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Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an add-on to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

As the first biologics produced by recombinant deoxyribonucleic acid (DNA) technology were approved in the late 1980s and consequently the exclusive marketing rights of most of these biological medicinal products have expired or will expire very shortly, it is quite evident that biosimilars are being developed and marketed in developed as well as developing countries in line with these expiries. Hence, there is an explosion of published papers and scientific programs on biological medicinal products and biosimilar insulins in the last decade or so. Each of these papers or scientific programs generated more questions than providing clinically useful answers. The specific aim of the medical literature or scientific programs were blurred due to lot of attention (created by the innovators) directed towards confusing terminologies, past mishaps with biosimilars (in the era with the absence of regulatory guidelines for biosimilars) diverting our attention from the matters relevant to clinicians and patients. One of the principle reason behind this phenomenon has been our poor understanding of the manufacturing process, regulatory pathways, and study endpoints involved in developing a biosimilar in the present era. This drawback resulted in a nonsystematic approach in analyzing the biosimilars and apparently resulting in confusion. This review attempts at demystifying certain facets of frequently encountered information on biosimilars and acquire a personal understanding on the same, rather than depending on conflicting versions floated at different continuing medical educations (CMEs) and Diabetes Congresses.

The diagnosis of idiopathic short stature (ISS) refers to children who are considerably shorter than average without any identified medical reason. The US Food and Drug Administration (FDA) authorised marketing of recombinant human growth hormone (hGH) for ISS in 2003, while the European Medicines Agency (EMA) refused it in 2007. This paper examines the arguments for these decisions as detailed in selected FDA and EMA documents. It combines argumentative analysis with an approach to policy analysis called ‘What’s the problem represented to be’. It argues that the FDA presents its approval as an argument for equity of access to the treatment (given that hGH was already authorised for other indications), describing short stature as a potential disadvantage, and assuming that height normalisation is a clinically meaningful result. The EMA, instead, refuses marketing authorisation with an argument that there is an imbalance of risks and benefits, describing ISS as a healthy condition, and arguing that hGH should provide some psychosocial and/or quality of life benefits to children with ISS other than height gain. This paper then discusses how these arguments could be read through different models of disability, particularly through the medical model of disability and the relational, experiential, and cultural understandings of disability.

