Health-related quality of life of patients after ischaemic stroke treated in a provincial hospital in Poland.

BACKGROUND: Ischaemic stroke (IS) is a major cause of death and disability and affects the quality of life of patients. Previous studies focused on urban populations. OBJECTIVE: To evaluate the health-related quality of life (QoL) of patients with history of IS and living in a rural area in Poland. PATIENTS: Rural population of 172 patients discharged from a district hospital in Zakopane, Poland with a diagnosis of IS in the period from 01.01.2005 to 31.10.2006. INTERVENTION: QoL was evaluated using the European Quality of Life Scale-5 Dimensions EQ-5D-3 L (EQ-5D) and the Short Form Health Survey - 12 version 2 (SF-12). RESULTS: In the EQ-5D survey, 57.3% of patients had only some problems with mobility, 40.3% with usual activities, 63.2% with pain/discomfort, 59% with anxiety/depression, and 32.2% with self-care. In the SF-12 survey, both summary components (physical and psychological) were reduced compared to the population norm. CONCLUSION: The quality of life in IS survivors is clearly reduced in the majority of domains assessed by the EQ-5D and SF-12 questionnaires. The most important factors affecting QoL were the functional state, depression and anxiety. A significant difference as compared to to urban and mixed populations was observed for a reduced SF-12 mental health component and for the EQ-5D visual analogue scale. We found no effect of gender, age or cognitive disorders on the outcomes of SF-12.

Non-profit drug research and development: the case study of Genethon.

Non-profit drug research and development (R&D) has the potential to deliver innovative treatments at affordable prices. Using the case study methodology, we discuss some ethical and economic issues, including the possible impact of non-profit companies on innovation efforts from for-profit firms. Like other non-profits, Genethon is willing to adopt an ethical attitude toward their donors by pricing their products affordably. It remains to be seen if the approach to internalize the marketing authorization, manufacturing and distribution activities prove to be efficient and sustainable. Also, the firm faces an ethical dilemma because lower prices of innovative drugs can dry the for-profit R&D in the area and prevent patient access to future innovations.

Heterogeneous Recommendations for Oncology Products Among Different HTA Systems: A Comparative Assessment.

Rising budget constraints and demands for healthcare services create additional complexity within the decision process for resource allocation. Innovations and scientific progress have been shown to be key drivers of the increase in healthcare expenditures (1). In the context of rising medical care costs and limited resources, Health Technology Assessment (HTA) was developed as a tool to inform decision-making and to provide the rationalization behind these decisions driving resource allocation and spending for health technology products. Furthermore, HTA agencies make the decision-making process more transparent. The HTA approach involves evaluating multiple aspects of a new product's value in order to maximize health gain provided within the setting of limited resources.

Patient-Reported Outcomes in Oncology, Beyond Randomized Controlled Trials.

The goal of the treatment of a disease has moved from treating organs and diseases through symptoms, biological parameters and imaging towards treating a human being as a whole. The treatments should deliver benefits that patients can personally perceive. However, the patient's perspective does not always match the one of those surrounding them. Illustratively, patients' symptom assessments are more predictable for daily health status, whereas clinicians' symptom measurements are more related to clinical outcomes. The term, patient-reported outcomes (PROs), includes any data that are reported directly by the patient without an intermediary, such as a family member or a healthcare professional. The use of PROs in oncology trials is increasing and the U.S. Food and Drug Administration has published guidelines on the review and evaluation of PROs. However, while PROs are increasingly used in clinical trials, they are rarely used in daily clinical practice. Further, healthcare payers are concerned with issues related to relevance, quality, and interpretability of these outcomes.

Orphan Drugs in Oncology.

Rare diseases represent a group of conditions affecting a very limited number of patients. Low profitability resulting from the small size of target population coupled with difficulties in conducting the research causes the lack of interest from the pharmaceutical industry. In order to promote research and development of medicines for rare diseases, a special 'orphan' legislation was introduced in a number of regions. These measures led to a significant increase in the number of approved orphan molecules. The high per patient cost of orphan drugs, as well the rapid growth of orphan drug sector, raised concerns regarding the sustainable funding of therapies for rare diseases. Rare cancers represent the majority of the current orphan drug market and are often associated with very high revenues. This chapter provides a review of orphan legislations and health technology assessment framework, analyses the position of oncology drugs on the orphan drug market and discusses future perspectives.

