countries where legislation to enforce registration is present, its remit is often limited to a sub-set of trials.[30,68]
With regards to enforcement, the commitment of the pharma- ceutical industry to clinicaltrialsregistration is important and the past development of a Joint Position of several pharmaceutical associations on the disclosure of clinical trial information via clinical trial registries and databases is laudable. However, the Joint Position needs revisiting on three important aspects. First, currently, it allows for registration after commencement of patient enrolment. This is in contradiction with policies on clinical trial registration by WHO and the International Committee of Medical Journal Editors (ICMJE).[1,2] Second, it allows trialists to withhold data specified by the WHO Minimum Trial Registration Data Set if they consider it sensitive. This, too, is in contradiction with policies on clinical trial registration by WHO and the ICMJE.[1,2] Third, the Joint Position mentions that ‘‘registration of clinicaltrials on any one of a number of free, publicly accessible, internet-based registries should achieve the intended objectives’’. To ensure the quality of registered trial data, the WHO ICTRP search portal only provides access to data from trials registered at registries that meet certain quality standards (excluding, for example, registries managed by for-profit agencies). To realize a single point of access to all clinical trial data conducted globally, it is important that the pharmaceutical associations include a commitment to registration in WHO approved registries in the next update of their Joint Position, as the ICMJE already has. Finally, enforcement of trial registration by the pharmaceutical industry would be further advanced if support for clinicaltrialsregistration and results reporting would not be limited to statements from the pharmaceutical associations, but if more individual pharmaceutical companies would subscribe to the AllTrials campaign, following the example of GlaxoSmith- Kline.
There is little research into timing of trial registration, and this study provides important information highlight- ing the extent of retrospective registration of published clinicaltrials. Our results differ from those of Huser and Cimino, who found that 60 % of clinicaltrials were reg- istered before participant enrolment. There are a num- ber of possible reasons for this. There are differences in the journals included; their study included only the five ICMJE founding journals with 2011 Impact Factors of ≥10.0 . These journals differ in a number of ways from the BMC series, including Impact Factor and threshold. Our methodology also differs to that used by Huser and Cimino. We applied strict criteria for classify- ing a study as retrospectively registered. Those regis- tered the day after enrolment of the first participant were counted as retrospective. This is based on similar criteria used by trial registries that add a ‘retrospectively registered ’ flag to trial registry records [personal com- munication with ISRCTN]. Husser and Cimino applied more generous criteria, allowing a 60-day grace period, to account for the 21-day grace period allowed by US law  and data quality assurance processes .
The trials evaluated a wide variety of outcome measures. Psychosocial outcomes, particularly those of psychiatric and psychological symptoms, were the most frequently evalu- ated. Physiological outcomes, particularly cardiovascular measures, and outcomes related to clinical events were also frequently assessed. Few clinicaltrials focused on cognitive and neuropsychological functions. Since hypertension and cardiovascular disorders rank as the two most studied con- ditions, it is not surprising that physiological outcomes were so prominently assessed. However, if psychiatric disorders and psychological factors are studied more, it is likely that the number of evaluations of psychosocial outcome mea- sures will continue to increase. There is also great diversity in the measures used to assess similar psychosocial con- structs, which often prevents comparisons across studies. Re- searchers would be well advised to attempt consensus on a core battery of outcome questionnaires that may be appro- priate for this type of research in specific patient populations. We assessed the quality of clinicaltrials on meditation published between 1956 and 2005. Overall, the methodolog- ical quality of most of the trials on meditation is poor, with significant threats to validity in every major category of qual- ity measured. This finding is not unique to the area of med- itation research, and the quality of reporting is a frequent problem in other areas of complementary and alternative
Nevertheless, interest in general practice and general practice research is growing , fuelled by the need to provide health care to an ageing and increasingly multi-morbid population while containing costs. In the last 10 years, the German federal government has run a few successful programmes to build up research cap- acity in general practice. However, these have not been sustained. Nevertheless, with respect to health services research or quality improvement studies in particular, their structural  and scientific outputs [39,41] have been remarkable. A recent publication of the German Advisory Council for the Assessment of Developments in the Health Care System points out the importance of strong primary care . The number of academic departments of general practice is slowly, but steadily increasing. Representation of GPs in decision-making and funding bodies is gradually improving: very recently, the German College of General Practitioners and Family Physi- cians was granted the right to propose candidates to the re- viewer boards of the German Research Foundation and one candidate (EHP) was elected.