Cilj istraživanja Cilj je ovog specijalističkog rada analizirati regulatorne smjernice Europske agencije za lijekove vezane za razvoj lijeka koji se primjenjuje udisanjem u pluća, proizvodnju, provjeru kakvoće i ispitivanja stabilnosti u postupku davanja odobrenja za stavljanje lijeka u promet na području Europske unije. Materijali i metode Literatura će biti pretraživana prema temi istraživanja, predmetu istraživanja, autorima i časopisu. Pretraživati će se od općih prema specijaliziranim člancima pri čemu će se odabirati članci relevantni za problematiku ovoga specijalističkog rada. Ciljana pretraga provedena je putem baza ScienceDirect, PubMed, Agencije za lijekove i medicinske proizvode. Regulatorne smjernice detaljno su istražene pretraživanjem baze Europske agencije za lijekove. Rezultati Farmaceutski oblici za primjenu lijeka udisanjem u pluća koji se koriste za liječenje astme i kronične opstruktivne bolesti pluća dostupni su više od 50 godina na tržištu. Veliki je interes farmaceutske industrije razvijati lijekove koji se primjenjuju udisanjem u pluća zbog velikog broja bolesnika koji boluju od astme i kronične opstruktivne plućne bolesti. Lijekovi koji se primjenjuju udisanjem u pluća dostavljaju se točno na mjesto djelovanja i mogu djelovati već unutar 5 minuta. Prednost ovih lijekova je način primjene, izravno u donje dišne putove gdje djelatna tvar ima učinak u relativno niskim dozama, dok je u isto vrijeme sustavna primjena lijeka minimalna čime su smanjene moguće nuspojave lijeka. Primjenom lijekova udisanjem u pluća izbjegava se metabolizam prvog prolaza kroz jetru, osigurava se djelovanje lijeka na mjestu upale, te se izbjegavaju sistemske nuspojave. Lijekovi koji se primjenjuju udisanjem u pluća dijele se u tri kategorije: stlačeni inhalati, prašci inhalata i pripravci za atomizator. Svi ovi lijekovi su kombinacija same formulacije lijeka i uređaja za inhaliranje. Formulacija lijeka je dizajnirana da pruži namijenjenu učinkovitost pacijentu, da postigne svoj cilj i da bude kompatibilna s inhalatorom. Inhalator mora pružiti dosljednu dozu sadržaja uz odgovarajuću aerodinamičku distribuciju čestica kako bi se osigurala dostava lijeka u pluća. Dobro dizajniran inhalator mora uzeti u obzir upotrebljivost za pacijenta u smislu da inhalator ne bude robustan, da bude jednostavan za korištenje, prenosiv i prikladan za sve uzraste. Svaki tip inhalatora ima posebnu formulaciju lijeka i kliničke prednosti. Zaključak Zahtjev za davanje odobrenja za lijekove koji se primjenjuju udisanjem u pluća u Europskoj uniji može biti podnesen prema Article 8(3) Direktive 2001/83/EC (cjelovita dokumentacija) ili prema Article 10(3) Direktive 2001/83/EC (hibridna aplikacija). Najveći izazov u razvoju generičkih/hibridnih lijekova koji se primjenjuju udisanjem u pluća je dokazivanje terapijske ekvivalencije. Terapijsku ekvivalentnost je potrebno dokazati kroz odgovarajuća klinička ispitivanja ako ekvivalentnost nije dokazana u skladu s in vitro zahtjevima te ako nije dokazana sistemska sigurnost i odlaganje čestica u pluća kroz farmakokinetičke studije. Klinička ispitivanja provode se kako bi se ispitala djelotvornost i sigurnost lijeka te se trebaju temeljiti na rezultatima o sigurnosti dobivenih u prijašnjim kliničkim ispitivanjima, kao i na podatcima dobivenim u nekliničkim ispitivanjima. Izostavljanje kliničkih ispitivanja je opravdano u slučaju kada hibridni lijek koji se primjenjuje udisanjem u pluća u usporedbi s referentnim lijekom zadovolji sva propisana in vitro ispitivanja. Objectives The aim of this paper is to describe biopharmaceutical peculiarities of inhaled medicinal products and contribute to the understanding of guidelines for preparation of documentation for marketing authorization laid down by the European Medicines Agency (EMA), which are related to drug development, production, quality control and stability testing. Materials and Methods Literature search was done by topic and subject of research, authors and journals, from general to specialized articles and guidelines relevant to the issues of this paper. The targeted search was carried out via the on-line databases such as ScienceDirect, PubMed, medicinal products database of the Agency for Medicinal Products and Medical Devices of Croatia. The regulatory guidelines have been detailed searched through the European Medicines Agency database. Results Inhalation drug products have been widely accepted for localized treatment for pulmonary diseases such as asthma and chronic obstructive pulmonary disease and they are available for over 50 years in the market. It is a major interest of the pharmaceutical industry to develop inhalation drug products due to the large number of patients suffering from asthma and chronic obstructive pulmonary disease. For local activities, the orally inhaled drugs are delivered directly to the site of action in the lung, providing fast onset action within 5 minutes. The advantage of these drugs products is the route of administration, directly in the lower respiratory tract where the active substance has effect at relatively low doses, while at the same time the systemic absorption of the drug is minimal, thereby reducing the possible side effects of the drug. By using the inhalation drug product, the first pass metabolism through the liver is avoided, the drug action is provided directly to the site of action, and systemic side effects are avoided. Inhalation drug products are commonly classified into three categories: pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI) and nebulizer. All these inhalation drug products are a combination of formulation and device. The formulation is designed to provide intended efficacy for patients, and to achieve this goal, it needs to be compatible and works together with a device. An inhalation product should be able to provide consistent dose content, along with suitable aerodynamic particle size distribution, to ensure that the drugs can be efficiently delivered to the target sites in the lung. A well designed inhaler must also consider its usability for patients use in terms of features such as robustness, ease of use, portability, and suitability for all ages in order to achieve good patient compliance with the technique instructions. Each type of inhaler has its specific formulation, device and clinical advantages. Conclusion Application for granting marketing authorization for inhaled medicinal products in EU can be submitted according to Article 8(3) of Directive 2001/83/EC (full dossier) or according to Article 10(3) of Directive 2001/83/EC (hybrid application). The greatest challenge in the development of generic / hybrid inhaled medicinal products is the demonstration of therapeutic equivalence between two inhaled products. Therapeutic equivalence should be demonstrated by means of appropriate clinical studies when equivalence is not shown according in vitro requirements and if it is not shown convincingly by investigation of systemic safety and pulmonary deposition. Clinical studies are conducted to examine the efficacy and safety of the inhaled medicinal product and should be based on the safety results obtained in previous clinical studies as well as data obtained in non-clinical studies. Exclusion of clinical studies is justified in cases where the hybrid inhaled medicinal product compared to the reference product satisfies all in vitro requirements.

