Luca Pani

Regulatory evaluation of Glybera in Europe — two committees, one mission

Representing the first gene therapy to be approved in the Western world, alipogene tiparvovec (Glybera; Uniqure) has recently been said to have had a “substantial impact from a regulatory perspective” (Nature Rev. Drug Discov. 11, 664; 2012) 1 . The therapy was granted marketing authorization in the European Union for the treatment of lipoprotein lipase deficiency, which results in a clinically heterogeneous condition with a risk of potentially life-threatening pancreatitis 2 , at the end of 2012. The decision followed a positive opinion by the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) 3

Biosimilars: the paradox of sharing the same pharmacological action without full chemical identity

The use of biotech medicines is increasing, with consequent mounting expenses for National Health Systems (NHSs). Biosimilars should be considered an opportunity to improve access to care. On the other side, the general public might suspect to receive low-quality medicines to save money. Actually, no drugs with a lesser degree of pharmaceutical quality with respect to existing alternatives can be authorized on the ground of a lower price. Biosimilars can be authorized only if their quality is of the same level as that of the originator. There is no chemical identity between biosimilars and the originators: any differences in quality attributes must be justified and shown not to impact on the safety and efficacy of the biosimilar by scientific investigations including pre-approval nonclinical and/or clinical studies. The biosimilar safety profile may be different from the originator or change over time for the same product. Hence caveats limiting the widespread use of biosimilars yet exist and should be solved by education on the main biological issues of biotech medicines, and on continuous update of the rules set up by the Regulatory Authorities to assess biosimilarity and to monitor post-approval safety.

Disclosure of grounds of European withdrawn and refused applications: a step forward on regulatory transparency.

The need for a greater transparency in the process of how regulatory authorities (RAs) evaluate new medicines has been advocated by the public and the scientific communities [1–3]. Also transparency about the outcomes of marketing authorization procedures is important for the purpose of a better understanding of the reasons why certain procedures tend to result in either a successful or a failed application [4]. While the US Food and Drug Administration (FDA) is not obliged to disclose information on drug applications withdrawn prior to the conclusion of the evaluation process or refused at the end of it [3], the European Union (EU) legislation requires the European Medicines Agency (EMA) to do so [5, 6]. Indeed, the EMA publishes on its website assessment reports of withdrawn and refused applications. We retrieved and evaluated such public assessment reports on withdrawals and refusals (i.e. a negative opinion given by the EMA) of all initial authorization applications published between 2003 (the date of publication of the first available refusal report) and 31 December 2010. A total of 86 drug applications could be identified with either a withdrawal (70 out of 86) or a refusal (16 out of 86). The main therapeutic categories in the failed submissions were the following: i) oncology/immunology (29 out of 86 drugs = 34%), ii) central nervous system (CNS) (15 out of 86 drugs = 17%), iii) cardiovascular/metabolic diseases (14 out of 86 drugs = 16%) and iv) infectious diseases (12 out of 86 drugs = 14%). The reasons for withdrawal or refusal were related to one or more of the three assessment criteria, i.e. quality, safety and efficacy. Overall, 156 major objections on these three criteria were raised by the EMA: 106 (67.9%) objections due to efficacy deficiencies, while 27 (17.3%) due to safety and 23 (21.6%) due to quality. Within the scope of efficacy major objections, five main categories could be identified: i) lack of clinical relevance (44 out of 106, 41.5%), ii) methodological deficiencies (23 out of 106, 21.6%), iii) pharmacokinetic (PK) issues, including bioequivalence (20 out of 106, 18.8%), iv) lack of statistical significance (13 cases, 12.2%) and v) major Good Clinical Practice (GCP) issues (5 out of 106, 4.7%) (see Figure 1). Within the safety objections, clinical safety (e.g. increased risk of adverse reactions and potential risk identified) was present in 23 out of 27 cases (85.2%). The objections concerned non-clinical safety/toxicological issues in only four cases (14.8%), (see Figure S1). Within the quality objections, two categories could be identified: one related to drug substance and/or drug product (19 cases, 82.6%) and one related to Good Manufacturing Practice (GMP) issues (4 cases, 17.4%). Withdrawal was due solely to quality issues in only two cases (Docetaxel Mylan and Mycrograb). In none of the cases, was withdrawal solely due to safety (clinical or non-clinical). Interestingly, in four cases following an initial refusal (i.e. Cimzia, Valdoxan/Thymanax, Yondelis) a subsequent submission at a later stage led to a positive opinion by the EMA. Figure 1 Types of efficacy deficiency per therapeutic area.: E1: methodological issues; E2: lack of statistical significance; E3: lack of clinical relevance; E4: GCP issues; E5: PK issues/bioequivalence Disclosure of the grounds behind failed applications is a step forward on regulatory transparency and can be considered as a positive implementation of the EU legislation 726/2004. We queried several other RAs across the world in order to check whether they have similar transparency measures in place on failed drug applications. Apart from the EMA, only Australia has introduced such a system in 2009 (see Table S1). The process for an increased transparency in Europe has been further strengthened with regard to pharmacovigilance [7]. In July 2012 the EMA announced that it will systematically publish all of its committees’ agendas and minutes before the end of 2013 [8]. Our analysis confirms that failed justification of the clinical relevance by the applicant is a main predictor for withdrawal or refusal of an application for a marketing authorization of a new medicine, in line with previous publications [9]. A clear propensity of a positive EMA opinion seems to be a robust clinical trial programme, with a good rationale, and an efficient trial performance. Statistical significance alone is not sufficient enough to acquire an approval, but most importantly robust clinical benefit to the patients to be treated with the new medicine must be demonstrated. Regulators have the legal task to evaluate all the available data and to come to an informed decision about the benefit-risk of the product under review. Withdrawn or refused applications provide an important insight into what may go wrong in bringing a product from bench to the clinic, and what could be improved in future applications. Over the last decade Europe has made important steps forwards in disclosing such withdrawal and refusal information. However, this should not be the end of improving transparency. Further studies are needed to gain better insight and understanding on failed drug development.