Patient-reported outcome claims in European and United States orphan drug approvals.

Purpose: We aimed to evaluate the rate of usage and the kind of patient-reported outcome (PRO) claims in orphan drug approvals from the European Medicines Agency (EMA) dated between 1/1/2012 and 31/12/2016 and to compare them to those from the US Food and Drug Administration (FDA). Methods: Orphan drug approval documentation was obtained from the EMA website. PRO-related language was extracted from the Summaries of Product Characteristics (SmPCs). Data were compared to a previously published analysis of the FDA approvals from the same time period. Results: Out of 60 approvals that met the inclusion criteria, 12 products approved by the EMA for 13 (21.7%) orphan indications contained PRO language in the Clinical Studies section of the SmPC. Twelve SmPCs contained PRO instruments based on symptoms, five of which also concerned patient functioning. Eight approvals included PRO claims related to quality of life (QoL) most commonly in cancer treatment. Conclusion: The rate of PRO claims was lower for orphan drugs specifically than for all drug approvals by the EMA. However, in accordance with previous findings, the EMA appeared more inclined to grant PRO claims including health-related QoL than the FDA.

Low rates of patient-reported outcome claims for orphan drugs approved by the us food and drug administration.

Background: Claims included in package inserts (PIs) for medicinal products approved by the US Food and Drug Administration (FDA) constitute the regulatory definition of drugs' benefits and risks. Objective: We sought to assess the usage of patient-reported outcome (PRO) claims in a comprehensive set of US FDA orphan drug approvals dated between 1/1/2012 and 31/12/2016, and characterize them. Study design: Orphan drug approval documentation was obtained from the US FDA website. Drug Package Inserts (PI) were analyzed to extract information on PRO-related language. Results: Among 178 drugs that met inclusion criteria, 16 (9%) products approved for 16 orphan indications contained PRO language in the Clinical Studies section of the PI. All PRO instruments concerned disease symptoms, and two also referred to patient functioning. The most common PRO instrument was a bleed-specific rating scale for four products approved for the treatment or prevention of bleeding episodes in patients with genetic bleeding disorders. Conclusions: There is a need to implement public incentives for academic development of PRO instruments for rare conditions and for regulatory policies that mandate the collection of PRO endpoints in pivotal trials of orphan drugs.

Non-profit Drug Research and Development at a Crossroads.

In wealthy nations, non-profit drug R&D has been proposed to reduce the prices of medicines. We sought to review the ethical and economic issues concerning non-profit drug R&D companies, and the possible impact that their pricing strategy may have on the innovation efforts from for-profit companies targeting the same segment of the pharmaceutical market. There are two possible approaches to pricing drugs developed by non-profit R&D programs: pricing that maximises profits and "affordable" pricing that reflects the cost of manufacturing and distribution, plus a margin that ensures sustainability of the drug supply. Overall, the non-profits face ethical challenges - due to the lack of resources, they are unable to independently commercialize their products on a large scale; however, the antitrust law does not permit them to impose prices on potential licensees. Also, reduced prices for the innovative products may result in drying the for-profit R&D in the area.

Quantifying the persisting orphan-drug shortage public health crisis in the United States.