Clinicaltrials are important for health professionals, re- searchers, patients, and governments because they pro- vide high quality evidence for clinical practice. However, for various reasons, the actual situation of clinicaltrials is less than satisfactory. Publication bias caused by se- lective reporting of trials with positive results while withholding trials with negative/neutral results has been documented [1-3]. It is estimated that only half of all controlled trials have been reported since the first ran- domized controlled trial (RCT) in 1948 . This will lead to biased decision-making in clinical practice, devel- opment of clinical practice guidelines, and resource allo- cation. Furthermore, patients participate in clinicaltrials as constituents of society, believing that they are con- tributing to medical knowledge for patients in the future. Hence, from an ethical perspective, trial results should be considered to be an important part of social property and given back to the public. Not reporting trial results will damage the trust between patients and investigators, as well as that between patients and research ethics re- view boards . Moreover, problems associated with how to promote patient enrollment in clinicaltrials and how to prevent possible intended modification of the original protocol after the start of a trial remain to be solved.
Although no effective therapy has been developed for COVID-19, various intervention measures have been adopted, including TCM, antiviral drugs, cell therapy, plasma therapy, behavioral intervention, and psychological intervention. In the retrieved studies, even with the administration of antiviral therapy, further interventions were still required. The antiviral drugs included azvudine, Ganovo/ritonavir, danoprevir, favi- piravir, ritonavir/ritonavir, baloxavir marboxil, remdesivir, oseltamivir, Arbidol, ritonavir, darunavir/cobicistat, and lopi- navir/ritonavir. These antiviral drugs are potentially effective for treating COVID-19. 6,19 A trial using favipiravir, an anti- in ﬂ uenza drug used to treat life-threatening RNA viral infections, 20 has been carried out (registration number chictr20000029600), and the results will soon be published.
For large organizations clinical QA should not be involved in the development and control of SOPs in the clinical and associated areas. Other mechanisms should be in place to incorporate new guidance text, new legislation and to implement corrective actions from audit trending and audit observations. QA may provide advice and consultancy. For smaller organizations, however, the QAU may be involved in the development of SOPs. The QAU should support SOP development to facilitate overall GCP and legal compliance without taking over the responsibility for actually writing or even approving the SOPs. The QAU should remain as independent as possible and act as reviewer for compliance issues. In cases where the owners of the processes are not able to write the clinical SOPs themselves, the QAU may help identifying competent contractors to develop the SOPs. In these cases the QAU may keep the role as SOP reviewer. The QAU may also be involved in the review process of other clinical documents such as protocols or clinical study reports. When this is done outside the audit programme, the role and responsibility of the QAU in the review process should be clearly defined, e.g. internal consistency, compliance issues. It is still not recommended that the QAU should formally approve operational documents (protocols, deviations or reports) as this would compromise their independence.
Clinical trial registration has improved transparency in clin- ical trial research by increasing access to information on clinicaltrials around the world. More than 20 000 clinicaltrials are now newly registered every year at 16 national and regional registries, and healthcare workers, researchers, patients and policymakers are increasingly bene ﬁ ting from the advantages offered by clinical trial registration. However, this study shows that trial registration has not developed equally in all parts of the world, and that good compliance with registration requires a coalescence of global and local measures that enforce and encourage registration. As local measures are not in place in most countries, compliance with registration remains a signi ﬁ - cant challenge that continues to undermine the potential bene ﬁ ts of clinical trial registration. Other important chal- lenges that remain include substandard quality of data in registered records of trials, inaccessibility of protocols, results and participant-level data, and the potential for improvement in registries ’ and the ICTRP ’ s searching, aggregating and linking functions. For most of these chal- lenges, effective solutions are available, but there is lack of widespread implementation. National and regional regis- tries around the world and the ICTRP have played a leading role in the implementation of such solutions in the past. It is important that they are supported to address the challenges that remain in the future, so that we can pro- gress further towards the goal of full accessibility to infor- mation on all clinicaltrials ’ methods and results.