Kounis Syndrome: An analysis of spontaneous reports from international pharmacovigilance database.

INTRODUCTION The coincidental occurrence of a cardiac symptomatology (e.g. an acute coronary syndrome or a myocardial infarction), during an anaphylactic or anaphylactoid episode is known as Kounis Syndrome. A variety of drugs, substances, food and environmental exposures are associated with this reaction. There is an exponential increase in the number of published scientific articles reports on this syndrome, but since it is rare, the largest case series published so far included only 10 and 6 patients. METHODS We searched the global World Health Organization database called VigiBase™ to detect all cases of Kounis Syndrome ever reported (last update December 31st 2014). RESULTS We identified 51 cases of Kounis Syndrome reported to International Pharmacovigilance Agency (VigiBase™). All these cases were reported in the period 2010-2014 and almost half cases (22 reports) belonged to the year 2014. Most cases occurred in the USA and non-steroidal anti-inflammatory drugs were the most frequent trigger drugs. DISCUSSION We collected pharmacovigilance international data representing the largest case series ever published on the recently identified Kounis Syndrome.

Insights Into the Decision Making of Advisory Groups to the Italian Medicines Agency

The Italian Medicines Agency (AIFA) is enhancing a strong transparency-oriented policy to improve information exchange and decision making with stakeholders. To this end, a questionnaire titled “Survey AIFA 2013” was sent to the 72 selected contacts on February 17, 2013 (closing date April 3, 2013), to assess influence on committees and secretariats’ opinions and decisions. The survey was divided into 2 sections (17 questions) with a 10-minute time limit. The results show that external resolutions have little influence on internal advisory groups, whereas internal ones carry more weight. So-called intellectual bias needs careful monitoring, as it can potentially condition decisions.

Reflections on Decisions Made on the Well-Established Use of Medicinal Products by EU Regulators and the ECJ

Abstract Background: In the European Union (EU), a medicinal product needs a marketing authorization (MA) to be placed on the market. The EU’s medicinal products’ legislative framework allows for a reduced application for medicines outside their data exclusivity. One such type of application is the well-established use (WEU) medicinal product application (i.e. bibliographic applications). Recently, these MA applications have been subject to arbitration procedures at the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) because of disagreements between member states during the authorisation process. This paper reflects on these cases and highlights their potential impact on future WEU applications. Methods: Decisions adopted by the European Commission on WEU applications between 2009 and 2012 were identified from the EU Community Register on medicinal products for human use. Subsequently, decisions were reviewed to understand the potential serious risk to public health (PSRPH) that EU regulators raised during MA application procedures. Results: Four decisions were adopted by the EU commission between 2009 and 2012. Three followed disagreements between member states on PSRPH grounds. One decision was the outcome of a centralised marketing authorisation application. Six key messages were identified from the four cases reviewed and presented. Conclusion: A guideline on WEU to implement the technical specifications to fulfil Annex I of Directive 2001/83/EC for MA applications is not available. Thus, reflections on recent decisions on WEU applications provide scientific direction to the industry as well as the medicinal product regulators on the documentation required to successfully file and obtain a WEU MA.

Nutraceuticals: opening the debate for a regulatory framework

Currently, nutraceuticals do not have a specific definition distinct from those of other food‐derived categories, such as food supplements, herbal products, pre‐ and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well‐being. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and efficacy information or in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma‐foods, a powerful toolbox to be used beyond the diet but before the drugs to prevent and treat pathological conditions, such as in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation.

Licensing of Generic Medicines: Are There Any Challenges Left? A Pharmaceutical Regulatory Perspective.

Abstract When an innovative product (innovator) is not covered anymore by intellectual property rights, cheaper equivalent medicinal products (generic products) may be marketed and used in clinical practice. The regulation of generic products is well-established, and is primarily based on standard rules for quality, therapeutic equivalence requirements (the latter in most instances proven through a bioequivalence study), and safety data for the innovator. The extensive experience from bringing generic products to the market over the last decades allows the conclusion that they are well-accepted and provide a useful alternative option for cost-effective pharmacotherapy. While supporting this conclusion, there are a number of issues to be considered during the assessment of a generic product application. Six scenarios are described in total, from an efficacy and a safety perspective, where potential concerns with the current regulatory standards could arise in the approval of generic products. We also propose solutions to these scenarios in order to foster debate on these issues.

Use and reimbursement of off‐label drugs in pediatric anesthesia: the Italian experience

Most of the drugs used in anesthesia are off‐label in children even if they present solid clinical evidence in adults. This lack of authorization is caused by multiple factors including the difficulty in conducting research in this area (due to the ethical concerns and/or the low number of available participants, the high variability of the outcome measures) and the lack of economic interest of the pharmaceutical companies (due to the limited market).