Market uptake of biologic and small-molecule—Targeted oncology drugs in Europe

Objective: The aim of this study was to investigate the market uptake of biologic and small-molecule—targeted oncology drugs in Europe.Methods: Targeted oncology drugs that were used in one of the selected European countries before the end of 2007 were eligible for inclusion in the analysis. The following European countries were included: Austria, Croatia, France, Germany, Hungary, Italy, Slovenia, and the United Kingdom. Monetary market uptake of targeted oncology drugs was assessed by using sales data (in euros) obtained from 2 large data- bases for the period 1997–2007. Market uptake was assessed in terms of expenditures for specific drugs in euros per capita and in market shares.Results: The monetary market uptake of targeted oncology drugs had an exponential growth from 1997 to 2007 in all comparison countries and reached 40% of the total oncology drug market in 2007. Although the various European countries allocate substantially different amounts of resources per capita for oncology drugs, the share of expenditures attributed to targeted oncology drugs did not differ substantially among the countries. Biologic molecules were used in clinical practice before the small-molecule—targeted oncology drugs. Targeted oncology drugs that were introduced first to clinical practice in most of the comparison countries (ie, rituximab, trastuzumab, imatinib mesylate) maintained the leading positions on the market throughout the period of the analysis. In 2007, ~25% of all expenditures for oncology drugs were attributed to biologic oncology drugs, and ~15% were spent on small-molecule—targeted oncology drugs.Conclusions: Expenditures on targeted oncology drugs have been increasing exponentially in Europe throughout the past decade and have reached a 40% share of the oncology drug market. As of 2007, the market share of biologic oncology drugs was higher than the market share of small-molecule-targeted oncology drugs.     

Do we need authorized orphan drugs when compounded medications are available?

What is known and Objective: Orphan drugs are used to diagnose, prevent or treat a rare disease. This Commentary aims to present a number of case studies questioning the need for designating compounded medications with a long history of effective use, which is well‐supported by published clinical evidence. Comment: Prior to the market introduction of orphan drugs, medication compounding was done in our hospital pharmacy for several rare diseases. Examples include amifampridine for the treatment of Lambert–Eaton myasthenic syndrome (Firdapse^®), ibuprofen for the treatment of neonatal patent ductus arteriosus (Pedea^®) and zinc acetate for the treatment of Wilson’s disease (Wilzin^®). Several ‘non‐orphan’ pharmaceutical products, used off‐label for the treatment of rare diseases, that became orphan medicinal products include Hydrea^® for the treatment of sickle‐cell syndrome (Siklos^®) and Viagra^® for the treatment of pulmonary arterial hypertension (Revatio^®). What is new and Conclusion: In our opinion, as indicated by our examples, a better balance should be struck between the development of orphan drugs along the recently established regulatory pathways and the pragmatic use of pharmacy‐compounded products and evidence‐based off‐label use of already available commercial products. Societal needs would be best met by focusing orphan drug development on rare diseases for which there is a high unmet medical need.     

Delays in psychiatric drug development in Japan

What is known and Objective: The lag in the approval and development of psychiatric drugs between Japan and other countries has been a major issue both for patients with psychiatric diseases and for psychiatrists. The objective of this study was to analyse factors contributing to delays in launching new psychiatric drugs in Japan. Methods: We analysed data from Japan, the USA, and the UK for the approval of 23 standard psychiatric drugs and examined potential factors that might have contributed the delay of their launch. Results: Of the 23 standard psychiatric drugs, all of which were approved in the USA and the UK, only 13 were introduced in Japan between September 2000 and July 2011. None of their development strategies adopted the ICH E5 guideline on simultaneous development of drugs on a global scale. Twelve of the 13 drugs (not including atomoxetine) were approved in Japan after their approval in the USA and the UK. The median review time (from approval application to approval) of these 13 drugs in Japan was 23 months, which was considerably longer than those of the US Food and Drug Administration and European Medicines Agency (10·0 and 13·5 months, respectively). The 10–13‐month difference in review time cannot explain the overall 87‐ and 51‐month delay in Japan after approval in the USA or UK. What is new and Conclusion: There remains a large gap between Japan and Western countries, such as the USA and the UK, with regard to access to standard psychiatric drugs, despite several important reforms in the Japanese drug approval system.     

Opioid purchases and expenditure in nine western European countries: 'are we killing off morphine?'

BACKGROUND: In clinical practice the major role of opioid drugs is the management of malignant and nonmalignant pain. The primary aim of this study is to evaluate the trend in sales of four opioid analgesic drugs (codeine, tramadol, morphine, fentanyl), from wholesalers to community pharmacies, as an indicator of opioid consumption in nine European countries in 2001, 2002 and 2003. Secondary aims are to compare: (a) the amount of each drug purchased by different countries in 2003; (b) the average price for each drug in the different countries in 2003; and (c) the total expenditure for each opioid from 2001 to 2003. METHODS: Data from the Statistical Report on drugs purchased by pharmacies was supplied by IMS Health, an internationally accepted information provider for the pharmaceutical and health care industries. FINDING: In the period 2001 2003, while the percentage increase of purchases of fentanyl and tramadol was considerable, that of morphine was the lowest in most of the nine countries. The largest consumer of codeine was the UK and of tramadol was Belgium. The consumption of morphine was the lowest reported in all the countries together and was three times lower than that of transdermal fentanyl. There was a high variability in the costs of the opioids among the different countries. In 2003, the total expenditure for fentanyl reached the highest total expenditure [corrected] followed by codeine. Morphine presents the lowest expenditure in all nine countries and over all three years. INTERPRETATION: These results open up many questions. What factors influence opioid purchasing and costs in these European countries? It would be interesting to have the answers from those people who know the actual situation in the individual countries.     

Pharmacology and drug development in rare diseases: the attractiveness and expertise of the French medical pharmacology

Developing drugs for rare disease can be challenging due to specific rare disease characteristics. The French Medical Pharmacology is structured and positioned to play a major role in orphan drug research and development due to the required expertise concentrated into pharmacology departments, exclusively implemented within the French university hospitals, public hospitals that are linked to a medical school (and often a pharmacy school) with numerous INSERM or CNRS labelled research units. In addition, these structures allow a close collaboration between researchers, academic institutions and biotech start‐up (most of them being spin‐off of the academic structures). Also, within university hospitals are located the clinical investigation centres, linking to the F‐CRIN network and also to Inserm and hospitals, that enable care staff and researchers to be associated and clinical research protocols to be carried out on site, in full respect with ethic and regulatory aspects. As a consequence, this intra and multidisciplinary expertise offers all resource to elaborate a tailored approach for orphan drug development, in new entities as well as in repositioning. For preclinical development: drug screening, candidate selection (taking into account PK, metabolism, variability and potential toxicity) and preclinical models (iPS, animal models) that could allow a better translation to human research. For clinical development, we will mention here dose determination, safety evaluation and Orphan Drug Designation and Protocol Assistance preparation and submission. For post marketing evaluation and surveys, the pharmacovigilance, addictovigilance and pharmacoepidemiology expertise, combined with access to large databases allow a better approach to orphan drug use and safety. As outlined through two success stories (Charcot Marie Tooth, vascular Ehlers‐Danlos syndrome) , the added value of French Medical Pharmacology structures and expertise has been evidenced in the know‐how, multidimensional and multidisciplinary approaches, allowing the development of numerous drugs that have been granted with Orphan Drug Designation and later Market Approval. Even if specific and possibly even more, the field of orphan drugs requires the respect of highest standards of safety and quality. French Medical Pharmacology intends to continue on this way and constantly improve his involvement in this field, committed to a single objective: answer the unmet medical need of patients with rare diseases.     

Anorexigènes et maladies cardiovasculaires : les liaisons dangereuses

In the past decades, obesity has been identified as an important driver of morbidity and mortality in the western countries. As a result, pharmacological approaches have been developed to fight obesity, including amphetamine-like drugs acting through a central appetite-suppressant effect. These compounds knew a significant marketing and sales success as early as the years 1960. Very soon after market access, caution has been raised on a potential risk for the cardiovascular system with the use of aminorex, leading to a first outbreak of “primary pulmonary hypertension” (PPH) in the European countries were it was available. A decade later, convincing epidemiological evidence accumulated supporting that both fenfluramine and dexfenfluramine were definite risk factor for the development of PPH, now called pulmonary arterial hypertension (PAH). In addition, these drugs appeared to be responsible for severe mitral and aortic regurgitations similar to carcinoid syndrome leading to surgery or death. Similar to aminorex, the cases of anorectic-drug induced complications abated after market withdrawal. Despite these serious warnings, the story repeated itself recently when a chemically similar compound called benfluorex, licensed to treat resistant diabetes and dyslipidemia, has been suspected to be responsible for almost identical cardiovascular complications. This is explained in a large part by the effect of norfenfluramine, the active metabolite of benfluorex, through it’s high affinity for the serotonin receptor 5-HT2B responsible for the fenfluramine-induced valvular heart diseases. Curiously, benfluorex has only been withdrawn from the French market after more than 20 years of access and six years after the first publication of suspected cases. A good decision? Very likely. The purpose of this article is to review the epidemiological and physiopathological evidence linking fenfluramine-derived drugs to cardiovascular complications, and to discuss the currently available data on benfluorex.     

Anticancer drug development from traditional cytotoxic to targeted therapies: evidence of shorter drug research and development time, and shorter drug lag in Japan

What is known and Objective: Concern about the drug lag, the delay in marketing approval between one country and another, for anticancer drugs has increased in Japan. Although a number of studies have investigated the drug lag, none has investigated it in relation to the transition of anticancer therapy from traditional cytotoxic drugs to molecularly targeted agents. Our aim was to investigate current trend in oncology drug lag between the US and Japan and identify oncology drugs approved in only one of the two countries. Methods: Publicly and commercially available data sources were used to identify drugs approved in the US and Japan as of 31 December 2010 and the data used to calculate the drug lag for individual drugs. Results and Discussion: Fifty‐one drugs were approved in both the US and Japan, whereas 34 and 19 drugs were approved only in the US or Japan, respectively. Of the 19 drugs approved only in Japan, 12 had not been subject to development for a cancer indication in the US, and all were approved before 1996 in Japan. Of the 34 drugs approved only in the US, 20 had not been subject to development in Japan, and none was in the top 25 by annual US anticancer drug‐class sales. For drugs approved in both countries, the mean approval lag of the molecularly targeted drugs (MTDs) was significantly shorter than that of the non‐molecularly targeted drugs (non‐MTDs) (3·3 vs. 5·4 years). Further, mean R&D time of the MTDs was significantly shorter than that of non‐MTDs (10·0 vs. 13·7 years). The price of MTDs had increased on average by 6·6% annually in the US, whereas it had decreased on average by 4·3% biyearly in Japan. What is new and Conclusion: The emergence of new molecularly targeted agents has contributed to reducing the approval lag, most likely due to improvements in R&D strategy.     

How much is the life of a cancer patient worth? A pharmaco‐economic perspective

What is known and Objective: Countries struggle to accommodate the introduction of new effective cancer medicines, while containing costs. Our objective is to comment on several pharmaco‐economic challenges involved in determining the value of cancer medicines by reviewing cost‐effectiveness thresholds for cancer medicines in several countries and by discussing the cost‐effectiveness of anti‐cancer biotechnology and orphan medicines. Comment: A literature search was carried out of PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews and EconLit up to August 2009. Health technology assessment agencies in England and Scotland are willing to incur a higher cost per quality‐adjusted life year for cancer medicines than for other medicines. Risk‐sharing arrangements have been implemented to optimize the value of cancer medicines. The cost‐effectiveness of biotechnology medicines in cancer care is challenged by their high price, and depends on the ability to identify the most responsive target population, through use of suitable biomarkers. The evaluation of orphan medicines in cancer care needs to balance the absence of an alternative therapy for a life‐threatening disease against the high cost‐effectiveness ratio, and usually weak clinical data. What is new and Conclusion: Current strategies used to inform decisions on the funding of expensive anti‐cancer medicines are commented on to highlight important issues and problems. Pharmaco‐economic evaluation is an important tool for assessing the value of cancer medicines and to inform evidence‐based decision making in cancer care. Value‐judgments such as preferential consideration of anti‐cancer medicines can then be made explicitly.     

The challenges of orphan drugs and orphan diseases: real and imagined

The Orphan Drug Act of 1983 in the United States and similar legislation in Europe in 1999 provided incentives for companies to develop and sell medicines for diseases with a small market. In this Commentary, we outline the European position on the regulation of orphan drugs and explain where it differs from the regulation in the United States.     

Consumption of three most widely used analgesics in six European countries

What is known and Objective: Analgesics are among the most widely used drugs and there is wide intercountry variability in the rates of consumption of different analgesics. Our objective is to determine and compare patterns of analgesic consumption in the Slovak Republic and a number of other European countries. Methods: We undertook a drug utilization study using WHO ATC/defined daily doses (DDD) methodology. Wholesale analgesic data collected by the Slovak State Institute for Drug Control were used. Utilization was calculated as DDD per 1000 inhabitants per day. Comparison with wholesale data from Czech Republic, Estonia, Finland, Norway and Denmark, published on the Internet, was made. Results and Discussion: Paracetamol/acetaminophen consumption varied only a little in Slovak Republic and Czech Republic, whereas consumption in Nordic countries was significantly higher (P < 0.05) and in Estonia significantly lower. Ibuprofen consumption was significantly higher in Czech Republic and Finland. Significantly lower consumption was in Norway. The lowest consumption of ASA/aspirin was in Denmark and in Norway. The highest consumption was in Finland. What is new and Conclusion: Effective therapy needs good prescribing and well‐informed prescribers and patients. Our study highlights wide differences in analgesic consumption even among similar European countries. The basis of these differences and their potential clinical impact require further investigation.     

Impact of biomarker usage on oncology drug development

What is known and Objective: The increasing cost of drug research and development and the decreasing number of new drugs being launched are serious issues for pharmaceutical companies. Biomarkers for predicting drug effectiveness are regarded as useful tools for combating these trends. However, the extent to which these biomarkers actually help in improving drug development is unclear. Here, we investigated the efficiency of biomarker usage in oncology drug development by focusing on stratification markers. Methods: Anti‐tumour agents for which clinical studies were initiated between 1998 and 2009 were identified using commercially available data sources, and clinical trials registered in ClinicalTrials.gov were examined to identify the use of stratification marker. Phase transition probability for each clinical phase was calculated and analysed along with various other factors that may affect the efficiency of the development process. Results and Discussion: Of 908 anti‐tumour agents identified, 121 (13·3%) utilized stratification markers in their clinical studies. Phase I, II and III transition probabilities for all agents were 76·4%, 50·8% and 58·5%, respectively. Corresponding Phase I, II and III transition probabilities of agents developed with stratification markers of 90·4%, 69·0% and 85·0%, respectively, were significantly higher than those for agents without stratification markers. Orphan designation positively affected phase transition probabilities of agents without stratification markers in all phases, while it did not affect transition probabilities of agents with stratification markers, except for Phase II. This shows that stratification markers help improve the probability of success in the development of agents without orphan designation. What is new and Conclusion: Stratification markers contribute to improving the efficiency of development of anti‐cancer drugs. The majority of non‐orphan drugs are still being developed without stratification markers. Finding reliable stratification markers for all drugs should improve the success rates in drug development.     

Health technology assessment and its role in the future development of the Indian healthcare sector

Public expenditure on healthcare in India is low by international comparison, and access to essential treatment pushes many uninsured citizens below the poverty line. In many countries, policymakers utilize health technology assessment (HTA) methodologies to direct investments in healthcare, to obtain the maximum benefit for the population as a whole. With rising incomes and a commitment from the Government of India to increase the proportion of gross domestic product spent on health, this is an opportune moment to consider how HTA might help to allocate healthcare spending in India, in an equitable and efficient manner. Despite the predominance of out-of-pocket payments in the Indian healthcare sector, payers of all types are increasingly demanding value for money from expenditure on healthcare. In this review we demonstrate how HTA can be used to inform several aspects of healthcare provision. Areas in which HTA could be applied in the Indian context include, drug pricing, development of clinical practice guidelines, and prioritizing interventions that represent the greatest value within a limited budget. To illustrate the potential benefits of using the HTA approach, we present an example from a mature HTA market (Canada) that demonstrates how a new treatment for patients with atrial fibrillation - although more expensive than the current standard of care - improves clinical outcomes and represents a cost-effective use of public health resources. If aligned with the prevailing cultural and ethical considerations, and with the necessary investment in expert staff and resources, HTA promises to be a valuable tool for development of the Indian healthcare sector.     

The Irish drinking habits of 2002—Drinking and drinking‐related harm in a European comparative perspective

Aims: To examine drinking habits and experiences of adverse consequences of drinking among men and women in Ireland 2002 and to compare some results with earlier European studies using similar data and methods.

Methods: Data on self‐reported drinking habits and experiences of alcohol‐related problems were obtained from a general population survey undertaken in 2002. Two approaches were used: (1) cross‐tabulations of drinking habits and the experience of adverse consequences in various demographic groups (2) logistic regressions predicting the likelihood of experiencing problems.

Results: Self‐reported alcohol consumption confirms statistics on alcohol sales; a lot of alcohol is consumed in Ireland today despite a large fraction of abstainers in the population. Binge drinking is very common, and, out of 100 drinking events, 58 end up in binge drinking for men and 30 for women. Irish drinkers also experience harmful drinking‐related consequences to a larger extent than in other western European countries. Both volume of drinking and binge drinking affect the likelihood of experiencing most alcohol‐related harms. Conclusions: Drinkers in Ireland drink more than in other western European countries and many have risky drinking habits that lead to adverse consequences. It will be an important challenge to find preventive measures that can reduce these problems in Ireland.     

Orphan Medicines for Pediatric Use: A Focus on the European Union

PurposeEuropean policy makers have provided a number of incentives for the development of medicines for orphan diseases as early as 1999 through the Orphan Regulation and created obligations for medicines developers to investigate their products in children through the Paediatric Regulation adopted in 2006. This article describes the challenges that developers of orphan medicines are facing with pediatric indications, discusses the interplay between the Orphan Regulation and the Paediatric Regulation, and provides some recommendations on how to optimize drug development under the current European Union regulatory framework.MethodsThis article discusses the European Union's Orphan Regulation, Paediatric Regulation, and the implications of the intersection of the regulations on the development of orphan medicines for pediatric use.FindingsAlthough these regulations have been successful in meeting their objectives separately, different regulatory frameworks entail separate governance, multiple assessments, varying approaches and priorities to unmet medical needs, and joined-up regulatory process coordination. Better integration of regulatory pathways would therefore be helpful in stimulating more global drug development of pediatric orphan medicines, including optimizing the interaction between both regulations, using innovative drug development approaches while considering alternatives to randomized clinical trials, better identification and prioritization of unmet medical needs in pediatrics, and ensuring the alignment of regulatory processes.ImplicationsRare diseases are categorized as “orphan diseases” because their occurrence in a small number of patients means that, regardless of the apparent high unmet medical need, there is limited public and market interest to justify the high development risk and significant investment to develop new treatments. However, unexplored potential within the area, as well as a conducive regulatory environment, can further support the development of medicines to treat rare diseases, including for children.     

Conditional approval and approval under exceptional circumstances as regulatory instruments for stimulating responsible drug innovation in Europe

The need for fast drug innovation and the public demand for risk-free drugs creates a dilemma for regulatory authorities: less restrictive procedures involve uncertainties about benefit/risk profiles of new drugs. The European Union has introduced two instruments that regulate early market access: conditional approvals (CAs) and approvals under exceptional circumstances (ECs). We have studied whether these instruments compromise the safety of new drugs and whether they lead to earlier access to innovative drugs. Our study shows that neither of these regulatory pathways accelerates the approval process for innovative drugs. However, the CA pathway shortens the clinical development period. Approvals under ECs are associated with longer clinical development periods, but this regulatory pathway may open up opportunities for specific drugs to be admitted into the market because less comprehensive data are required. Despite the fact that these advanced approvals are based on limited safety databases, there are no special safety issues associated with using these pathways.     

Impact of rosiglitazone safety alerts on oral antidiabetic sales trends: a countrywide study in Portugal

Pharmacovigilance systems are important to monitor the safety of on‐market drugs after approval. The aim of this study was to assess the impact of rosiglitazone safety alerts on trends in the sale of rosiglitazone and other oral antidiabetic drugs. An ecological study was conducted, using temporally aggregated data and linking safety alerts to countrywide sales of all oral antidiabetic drugs in Portugal from January 2002 to December 2012. Sales figures for oral antidiabetic drugs marketed in Portugal were supplied by IMS Health Portugal with a breakdown by active substance and fixed combinations. The number of defined daily doses per 1000 inhabitants per day (DIDs) of each oral antidiabetic drug sold to the estimated diabetic population using oral antidiabetic drugs in Portugal was calculated. Particular attention was paid to the case of rosiglitazone, with the results being adjusted for changes in rosiglitazone reimbursement policies. A total of four safety alerts were issued about rosiglitazone. Rosiglitazone sales registered an increase of 32.9% (0.202 DIDs; P < 0.001) after the first alert (risk of macular oedema or worsening of pre‐existent macular oedema) in January 2006. After subsequent alerts about cardiovascular risks, this trend was not, however, repeated and sales fell. Following the January 2006 and January 2008 safety alerts, rosiglitazone sales described a long‐term downward trend, with decreases of 3.75% (?0023 DIDs; P > 0.05) and 0.24% (?0.001 DIDs; P > 0.05), respectively. It is important to promote the dissemination and publication of drug safety alerts.     

Common threads? Palliative care service developments in seven European countries

Since the late 1960s hospice and palliative care services have been developing in many European countries. Although attention has been given to patterns of development in specific national contexts, so far we lack a comparative understanding of how these services are organized and delivered. Such a comparison poses certain practical and methodological difficulties. It does, however, allow a wider view of the current provision of palliative care in Europe, together with a consideration of implications for the future. We report on an analysis of palliative care developments in seven European countries which gave attention to early origins, patterns of provision, and structural and policy integration. We conclude that, despite different processes of development, the emergent discipline of palliative care now finds its most congenial home within the structures of the formal health care system. Accordingly, inequities between the seven countries can be more clearly identified, posing continuing challenges to policy makers and planners who operate with a European perspective.