Background: Orphan drugs (ODs) are pharmaceuticals manufactured for rare conditions that affect less than 200,000 people in the US. ODs are therefore produced in small quantities to meet sparse demand. Since 2010, OD shortages have become frequent, but no comprehensive, quantitative studies exist. Objective: The objective of this study is to assess the rates of OD shortages per therapeutic class and their trends over time in the United States. Study design: OD approvals were collected from publicly available information on the US Food and Drug Administration (FDA) website on 13 June 2016. Data on OD shortages were collected from the FDA and the American Society of Health-System Pharmacists (ASHP) websites. We reviewed the number of shortages per year and per therapeutic area. Multiple indications for the same drug were counted individually. Results: Of 569 ODs approved, 50% were approved in the decade ending in 2015. Oncology was found to be the most represented therapeutic area (34% of all OD approvals), followed by endocrinology (11%). Shortage data were available from 2008. In total, there were 66 (12%) OD shortages, with an average shortage duration of 455.5 days. Shortages were observed mainly for oncology products (19 cases, 13% of oncology ODs) and endocrinology products (14 cases, 22% of endocrinology ODs) Conclusion: Despite the FDA strategic plan for preventing and mitigating drug shortages (October 2013), remaining OD shortages still pose an enduring challenge to patient care, with a median shortage duration of almost 15 months. In many instances, ODs are the only available therapy for rare diseases, and OD shortages can lead to serious health deterioration and death. More research is needed to elucidate the causes of shortages and their impact on patients' health.

The Use of Surrogate and Patient-Relevant Endpoints in Outcomes-Based Market Access Agreements : Current Debate.

The high cost of novel treatments is the major driver of negative or restricted reimbursement decisions by healthcare payers in many countries. Costly drugs can be subject to Market Access Agreements (MAAs), which are financial (Commercial Agreements [CAs]) or outcomes-based (Payment for Performance Agreements [P4Ps] or Coverage with Evidence Development agreements [CEDs]). Outcomes in outcomes-based MAAs are assessed through changes in surrogate endpoints (SEPs) or patient-relevant endpoints (PEPs). In May 2015, we reviewed published and grey literature on MAAs between manufacturers and large, institutionalised payers from all geographical areas, and classified the schemes into CAs, P4Ps and CEDs, as well as by therapeutic area and country. Outcomes-based MAAs were further categorized by the endpoint used. Overall, we identified 143 MAAs, 56 (39.2 %) of which were pure CAs, 53 (37.1 %) were CEDs, and 34 (23.8 %) were P4Ps. Among the CEDs, 49 were PEP CEDs and four were SEP CEDs; of the 34 P4Ps, 29 were SEP P4Ps for 30 drugs, and five were PEP P4Ps for at least six drugs; and among 87 outcomes-based MAAs (CEDs + P4Ps), PEP CEDs were the most common (56.3 %), followed by SEP P4Ps (34.1 %). The high proportion of SEPs used in P4Ps contrasts with the high proportion of PEPs used in CEDs. CEDs employ PEPs and it appears that they are used to reduce uncertainty about a drug's clinical outcomes and/or real-life use, and thus allow payers to align a product's value with price. We argue that P4Ps do not reduce uncertainty about real-life effectiveness and can only constitute an outcome guarantee for payers if they are based on PEPs or validated SEPs.

Sipuleucel-T (Provenge(®))-Autopsy of an Innovative Paradigm Change in Cancer Treatment: Why a Single-Product Biotech Company Failed to Capitalize on its Breakthrough Invention.

Approved by the US Food and Drug Administration (FDA) in 2010, sipuleucel-T (Provenge(®)) was the first 'personalized' cancer vaccine for the treatment of prostate cancer in a metastatic, non-symptomatic population of 30,000 men in the USA. Sipuleucel-T is prepared individually for each patient and infused in three sessions over a period of 1 month. However, in 2015, Dendreon, the owner of sipuleucel-T, filed for bankruptcy. This opinion paper reviews the probable reasons this innovative product failed to achieve commercial success. PubMed and internet searches were performed focused on pricing, reimbursement, and market access. We found that sipuleucel-T's FDA approval was delayed by 3 years, reportedly because of the vaccine's new mechanism of action. Sipuleucel-T was cleared by the European Medicines Agency 2 years later, but other national agencies were not approached. It was priced at $US93,000 for a course of treatment, and this high price combined with the company's late securement of reimbursement for the vaccine by the US Centers for Medicare and Medicaid Services (CMS) resulted in another year's delay in accessing the market. Despite a positive recommendation by the National Comprehensive Cancer Network, sipuleucel-T's complex administration, high price, and uncertainty about the reimbursement status deterred doctors from prescribing the product. Furthermore, the vaccine's supply was limited during the first year of launch due to limited manufacturing capacity. In addition, two oral metastatic prostate cancer drugs with similar survival benefits reached the US market 1 and 2 years after sipuleucel-T. Also, even though Dendreon's market capitalization topped $US7.5 billion following the FDA's approval of sipuleucel-T, this value degraded gradually until the firm's bankruptcy 5 years later. We conclude that the bankruptcy of Dendreon was largely due to the delay in securing FDA approval and CMS coverage, as well as the high cost that had to be incurred by providers up-front. Licensing sipuleucel-T to a pharmaceutical company more experienced in the market access pathway may have saved the company and the product.

