Pharmaceuticals Policy and Law - Volume 12, issue 1,2
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The new international review,
Pharmaceuticals Policy and Law, appears with the aim of studying and evaluating the
legal status of medicinal products in the European Union, and its implications in other markets such as the USA and Japan, without neglecting the specific problems of developing countries.
Pharmaceuticals Policy and Law intends to participate in the process of world convergence of pharmaceutical legislation helped by a network of academic centers specializing in pharmaceutical law, without omitting a scientific, economic and social approach to medicinal products.
The specificity of medicinal products conditions their legal status. Legislation regulating other goods cannot be applied to them. To begin with, they are the result of scientific and technical innovation. Research policies determine their progress. The pharmaceutical industry is, by nature, multinational. But, next to these global trends, different traditions still remain at a national level. Within the EU, barriers to free trade in medicinal products still remain despite more than thirty years of harmonisation. The social dimension of medicinal products is complex and very significant in the preoccupations of our societies. Patenting is essential but not sufficient. The life-cycle of medicinal products is protected by professional responsibility, required in the general concept of health safety. It is important to remember their ethical dimension, including research and innovation in new fields such as genetic manipulation and biotechnology, which requires social consent to preserve human dignity and fundamental rights.
Abstract: The strategy for innovation at EMA is defined in the Pharmaceutical Legislation (Reg (EC) No 726/2004). EMA has also outlined a Road Map up to 2010 with two main objectives: to stimulate research and innovation from pharmaceutical and biotechnology enterprises within Europe, and to address hurdles encountered during innovative drug development . In order to support the activities on innovative products, the pharmaceutical legislation offers the definitions and references for innovative medicines.
Keywords: Innovation, pharmaceutical legislation, Road Map, EMA
Abstract: The Innovative Medicines Initiative is a unique and novel long term european public-private partnership designed by the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The initiative was promoted to accelerate the discovery and development of better medicines by removing bottlenecks in the drug development process. It focuses on creating better methods and tools that improve and enhance the drug development process, rather than on developing specific, new medicines.
Keywords: Innovative Medicines Initiative, Joint Technology Initiative, R&D investment, European Federation of Pharmaceutical Industries and Associations
Abstract: Advanced therapies represent new possibilities of treatment for human disorders. Advanced Therapy Medicinal Products (ATMPs) are novel and complex entities which need to be supported by adequate regulation in order to preserve public health.
Abstract: Following the opinion of the European Parliament on 25 April 2007, the European Council of Ministers approved the Regulation on Advanced Therapies Medicinal Product (ATMP) . The Regulation was translated into all EU official languages and on 30 October 2007 the Advanced Therapy Regulation was formally adopted by the EU Council. The Regulation was published in the EU Official Journal on 10 December 2007. From December 30, 2008, the new European Regulation, (EC) No 1394/2007, applies.…This means that Europe has now a common legislation for this type of products which have previously been handled differently in different countries. For the first time, the ATMP Regulation brings all "advanced therapies" (gene, cellular and tissue-based treatments) together within a single, integrated European regulatory framework, in order to ensue consistency across member states. The implementation plan of ATMP Regulation has been developed and agreed with the European Medicines Agency (EMA), and the a new scientific committee, the Committee on Advanced Therapy (CAT), has been created at the EMA to assess quality, safety and efficacy of advanced medicinal products and to follow scientific developments in the field. The committee will also provide scientific advice to companies developing advanced therapy medicinal products. In Italy it is established that the standard for ATMP development and clinical trials should follow both the specific tailor-made technical requirements of the Regulation and those defined by European Directives on clinical trials, "Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001, on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use"  and "Directive 2005/28/EC, laying down principles and detailed guidelines for good clinical practice as regards to investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products" . This implies that GXP rules [Good Manufacturing Practice (GMP) for production, Good Laboratory Practice (GLP) for non clinical safety studies and Good Clinical Practice (GCP) for registration clinical trials] should be followed during development.