This study aims to investigate the barriers that exist when implementing continuous improvement methodologies, such as Lean Six Sigma (LSS), within the Irish Pharma industry. The main finding of this study is that 45% of participants perceived that a highly regulated environment could be a barrier to continuous improvement implementation, while 97% of respondents utilised Continuous improvement (CI) methods, such as Lean, Six Sigma, and LSS, within their organisations. While the International Conference of Harmonisation integrates CI into its Pharmaceutical Quality Systems (PQS) regulations, the highest motivation for CI implementation amongst the Irish Pharma industry is to improve Productivity and Quality. The main obstacles highlighted for CI implementation in Pharma attributed to stringent regulatory regimes were fear of extra validation activity, a compliance versus quality culture, and a regulatory culture of being “safe”. Another relevant finding presented in this paper is that participants CI LSS tools are very strongly integrated into the pharma industries corrective and preventative action system, deviations, and internal audit systems. Limitations of the research are that all the data collected in the survey came from professionals working for multinational Pharmaceutical companies based in Ireland. The authors understand that this is the first research focused on the barriers and status of CI initiatives in the pharmaceutical industry. The results of this study represent an important step towards understanding the enablers and obstacles for the use of continuous improvement methodologies in pharmaceutical manufacturing industries on a global scale.

Biopharmaceuticals are associated with the revolutionary treatment of various diseases, and according to the European Medicines Agency, biopharmaceuticals derived from biological sources are perceived to not cause significant environmental risk. However, there is currently no broadly recognized definition or categorization of biopharmaceuticals despite the fact that improved technology has made it possible to modify them to obtain more efficient medicines, thereby raising questions about their biological origins and risks. The aim of this paper, based on a literature review, is to derive a clear definition of biopharmaceuticals and evaluate the European Union's regulation and environmental risk assessment (ERA) procedures for them. Nine different definitions were identified, and it is evident that the term “biopharmaceuticals” is used ambiguously. We therefore recommend that biopharmaceuticals are defined as complex molecules derived from a biological source, with the purpose to diagnose, prevent, treat, or cure diseases or conditions of human beings. Furthermore, we recommend that biopharmaceuticals should be categorized according to their biological structure: 1) amino acids, 2) nucleic acids, and 3) vaccines. Only 11 studies were identified as being relevant to ERA, and we lack useful data for hazard identification. More research is needed to examine the ecotoxicity, fate, and stability of most biopharmaceuticals—and categorical regulatory exclusion seems unfavorable in this regard.

On 18 September 2017, a marketing authorisation valid through the European Union (EU) was issued for midostaurin in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are Fms-like tyrosine kinase 3 mutation positive and as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL). The recommended dose of midostaurin is 50 mg orally twice daily for AML and 100 mg orally twice daily for ASM, SM-AHN and MCL. Midostaurin was evaluated in two pivotal studies. Study A2301 (RATIFY) included 717 patients with AML. Overall survival (OS) was statistically significantly different between the two groups, and the median OS was 74.7 months in the midostaurin+daunorubicin+cytarabine group and 25.6 months in the placebo+daunorubicin+cytarabine group (HR 0.774; 95% CI 0.629 to 0.953; p=0.0078). Study D2201 included 116 patients with ASM, SM-AHN or MCL. An overall response rate, by IWG-MRT/ECNM (international working group – myelofibrosis research and treatment/European competence network on mastocytosis) criteria of 28.3% was observed in all patients and 60.0%, 20.8% and 33.3% in patients with ASM, SM-AHN and MCL respectively. The most common adverse drug reactions (ADRs) with midostaurin treatment in AML were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and fever. In ASM, SM-AHN, MCL the most common ADRs were nausea, vomiting, diarrhoea, peripheral oedema and fatigue. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU.

The development of novel regulatory tools such as adaptive clinical trial design and utilization of real-world evidence are topics of high interest. Recently, the European Medicines Agency (EMA) introduced the Adaptive Pathways (AP) that represents an innovative tool in healthcare systems allowing the early dialogue with multiple stakeholders on promising and innovative medicinal products in areas with an high unmet medical need. The innovative aspect in the AP is the early involvement of several stakeholders such as pharmaceutical industry, the Academia, Health Technology Assessment (HTA) bodies, and patient representatives bringing their real experience with the disease and their expectations about the treatment. AP is not a new licensing tool but an opportunity for a very early discussions, before starting the phase II studies, among all stakeholders, including regulators, companies, HTA bodies, and patient representatives on a new potential medicine in areas of high unmet medical need. The aim of this paper is to describe the evolution of the AP approach from the beginning of the pilot project to date, highlighting major advances, and achievement at European level.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

