The health of European medical research. Attempts are under way to update EU regulations, with the aim of harmonizing clinical research across the continent

The 2001 EU Clinical Trials Directive aimed to harmonize the regulation of medical research, but achieved the opposite. Various attempts are underway to update the directive to make it easier to safely conduct medical research in Europe.Medical research, similarly to finance and business, works best with light regulation; however, protecting patients during clinical trials, and afterwards when treatments have been approved, requires regulation. Attempts to square this circle and the challenge of testing sophisticated drugs and therapies have resulted in increasingly strict regulation of clinical research, particularly in Europe''s leading medical research powers Germany, France, the Netherlands and the UK. There is growing concern among these countries with established pharmaceutical industries that clinical trials are increasingly hard to conduct; in fact, the number of applications has declined significantly during the past decade (Cressy, 2010).There is growing concern among these countries with established pharmaceutical industries that clinical trials are increasingly hard to conduct…Meanwhile, the number of applications for clinical trials has increased in the USA, Canada and some southern European countries, notably Italy and Spain, where the regulatory touch has been lighter and combined, in some cases, with financial incentives, according to Paul Stewart, Dean of Medicine at the University of Birmingham in the UK. There is a danger therefore that Europe''s leading research nations could lose their competitive edge in medical research at a time when radical new treatments are on the horizon. “Europe''s weight in clinical research is diminishing,” commented Markus Hartmann, senior consultant at European Consulting & Contracting in Oncology (Saarbrücken, Germany), which provides advice about medical regulatory affairs. The risk of falling behind extends beyond drug-based therapies to surgery and medical devices, Hartmann added. He explained that the European Commission now considers medical devices and drugs as ‘products'' that can be sold in the internal market, and therefore require a common and harmonized regulatory framework.Hartmann, along with other researchers, traces the recent decline in European clinical trial activity back to the European Union (EU)''s Clinical Trials Directive (CTD) 2001/20, which was supposed to provide a common framework for unifying regulation within the EU by 2020. “The Clinical Trials Directive is contributing to this effect, but is not the only factor,” said Hartmann.The root cause of the problem might be growing aversity to risk—which puts more emphasis on patient protection even when this is not necessary—but the EU directive has certainly fuelled this mood. “That initial EU Directive was actually quite a sensible document, but what was crazy was the legal creep that followed,” said Stewart. “What the lawyers did was legislate for the worst possible scenario, instead of seeing the directive as a facilitating document enabling people to go and do research.”The directive actually had the opposite effect from the original intent: it led to even more regulatory fragmentation within the EU. This was first identified in a 2006 report, co-authored by Hartmann, which cited significant divergence in the national implementations of the EU directive (Hartmann & Hartmann-Vareilles, 2006). France was found to have the strictest regime, in which all trials including those involving cosmetics were rigorously supervised.The directive actually had the opposite effect from the original intent: it led to even more regulatory fragmentation within the EUThis divergence still exists. “Basically, the lack of harmonisation has not been resolved, as the Clinical Trials Directive has been transposed into national legislation in the form of laws, ordinances and rules of implementation that still differ in so many procedural and technical aspects,” said Hartmann.Moreover, although the 2001 directive underlined maintaining current levels of patient protection, Hartmann argued that it has done little if anything to improve safety. “Do not forget the TeGenero disaster with compound TGN1412, tested in spring 2006 in a Northern London hospital,” he said. “This was Europe''s largest clinical research catastrophe so far and happened in the UK, after the UK switched from a very liberal trial notification system, where phase I trials with healthy volunteers were even exempted from notification or authorisation, to the provisions laid down by the Clinical Trials Directive.”These problems have now been acknowledged by both national governments and the EU itself, according to Liselotte Højgaard, chair of the Standing Committee of the European Medical Research Councils, and a medical imaging specialist at the University of Copenhagen in Denmark. “We have had very many meetings in Brussels about the issue […] and in the last year the EU has become convinced it is a problem,” she said. As a result the directive is going to be redrafted well before it runs its full 20-year course. “We have been invited to help them draft a new directive,” said Højgaard. “That is a major achievement.”The aim is to learn from previous mistakes and frame the new document to encourage harmonization and a reduction in bureaucracy and paperwork. “We must make it easier to implement in each member state,” commented Højgaard, who added that the approval process also needs to be streamlined so that clinical trial teams do not have to repeat the same steps at different stages of the approvals process. “One of the things we are thinking about here in Denmark is whether we can make a one-stop-shop approvals process so you don''t have to go in and send an application to the medicinal agency, and also to the ethical committee, and also to clinicaltrials.gov,” said Højgaard. She hopes this new structure will be in place by the time Denmark holds the EU presidency in early 2012, and will encourage the rest of Europe to adopt a similar approach.The aim is to learn from previous mistakes and frame the new document to encourage harmonization and a reduction in bureaucracy and paperworkHartmann also acknowledges progress on the harmonization front. He cited the Voluntary Harmonisation Procedure (VHP), which was introduced in early 2009 by a network of national authorities, the Clinical Trials Facilitation Group (CTFG). It was set up precisely to coordinate implementation of the 2001/20 directive across EU member states, with little success at first. Now, the VHP allows applicants to submit protocols for trials to be conducted in many EU countries to the respective authorities, which agree on an assessment. “Then in a subsequent