Abstract: The necessity of a consistent approach and a regulatory "memory" was addressed by the EU with the promulgation of the Regulation 1394/2007/EC and the creation of a new committee for the evaluation of the Marketing Authorisation Application (MAA) of ATMPs, the Committee for Advanced Therapies (CAT). However, the scientific background of the ATMPs is rapidly changing due to a high rate of innovation. In fact, often the time frame required to perform the clinical development, usually…of at least 5 years, is such that the product or some of its assumption might be obsolete at the moment of the Marketing Application. To favour the Small and Medium Enterprises (SMEs) and academic sponsors, the Regulation contains provisions which are intended to help this transition and to smooth the regulatory hurdles.
Keywords: ATMP, CAT, EMA, preclinical data certification, clinical studies
Abstract: The orphan status of a medicinal product in Europe is regulated by Reg (EC) No 141/2000 and Reg (EC) No 847/2000 that states that: "Persons suffering from rare conditions should be entitled to the same quality of treatment as other patients" but "the pharmaceutical industry would be unwilling to develop the medicinal product under normal market conditions" as "some conditions occur so infrequently that the cost of developing and bringing to the market a medicinal product ……would not be recovered by the expected sales".
Abstract: The orphan designation procedure relates to medicinal products for human use aimed at the treatment, prevention or diagnosis of diseases. It is a free of charge procedure and can be requested at any stage of the development by a sponsor who can be either a company or an individual, as long as is established in EU, Iceland, Liechtenstein, and Norway. Once the Committee for Orphan Medicinal Products (COMP) adopts opinion on designation, the European Commission grants…a decision that gives access to the incentives.
Abstract: Having achieved orphan designation, sponsors complete clinical investigations and submit the outcome of these investigations to the regulatory authorities to gain marketing authorisations. The (mandated) centralised review process for such applications is similar to that for non-orphan applications, relying on demonstration of adequate product quality, clinical safety and efficacy. However, due to the rarity of the condition under investigation it is likely that the data package provided with respect to clinical safety and…efficacy will be more limited and may lead to the CHMP having to work with the PDCO to assess whether benefit risk has been appropriately demonstrated to the full extent possible and whether conditions should be placed on any marketing authorisation issued due to the limited available evidence. This may lead to conditional or exceptional marketing authorisation approvals where the company is either able or unable (respectively) to eventually provide a complete evidence package. Such approval status for an orphan drug would have to be clearly highlighted in corresponding labelling and would require more regular reporting of safety experience due to a less well documented risk profile for the product. In addition companies may be required to commit to further clinical investigations to the extent permitted by the prevalence of the disease. These post marketing conditions (PMCs) or follow up measures would be reported on a regular basis allowing a more frequent re-assessment of the current benefit risk profile of the product in the disease. Amgen has experience of approval of a non-orphan designated product gaining a conditional approval and of regulatory assessment of a marketing authorisation application for an orphan designated product.
Keywords: Orphan designation, centralized procedure, post marketing condition
Abstract: In 1983, the United State's Congress passed the U.S. Orphan Drug Act, which established public policy that the Federal Government would assist in the development of products for the diagnosis, prevention, or treatment of rare diseases or conditions . The Orphan Drug Act defined an "orphan product" as one that is intended to treat a rare disease or condition that affects fewer than 200,000 people in the United States OR as a product which will not…be profitable within seven years of approval by the FDA. There are over 6,000 conditions that meet the definition of a rare disease. The Orphan Drug Act allows the government to provide a package of financial incentives to companies who decide to undertake the development of products for a rare disease or condition. The Office of Orphan Products Development (OOPD) conducts scientific and regulatory review of orphan product and humanitarian use device designation requests and administers a scientific grant program to defray the cost of clinical studies for orphan product development.
Keywords: FDA, office of orphan products development, orphan designation, orphan drug act
Abstract: The randomised, controlled trial (RTC) is considered the gold standard for the assessment of the effect of any therapeutic intervention. However, rare diseases carry several issues in terms of population size, life-threatening nature of the condition and lack of other available treatments, which basically render this approach not always feasible. Alternative methodological approaches are being developed to better suit the need of an orphan drug development.
