Wim G. Goettsch

From Adaptive Licensing to Adaptive Pathways: Delivering a Flexible Life-Span Approach to Bring New Drugs to Patients

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.

The costs of benzodiazepine-associated hospital-treated fall injuries in the EU: a PHARMO study

ObjectiveTo estimate the hospitalisation costs of accidental fall injuries in the EU resulting from the use of benzodiazepines.MethodsRisk and exposure data were obtained from the Dutch Pharmo system, a population-based register of drug-dispensing records and hospital records. The population attributable risk (PAR) was calculated using the age-specific prevalence estimates of benzodiazepine use and the corresponding relative risk (RR), obtained from a case-control study in community-dwelling inhabitants over 55 years of age in defined areas of The Netherlands covering the period 1985–2000. Annual hospitalisation costs of benzodiazepine-related fall injuries were based on the age-specific PARs and extrapolated to the European population using accident and demographic data of the EU. All analyses were performed from the perspective of a third-party payer.ResultsFall injuries in the study population were significantly associated with benzodiazepine use (RR 1.6, 95% CI 1.4–1.7), especially in those aged over 85 years (RR 3.6, 95% CI 2.9–4.5). The total annual hospital direct medical costs in 2000 of fall-related injuries attributable to benzodiazepine use were €1.8 billion (95% CI €1.5-2.2 billion) in the EU.ConclusionsThe estimated costs of hospitalisations of accidental-fall injuries related to benzodiazepine use in the EU varied between €1.5 and €2.2 billion each year. More than 90% of these costs were in the elderly, with hip fractures as the major contributor. Discontinuing benzodiazepines in the elderly and/or substituting them with other drugs not associated with the risk of falls in the elderly will to a large extent prevent these accidents.

Relative Effectiveness Assessment of Pharmaceuticals: Similarities and Differences in 29 Jurisdictions

OBJECTIVE Assessment of the effectiveness compared with alternative treatment(s) plays an important role in many jurisdictions in determining the reimbursement status of pharmaceuticals. This type of assessment is often referred to as a relative effectiveness assessment (REA) and is carried out by many jurisdictions. Increased sharing of information across jurisdictions may save costs and reduce duplication. The objective of this study was to explore the main similarities and differences in the major methodological aspects of REA in multiple jurisdictions. METHODS Data were gathered with a standardized data extraction form by searching publicly available information and by eliciting information from representatives at relevant organizations. RESULTS Of the initially included 35 jurisdictions, data were gathered for 29 jurisdictions. There seem to be substantial similarities on the choice of the comparator, the role of indirect comparisons, and preferred end points in REAs (except for the use of health state utilities). Jurisdictions, however, differ in whether effectiveness (usual circumstances of health care practice) is estimated in case no (comparative) effectiveness data are available and how this is done. CONCLUSION Some important methodological aspects for REA are approached in a similar way in many jurisdictions, indicating that collaboration on assessments may be feasible. Enhanced collaboration in the development of methods and best practices for REA between jurisdictions will be a necessary first step. Important topics for developing best practice are indirect comparisons and how to handle the gap between efficacy and effectiveness data in case good quality comparative effectiveness data are not yet available at the time of reimbursement decisions.

Statins are less effective in common daily practice among patients with hypercholesterolemia: the REALITY-PHARMO study;

SUMMARY Background: To study the use and effectiveness of lipid-lowering drugs with respect to lowering of cholesterol levels in routine daily practice. Methods: 20 392 patients for whom lipid levels records were available between January 1991 and December 2001 were included in this retrospective population based cohort study. From this group of patients 1899 patients started treatment during the study period and had at least one baseline cholesterol measurement during the six months prior to the initiation of lipid lowering drugs and at least one cholesterol measurement after initiation. A patient was defined to be ‘at goal’ if the patient had a total cholesterol less than 5.0 mmol/L. Results: Our results indicate that only 30.2% of all treated patients achieved goal in the first year of treatment. After the introduction of new guidelines in 1998, recommending more aggressive treatment, the goal attainment percentage rose from 22.4% of those patients treated before 1998 to 42.3% for those in whom treatment was initiated after 1998. Conclusion: The percentage of patients achieving guideline recommended goal is low in real-life even in patients treated with high dose statins.