step, the applicant can submit the protocol to the national authorities for authorisation,” said Hartmann. “The VHP pilot aims to prevent divergent outcomes in the trial authorisation process, for example when a protocol approved in one country is blocked in another country.”These developments could eventually lead to a Europe-wide agency dedicated to clinical research regulation, along the same lines as the European Research Council for fundamental research, which Højgaard described as a great success. Such an agency would organize trials across the whole continent through a single streamlined approvals process, thereby covering a population of 500 million people.Attempts to amend the EU 2001 directive have also been welcomed by big funding bodies such as the Wellcome Trust in the UK, a charitable foundation that funds medical and clinical research globally. “We recently issued a response to a public consultation paper from the European Commission, Assessment Of The Functioning Of The “Clinical Trials Directive” 2001/20/EC, in which we highlighted areas where the Directive could be streamlined to reduce bureaucracy, while maintaining an appropriate regulatory framework,” said David Lynn, Head of Strategic Planning and Policy at the Wellcome Trust. “We would like to see a more risk-based approach to regulation of clinical trials, a rationalisation of the multiple layers of bureaucracy and the approvals process.”Bureaucracy notwithstanding, a fundamental problem is finding the right balance between risks associated with different drugs or therapies. The 2001 directive has instead led to a one-size-fits-all approach, according to Stewart. “Part of the work we''ve been doing at the level of the UK Clinical Research Consortium is to look at risk–benefit analysis, so that you have a lower level of regulation on some things and higher on others that are unproven.” If, for example, an existing drug turns out to be effective against a disease for which it was not originally developed, it would not be necessary to conduct thorough safety trials. This was the case with aspirin, initially developed as a pain killer over a century ago, which also protects against both vascular disease and bowel cancer (ATT Collaboration, 2009; Din et al, 2010). During these trials, safety was still an issue as the drug was being used in a different context, but, even so, it was clear that acute side effects were highly unlikely.Bureaucracy notwithstanding, a fundamental problem is finding the right balance between risks associated with different drugs or therapiesWhile medical regulations in Europe err on the side of safety, they do little to regulate and harmonise the reporting of results after trials have occurred. The results from many clinical trials are never published as they fall victim to reporting bias for various reasons, notably because the pharmaceutical companies providing funding have an interest in promoting results favourable to their products and suppressing negative findings. A recent study by the Institute for Quality and Efficiency in Health Care (IQWiG) in Cologne, Germany, confirmed widespread publication bias in the past, which harmed patients through under-reporting of side effects (McGauran et al, 2010).“The most prominent example of harm caused by publication bias is probably the case of Class I anti-arrhythmic drugs,” said Beate Wieseler, deputy head of IQWiG''s Drug Assessment Department. In this 1980 trial, 9 of 49 patients with suspected acute myocardial infarction who were treated with a class I anti-arrhythmic drug (lorcainide) died, compared with only one patient in the placebo group, and yet the investigators ludicrously dismissed this as chance (Cowley et al, 1993). The results of the trial were not published until 1993 and, although the development of lorcainide was discontinued for commercial reasons, the investigators concluded that as a result of this delay in publication, the continuing use of class I drugs had led to several unnecessary deaths.By the same token, ineffective drugs have sometimes gained market approval after over-reporting of their benefits, in some cases ignoring other, more negative, studies. Wieseler and colleagues found that studies reporting positive results for a particular drug were published in higher impact journals and were more likely to be picked up by other publications and the mass media.Many cases of reporting bias, especially involving suppression of negative results, occurred 10 or more years ago. According to Stewart the situation has improved, although he concedes that, almost inevitably, journals will be drawn towards positive results given the increasing competition for readers and advertisers. “Whether publication bias goes on to the same extent now is debatable,” said Stewart, pointing out that clinical trials now have to be registered in Europe and the USA so that the data is public, even if it is not published in a journal.There will inevitably be some risk of bias in research funded by pharmaceutical companies, which, after all, are in the business to make money. It is therefore important to support ‘investigator-driven'' trials that are independent of any company, and it is here that the Wellcome Trust has an important role. “The Wellcome Trust supports the proposal for Investigator Driven Clinical Trials as joint collaborations across Europe,” said Lynn. “We fund academic clinical trials, which are usually independent of drug company interests.”Independent money for academic clinical trials has indeed been more crucial during the past few years, since the EU 2001/20 directive tends to favour research funded by drug companies with the money and resources to overcome the increasingly high bureaucratic hurdles. Lynn commented that universities had not been well served by recent legislation. “Academic institutions are less-well resourced and equipped than commercial sponsors to deal with the bureaucratic burden imposed by the Directive,” he said.In some cases these burdens have caused even young scientists to give up on promising research because they cannot stomach the paperwork involved…In some cases these burdens have caused even young scientists to give up on promising research because they cannot stomach the paperwork involved, according to Højgaard. “For the first time in my life as a boss, I had the experience when I came in to a morning conference and asked one of the young consultants ‘shouldn''t we do a clinical study on this'' and he said ‘no I simply haven''t got the energy for all this paper workload''.” This experience spurred her to lobby for change. Critics such as Højgaard and others therefore hope that the redrafting of the amendment and the ensuing changes in national legislation will liberate European medical research from the regulatory shackles that have held it back.     