In eHealth in India today, the nature of work, the challenges and the finances: an interview-based study.

BACKGROUND: India is a country with vast unmet medical needs. eHealth has the potential to improve the quality of health care and reach the unreached. We have sought to understand the kinds of eHealth programmes being offered in India today, the challenges they face and the nature of their financing. METHODS: We have adopted an interview-based methodology. The 30 interviews represent 28 organizations, and include designers, implementers, evaluators and technology providers for eHealth programmes. RESULTS: A range of programmes is being run, including point-of-care in rural and urban areas, treatment compliance, data collection and disease surveillance, and distant medical education. Most programmes provide point-of-care to patients or other beneficiaries in rural areas. Technology is not a limiting factor but the unavailability of suitable health personnel is a major challenge, especially in rural areas. We have identified a few factors that help this situation. Financial sustainability is also a concern for most programmes, which have rarely been scaled up. There are recent for-profit efforts in urban areas, but no reliable business model has been identified yet. Government facilities have not been very effective in eHealth on their own, but collaborations between the government and non-profit (in particular) and for-profit organisations have led to impactful programmes. CONCLUSIONS: It is unlikely that eHealth will have widespread and sustainable impact without government involvement, especially in rural areas. Nevertheless, programmes run solely by the government are unlikely to be the most effective.

Case studies of innovative medical device companies from India: barriers and enablers to development.

BACKGROUND: Over 75% of the medical devices used in India are imported. Often, they are costly and maladapted to low-resource settings. We have prepared case studies of six firms in Bangalore that could contribute to solving this problem. They have developed (or are developing) innovative health care products and therefore are pioneers in the Indian health care sector, better known for its reverse engineering skills. We have sought to understand what enablers and barriers they encountered. METHODS: Information for the case studies was collected through semi-structured interviews. Initially, over 40 stakeholders of the diagnostics sector in India were interviewed to understand the sector. However the focus here is on the six featured companies. Further information was obtained from company material and other published resources. RESULTS: In all cases, product innovation has been enabled by close interaction with local medical practitioners, links to global science and technology and global regulatory requirements. The major challenges were the lack of guidance on product specifications from the national regulatory agency, paucity of institutionalized health care payers and lack of transparency and formalized Health Technology Assessment in coverage decision-making. The absence of national evidence-based guidelines and of compulsory continuous education for medical practitioners were key obstacles in accessing the poorly regulated and fragmented private market. CONCLUSIONS: Innovative Indian companies would benefit from a strengthened capacity and interdisciplinary work culture of the national device regulatory body, institutionalized health care payers and medical councils and associations. Continuous medical education and national medical guidelines for medical practitioners would facilitate market access for innovative products.

Why are inaccurate tuberculosis serological tests widely used in the Indian private healthcare sector? A root-cause analysis.

Serological tests for tuberculosis are inaccurate and WHO has recommended against their use. Although not used by the Revised National TB Control Programme (RNTCP), serodiagnostics are widely used in the private sector in India. A root-cause analysis was undertaken to determine why serological tests are so popular, and seven root causes were identified that can be grouped into three categories: technical/medical, economic, and regulatory. Technical/medical: RNTCP's current low budget does not allow scale-up of the newer, WHO-endorsed technologies. Thus, under the RNTCP, most patients have access to only smear microscopy, a test that is insensitive and underused in the private sector. Because there is no accurate, validated, point-of-care test for TB, serological tests meet a perceived need among doctors and patients. Economic: While imported molecular or liquid culture tests are too expensive, there are no affordable Indian versions on the market, leaving serological tests as the main alternative. Although serological tests are inaccurate, various players along the value chain profit from their use, and this sustains a market for these tests. Regulatory: TB tests are poorly regulated and a large number of serological kits are on the market. Private healthcare in general is poorly regulated, and doctors in the private sector are outside the scope of RNTCP and do not necessarily follow standard guidelines. A clear understanding of these realities should facilitate market-based strategies that can help replace serological tests with accurate, validated tools.