Studies which have yielded ‘disappointing’ or ‘negative’ results are less likely to be presented at scientific meetings, reported in print, published promptly, in full reports, in jour- nals that are widely read, in English, and in more than one report; and they are less likely to be cited in reports of later studies . On average, these reporting biases will tend to lead to inferences that interventions are more effective than they are in fact. Journals can help to reduce these biases by requiring authors of reports of controlled trials to state the trial registration details. In addition, although only very basic information about a trial need be submitted to achieve registration, this process offers an opportunity to provide more details about studies. The Lancet, for example, has pioneered journal peer review and publication of trial protocols, undertaking to accelerate peer review of reports of such trials on completion , a process that will reduce result-dependent biases among reviewers. Current Controlled Trials will offer a similar service. One of the most important undertakings of Current Con- trolled Trials is to publish all trials judged by peer review to have been carried out correctly, irrespective of their results. This undertaking is particularly important in respect of reports of controlled trials that are ‘unexciting’, but nevertheless can contribute, however modestly, to the sum of knowledge relevant to a particular question. Authors of reports of such trials often find themselves sub- mitting to a succession of print journals, each of which requires submissions in a slightly different format, only to find that none of the journals is prepared to allocate their limited page space to the studies concerned. Not surpris- ingly, authors may stop trying to publish these studies. The undertaking made by Current Controlled Trials will help to reduce these unproductive efforts. This will be of particu- lar help to pharmaceutical companies, which often under- take routine or repetitive trials to fulfil regulatory requirements. Several companies have recently committed to publish results from all their trials by endorsing a set of
6. Additional characteristics of trials
To understand more about additional characteristics of the trials in our data set and to shed light on what types of trials were registered between 2004 and 2013, we also collected information on trials ’ study phase and target sample size in addition to the information that we col- lected on trials ’ countries of recruitment, and calculated aggregates for the period 2005 –2013 (we chose this period because trials from before 2005 were only regis- tered sporadically). Collecting information on other characteristics of interest was not possible for our data set because most data ﬁelds in the ICTRP data set do not consist of standardised categories; these are free-text. Several studies have been conducted on samples of the ICTRP data set in the past that have shed light on trials ’ characteristics in terms of primary sponsor type, inter- vention type, study design, disease or other health problem under study and age and sex of study partici- pants. 15 16 In addition, some individual registries that provide data to the ICTRP do use standardised categor- ies and provide opportunity for automated analyses of such characteristics. 17 18
S EKINE , I., N OKIHARA , H., Y AMAMOTO , N., K UNITOH , H., O HE , Y., S AIJO , N. and T AMURA , T. Problems with Registration-Directed ClinicalTrials for Lung Cancer in Japan. Tohoku J. Exp. Med., 2007, 213 (1), 17-23 ── New anticancer agents against lung cancer are needed because efficacy of chemotherapy is limited. The long time required, low quality, and considerable costs of registration-directed clinicaltrials in Japan (“Chiken”) have been pointed out. The quality of 24 phase I and 41 phase II trials of an anticancer drug for lung cancer were analyzed according to the approval year of the drug. The human resources and infrastructure to support oncology clinical practice and clinicaltrials were compared between Japan and the USA. A maximum tolerated dose was not defined in any of seven phase I trials before 1989, and was determined in two of six trials between 1989 and 1996 and in seven of 10 trials thereafter. Before 1989, 29 (20%) of 142 patients registered in two trials were ineligible, and the number of ineligible patients was not reported in the five trials. Sample size calculations were not performed in any of seven phase II trials before 1989 and were performed in only four of 10 trials between 1989 and 1996 and in all 23 tri- als conducted thereafter. The shortage of human resources, including medical oncologists, oncology nurse practitioners and clinical research coordinators, is serious and acute. The infrastructure to support clinicaltrials also remains insufficient in Japan. In conclusion, registration-directed clinicaltrials of anticancer agents have advanced significantly during last three decades but remain unsatisfactory. The development of infrastructure and human resources is an urgent task to ensure high-qualityclinicaltrials without unnecessary delays. ──── clinicaltrials; medical oncologists; nurse practitioners; lung cancer; anticancer agents
We extracted the study start date from the trial registry record. Some manuscripts may also have included details of trial start dates. We did not check if registry/manu- script dates matched. It is possible that some start dates recorded in trial registries were inaccurate, i.e., that the trial started later than reported. This may mean that we had incorrectly classified some trials as retrospectively registered when in fact they were prospectively registered. However, we assert that it is the responsibility of the re- search team to ensure that their trial registry entry is up to date and correct. We would recommend that in future studies of this type, both registry and manuscript recorded start dates are extracted, checked, and any inconsistencies resolved with the trial corresponding author.