Proposals to enhance the quality of observational cohort studies

For herbal medicinal products the methodology of observational cohort studies (observational studies, drug monitoring studies, Anwendungsbeobachtung) represents a useful addition to clinical trials. The key objectives are the documentation of efficacy in particular under conditions of everyday medical practice in authentic patients and the documentation of the safety profile. Supplementary to earlier activities, members of the "Clinical Trials of Herbal Medicinal Products" Working Party of the German Society for Phytotherapy have therefore again addressed the issue of observational cohort studies for to enhance the informative value and importance of this clinical research methodology. Recommendations were developed on quality aspects, methodological approaches of observation parameters, and for the reporting of the study's results. Properly planned and conducted observational cohort studies may contribute to the documentation and proof of well-established medicinal use according the EU Directive 2001/83/EC.     

National and European perspectives on climate change sensitivity of the habitats directive characteristic plant species

The main goal of the Habitats Directive, a key document for European conservation, is to maintain a ‘favourable’ conservation status of selected species and habitats. In the face of near-future climatic change this goal may become difficult to achieve. Here, we evaluate the sensitivity to climate change of 84 plant species that characterise the Danish habitat types included in the Habitats Directive. A fuzzy bioclimatic envelope model, linking European and Northwest African species’ distribution data with climate, was used to predict climatically suitable areas for these species in year 2100 under two-climate change scenarios. Climate sensitivity was evaluated at both Danish and European scales to provide an explicit European perspective on the impacts predicted for Denmark. In all 69–99% of the species were predicted to become negatively affected by climate change at either scale. Application of international Red List criteria showed that 43–55% and 17–69% would become vulnerable in Denmark and Europe, respectively. Northwest African atlas data were used to improve the ecological accuracy of the future predictions. For comparison, using only European data added 0–7% to these numbers. No species were predicted to become extinct in Europe, but 4–7% could be lost from Denmark. Some species were predicted to become positively affected in Denmark, but negatively affected in Europe. In addition to nationally endangered species, this group would be an important focus for a Danish conservation strategy. A geographically differentiated Danish conservation strategy is suggested as the eastern part of Denmark was predicted to be more negatively affected than the western part. No differences in the sensitivity of the Habitats Directive habitats were found. We conclude that the conservation strategy of the Habitats Directive needs to integrate the expected shifts in species’ distributions due to climate change.     