Keywords: Randomised, controlled trial, population size, rare disorder
Abstract: Orphan legislation provides incentives to industry to investigate rare conditions that otherwise would be unlikely to be investigated. These incentives include, free access to scientific advice during the development of their clinical programs ('protocol assistance'); reduction in fees payable to EMA for review of the marketing authorisation and subsequent licence maintenance fees; sustained market protection in the form of market exclusivity in addition to a range of national incentives. To qualify for these incentives…companies must apply for orphan designation confirming the seriousness of the condition which has inadequate alternative therapeutic options (for the diagnosis, prevention or treatment) and that the condition qualifies in terms of low prevalence in the European community. The company must also provide evidence of medical plausibility including likely significant medical benefit for patients to be treated with the product for the proposed orphan indication. If an application for orphan designation is not accepted then a company is able to appeal providing detailed grounds for reassessment and will receive a second opinion from the PDCO. The period of market exclusivity awarded by orphan designation will require that future applications received by the EMA for the same condition have to undergo an assessment of similarity to ensure that no variations or new applications for 'similar' medicinal products are granted licences during this ten year period. Products gaining orphan designation provide regular/annual reports regarding their development status, status of global regulatory submissions and any change likely financial returns predicted for the indication.
Abstract: Scientific advice constitutes an important part of the development strategy as it can increase the likelihood of regulatory success. For this reason, its timing has to be carefully planned. There are essentially two routes which can be followed to get scientific advice in the EU: a "national advice", which is a decentralised procedure and involves meeting with one national authority; a "scientific advice" at the CHMP level, which is centralised, called protocol assistance for designated…orphan drugs. This is a pan-European advice, which is adopted by the CHMP based on the recommedations of the SAWP.
Keywords: Scientific advice, centralised procedure, national scientific advice, CHMP, SAWP
Abstract: Evidence from a limited population may be inappropriate to characterise exposure-response relationships and subsequently define dosing recommendations for a wider target group. This limitation is particularly important if standard trial designs and data analysis methods are used to assess pharmacokinetics and pharmacodynamics. Models are a theoretical representation of a phenomenon. According to this definition, PKPD models can be applied to the development of new compounds, enabling inferences about efficacy and safety, which…cannot be obtained otherwise.
Abstract: The European Parliament, and the Council Regulation on Medicinal Products for Paediatric Use, intend to increase children's health in Europe by promoting research, development and authorisation of medicines for paediatric use. The main objectives are: to increase the development of medicine for children to ensure that paediatric medicines are subject to high quality research to ensure that medicines for children are appropriately authorised for paediatric use to improve information available on the…use fo medicines for children to avoid unnecessary studies in children.
Abstract: The introduction of innovation into the drug development process is expected to bring to patients, including children, in the upcoming years a faster treatment, increased safety in term of side effects and tolerability, decreased interactions with other drugs, increased compliance, new treatments for untreated disorders, and increased quality of life and life duration. The implementation of the European Regulation EC/1901/2006 "Better Medicines for the Children of Europe" and EC/1902/06 foresaw the creation at the EMA of a…new Paediatric Committee and assigned it a number of tasks. The legal provision also forced Industry to develop their new drugs for children as soon as reasonably sound, as appropriate. An early paediatric investigation plan (PIP) is to be submitted to the PDCO as soon as the concept of the candidate medicinal product is sufficiently established in adults, at the end of phase I. The PIP has to be agreed by the PDCO, some room being left over for discussions, modifications and amendments whilst the candidate medicinal product will evolve along its life cycle.
Abstract: Rare diseases are frequently genetically determined and caused by an inborn metabolic error, thus occurring early in life and affecting normal growth, and sexual and CNS maturation. The development of a paediatric orphan medicine presents a real hurdle for pharmaceutical companies because of the nature of the patient population where little knowledge is available. In addition, clinical trials are more difficult to run, take longer and cost more. An overview of the current situation in the paediatric…orphan medicines field in Europe is provided below through the identification of unmet therapeutic needs still existing in the field (TEDDY NoE work), which represents a description of the orphan drugs so far authorised in Europe and of the paediatric drugs under development (Paediatric Investigation Plan – PIP).