Market Access Agreements for pharmaceuticals in Europe: diversity of approaches and underlying concepts.

BACKGROUND: Market Access Agreements (MAA) between pharmaceutical industry and health care payers have been proliferating in Europe in the last years. MAA can be simple discounts from the list price or very sophisticated schemes with inarguably high administrative burden. DISCUSSION: We distinguished and defined from the health care payer perspective three kinds of MAA: Commercial Agreements (CA), Payment for Performance Agreements (P4P) and Coverage with Evidence Development (CED). Apart from CA, the agreements assumed collection and analysis of real-life health outcomes data, either from a cohort of patients (CED) or on per patient basis (P4P). We argue that while P4P aim at reducing drug cost to payers without a systematic approach to addressing uncertainty about drugs' value, CED were implemented provisionally to reduce payer's uncertainty about value of a medicine within a defined time period. SUMMARY: We are of opinion that while CA and P4P have a potential to reduce payers' expenditure on costly drugs while maintaining a high list price, CED address initial uncertainty related to assessing the real-life value of new drugs and enable a final HTA recommendation or reimbursement and pricing decisions. Further, we suggest that real cost to health care payers of drugs in CA and P4P should be made publicly available in a systematic manner, to avoid a perverse impact of these MAA types on the international reference pricing system.

Design of patient access schemes in the UK: influence of health technology assessment by the National Institute for Health and Clinical Excellence.

BACKGROUND: Patient Access Schemes (PAS) are alternative market access agreements between the UK Department of Health and drug manufacturers. They are implemented to enable the UK National Institute for Health and Clinical Excellence (NICE) to recommend expensive medicines for use in the UK NHS. OBJECTIVE: We aimed to analyse the extent to which NICE drug appraisals influence the construction of PAS and what rationale underlies the variety of approaches to their design. METHODS: We analysed publicly available documentation on PAS developed as a part of the NICE Health Technology Assessment process. RESULTS: We demonstrate how the design of PAS is determined by the kind of evidence that is available to model cost effectiveness of a drug and by the incremental cost-effectiveness ratio that is deemed acceptable in a given patient population. PAS aimed to reduce drug cost to the NHS by means of various discounts or rebates on a per-patient basis rather than by lowering the list price of drugs. While almost all schemes were proposed by the industry in reply to negative draft recommendations by NICE, motivations of the stakeholders to implement PAS are not disclosed in the publicly available documentation. CONCLUSION: A more transparent process might be necessary to protect against a perverse impact of PAS on international reference pricing that uses list prices rather than the real cost of purchasing medicines that the NHS incurs.

High-resolution architecture of the outer membrane of the Gram-negative bacteria Roseobacter denitrificans.

The outer membrane of Gram-negative bacteria protects the cell against bactericidal substances. Passage of nutrients and waste is assured by outer membrane porins, beta-barrel transmembrane channels. While atomic structures of several porins have been solved, so far little is known on the supramolecular structure of the outer membrane. Here we present the first high-resolution view of a bacterial outer membrane gently purified maintaining remnants of peptidoglycan on the perisplasmic surface. Atomic force microscope images of outer membrane fragments of the size of approximately 50% of the bacterial envelope revealed that outer membrane porins are by far more densely packed than previously assumed. Indeed the outer membrane is a molecular sieve rather than a membrane. Porins cover approximately 70% of the membrane surface and form locally regular lattices. The potential role of exposed aromatic residues in the formation of the supramolecular assembly is discussed. Finally, we present first structural data of the outer membrane porin from the marine Gram-negative bacteria Roseobacter denitrificans, and we perform a sequence alignment with porins of known structure.

