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Background: Ten years have passed since Latvia became a Member State of the EU in 2004. As a result European regulations, including those related to rare diseases and orphan drugs, have been applied to Latvian legislative system. Orphan diseases have been recognized as a priority area for action in the public health system, though there are significant differences in the national healthcare services for rare diseases among the EU States. This study aims to determine situation in the field of rare diseases in Latvia and compare it with other European countries., Methods: We used the national plan for rare diseases, EUCERD reports, Orphanet data, Latvian and European regulations, publicly available data from the state agencies, and directly contacted drug manufacturers and wholesalers., Results: National plan for rare diseases was developed and approved in 2013. Although there are no official designated centers of expertise as well as no specific register for rare diseases. Newborns are screened for only two disorders: phenylketonuria and congenital hypothyroidism. Currently 34 orphan drugs are available on Latvian market. Three medicines (8.8%) are included in the reimbursement drug list, all indicated for Ph + CML. 15 drugs (44.1%) were reimbursed within the framework of individual reimbursement system, and five drugs (14.7%) were provided within the program of medicinal treatment of rare diseases in children., Conclusions: Majority of orphan drugs authorized in the EU are not available in Latvia, moreover those drugs that are available are often not accessible because they are insufficiently reimbursed. Besides, approval of the national plan might be an important step towards improving situation in the field of rare diseases.

Background: Legal medical marijuana has been commercially available on a widespread basis in Colorado since mid-2009; however, there is a dearth of information about the impact of marijuana commercialization on impaired driving. This study examined if the proportions of drivers in a fatal motor vehicle crash who were marijuana-positive and alcohol-impaired, respectively, have changed in Colorado before and after mid-2009 and then compared changes in Colorado with 34 non-medical marijuana states (NMMS)., Methods: Thirty-six 6-month intervals (1994-2011) from the Fatality Analysis Reporting System were used to examine temporal changes in the proportions of drivers in a fatal motor vehicle crash who were alcohol-impaired (≥0.08 g/dl) and marijuana-positive, respectively. The pre-commercial marijuana time period in Colorado was defined as 1994-June 2009 while July 2009-2011 represented the post-commercialization period., Results: In Colorado, since mid-2009 when medical marijuana became commercially available and prevalent, the trend became positive in the proportion of drivers in a fatal motor vehicle crash who were marijuana-positive (change in trend, 2.16 (0.45), p<0.0001); in contrast, no significant changes were seen in NMMS. For both Colorado and NMMS, no significant changes were seen in the proportion of drivers in a fatal motor vehicle crash who were alcohol-impaired., Conclusions: Prevention efforts and policy changes in Colorado are needed to address this concerning trend in marijuana-positive drivers. In addition, education on the risks of marijuana-positive driving needs to be implemented., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

This article describes the shortage of generic injectable medications in Canada that affected hospitals in 2012. It traces the events leading up to the drug shortage, the causes of the shortage, and the responses by health administrators, pharmacists, and ethicists. The article argues that generic drug shortages are an ethical problem because health care organizations and governments have an obligation to avoid exposing patients to resource scarcity. The article also discusses some options governments could pursue in order to secure the drug supply and thereby fulfill their ethical obligations.

Application of personalized medicine in drug development and regulation has been limited by similar logistical, informatics, and cultural barriers that limit use of pharmacogenetics in the clinic. An additional challenge is coordinated codevelopment of new drugs and diagnostic tests. Nevertheless, the impact of personalized medicine strategies (e.g., pharmacogenomics) is being realized. We highlight some of our experiences to date and considerations for the development of the next generation of targeted therapies.

The R&D productivity of pharmaceutical firms has become an increasingly significant concern of industry, regulators, and policymakers. To address an important aspect of R&D performance, public and private data sources were used to estimate clinical phase transition and clinical approval probabilities for the pipelines of the 50 largest pharmaceutical firms (by sales) by 3 firms size groups (top 10 firms, top 11-20 firms, and top 21-50 firms). For self-originated compounds, the clinical approval success rates were 14.3%, 16.4%, and 18.4% for top 10 firms, top 11-20 firms, and top 21-50 firms, respectively. The results showing higher success rates for smaller firms were largely driven by outcomes for the small-molecule drugs. Adjustments for the relatively small differences in therapeutic class distributions across the firm size groups showed that the success rate for small-molecule self-originated drugs was 6% below average for top 10 firms and 17% above average for top 21-50 firms. Although success rates for small firms were higher, this advantage was offset to some degree by lower returns on approved drugs, suggesting different strategic objectives with regard to risk and reward by firm size.

