3 long-chain polyunsaturated fatty acids may reduce the risk for a variety of diseases, including cardiovascular, neurological and immunological disorders, diabetes and cancer. This article focuses on the role of marine n-3 long-chain polyunsaturated fatty acids in brain functions, including the development of the central nervous system and neurological disorders. An overview of the major animal studies and clinical trials is provided here, focusing on fatty acid supplementation during pregnancy and infancy, and prevention and management of Alzheimer's disease, schizophrenia, depression and attention deficit hyperactive disorder. Although an optimal balance in n-3/n-6 long-chain polyunsaturated fatty acid ratio is important for proper neurodevelopment and cognitive functions, results from randomized controlled trials are controversial and do not confirm any useful effect of supplementation on development of preterm and term infants. The relationship between fatty acid status and mental disorders is confirmed by reduced levels of n-3 long-chain polyunsaturated fatty acids in erythrocyte membranes of patients with central nervous system disorders. Nevertheless, there are very little data supporting the use of fish oil in those patients. The only way to verify whether n-3 long-chain polyunsaturated fatty acids are a potential therapeutic option in the management and prevention of mental disorders is to conduct a large definitive randomized controlled trials similar to those required for the licensing of any new pharmacological treatment.