The quality of registration of clinical trials

Background

Lack of transparency in clinical trial conduct, publication bias and selective reporting bias are still important problems in medical research. Through clinical trials registration, it should be possible to take steps towards resolving some of these problems. However, previous evaluations of registered records of clinical trials have shown that registered information is often incomplete and non-meaningful. If these studies are accurate, this negates the possible benefits of registration of clinical trials.

Methods and Findings

A 5% sample of records of clinical trials that were registered between 17 June 2008 and 17 June 2009 was taken from the International Clinical Trials Registry Platform (ICTRP) database and assessed for the presence of contact information, the presence of intervention specifics in drug trials and the quality of primary and secondary outcome reporting. 731 records were included. More than half of the records were registered after recruitment of the first participant. The name of a contact person was available in 94.4% of records from non-industry funded trials and 53.7% of records from industry funded trials. Either an email address or a phone number was present in 76.5% of non-industry funded trial records and in 56.5% of industry funded trial records. Although a drug name or company serial number was almost always provided, other drug intervention specifics were often omitted from registration. Of 3643 reported outcomes, 34.9% were specific measures with a meaningful time frame.

Conclusions

Clinical trials registration has the potential to contribute substantially to improving clinical trial transparency and reducing publication bias and selective reporting. These potential benefits are currently undermined by deficiencies in the provision of information in key areas of registered records.     

Differential Globalization of Industry- and Non-Industry–Sponsored Clinical Trials

Background

Mapping the international landscape of clinical trials may inform global health research governance, but no large-scale data are available. Industry or non-industry sponsorship may have a major influence in this mapping. We aimed to map the global landscape of industry- and non-industry–sponsored clinical trials and its evolution over time.

Methods

We analyzed clinical trials initiated between 2006 and 2013 and registered in the WHO International Clinical Trials Registry Platform (ICTRP). We mapped single-country and international trials by World Bank''s income groups and by sponsorship (industry- vs. non- industry), including its evolution over time from 2006 to 2012. We identified clusters of countries that collaborated significantly more than expected in industry- and non-industry–sponsored international trials.

Results

119,679 clinical trials conducted in 177 countries were analysed. The median number of trials per million inhabitants in high-income countries was 100 times that in low-income countries (116.0 vs. 1.1). Industry sponsors were involved in three times more trials per million inhabitants than non-industry sponsors in high-income countries (75.0 vs. 24.5) and in ten times fewer trials in low- income countries (0.08 vs. 1.08). Among industry- and non-industry–sponsored trials, 30.3% and 3.2% were international, respectively. In the industry-sponsored network of collaboration, Eastern European and South American countries collaborated more than expected; in the non-industry–sponsored network, collaboration among Scandinavian countries was overrepresented. Industry-sponsored international trials became more inter-continental with time between 2006 and 2012 (from 54.8% to 67.3%) as compared with non-industry–sponsored trials (from 42.4% to 37.2%).

Conclusions

Based on trials registered in the WHO ICTRP we documented a substantial gap between the globalization of industry- and non-industry–sponsored clinical research. Only 3% of academic trials but 30% of industry trials are international. The latter appeared to be conducted in preferentially selected countries.     

临床试验进展：临床数据与实验室质量管理规范

将临床研究数据用于临床日常规范及健康相关决策的制定对于改善全球医疗保健至关重要。汤森路透Cortellis 临床试验情报对临床试验数据的应用价值及各国临床实验室质量管理规范的实施情况进行了介绍,提供描绘临床图景关键元素和当前趋势的专家分析,从而指导临床开发决策。     

Developing a classifier for the Habitats Directive grassland types in Denmark using species lists for prediction

Abstract. This paper describes the use of supervised methods for the classification of vegetation. The difference between supervised classification and clustering is outlined, with reference to their current use in vegetation science. In the paper we describe the classification of Danish grasslands according to the Habitats Directive of the European Union, and demonstrate how a supervised classification can be used to achieve a standardized and statistical interpretation within a local flora. We thereby offer a statistical solution to the legal problem of protection of certain selected habitat types. The Habitats Directive protects three types of Danish grassland habitats, whereas two remaining types fall outside protection. A classification model is developed, using available Danish grassland data, for the discrimination of these five types based on their species composition. This new Habitats Directive classification is compared to a previously published unsupervised classification of Danish grassland vegetation. An indicator species analysis is used to find significant indicator species for the three protected habitat types in Denmark, and these are compared to the characteristic species mentioned in the interpretation manual of the Habitats Directive. Eventually, we discuss the pros and cons of supervised and unsupervised classification and conclude that supervised methods deserve more attention in vegetation science.     