Abstract: The development of medical devices for children is probably the next frontier in scientific and regulatory development. While some pediatric devices may have a potentially large market share, many do not and this makes them "orphans" in their own right. Recently the U.S. government has started to pay new attention to the area of pediatric device development. There are several challenges to paediatric device development and as, a consequence, it currently lags…5 to 10 years behind those for adults. Thus, many physicians and surgeons are forced to adapt adult devices in order to suit their paediatric patients. Challenges in paediatric device development reside in the fact that children differ from adults not only in terms of their size, but also because they are growing, so often a static device may not be adequate for a growing child. In addition, after a few months to years, an infant or child may outgrow a device and need a new one.
Abstract: The Paediatric Committee (PDCO) is a multidisciplinary setting composed by 5 CHMP members, 22 experts from the National Competent Authorities, 2 EEA, 3 patient/family's organisation representatives and 3 health professionals. The PDCO is accountable for providing opinion on PIPs, with deferrals/waivers and on compliance, and expert opinion on quality, safety and efficacy upon request by CHMP (marketing authorisations, scientific advice). In addition, PDCO is responsible for surveying paediatric needs, promoting…networking, and monitoring Eudra CT.
Keywords: Paediatric committee, paediatric investigation plan, paediatric working party
Abstract: In US three governance models related to funding type are available: grant: Investigator led with funding organization oversight; cooperative agreement: partnership between investigators and funding organisation; contract: investigators provide services to funding organization. Hybrid funding models are also plausible and functional.
Abstract: Pediatric rheumatic diseases (PRD) encompass an heterogeneous group of rare diseases, ranging from juvenile idiopathic arthritis (JIA), juvenile systemic lupus erythematosus (JSLE) to juvenile dermatomyositis (JDM) and others. The PRD constitute a small market which is of little interest for pharmaceutical industries. Difficulties in operating in this specific area relate to problems which are peculiar to children, such as specific methods for the assessment of the primary outcome, or paediatric formulations, with the…need of setting large networks in order to collect in a reasonable time frame an adequate number of patients.
Abstract: Childhood cancer affects 12,000 new patients/year in Europe with more than 60 different malignancies. To date, the overall cure rate at 5 years is around 80% in Europe  and U.S. , with a powerful increase as compared to the cure rates accessible 15 years ago. Although cancer in children is a rare condition, being only 1% of all cancers, it remains the first cause of death in children older than 1 year; still, 3,000 deaths are reported every…year. Accordingly, paediatric cancer still represents a therapeutic need and new efficient treatments must be developed, regardless the present cure rates allow to figure out that one adult aged from 16 to 45 years out of 900 individuals has been cured by cancer during childhood .
Abstract: The Ministry of Health, Labour and Welfare (MHLW) and related government agencies have been implementing strategies to facilitate clinical trials in the last few years , and the infrastructure for paediatric clinical trials is being strengthened. The revision of the Pharmaceutical Affairs Law (PAL) in 2002 has enabled physicians to conduct sponsor-investigator trials in Japan. There have been 9 protocols for 6 drugs funded by the MHLW in children completed or ongoing as of…August, 2009. The National Centre for Child Health and Development (NCCHD) has been involved in 7 of these protocols. Of these 7 protocols, NCCHD has been involved in project management for 5 protocols.
Abstract: In the past, drug discovery developed in an environment where resources in healthcare where believed to be adequate, and all patients affected by a given disease where considered similar, therefore in need of a similar treatment. However, these concepts are no longer valid, and the present reality shows that current circumstances are characterised by limited financial resources in the presence of always growing expectations. In addition, current research trend is progressing toward the identification of novel…molecular targets and a personalised medicine approach.
Keywords: Innovation, R&D expenditure, risk-sharing, Italian Medicines Agency
Abstract: Key figures of the sector demonstrate that the pharmaceutical companies play a pivotal role in health research, in terms of resources and investments. Despite these efforts, only 1 substance out of 5–10.000 successfully passes the necessary tests, and 2 drugs out of 10 can defray R&D costs . This inevitably leads to the need of new R&D models which may include more focused clinical studies with e-designed mechanisms (Fig. 1) and open source protection of intellectual…property. Innovation is also expected to boost the research environment and the pharmaceutical industries are responding by outsourcing and buyout biotech companies, with investing only 20% in in-house research . In the Italian environment an integrated approach for the formation of a public-private network with pharmaceutical and biotech companies, public R&D institutions and universities, with patient and non-profit organisation is believed to be the key for success by offering the possibility to link internal excellence to the international research network.