Improving the Contribution of Regulatory Assessment Reports to Health Technology Assessments—A Collaboration between the European Medicines Agency and the European network for Health Technology Assessment

In response to a recommendation from the Pharmaceutical Forum, the European Medicines Agency and the European network for Health Technology Assessment initiated a collaboration with the aim to improve the contribution regulatory assessment reports can make to the assessment of relative effectiveness of medicinal products by health technology assessment bodies. This collaboration on improving European Public Assessment Reports (EPARs) started in February 2010 and was performed over 2 years. As a result, the templates for preparing EPARs were revised to better address the needs of heath technology organizations. The better understanding of information needs was a key outcome of the collaboration. To ascertain whether these template changes led to the inclusion of relevant information, a review of a small set of EPARs for recently approved medicinal products was carried out in parallel by both the European network for Health Technology Assessment and the European Medicines Agency. This report provides an account of this project on improving EPARs, which is part of the ongoing dialogue between regulators and health technology assessment bodies on a European level to support policymaker decisions in the future.

Quality of life of patients with irritable bowel syndrome is low compared to others with chronic diseases

Background Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal dysmotility disorder. This study aimed to estimate the burden of illness of a Dutch population of community dwelling patients suffering from IBS. Methods Patients identified at community pharmacies, using mebeverine as a proxy for IBS, were administered a questionnaire regarding (1) the Rome II criteria for IBS, (2) predominant type of stool during complaints, (3) severity of symptoms (abdominal pain and discomfort), (4) generic and disease-specific quality of life, (5) current health status (utilities), and (6) loss of productivity. Results Three hundred and seventy-five users of mebeverine were identified of which 169 patients met the Rome II criteria for IBS, and were included in the study. More than half (58%) of the IBS patients reported severe abdominal pain and complaints. Generic and disease-specific quality of life outcomes showed impairment on all dimensions. Current health status in IBS patients, calculated on the basis of the EQ-5D VAS, was perceived on 62% of full health (95% CI, 60–66%). A calculation of health status in these patients based on the SF-6D algorithm showed a comparable score of 0.67 (1 is full health; 95% CI, 0.65–0.68). The loss in productivity of IBS patients was 1.8 days (95% CI, 1.1–2.5) per month. Conclusions This study confirmed that the burden of illness of IBS in the Netherlands is substantial. IBS patients treated with mebeverine experienced low quality of life and suffered from severe pain. Based on these results, more attention for the diagnosis and treatment of IBS seems to be justified.

Inadequate Prevention of NSAID-Induced Gastrointestinal Events

BACKGROUND Use of nonsteroidal antiinflammatory drugs (NSAIDs) is a well-known cause of gastrointestinal (GI) adverse events. To protect patients at risk, several strategies are advised, including concomitant treatment with proton-pump inhibitors or switching to cyclooxygenase (COX)-2 selective NSAIDs. It is as yet unknown how many patients at risk for NSAID-induced events are protected. OBJECTIVE To estimate the number of patients using GI preventive treatment while at risk for NSAID-induced GI events. METHODS Records of patients using NSAIDs consecutively for at least 100 days (from 2001 to 2002) were obtained from the PHARMO system in the Netherlands (N = 1 000 000). GI preventive treatments were classified as adequate or inadequate based on evidence-based criteria. Adequate treatment was defined as concomitant use of misoprostol (>400 μg daily), histamine2-antagonists (≥2 times recommended dose) or proton-pump inhibitors (≥1 recommended dose), or alternative treatment with COX-2 selective inhibitors. RESULTS A total of 10 121 patients met the study inclusion criteria; 70% were women. One or more preventive strategies were prescribed in 4340 patients (42.9%), of which 2799 (64.5%) were adequate and 1541 (35.5%) inadequate. Prescribing of adequate preventive treatments increased with the number of risk factors, from 13.3% among those with no additional risk factors to 61.9% for those with ≥4 risk factors. CONCLUSIONS Although risk factors for GI damage were recognized, a large number of patients in the Netherlands were not or were inadequately protected against potential NSAID-associated GI damage. Despite recommendations, and even in the presence of ≥4 risk factors, almost 40% of these patients were not prescribed adequate GI preventive treatment.