The Role of Systematic Reviews in Pharmacovigilance Planning and Clinical Trials Authorisation Application: Example from the SLEEPS Trial

Background

Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug.

Methodology/Principal Findings

The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions.

Conclusions/Significance

No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.     

Danish A.I. field data with sexed semen

The objective of this study was to compare conception rates, non-return rates and sex ratios of sexed and conventional semen from the same sires in commercial dairy herds in Denmark. The semen was produced from three bulls from each of the three major dairy breeds in Denmark: Holstein, Jersey and Danish Red Dairy Breed (nine bulls total), in order to answer questions on breeds differences in field results. AI was performed by trained technicians using a minimum of 150 doses of sorted sperm and 50 control doses from each bull. During the trial, a total of 2087 doses were used in 63 herds.The trial showed that the conception rate using sorted semen was 5% points lower than with conventional doses for Danish Reds, 7% points for Jerseys, and 12% points for Holsteins. Translating this into non-return rate revealed differences of 10-20% points among bulls. These differences are thought to be a good indicator of what to expect from commercial use of sexed semen.The sex ratios varied from 89% to 93% female calves among breeds, which on average is consistent with the theoretical average sex ratio of 93% females considering the low number of inseminations.     

The search for reference conditions for stream vegetation in northern Europe

1. The European Water Framework Directive provides a framework for improving the ecological quality of stream ecosystems, with deviation from reference used as a measure of ecological status.
2. Here we examine the possibility of using less impacted stream sites from Latvia, Lithuania and Poland to establish a Danish reference network for macrophyte assemblages, and as a guiding image for identification of possible references sites within Denmark. Both approaches were evaluated using historical Danish records.
3. Four different macrophyte assemblages were identified for mid-sized streams in the Central and Eastern Lowland ecoregions. Macrophyte assemblages could not be delineated using physical stream site characteristics; however a gradual change in assemblage composition was attributed to differences in alkalinity and human impact.
4. Assemblages of contemporary vegetation in Denmark were quite similar to those found in Polish, Latvian and Lithuanian streams (26–35%). However, more importantly, from species-based predictions we noted higher similarity, particularly with Latvian and Lithuanian streams, before intensive land use commenced in Denmark ( c. 1900). These results show that stream sites from these three countries can be considered in a Danish reference network.
5. Two of the four macrophyte assemblages comprised species such as Fontinalis antipyretica, Myriophyllum spicatum , Nuphar lutea , Potamogeton alpinus and P. perfoliatus that have a very scattered occurrence in the contemporary vegetation in Denmark. These groups were closely associated with the predictions from historic records, thereby lending support the conjecture that these assemblages could be part of the guiding image for the identification of potential reference sites within Denmark.     

The effect of the EU Tissues and Cells Directive on bone banking in Denmark: a case study

As a result of the EU Tissues and Cells Directive (2004/23/EC), therapeutic tissue banking is currently being restructured throughout Europe. The stated objectives are to enhance a safe and stable supply of bone and tissue in Europe and to facilitate internal exchange. We conducted an interview study to explore the effect of the Directive on Danish bone banks in terms of (1) organizational restructuring, (2) supply and range of exchange, (3) economic costs. We found that the Directive stimulated extensive re-organization of bone banks with a substantial adjoining workload; that it is doubtful whether it will increase supply and range of exchange; and that the transposition of the Directive is associated with considerable extra cost. Additionally, we found that elements in the documentation of safety were fabricated by surgeons to avoid what was seen as unnecessary questioning of potential donors.     

Selected highlights from the 50th Annual Scientific Session of the American College of Cardiology, Orlando, USA, 18-21 March 2001

The recent scientific session of the American College of Cardiology (ACC), held in Orlando, provided a forum for ongoing cardiovascular clinical trials from around the world. The high point was clearly the first ever release of results from the CURE study. The Late-Breaking Clinical Trials sessions also featured results and interim data from other trials such as MIRACLE, CAPRICORN, SVG WRIST, RITZ 2, SoS and PRINCE. New applications for data from the OPUS-TIMI16 trial were discussed and promising results from initial studies into the experimental drug ALT-711 showed the way for further studies.     