Structural information, resolution, and noise in high-resolution atomic force microscopy topographs.

AFM has developed into a powerful tool in structural biology, providing topographs of proteins under close-to-native conditions and featuring an outstanding signal/noise ratio. However, the imaging mechanism exhibits particularities: fast and slow scan axis represent two independent image acquisition axes. Additionally, unknown tip geometry and tip-sample interaction render the contrast transfer function nondefinable. Hence, the interpretation of AFM topographs remained difficult. How can noise and distortions present in AFM images be quantified? How does the number of molecule topographs merged influence the structural information provided by averages? What is the resolution of topographs? Here, we find that in high-resolution AFM topographs, many molecule images are only slightly disturbed by noise, distortions, and tip-sample interactions. To identify these high-quality particles, we propose a selection criterion based on the internal symmetry of the imaged protein. We introduce a novel feature-based resolution analysis and show that AFM topographs of different proteins contain structural information beginning at different resolution thresholds: 10 A (AqpZ), 12 A (AQP0), 13 A (AQP2), and 20 A (light-harvesting-complex-2). Importantly, we highlight that the best single-molecule images are more accurate molecular representations than ensemble averages, because averaging downsizes the z-dimension and "blurs" structural details.

Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes.

The phenotypes of single- (SKO) and double-knockout (DKO) lines of dihydrofolate reductase-thymidylate synthase (DHFR-TS) of bloodstream Trypanosoma brucei were evaluated in vitro and in vivo. Growth of SKO in vitro is identical to wild-type (WT) cells, whereas DKO has an absolute requirement for thymidine. Removal of thymidine from the medium triggers growth arrest in S phase, associated with gross morphological changes, followed by cell death after 60 h. DKO is unable to infect mice, whereas the virulence of SKO is similar to WT. Normal growth and virulence could be restored by transfection of DKO with T. brucei DHFR-TS, but not with Escherichia coli TS. As pteridine reductase (PTR1) levels are unchanged in SKO and DKO cells, PTR1 is not able to compensate for loss of DHFR activity. Drugs such as raltitrexed or methotrexate with structural similarity to folic acid are up to 300-fold more potent inhibitors of WT cultured in a novel low-folate medium, unlike hydrophobic antifols such as trimetrexate or pyrimethamine. DKO trypanosomes show reduced sensitivity to these inhibitors ranging from twofold for trimetrexate to >10 000-fold for raltitrexed. These data demonstrate that DHFR-TS is essential for parasite survival and represents a promising target for drug discovery.

Direct visualization of KirBac3.1 potassium channel gating by atomic force microscopy.

KirBac3.1 belongs to a family of transmembrane potassium (K(+)) channels that permit the selective flow of K-ions across biological membranes and thereby regulate cell excitability. They are crucial for a wide range of biological processes and mutations in their genes cause multiple human diseases. Opening and closing (gating) of Kir channels may occur spontaneously but is modulated by numerous intracellular ligands that bind to the channel itself. These include lipids (such as PIP(2)), G-proteins, nucleotides (such as ATP) and ions (e.g. H(+), Mg(2+), Ca(2+)). We have used high-resolution atomic force microscopy (AFM) to examine KirBac3.1 in two different configurations. AFM imaging of the cytoplasmic surface of KirBac3.1 embedded in a lipid bilayer has allowed visualization of the tetrameric assembly of the ligand-binding domain. In the absence of Mg(2+), the four subunits appeared as four protrusions surrounding a central depression corresponding to the cytoplasmic pore. They did not display 4-fold symmetry, but formed a dimer-of-dimers with 2-fold symmetry. Upon addition of Mg(2+), a marked rearrangement of the intracellular ligand-binding domains was observed: the four protrusions condensed into a single protrusion per tetramer, and there was an accompanying increase in protrusion height. The central cavity within the four intracellular domains also disappeared on addition of Mg(2+), indicating constriction of the cytoplasmic pore. These structural changes are likely transduced to the transmembrane helices, which gate the K(+) channel. This is the first time AFM has been used as an interactive tool to study K(+) channels. It has enabled us to directly measure the conformational changes in the protein surface produced by ligand binding.