Bridging Trial and Decision: A Checklist to Frame Health Technology Assessments for Resource Allocation Decisions

OBJECTIVE Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the decision problem. HTAs may therefore not meet the needs of decision makers. Our objective was to develop and apply a checklist to: 1) systematically frame HTAs in a way that they are applicable to the decision problem; and 2) assess if a decision problem can be informed by an available HTA. METHODS We reviewed published literature to identify factors that should be considered when framing HTAs for resource allocation decisions. The checklist was finalized in collaboration with clinicians and policy makers. We applied the checklist to the economic evaluation of trastuzumab in early breast cancer. We defined a reference case and for each study, retrieved through a systematic review, we examined if each factor was explicitly considered. RESULTS A checklist was developed with 11 factors (e.g., clinical practice, consequences, and patient use). In the case of trastuzumab, most factors were considered by the 11 retrieved economic evaluations. Two factors, being the inclusion of all relevant comparators and professional use, were considered by none of the studies. CONCLUSIONS We developed a comprehensive checklist with 11 factors to frame HTAs and to assess the applicability of HTAs to resource allocation decisions. Economic evaluations on trastuzumab considered some of these factors, but overlooked others. The proposed checklist assists in systematically considering all factors in developing the conceptual model of an HTA, to make HTAs better reflect the decision problem.

Practical feasibility of outcomes research in oncology: lessons learned in assessing drug use and cost-effectiveness in The Netherlands.

OBJECTIVE To investigate the practical feasibility to develop evidence on drug use and cost-effectiveness in oncology practice. PATIENTS AND METHODS Feasibility was examined using three Dutch case studies. Each case study investigated the degree of appropriate drug use and its incremental cost-effectiveness. Detailed data were retrospectively collected from hospital records. In total, 391, 316 and 139 patients with stage III colon cancer, metastatic colorectal cancer and multiple myeloma were included in 19, 29 and 42 hospitals, respectively. RESULTS The methods used in the case studies were feasible to develop evidence on some aspects of drug use including types of treatments used, dosages, dose modifications and healthcare costs. Aspects such as baseline patient characteristics, reasons to start or stop a treatment and treatment effects were less feasible because of missing values. Despite difficulties to correct for confounding by indication, it was possible to estimate incremental cost-effectiveness by synthesising evidence in two of the three case studies. CONCLUSION It is possible to generate evidence about drug use and cost-effectiveness in oncology practice to facilitate informed decision-making by both payers and physicians. This can improve quality of care and enhance the efficient allocation of resources. However, the optimal approach differs between drugs and their indications. Generating high-quality evidence requires active interdisciplinary collaboration. Patient registries can facilitate data collection but cannot resolve all issues. In most circumstances it is inevitable to use data-synthesis to obtain valid incremental cost-effectiveness estimates, but for some indications it will not be feasible to derive a valid and precise estimate.

European collaboration on relative effectiveness assessments: What is needed to be successful?

OBJECTIVE The objective of this study is to identify the possible barriers and critical success factors for the implementation of European collaboration in the field of relative effectiveness assessment (REA) of drugs. METHODS Data were gathered through semi-structured interviews with representatives from eight European health technology assessment (HTA) organisations involved in assessment of drugs for coverage decision-making (AAZ, AIFA, AHTAPol, HAS, HVB, IQWIG, NICE and ZiN). RESULTS Potential barriers identified mainly relate to methodology, resources and challenges with implementation in the respective national processes (e.g. legal restrictions). The most critical success factors for production of cross-border assessments were the continuous cooperation of competent partners, and the quality and timely availability of the assessment. CONCLUSION Further adaptation of the process and methods is required for optimal collaboration. In the near future it can be expected that cross-border assessments will meet in particular the needs of smaller/middle-sized European countries and also European countries with less developed HTA systems as the potential efficiency/quality gains are the highest for these countries. Therefore, national implementation of cross-border assessments is especially likely in these countries in the coming years. Once more experience is gained with cross-border assessments, and successes become more evident, efficiency/quality gains may also be likely for some larger countries with well established processes.