Many, if not most, commercially available diabetes treatment products are protected by some form of intellectual property. This article discusses the development and commercialization of products in view of the state of intellectual property for the diabetes treatment market, with respect to possible discouragement, for some, from seeking patent protection or commercializing a new product under the belief that patent protection is either unavailable or difficult to come by, or for fear of infringing existing patents. Upon closer investigation, the evolution of technology almost always creates opportunities for new improvements, which likely can be patent protected. Furthermore, while avoiding the claims of existing patents is sometimes challenging and opinion based, and thus not a guarantee of avoiding a patent litigation, patent litigation may be delayed and is often settled early on., (© 2013 Diabetes Technology Society.)

During the relatively short history of class proceedings in Canada, developers and manufacturers of medical devices and pharmaceuticals ("medical products"), including medical products designed for patients with diabetes, have found themselves at the receiving end of a significant number of class action claims. As a result, medical products litigation has become the battleground for some of the most significant developments in Canadian class actions law. This article provides a broad overview of some of the most significant developments. The authors pay particular attention to developments regarding the test for class action certification and consider whether high-profile dismissals of certification motions represent a trend toward raising the threshold for plaintiffs seeking to obtain certification of a proposed class action. The authors also consider a decision arising out of a lengthy class action common issues trial in which the medical device company was victorious. In the authors' view, the class action pendulum in Canada, particularly as it relates to medical products claims, remains in motion. It behooves all affected players to keep their eye on this ball with rapt attention to see where it may move next., (© 2013 Diabetes Technology Society.)

Problem: During the 1980s, Spain had very strict laws limiting access to opioid agonist maintenance treatment (OAMT). Because of this, mortality among people who used illicit opioids and other illicit drugs was high. Spain was also the European country with the highest number of cases of acquired immunodeficiency syndrome transmitted through illicit drug injection., Approach: The rapid spread of human immunodeficiency virus (HIV) infection among people using heroin led to a shift from a drug-free approach to the treatment of opioid dependence to one focused on harm reduction. A substantial change in legislation made it possible to meet public health needs and offer OAMT as part of harm reduction programmes in the public health system, including prisons., Local Setting: Legislative changes were made throughout the country, although at a different pace in different regions., Relevant Changes: Legal changes facilitated the expansion of OAMT, which has achieved a coverage of 60%. A parallel reduction in the annual incidence of HIV infection has been reported. Reductions in morbidity and mortality and improved health-related quality of life have been described in patients undergoing OAMT., Lessons Learnt: The treatment of opioid dependence has been more heavily influenced by moral concepts and prejudices that hinder legislation and interfere with the implementation of OAMT than by scientific evidence. To fulfil public health needs, OAMT should be integrated in harm reduction programmes offered primarily in public facilities, including prisons. Longitudinal studies are needed to detect unmet needs and evaluate programme impact and suitability.

A new illegal psychotropic substance appeared in Hungary during the first months of 2011. Acutely hospitalized patients with psychosis disclosed using a new type of designer drug, previously unknown to clinicians. As the new drug became better known, the cases with acute intoxication were often also transported to toxicology departments. In this study we summarize 5 short case studies that demonstrate the heterogeneous symptoms associated with MDPV abuse, and draw attention to the frequently occurring delusions, and the extended risk of intravenous substance use. Present case studies include patients with and without psychiatric history, regular and occasional users, intravenous and other routes of administration. In the short run antipsychotic therapy reduced the symptoms in all cases, but there is no clear therapeutic guideline for the treatment of patients having psychiatric problems associated with these drugs at the present time. The laboratory examination is unresolved as well. Mephedrone, MDPV and recent drugs have drawn attention to the problem of designer drugs again. This article examines the interaction of drug consumption trends and changes in law, apropos of the presented cases. This information can be helpful for the future treatment of MDPV or other designer drug users. Possible research and therapeutic implications are also discussed.