On 1 February 2013, a marketing authorisation valid throughout the European Union was issued for aflibercept (Zaltrap) in combination with irinotecan/5-fluorouracil/folinic acid chemotherapy for the treatment of adults with metastatic colorectal cancer resistant to or progressive after an oxaliplatin-containing regimen. Aflibercept is a recombinant fusion protein which blocks the activation of vascular endothelial growth factor (VEGF) receptors and the proliferation of endothelial cells, acting as a soluble decoy receptor that binds to VEGF-A with higher affinity than its native receptors, as well as placental growth factor and VEGF-B. The use of aflibercept was studied in a randomised, double-blind, placebo-controlled phase III study, in patients with metastatic colorectal cancer (mCRC) who had previously been treated with an oxaliplatin-based treatment with or without prior bevacizumab. Aflibercept (n=612) was compared with placebo (n=614), both in combination with FOLFIRI (infusional fluorouracil, leucovorin and irinotecan). The primary endpoint of the study was overall survival (OS). The median OS in the intent-to-treat population was 13.5 months in subjects treated with aflibercept compared with 12.1 months for subjects in the control arm (stratified HR=0.817, 95% CI 0.714 to 0.935, stratified pvalue=0.0032). The frequency of adverse events was higher in the aflibercept arm compared with the placebo arm, reflecting the toxicity profile of anti-VEGF agents in combination with chemotherapy. This paper is based on the scientific review of the application leading to approval of aflibercept in the EU. The detailed scientific assessment report and product information for this product are available on the European Medicines Agency website (http://www.ema.europa.eu). Trial registration number NCT00561470, Results.

Medicines receiving a conditional marketing authorization through Medicines Adaptive Pathways to Patients (MAPPs) will be a challenge for payers. The “introduction” of MAPPs is already seen by the European Medicines Agency (EMA) as a fait accompli, with payers not consulted or involved. However, once medicines are approved through MAPPs, they will be evaluated for funding by payers through different activities. These include Health Technology Assessment (HTA) with often immature clinical data and high uncertainty, financial considerations, and negotiations through different types of agreements, which can require monitoring post launch. Payers have experience with new medicines approved through conditional approval, and the fact that MAPPs present additional challenges is a concern from their perspective. There may be some activities where payers can collaborate. The final decisions on whether to reimburse a new medicine via MAPPs will have more variation than for medicines licensed via conventional processes. This is due not only to increasing uncertainty associated with medicines authorized through MAPPs but also differences in legal frameworks between member states. Moreover, if the financial and side-effect burden from the period of conditional approval until granting full marketing authorization is shifted to the post-authorization phase, payers may have to bear such burdens. Collection of robust data during routine clinical use is challenging along with high prices for new medicines during data collection. This paper presents the concept of MAPPs and possible challenges. Concerns and potential ways forward are discussed and a number of recommendations are presented from the perspective of payers., peer-reviewed

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally. Copyright © 2016 John Wiley & Sons, Ltd.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally. Copyright © 2016 John Wiley & Sons, Ltd.

The concept of transparency has gained widespread appeal in the European pharmaceutical domain, not least at the European Medicines Agency (EMA). Agency policies have two main objectives: (1) to enable the reuse of data (e.g. clinical study reports) and (2) to empower patients to directly and indirectly make more informed decisions on medicines. Past research has almost exclusively focused on the perspectives of external researchers intending to reanalyse data made publically available. Few studies, however, have explored what can be learnt from the perspectives of other actors (e.g. health care professionals, patients, the regulators themselves, industry and others). This empirical study explores the EMA's transparency policies from the perspectives of patients. After presenting the results of a survey (N=1010) with a sample of individuals diagnosed with five specific medical conditions (HIV/AIDS, multiple sclerosis, rheumatoid arthritis, osteoporosis and idiopathic pulmonary fibrosis) from four EU countries (Germany, Spain, France and the UK), the authors argue that EMA's transparency policies do not adequately address the real-world complexities of communicating with patients. In turn, the paper concludes that the perspective of patients provides an essential contribution to understanding the full net effects (positive, negative and/or limited) of EMA's transparency policies.

Quality by design (QbD) is an innovative approach to drug development that has started to be implemented into the regulatory framework, but currently mainly for chemical drugs. The recent marketing authorization of the first monoclonal antibody developed using extensive QbD concepts in the European Union paves the way for future further regulatory approvals of complex products employing this cutting-edge technological concept. In this paper, we report and comment on insights and lessons learnt from the non-public discussions in the European Medicines Agency's Biologicals Working Party and Committee for Medicinal Products for Human Use on the key issues during evaluation related to the implementation of an extensive QbD approach for biotechnology-derived medicinal products. Sharing these insights could prove useful for future developments in QbD for biotech products in general and monoclonal antibodies in particular.