One of the benefits of setting tolerance limits early at the time of risk identification is to allow detection of the deviations from the tolerance range. This would be conducive to rectify or modify the processes to benefit the scope of the study. The other benefit of introducing quality tolerance limits directs the oversight and the monitoring on the parameters that matter to the study endpoints including safety endpoints and help to design more focused management procedures (e.g. data monitoring plan) The following are examples of areas for which variation or tolerance limits could be established: a) Trial data
idea that the capital small businesses are seeking greatly outweighs what’s being made available to them. There have been governmental efforts to address this lack of credit, but there is still much work to be done. The bipartisan Small Business Lending Fund provided more than $4 billion to 332 community banks and community development loan funds in hopes that they would lend to small businesses. Likewise, the Small Business Administration has backed record numbers of loans (worth more than $30 billion in 2011). However, this increase has not fully made up for a decrease in non-SBA lending, and likely displaced at least some lending that would have happened without the SBA. 13 As a result of this
In next section we state the sample size problem and introduce the notation. The objective function, which is the expected net benefit of conducting the trial, is also introduced in next section. In “Results and Discussion” the regulatory authority as the third decision maker is introduced. We present two algorithms for the sample size determination problem for both the cases with a frequentist authority and with a Bayesian authority.
tests than the central reading method, this combined precision- and accuracy-based method achieved three main benefits. Firstly, it had a strong agreement with the rigid criterion-based approach (84 % agreement between methods). Secondly, it had a relatively high acceptance rate (48 %) without compromising narrow measurement CV compared with the criterion method (Table 2). Lastly, it had a low CV of CPET measurements; ~50 % lower CV than that compared with central precision- based QC approaches that form the basis of guideline recommendations. This latter point is of considerable importance for the design and conduct of multicenter clinicaltrials with CPET measurement outcomes. By ap- plying a z-score-based BioQC method across all centers,
program are the most important research program based on clinical practice in China. Up to now, these projects are respectively the largest clinical trial involved in the spe- cific physiological effects of acupoints, and one of the largest randomized controlled trials addressing the effec- tiveness of acupuncture treatment, and the best acupunc- ture treatment method for Bell's palsy Monitoring work in these multi-centre large sample acupuncture clin- ical trials are as serious and scientific as pharmaceutical clinical test, which is essential for data accuracy and proper evaluation of study objectives in clinicaltrials. Monitors should look up all of the source documents and source data, and assess whether the coordinators carry out these researches under the requirement of GCP with an objective, rigorous, careful, and scientific attitude. Monitoring provides clinicians and assessors with the opportunity to discover problems early enough so that they can be resolved. If data quality drops at the end of the study, the results will have little value beyond providing a cautionary example for future studies. Through the review once a month at least, we can assist with corrective action as needed. Points for attention during the monitoring processes:
These five stages reflect the life cycle of a trial. There- fore, developing a management plan is key for effective trial management. It is essential that a project manage- ment plan include details of the arrangements for devel- oping and monitoring all aspects of a trial, including servicing the steering committee and the independent data monitoring committee but, most important, how the day-to-day running of the trial will be planned and mana- ged. The development of a robust statistical analysis plan supported with sufficient resources and time to conclude the trial efficiently is a crucial element of this plan. The project plan should also describe who will be responsible for essential activities, such as staff recruitment, staff management, communication with the collaborative group, recruitment monitoring, data management, and raising project awareness (promotion), through to safety reporting, analysis, report writing and dissemination of the trial results. The project plan should describe what the trialists are trying to achieve, how resources will be used and within what time frame. It should also include how the planned processes will be monitored to ensure that the project is being delivered as planned. The plan can then be reviewed and refined, if necessary, as the trial progresses. Clear processes, both inside and outside the office, need to be established and documented. The abil- ity to constantly review and adapt the project plan is cru- cial as a trial can be hit side-on by events outside its control, e.g., emerging evidence, war leading to lack of recruitment and natural disasters. Sensible risk assess- ment, tailored quality assurance management systems and real-time monitoring are essential if a trial is to opti- mise its potential and provide reliable evidence.