Introduction: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals. Therefore, until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis. 30 years of experience has since expanded the knowledge base in this area, in the hope to design a preclinical safety evaluation procedure suited to biopharmaceuticals., Areas Covered: This review describes how the preclinical safety evaluation of biopharmaceuticals has evolved. It shows that, as result of the risk-averse behavior of regulators and industry, classical procedures were taken as starting point although state-of-the-art knowledge on biopharmaceuticals was directed towards creating a new procedure, driven by the specific properties of biopharmaceuticals., Expert Opinion: Current preclinical safety evaluation guidance of biopharmaceuticals is criticized because it employs a checkbox approach. The adverse effects induced by biopharmaceuticals are on-target or immune system-induced, therefore, the preclinical safety evaluation should not be standardized, but rather driven by product specific safety concerns.

Background: It is now a decade since the World Trade Organization (WTO) adopted the "Declaration on the TRIPS Agreement and Public Health" at its 4th Ministerial Conference in Doha. Many anticipated that these actions would lead nations to claim compulsory licenses (CLs) for pharmaceutical products with greater regularity. A CL is the use of a patented innovation that has been licensed by a state without the permission of the patent title holder. Skeptics doubted that many CLs would occur, given political pressure against CL activity and continued health system weakness in poor countries. The subsequent decade has seen little systematic assessment of the Doha Declaration's impact., Methods and Findings: We assembled a database of all episodes in which a CL was publically entertained or announced by a WTO member state since 1995. Broad searches of CL activity were conducted using media, academic, and legal databases, yielding 34 potential CL episodes in 26 countries. Country- and product-specific searches were used to verify government participation, resulting in a final database of 24 verified CLs in 17 nations. We coded CL episodes in terms of outcome, national income, and disease group over three distinct periods of CL activity. Most CL episodes occurred between 2003 and 2005, involved drugs for HIV/AIDS, and occurred in upper-middle-income countries (UMICs). Aside from HIV/AIDS, few CL episodes involved communicable disease, and none occurred in least-developed or low-income countries., Conclusions: Given skepticism about the Doha Declaration's likely impact, we note the relatively high occurrence of CLs, yet CL activity has diminished markedly since 2006. While UMICs have high CL activity and strong incentives to use CLs compared to other countries, we note considerable countervailing pressures against CL use even in UMICs. We conclude that there is a low probability of continued CL activity. We highlight the need for further systematic evaluation of global health governance actions. Please see later in the article for the Editors' Summary.

In France, the Médiator(®) scandal and the trauma it has created, are the source of Law n° 2011-2012 of 29 December 2011 on strengthening safety of drug and health products, intended by the Ministry of Labour, Employment and Health, adopted by the National Assembly and promulgated in order to restore confidence and enhance safety of drug and health products. This new law affects all stakeholders and health professionals impacts key points in the life cycle of the drug: MA, reimbursement, advertising, promotion, distribution, prescription, dispensing, and pharmacovigilance. It also provides for financial, administrative or criminal penalties, which are intended deterrent. Beyond strengthening constraints on safety of health products, this new law in France foreshadowed a revolution in behaviour, attitudes and overall scenery of the health system and no one today knows exactly the outline., (© 2012 Société Française de Pharmacologie et de Thérapeutique.)

The medicinal and recreational use of cannabis has been controversial, especially in the United States. Marijuana for medicinal use is approved in 14 U.S. states and has recently been considered for legalization in several additional states. Given its demonstrated efficacy in symptom management, marijuana has a potential role in palliative care. This study utilized a 16-item questionnaire to assess the knowledge, experience, and views of hospice professionals regarding the use of marijuana in terminally ill patients. The study results revealed that, like the general public, hospice health care providers are generally in favor of legalization of marijuana and, if legalized, would support its use in symptom management for their terminally ill patients.

