Jarno Hoekman

Spatial scientometrics : towards a cumulative research program

We propose a research program to analyse spatial aspects of the science system. First, we provide a review of scientometric studies that already explicitly take the spatial dimension into account. The review includes studies on (i) the spatial distribution of research and citations, (ii) the existence of spatial biases in collaboration, citations and mobility, and (iii) the citation impact of national versus international collaborations. Then, we address a number of methodological issues in dealing with space in scientometrics. Finally, to integrate spatial and non-spatial approaches, we propose an analytical framework based on the concept of proximity. A proximity approach allows for combining hypotheses from different theoretical perspectives into a single framework.

Drug-Induced Reduction in Albuminuria Is Associated with Subsequent Renoprotection: A Meta-Analysis

Albuminuria has been proposed as a surrogate end point in randomized clinical trials of renal disease progression. Most evidence comes from observational analyses showing that treatment-induced short-term changes in albuminuria correlate with risk change for ESRD. However, such studies are prone to selection bias and residual confounding. To minimize this bias, we performed a meta-analysis of clinical trials to correlate the placebo-corrected drug effect on albuminuria and ESRD to more reliably delineate the association between changes in albuminuria and ESRD. MEDLINE and EMBASE were searched for clinical trials reported between 1950 and April 2014. Included trials had a mean follow-up of ≥1000 patient-years, reported ESRD outcomes, and measured albuminuria at baseline and during follow-up. Twenty-one clinical trials involving 78,342 patients and 4183 ESRD events were included. Median time to first albuminuria measurement was 6 months. Fourteen trials tested the effect of renin-angiotensin-aldosterone-system inhibitors and seven trials tested other interventions. We observed variability across trials in the treatment effect on albuminuria (range, -1.3% to -32.1%) and ESRD (range, -55% to +35% risk change). Meta-regression analysis revealed that the placebo-adjusted treatment effect on albuminuria significantly correlated with the treatment effect on ESRD: for each 30% reduction in albuminuria, the risk of ESRD decreased by 23.7% (95% confidence interval, 11.4% to 34.2%; P=0.001). The association was consistent regardless of drug class (P=0.73) or other patient or trial characteristics. These findings suggest albuminuria may be a valid substitute for ESRD in many circumstances, even taking into account possible other drug-specific effects that may alter renal outcomes.

Big Pharma, Little Science? A Bibliometric Perspective on Big Pharma’s R&D Decline

There is a widespread perception that pharmaceutical R&D is facing a productivity crisis characterised by stagnation in the numbers of new drug approvals in the face of increasing R&D costs. This study explores pharmaceutical R&D dynamics by examining the publication activities of all R&D laboratories of the major European and US pharmaceutical firms (Big Pharma) during the period 1995–2009. The empirical findings present an industry in transformation. In the first place, we observe a decline of the total number of publications by large firms. Second, we show a relative increase of their external collaborations suggesting a tendency to outsource, and a diversification of the disciplinary base, in particular towards computation, health services and more clinical approaches. Also evident is a more pronounced decline in publications by both R&D laboratories located in Europe and by firms with European headquarters. Finally, while publications by Big Pharma in emerging economies sharply increase, they remain extremely low compared with those in developed countries. In summary, the trend in this transformation is one of a gradual decrease in internal research efforts and increasing reliance on external research. These empirical insights support the view that Big Pharma are increasingly becoming ‘network integrators’ rather than the prime locus of drug discovery.

Death of distance in science? : a gravity approach to research collaboration

One of the major transitions in recent scientific research is the rise of network theory motivating a variety∈dexvariety of new research programmes in and across various disciplines. Economic geography∈dexgeography has been no exception. The work on networks in economic geography can be divided into two types of research. First, there are studies on inter-firm networks and their impact on firm performance. For a large part, such studies have been carried out in the context of geographical clusters, which are often characterised by strong network relations (Uzzi, 1997). A second approach, an example of which is presented below, concerns the study of inter-regional networks and their impact on regional growth. Here, the unit of analysis are territories, typically sub-national regions. The interest in this topic stems from Castells (1996) and others who have argued that regional growth increasingly depends on a region’s position in global networks rather than its specific local characteristics such as institutions, endowments and amenities (‘space of flows’ versus the ‘space of places’).