Background In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. Results 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. Conclusions Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally. Copyright © 2016 John Wiley & Sons, Ltd.

Across Europe, around one in four adults experience a mental health problem in any 1 year. It is estimated that 2-6% of children and adolescents suffer from depression and suicide is now the third leading cause of death in 10-19 year olds. Despite traditional Freudian teachings that children rarely suffer from clinically diagnosed depression, treatment figures for juvenile depression have soared in recent years. For adults, the current treatment trend, as advocated by the National Institute for Health and Clinical Excellence (NICE), is the use of Selective Serotonin Reuptake Inhibitors (SSRIs), such as Prozac. For children, efficacy of such treatment remains difficult to judge as all SSRI use in paediatric care remains 'off-label' or unlicensed. Notwithstanding this, in 2006 the European Medicines Agency (EMEA) advocated the use of Prozac within the EU for children from the age of eight, a position that reinforced the stance adopted by NICE in 2005. These recommendations have been made despite growing concern that many SSRIs have some serious side effects. In new legislation for paediatric medicines, that came into effect on 26th January 2007, the European Union (EU) has attempted to address several unresolved issues relating to children's needs for medicines in Europe. This paper considers the position of off-label drug-therapy for juvenile depression, and assesses the effectiveness of available legal mechanisms that can protect juveniles from harm when involved in clinical drug trials, most notably the Clinical Trial Regulations 2004. It further reviews the new EU legislation and evaluates its likely impact. © 2008 Springer Science+Business Media B.V.

What is already known about this subject • We recently proposed an algorithm to assess the degree of therapeutic innovation of new therapeutic agents. It was based on the disease seriousness, the availability of previous treatments and the extent of the therapeutic effect, and was applied to all therapeutic agents approved by the EMEA in the period 1995–2003. • A low percentage (32%) of important therapeutic innovation was found. This figure may be an underestimate of the actual level of innovation, because common biotechnological products, such as recombinant human insulins, must follow the centralized procedure. What this study adds • Details for each agent, focusing on the comparison of the degree of therapeutic innovation between biotechnological and nonbiotechnological therapeutic agents approved by EMEA during the its first decade of activity (1995–2004). The underlying hypothesis was that the latter have a higher degree of innovation because they followed the centralized procedure on the assumption that they are innovative. • The percentage of important therapeutic innovation was low not only for biotechnological products (25%), as expected because they include many already known products such as insulins, but also for nonbiotechnological therapeutic agents (29%). Aims In a previous paper, we proposed an algorithm to assess the degree of therapeutic innovation of the agents approved by the European centralized procedure, which must be followed by biotechnological products and is optional for drugs claimed as innovative. A low overall degree of therapeutic innovation (about 30%) was found. This figure may be an underestimate of the actual level of innovation, because common biotechnological products, such as recombinant human insulins, must follow this procedure. To test the hypothesis that therapeutic innovation prevails among nonbiotechnological products, we evaluated separately the degree of therapeutic innovation of biotechnological vs. nonbiotechnological agents in the first decade of European Medicines Agency activity, also studying a possible time trend. Methods We assessed, for each drug: (i) the seriousness of the target disease, (ii) the availability of previous treatments, and (iii) the extent of therapeutic effect according to the previously proposed algorithm. Results Our analysis considered 251 medicinal products corresponding to 198 active substances, classified according to four main areas as therapeutic agents (88.9%), diagnostics (5.5%), vaccines (5.1%) and life-style drugs (0.5%). Among all therapeutic agents, 49 out of 176 agents (28%) were classified as having an important degree of therapeutic innovation. Fifteen out of 60 biotechnological therapeutic agents were considered important therapeutic innovations (25%), whereas this figure was 29% for nonbiotechnological agents. Conclusions Among active substances claimed as innovative by the manufacturers, only a minority deserve this definition according to our algorithm.

Pertuzumab is a recombinant humanized monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of HER2. Based on the positive opinion from the European Medicines Agency (EMA) on March 4, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. In the primary analysis, median progression-free survival was 18.5 months in the pertuzumab group compared with 12.4 months in the placebo group (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.51–0.75; p < .0001). For the secondary endpoints, overall survival (HR: 0.66; 95% CI: 0.52–0.84; p = .0008) and objective response rate (80.2% vs. 69.3%) were also favored in the pertuzumab group. Toxicity was similar between groups except for higher incidence of diarrhea, rash, mucosal inflammation, dry skin, and neutropenia for pertuzumab compared with placebo. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu).