Meeting the challenges to European healthcare: lessons learned from the 'Stockholm Revolution'

Healthcare is a political 'hot potato' in Sweden, just as it is throughout Europe. Regardless of whether the focus is on the 'Swedish model' or a 'European model', the operative term should be 'Culture - a set of values common to European healthcare systems'. An analysis of change and challenge in European healthcare systems must examine these values in the context of technological and societal forces before addressing the overarching concerns of where the money will come from. Discussion of the reform evidenced by the 'Stockholm Revolution' will serve as a model of how European healthcare systems can adapt to new conditions by the following approaches: modernising services through incentives; making the consumer a partner by focusing on consumer-related outcomes; building employee networks that encourage responsibility and problem solving; making healthcare an attractive labour market; and creating self-employment opportunities in the healthcare market to increase efficiency and emphasis on consumer satisfaction.     

Risk management strategies in the postmarketing period : safety experience with the US and European bosentan surveillance programmes.

In view of the shortcomings of the current system for postmarketing drug surveillance that is based on voluntary spontaneous adverse drug reaction (ADR) reporting, new approaches are needed.We describe an approach involving a combination of limited distribution, patient and physician education, as well as a novel pharmaco-vigilance system that is capable of promoting the safe and adequate use of a new drug. Importantly, it provides the possibility of calculating true ADR occurrence rates, as the exposed population (denominator) and the number of patients with events (numerator) are known. These measures were taken for the oral dual endothelin ET(A)/ET(B) antagonist bosentan (Tracleer). In recent guidelines issued by the European Society of Cardiology, American College of Chest Physicians and the WHO, this drug is considered as first-line oral treatment for the treatment of pulmonary arterial hypertension, a devastating orphan disease associated with a poor prognosis. Bosentan was approved in 2001/2 on the basis of two pivotal studies that showed improved exercise capacity and haemodynamic parameters while delaying time to clinical worsening. Elevations in serum liver aminotransferase levels of >3 times the upper limit of normal were noted in 10.2% of patients (placebo-subtracted incidence). Therefore, liver function tests have to be performed on a regular basis. In addition, bosentan has potential as a teratogen.In the US, a controlled distribution network for bosentan (Tracleer) Access Program [T.A.P.]) and the development of a patient database to follow patients was set up. Accompanied by comprehensive physician and patient education programmes, T.A.P. was developed to provide a mechanism to assist with the primary risk management goals for bosentan therapy, namely pregnancy prevention and liver enzyme monitoring and prevention of hepatic injury.In Europe, the Tracleer) Excellence (TRAX PMS) database is a novel European non-interventional, prospective, internet-based surveillance system initiated by the manufacturer in cooperation with the European Medicines Agency. It collected potential safety signals associated with bosentan use including adverse events, elevations of liver aminotransferase levels, other abnormal laboratory values, death and hospitalisation. TRAX PMS has accrued 79% of all known patients in the EU and the data provide supportive 'real-life' evidence on the long-term safety of bosentan.The two different systems had similar goals and outcomes. The data received concerning thousands of patient-years of use have confirmed the clinical trial results regarding product safety and the favourable benefit/risk ratio of bosentan, especially with regard to known type A adverse events. The clinical monitoring algorithm has also been confirmed. In addition, no rare type B events were uncovered despite the increased reporting rate. These systems might serve as templates for future pharmaco-vigilance efforts regarding drugs that require particular safety attention.     

Pharmacogenomic profiling in postmarketing surveillance: prospects and challenges

Adverse drug reactions (ADRs) represent a major public health and economic global problem. Growing evidence suggests that pharmacogenomics may potentially play a role in reducing drug-induced adverse events. Research efforts are increasingly directed towards this goal. However, knowledge about whether or not pharmacogenomics may be useful as a novel approach in postmarketing surveillance programs is at present rather limited. A critical analysis of some of the methodological design and ethical issues generated by the potential incorporation of pharmacogenomic profiling into pharmacosurveillance programs is presented.     

Antivirals for influenza: historical perspectives and lessons learned

The development of the currently available classes of antivirals, the M2 proton channel inhibitors and the neuraminidase inhibitors, provides valuable perspectives relevant to the field of antiviral chemotherapy in general and insights into aspects of viral pathogenesis and antiviral resistance relevant specifically to influenza. The efficacy observed with these antiviral drugs has proven the importance of these antiviral targets, as well as the principle that chemoprophylaxis and early treatment are possible in influenza infections with small molecular weight inhibitors.     

Record linkage studies for postmarketing drug surveillance: data quality and validity considerations

Large automated databases are the source of information for many record linkage studies, including postmarketing drug surveillance. Despite this reliance on prerecorded data, there have been few attempts to assess data quality and validity. This article presents some of the basic data quality and validity issues in applying record linkage methods to postmarketing surveillance. Studies based on prerecorded data, as in most record linkage studies, have all the inherent problems of the data from which they are derived. Sources of threats to the validity of record linkage studies include the completeness of data, the ability to accurately identify and follow the records of individuals through time and place, and the validity of data. This article also describes techniques for evaluating data quality and validity. Postmarketing surveillance could benefit from more attention to identifying and solving the problems associated with record linkage studies.     

Losartan: lessons learned from the RENAAL study

Renal and cardiovascular diseases associated with Type 2 diabetes are increasing at rapid rates, and are significant burdens to patients and healthcare systems. The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study was conducted from 1996 to 2001. This landmark clinical trial provided the opportunity to study renal and cardiovascular outcomes, as well as risk predictors, in a relatively large number of patients with Type 2 diabetes and nephropathy. The RENAAL study also provided information that will be valuable to those designing future clinical trials in this patient population. This review highlights key findings from the RENAAL study.     

Saudi Vigilance Program: Challenges and lessons learned

Pharmacovigilance is vital to public health. Adopting a robust spontaneous reporting system for adverse drug events can counteract most hazards that arise from utilizing medicinal products. Prior to the establishment of the Saudi Food and Drug Authority (SFDA), the number of pharmacovigilance-related activities in Saudi Arabia was limited. In 2009, the SFDA established the National Pharmacovigilance and Drug Safety Center (Saudi Vigilance). The pharmacovigilance system has remarkably improved during the past few years. Several initiatives have been taken to improve the program’s performance. These initiatives include initiation of pharmacovigilance guidelines, enhancement of communication and reporting tools, training sessions for concerned staff and healthcare providers, and compliance from stakeholders. This review article provides an overview of what the Saudi Vigilance program is, focusing on the scope, mission and vision, hierarchy, operational themes, and overall work processes. Additionally, we will shed light on the challenges we encountered during the early phase and on our future plans.     

Unwanted immunogenicity: lessons learned and future challenges

All biological therapeutics have the potential to induce an immune response in recipients of these products. Elicitation of an immune response can result in variable clinical impact, ranging from benign to severe adverse effects, a diminution in clinical efficacy or, in some cases, hypersensitivity or allergic reactions. Consequently, assessment of unwanted immunogenicity is an important element of the data required for regulatory submission for product approval. However, issues relating to immunogenicity occur throughout the life-cycle of a biotherapeutic and need to be considered appropriately when introducing any product change(s). Evaluation of immunogenicity of a product requires a well-considered strategy and a panel of appropriately validated (or 'fit-for-purpose') assays for antibody detection and characterization in clinical samples. An overview of the bioanalytical methods that are currently being used for assessment of immunogenicity of biotherapeutics and the guidance available along with some of the challenges facing the industry are discussed in this review.     

Approaches for discovering anti-prion compounds: lessons learned and challenges ahead

Introduction: Recent years have witnessed major advances in our understanding of the molecular bases of prion diseases. These studies not only highlight the protein misfolding as a potential initiator of a neurodegenerative process, they also provide a foundation for considering whether such a process can be common to many neurodegenerative diseases, including Alzheimer’s disease. This makes prion diseases a sort of prototype of neurodegenerative disease, endowed with some intrinsic positive features in terms of drug development. Thanks to the fact that disappearance of the scrapie protein can serve as a clear readout of drug efficiency, phenotypic approaches have high potential for prion disease drug discovery.

Areas covered: In this review, the authors discuss phenotypic screening and how it lends itself to drug repositioning. Furthermore, they discuss the advantages of working with a molecule with proven safety, tolerability and drug-like properties in combination with a reliable phenotypic screening and how it could improve the success rate for prion drug development. They also provide examples of several interesting candidates that have been identified using this approach, including quinacrine, astemizole, guanabenz and doxycycline.

Expert opinion: The availability of persistently scrapie-infected murine neuroblastoma cells has greatly helped to identify compounds that inhibit prion formation. However, a human neuronal model infected with the human isoform would ultimately serve as the ideal disease model toward the discovery of effective drugs.     

Development of quantitative systems pharmacology and toxicology models within consortia: experiences and lessons learned through DILIsym development

The development of new pharmaceuticals for the treatment of human disease is increasingly challenging. New methods such as quantitative systems pharmacology (QSP) and quantitative systems toxicology (QST) can help address drug development challenges. Despite its promise, QSP/QST is not without its challenges. An investment is required to collect the necessary input data and ensure key components are represented qualitatively and quantitatively well. One strategy for addressing these concerns is conducting model development within consortia. Consortia offer companies the ability to share data, seek feedback from health authorities collectively, guide model development, learn from others, and share platform development costs. This article highlights lessons learned from past experiences associated with The DILI-sim Initiative – a collaborative effort focused on developing DILIsym software for predicting drug-induced liver injury (DILI).     

The role of pharmacists in the recruitment of a cohort for postmarketing surveillance

In October 1990, a recall procedure was issued regarding the drug acitretin. The recommended post-therapy contraception period after acitretin therapy was extended from 2 months to 2 years. For a postmarketing surveillance study, we recruited a cohort from the source population of women aged 15–45 years who were exposed to acitretin. Recruitment occurred through dermatologists, and pharmacists plus dispensing general practitioners. We describe the speed of and the response to the recruitment procedures, and the representativeness of the recruited cohort. We also studied whether the individuals who gave informed consent would have preferred to be recruited by either dermatologists or pharmacists, and whether the information obtained from pharmacists and dispensing general practitioners was valid. This study revealed that pharmacists and dispensing general practitioners (drug dispensers) recruited their subjects rapidly, with no or little selection; they attained a 42% response. Dermatologists recruited their subjects slowly and selectively; they attained a 24% response. The majority of women (60%) recruited by dermatologists would have given their informed consent if they would have been recruited by their pharmacists. Drug dispensers are essential contributors to the recruitment of a study population. We do advise that such recruitment for a postmarketing surveillance study occurs by means of a collaboration between pharmacists and physicians.     

Drug withdrawals and the lessons within

Drug withdrawals over recent decades have triggered changes in the way that drug targets and screening programs are researched and designed. In the cases having the greatest impact, the reason for withdrawal was the reversible interaction of a drug or its metabolite with a single receptor, ion channel or enzyme (primary or secondary pharmacology). Once this interaction is identified, screens can be established and validated. When the mechanism is complex (eg, organ toxicity), however, such screens are difficult to implement and usually examine only the initial step, leading to considerable problems in extrapolation and risk definition. This review classifies drugs withdrawn from the US market over the last 25 years by their reasons for withdrawal, and examines how drug discovery programs have been modified in response to these events.     

Exploration of therapeutic targets for sexual dysfunctions: lessons learned from the failed stories

INTRODUCTION: The ratio between research and successful targets in a disease class gives a good indication about the extent of the exploration of additional targets for diseases in that class. This ratio is still very low for the field of sexual medicine. 'Failures' in drug development can be highly instructive, but are not often addressed. AREAS COVERED: We performed a review of the literature based on published data on four failure stories including targeting adrenergic receptors for erectile dysfunction (ED), targeting dopamine receptors by apomorphine for ED, serotonergic transporters as a target for premature ejaculation and PDE5 as a target for female sexual dysfunctions. The search included: i) a MEDLINE search from 1966 through November 2010 limited to English language medical literature, ii) relevant abstracts from 2009 and 2010 and iii) a pipeline search for therapeutics in development. The aim is to inform readers about the lessons learned from four selected failed therapeutic stories during therapeutic target exploration for sexual dysfunctions. Expert opinion: By learning from failures, a drug may not only be kept alive, but also better therapeutic strategies and design of new drugs may be developed.     

Exploration of therapeutic targets for sexual dysfunctions: lessons learned from the failed stories

Introduction: The ratio between research and successful targets in a disease class gives a good indication about the extent of the exploration of additional targets for diseases in that class. This ratio is still very low for the field of sexual medicine. ‘Failures’ in drug development can be highly instructive, but are not often addressed.

Areas covered: We performed a review of the literature based on published data on four failure stories including targeting adrenergic receptors for erectile dysfunction (ED), targeting dopamine receptors by apomorphine for ED, serotonergic transporters as a target for premature ejaculation and PDE5 as a target for female sexual dysfunctions. The search included: i) a MEDLINE search from 1966 through November 2010 limited to English language medical literature, ii) relevant abstracts from 2009 and 2010 and iii) a pipeline search for therapeutics in development. The aim is to inform readers about the lessons learned from four selected failed therapeutic stories during therapeutic target exploration for sexual dysfunctions.

Expert opinion: By learning from failures, a drug may not only be kept alive, but also better therapeutic strategies and design of new drugs may be developed.