Biotechnology derived medicinal products are presently the best characterized biologicals with considerable production and clinical experience, and have revolutionized the treatment of some of the most difficult-to-treat diseases, prolonging and improving the quality of life and patient care. They are also currently one of the fastest growing segments of the pharmaceutical industry market. The critical challenge that the biopharmaceutical industry is facing is the expiry of patents for the first generation of biopharmaceuticals, mainly recombinant DNA derived products, such as interferons, growth hormone and erythropoetin. The question that immediately arose was how should such copies of the originator products be licensed, bearing in mind that they are highly complex biological molecules produced by equally complex biological production processes with their inherent problem of biological variability. Copying biologicals is much more complex than copying small molecules and the critical issue was how to handle the licensing of products if relying in part on data from an innovator product. Since 2004 there has been considerable international consultation on how to deal with biosimilars and biological copy products. This has led to a better understanding of the challenges in the regulatory evaluation of the quality, safety and efficacy of "biosimilars", to the exchange of information between regulators, as well as to the identification of key issues. The aim of this article is to provide a brief overview of the scientific and regulatory challenges faced in developing and evaluating similar biotherapeutic products for global use. It is intended as an introduction to the series of articles in this special issue of Biologicals devoted to similar biotherapeutic products., (Copyright © 2011. Published by Elsevier Ltd.)

Ethnopharmacological Relevance: Herbal drugs are gaining worldwide prominence due to their distinct advantages. Developing countries have started exploring the ethnopharmacological approach of drug discovery and have begun to file patents on herbal drugs. The expansion of R&D in Indian herbal research organizations and presence of manufacturing units at non-Indian sites is an indication of the capability to develop new products and processes. The present study attempts to identify innovations in the Indian herbal drug sector by analyzing the patenting trends in India, US and EU., Methodology: Based on key word and IPC based search at the IPO, USPTO, Esp@cenet and WIPO databases, patent applications and grant in herbal drugs by Indian applicants/assignees was collected for the last ten years (from 1st January 2001 to 31st October 2010). From this collection patents related to human therapeutic use only were selected. Analysis was performed to identify filing trends, major applicants/assignees, disease area and major plant species used for various treatments., Result: There is a gradual increase in patent filing through the years. In India, individual inventors have maximum applications and grants. CSIR, among research organizations and Hindustan Unilever, Avesthagen, Piramal Life Science, Sahajanand Biotech and Indus Biotech among the companies have the maximum granted patents in India, US and EU respectively. Diabetes, cancer and inflammatory disorders are the major areas for patenting in India and abroad. Recent patents are on new herbal formulations for treatment of AIDS, hepatitis, skin disorders and gastrointestinal disorders., Conclusion: A majority of the herbal patents applications and grants in India are with individual inventors. Claim analysis indicates that these patents include novel multi-herb compositions with synergistic action. Indian research organizations are more active than companies in filing for patents. CSIR has maximum numbers of applications not only in India but also in the US and EU. Patents by research organizations and herbal companies are on development of new processes for active compound isolation and standardization of such components in addition to new compositions for therapeutic use. Pharmaceutical companies such as Ranbaxy, Lupin and Panacea Biotec are increasingly patenting on herbal drugs. There is increased patenting activity related to diabetes, cancer, cardiovascular diseases, asthma and arthritis in India and abroad., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Regulatory agencies play a critical role in the licensing of new antimicrobial agents. To address the pivotal role played by regulatory agencies, particularly in the context of a paucity of new drugs active against bacteria resistant to currently available drugs, the BSAC formed the 'Urgent Need' Working Party to address the regeneration of antibacterial drug discovery and development. The Working Party identified a number of issues, including: increased application of pharmacokinetic/pharmacodynamic principles to expedite drug development; the need to prioritize licensing of drugs (including 'orphan' drugs) active in life-threatening infections; and expansion of the use of surrogate markers and rapid point of care diagnostics to facilitate drug development.