Use of the conditional marketing authorization pathway for oncology medicines in Europe

Conditional marketing authorization (CMA) in the European Union (EU) is an early access pathway for medicines that show promising therapeutic effects, but for which comprehensive data are not available. Using a mixed quantitative‐qualitative research design, we evaluated how CMA has been used in marketing authorization of oncology medicines in the period 2006 to 2013. We show that compared to full marketing authorization, CMA is granted based on less comprehensive data. However, this is accompanied by significantly longer assessment times and less consensus among regulators about marketing authorization. Moreover, development time from first‐in‐human testing to marketing authorization did not differ between full marketing authorization and CMA, but was significantly longer for CMA compared to accelerated approved products in the United States (US). Results indicate that CMA is not used by companies as a prospectively planned pathway to obtain early access, but as a “rescue option” when submitted data are not strong enough to justify full marketing authorization.

The Geographical Distribution of Leadership in Globalized Clinical Trials

Background Pharmaceutical trials are mainly initiated by sponsors and investigators in the United States, Western Europe and Japan. However, more and more patients are enrolled in Central and Eastern Europe, Latin America and Asia. The involvement of patients in new geographical settings raises questions about scientific and ethical integrity, especially when experience with those settings is lacking at the level of trial management. We therefore studied to what extent the geographical shift in patient enrolment is anticipated in the composition of trial management teams using the author nationalities on the primary outcome publication as an indicator of leadership. Methods and Findings We conducted a cohort-study among 1,445 registered trials in www.clinicaltrials.gov that could be matched with a primary outcome publication using clinical trial registry numbers listed in publications. The name of the sponsor and the enrolment countries were extracted from all registrations. The author-addresses of all authors were extracted from the publications. We searched the author-address of all publications to determine whether enrolment countries and sponsors listed on registrations also appeared on a matched publication. Of all sponsors, 80.1% were listed with an author-address on the publication. Of all enrolment countries, 50.3% appeared with an author-address on the publication. The listing of enrolment countries was especially low for industry-funded trials (39.9%) as compared to government (90.4%) and not-for-profit funding (93.7%). We found that listing of enrolment countries in industry-funded trials was higher for traditional research locations such as the United States (98.2%) and Japan (72.0%) as compared to nontraditional research locations such as Poland (27.3%) and Mexico (14.1%). Conclusions Despite patient enrolment efforts, the involvement of researchers from nontraditional locations in trial management as measured by their contribution to manuscript writing is modest. This division of labor has significant implications for the scientific and ethical integrity of global clinical research.

The Importance of Short-Term Off-Target Effects in Estimating the Long-Term Renal and Cardiovascular Protection of Angiotensin Receptor Blockers

Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short‐term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes. The score was used to predict renal/cardiovascular risk at baseline and at month 6 in the ARB treatment arm of the Reduction of Endpoints in NIDDM (noninsulin‐dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan (RENAAL) trial. The net risk difference at these time points indicated the estimated long‐term renal/cardiovascular treatment effect. Predicted relative risk reductions (RRRs) based on multiple markers were close to observed RRRs for renal (RRRpredicted: 30.1% vs. RRRobserved: 21.8%; P = 0.44) and cardiovascular outcomes (RRRpredicted: 9.4% vs. RRRobserved: 9.2%; P = 0.98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long‐term renal/cardiovascular ARB effects are more accurate when considering short‐term changes in multiple risk markers, challenging the use of single markers to establish drug efficacy.

Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers

Background A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. Design We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. Methods We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. Results The PRE score predicted renal risk changes of −23% and −30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. Conclusions Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.

European infrastructure networks and regional innovation in science-based technologies

We analyse the innovative activity of European regions in the fields of biotechnology and semiconductor technology. We explain regional patenting levels from publication levels within each region and nearby regions to account for local knowledge spillovers. We extend this approach by including connectivity measures for each region in order to indicate their position in the pan-European networks of Internet backbone providers, airline routes and global banks. We hypothesise that a regions position in all these networks contributes to its innovation capability as these networks provide high-quality and relative cheap access to digital information (Internet), fellow researchers (airlines) and financial resources (banks). The results show that connectivity indeed supports a regions patenting level in science-based technologies. In particular, we found that connectivity through the Internet backbone and through global banks enhance innovative activity, while airline connectivity does not. A second conclusion holds that while local knowledge spillovers are found to be very strong for patenting in biotechnology, this effect is found to be absent in semiconductor patenting. This result indicates that the importance of geographical proximity in generating knowledge spillovers is highly technology-specific.

A prediction of the renal and cardiovascular efficacy of aliskiren in ALTITUDE using short-term changes in multiple risk markers

Introduction We recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted. Methods We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change. Results Based on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of −7.9% (95% CI −2.5 to −13.4) for the cardio-renal endpoint, a risk change of −5.1% (−1.2 to −9.0) for the CV endpoint and a non-significant risk change of −19.9% (−42.1 to +2.1) for the renal endpoint. Conclusions PRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.