Do we want more cancer patients on clinical trials If so, what are the barriers to greater accrual

It is often stated that only a small proportion of adult cancer patients participate in clinical trials. This is said to be a bad thing, with calls for more trials to include more patients. Here I argue that whether or not greater accrual to clinical trials would be a good thing depends on the trials we conduct. The vast majority of clinical trials in cancer are currently early phase trials, and most do not lead to further studies even if they have encouraging results. The key metric is thus not the number of patients on clinical trials, but the number on the sort of large, randomized, Phase III trials that can be used as a basis for clinical decisions. I also address two important barriers to greater clinical trial participation. The first barrier is financial: clinical research has long been the poor cousin of basic research, with perhaps no more than a nickel in the cancer research dollar going to clinical research. The second barrier is regulatory: clinical research has become so overburdened by regulation that it takes years to initiate a trial, and dedicated staff just to deal with the paperwork once the trial starts. This not only adds significantly to the costs of clinical research, but scares many young investigators away. It has been estimated that nearly half of all US-sponsored trials are being conducted abroad, and it is plausible that excessive regulation is at least partly responsible. That statistic should serve as a wake-up call to the US clinical research community to implement the recommendations of the now decade-old report of National Cancer Institute Clinical Trials Program Review Group, which largely center around simplifying trials and streamlining trial procedures.     

间充质干细胞基础研究与临床转化的中美比较

目的：从基础研究、专利申请、临床试验角度对比分析中美间充质干细胞领域发展现状和趋势,了解中美间充质干细胞领域研究的主要特征,为中国间充质干细胞领域的发展提供建议。方法：检索SCI论文数据、DII专利数据及Clinical Trials临床试验数据及新药审批情况,利用Excel、DDA工具对检索结果进行定量分析和讨论。结果：中国在间充质干细胞基础研究、专利申请及临床试验方面虽起步较晚,但近年来发展迅速,论文、专利和临床试验数量快速增长,2014年起发表论文数量及2016年申请专利数量均超过美国,临床试验注册已达200余项;在骨质疏松、脊髓损伤等研究领域,内分泌系统疾病、自体免疫疾病等临床试验方面形成一定优势,已具备坚实的团队与技术基础。但我国间充质干细胞研究仍面临激烈的竞争,存在进步与发展空间。结论：我国间充质干细胞研究应发挥已有优势,加强战略性布局;重视发展以企业为主导的新药开发路径;做精做细以增强国际竞争力与影响力;加大资金投入和产业政策的支持;健全监管机制及评价体系,抓住机遇的同时积极迎接挑战。     

Differences in Investigator-Initiated Trials between Japan and Other Countries: Analyses of Clinical Trials Sponsored by Academia and Government in the ClinicalTrials.gov Registry and in the Three Japanese Registries

Background

Following the amendment of the Pharmaceutical Affairs Law in Japan in 2003 researchers were permitted to begin investigator-initiated trials (IITs). In subsequent years, however, the number of IITs remained low. In other countries in Asia as well as in Europe, North America, and South Africa, the number of IITs has increased over the past decade. The differences in the characteristics of IITs between Japan and other countries are unknown. Some studies have analyzed the characteristics of all clinical trials according to registry databases, but there has been less research focusing on IITs.

Aims

The purpose of this study is to analyze the characteristics of IITs in the ClinicalTrials.gov registry and in the three Japanese registries, to identify differences in IITs between Japan and other countries.

Methods

Using Thomson Reuters Pharma™, trials sponsored by academia and government as IITs in 2010 and registered in ClinicalTrials.gov were identified. IITs from 2004 to 2012 in Japan were identified in the three Japanese registries: the University Hospital Medical Information Network Clinical Trials Registry, the Japan Pharmaceutical Information Center Clinical Trials Information, and the Japan Medical Association Center for Clinical Trials, Clinical Trials Registry. Characterization was made of the trial purposes, phases, participants, masking, arms, design, controls, and other data.

Results

New and revised IITs registered in ClinicalTrials.gov during 2010 averaged about 40% of all sponsor-identified trials. IITs were nearly all early-phase studies with small numbers of participants. A total of 56 Japanese IITs were found over a period of 8 years, and these were also almost nearly all early-phase studies with small numbers of participants.

Conclusion

There appear to be no great differences between Japan and other countries in terms of characteristics of IITs. These results should prompt a new review of the IIT environment in Japan.