Abstract: The mission of the Telethon Foundation is to boost research towards a therapy for muscular dystrophies and other genetic disorders, giving priority to those diseases neglected by public or private funding. Telethon operates in the Italian environment and has adopted a transparency policy on how donations are distributed to finance research.
Abstract: A public debate is currently ongoing on the perception that the licensing regulations tend to give precedence to the interests of drug companies with programs, such as the "fast-track" program, aimed at shortening review times and allowing approval at much earlier stages of clinical development in order to allow early access to new drugs. The main concern is that lower standards may become acceptable, with serious consequences to public health. To this end, NICE developed a…series of national clinical guidelines to secure consistent, high quality, evidence based assessment of clinical trial practice.
Abstract: To date, prescription of drugs which are unlicensed and/or unlabelled in the paediatric population is a concerning reality, particularly in the neonatal units (90%) and in the paediatric units (49%). Therefore, there is the need to develop effective and safe pharmacological treatments for the paediatric population in general.
Keywords: Paediatric population, clinical trial, orphan drug
Abstract: MolMed developed a TK cell based therapy to enable safe and effective haematopoietic stem cell transplantation (HSCT) from partially compatible donors (haplo-HSCT), currently in clinical development for high-risk leukaemia patients (AML and ALL). TK acquired the Orphan Drug status in EU (2003) and in US (2005).
Keywords: Haematopoietic stem cell transplantation, TK cell based therapy, leukaemia
Abstract: More than half (55%) of the drugs that received a positive opinion on orphan designation are for medical conditions affecting children (Fig. 1). Orphan drug designations for haematological conditions represent a substantial portion of all OD designations granted in the period 2000–2009 in EU. According to the EU regulation 141/2000 , all cancers, with the exception of breast, lung, colorectal, prostate and bladder, are rare diseases, with the consequence that all haematological diseases are…orphan diseases, with 70% of orphan designated conditions affecting less that 1 in 10,000 people. In the period 2000–2007 orphan designed medicines to treat oncological (17%) and haematological (33%) conditions have received more marketing authorisations from EC than those of any other therapeutic area.
Abstract: In 1970 the World Health Organization stated that the function of the clinical pharmacologist was: 1) to improve patient care by promoting safer and more effective use of drugs, 2) to increase knowledge through research, 3) to pass on knowledge through teaching and 4) to provide services (e.g., analyses, drug information, and advice in the design of experiments). The role of the clinical pharmacologist in the fields of drug discovery, drug development, and regulatory sciences has…significantly changed over the last decades. There is no discussion about the pivotal role of clinical pharmacologists in ensuring rational use of drugs, in translating pharmacological concepts from the bench to the clinic, in clinical drug development, or in teaching the discipline to medical and pharmacy students. Specifically, the role of paediatric clinical pharmacology is evolving and changing dramatically. This paper will summarize the current role of the (paediatric) clinical pharmacologist.
Keywords: Paediatric protocol, drug research, neonates, infants, paediatric clinical pharmacologist, pharmacokinetics, therapeutic drug monitoring, population pharmacokinetics, pharmacogenetics
Abstract: Modern paediatric intensive care became organized in Europe in 1970s. Since that, time medical and technological advances resulted in a significant improvement of the treatment for infants, children and adolescents admitted to the Paediatric Intensive Care Units (PICUs) with a wide range of medical and surgical conditions. Now numerous conditions that were previously considered fatal have become treatable with an overall survival rate of 85–98%. However, the profile change of patients and the appearance of new…conditions (CLD, VAP, VILI) have caused new problems, together with the consideration that 90% of medicinal products used in PICUs are still unauthorised or administered off-label. PICU constitutes a unique setting for pharmacotherapy, as the patient is often characterised by respiratory or multiorgan failure, with an underlying pathology, and for which drug interaction, mode of administration and organ maturation are not properly taken into account.