Hormonal and antimicrobial therapies are essential to regulate and maintain healthy reproduction in domestic animals. The appropriate and legal use of these compounds is ultimately the responsibility of the veterinarian and other users, with a primary mission to directly protect and promote the health of animals, and indirectly the health of people. The appropriate use of these products is defined by the Federal Food, Drug, and Cosmetic Act, 21 United States of America § 301 et seq and implementing regulations in the Code of Federal Regulations. In the past, use of a drug in an animal for an unapproved use violated this Act. However, passage of the Animal Medicinal Drug Use Clarification Act 1994 legalized the extra-label use of certain animal and human drugs in veterinary practice for treating diseases. This manuscript reviews currently approved hormonal and antimicrobial drugs for use in theriogenology. Considering the ever increasing knowledge in the area of veterinary reproduction, particularly in the treatment and control of reproduction using antimicrobials and hormones, it would be beneficial to widen the therapeutic options in these categories. The potential for widening the therapeutic options is also discussed in this review, by providing a non-exhaustive but essential list of potential new drugs for use in clinical animal reproduction (theriogenology)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Unlabelled: New natural and synthetic compounds are continuously introduced into the illicit drug market. Their origin, composition, main and side-effects are often not exactly known by the users themselves. Thus, the control of these substances is extremely difficult., Aims: In year 2008, a new synthetic drug called mephedrone (2-metilamino-1-(4-metilfenil) propan-1-on) appeared in Hungary. This work summarizes its frequency in biological samples investigated for illicit drugs, and experiences of the medical examination of mephedrone-users., Methods: Toxicological analyses of biological samples (urine and/or blood) were carried by GC-MS at the Institute of National Toxicology and at Department of Forensic Medicine, University Szeged., Results: Altogether 5386 samples were analyzed in 2010 (4922 in Budapest and 464 in Szeged), and mephedrone was identified in 363 cases (7%)., Conclusions: Mephedrone is banned in Hungary since January 1st, 2011, but it still available in the illegal drug market. At present we do not have sufficient experience with its long-term effects, tolerance, addiction, withdrawal symptoms or toxic dose. Thus, it is difficult to establish whether addiction and/or mental disorder occurred.

The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well-established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the United Kingdom or elsewhere in Europe that might allow systematic collection of clinical data and outcomes after drug overdose. Toxicological effects are normally ascertained from individual patient reports or small case series from a few specialised poisons units, so that these data are generally under-represented in post-marketing consideration of risks and benefits. Safety concerns may lead to withdrawal of the Marketing Authorisation or restricted prescribing conditions, which are conveyed to health care professionals by means of safety warnings. These may have a variable impact, and three selected examples are presented to illustrate the complex interaction between drug regulation and clinical toxicology. First, the effects of the withdrawal of rofecoxib in 2004 shows that regulatory responses may reduce the prescribing of drugs across a particular class, and this has resulted in fewer enquiries to Poisons Control Centres regarding all cyclooxygenase-2 selective inhibitors. Secondly, data concerning the impact of safety warnings about antipsychotic medications illustrate that regulatory decisions may have a variable impact due to other factors that influence prescribing, including clinical guidelines, marketing pressures, and lack of alternative safe medications. Finally, the recent withdrawal of co-proxamol serves as an example of how clinical toxicology data can inform the drug regulation process and improve safety by minimising the risk of death associated with overdose. Greater reliance on clinical toxicology data could better inform the drug regulation process, perhaps through coordinated data collection systems that already exist in certain national poisons centres. Routine collection of high quality data concerning the effects of drug overdose could allow a more comprehensive review of risk and benefit by the regulatory authorities.

There has been considerable progress identifying pathophysiologic mechanisms of neuropathic pain, but analgesic medications with improved efficacy, safety, and tolerability still represent an unmet public health need. Numerous treatments examined in recent randomized clinical trials (RCTs) have failed to show efficacy for neuropathic pain, including treatments that had previously demonstrated efficacy. This suggests that at least some negative results reflect limited assay sensitivity of RCTs to distinguish efficacious treatments from placebo. Patient characteristics, clinical trial research designs and methods, outcome measures, approaches to data analysis, and statistical power may all play a role in accounting for difficulties in demonstrating the benefits of efficacious analgesic treatments vs placebo. The identification of specific clinical trial characteristics associated with assay sensitivity in existing data has the potential to provide an evidence-based approach to the design of analgesic clinical trials. The US Food and Drug Administration recently launched the Analgesic Clinical Trial Innovations, Opportunities, and Networks (ACTION) public-private partnership, which is designed to facilitate the discovery and development of analgesics with improved efficacy, safety, and tolerability for acute and chronic pain conditions. ACTION will establish a collaborative effort to prioritize research objectives, develop a standardized analgesic database platform, and conduct methodologically focused studies to increase the assay sensitivity and efficiency of analgesic clinical trials. The results of these activities have the potential to inform and accelerate the development of improved pain management interventions of all types, not just pharmacologic treatments., (Wiley Periodicals, Inc.)