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Registration of trials in children: update of current international initiatives
  1. Chiara Pandolfini1,
  2. Maurizio Bonati1,
  3. Helen M Sammons2
  1. 1
    Laboratory for Mother and Child Health, Department of Public Health, “Mario Negri” Pharmacological Research Institute, Milan, Italy
  2. 2
    Academic Division of Child Health, University of Nottingham, Derbyshire Children’s Hospital, Derby, UK
  1. Correspondence to Chiara Pandolfini, Laboratory for Mother and Child Health, Department of Public Health, “Mario Negri” Pharmacological Research Institute, Via Giuseppe La Masa 19, 20156 Milan, Italy; pandolfini{at}marionegri.it

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The last few years have been characterised by an increasing awareness of the inadequacy of children’s therapeutic options and of science’s insufficient knowledge in this area.1 2 The well-documented, frequent use of off-label and unlicensed medications in the young,3 4 with the increased risks it carries,5 can be seen as an indicator of the still limited knowledge on paediatric drug therapies. This lack of data is generally due to the greater difficulties inherent (ethical, practical and economic) in carrying out clinical trials in children. In such a context, given the scant evidence available on the safety and efficacy of drug therapies, the use of drugs in children is often inappropriate and not rational.6

Reasons for registers

With the awareness of the inadequate situation came the need to study paediatric research more closely to identify which disease areas are being addressed and which therapeutic needs of children are being ignored. The systematic analysis of drug use (also in children)7 and the analysis of off-label and unlicensed drug use data can be useful to highlight areas in which therapeutic knowledge is lacking. However, in order to direct research towards areas that are not being covered, as opposed to areas that are well-defined or over-exposed to research, knowledge of ongoing and planned research is also necessary; thus the importance of trial registers. Registers are the means by which researchers and anyone working in the healthcare field can access data on research being carried out and use such data to orient their therapeutic choices, their work and their research plans. In order for registers to be useful, however, data on all trials must be reported, even if fear of competition may hinder participation.8 Trial registration is, in fact, fundamental, and it is so for numerous reasons related to aspects of research ranging from avoiding the waste of human and economic resources to avoiding the unethical involvement of patients in trials that are not needed or whose results may never become part of the public knowledge base.9 In general, registering trials would satisfy the right of those who participated as subjects to know that their effort has contributed to scientific knowledge, promote collaboration between researchers, assist the planning of new studies, avoid duplication of effort in carrying out trials on drugs on which knowledge already exists,10 facilitate patient access and recruitment into trials, and allow for proper prioritisation of research programmes.11 Furthermore, registering trials serves to prevent knowledge from being lost to the public record, since most trials become public only if (and when) the results are published. Oftentimes, studies that are stopped prematurely or with insignificant results remain unpublished12 13 and cannot contribute to healthcare decisions. This publication bias can lead to the concealment of risks related to the use of substances14 and to biased findings in systematic reviews and meta-analyses.15 16 17 18 In order to ensure that children receive the safest and most effective treatment, health professionals need the complete information.19

Registers are, therefore, not only databases of completed, planned or ongoing clinical research, but are also ethically relevant tools.12 Although their usefulness has been mentioned in the past,20 only in the last few years do they seem to have become a priority.

Recently, data from a European register21 on paediatric drug therapy trials were used to assess the paediatric research situation in Europe. The trial data were analysed22 and, although limited, were used to identify research’s priority areas as well as the areas omitted. In order to put the research efforts into context, the data were compared with published paediatric research and with documented childhood therapeutic needs at the European level.23 The results showed that both ongoing and published research scarcely addressed the diseases listed in the World Health Organization’s (WHO) European region’s top seven conditions by burden of disease for 0–14-year olds. The condition most commonly addressed by the research was that with lowest burden on the list: asthma. When compared to European children’s therapeutic needs, using the EMEA’s priority list for studies into off-patent paediatric medicinal products,24 the finding was similar. The published research only addressed the therapeutic needs of four of the 25 priority conditions (involving 22.5% of the trials) and the ongoing research addressed five (15.6%). Between the two, the conditions covered were: malignant diseases, asthma, sedation, pain, gastroesophageal reflux and tubulopathies.

In general, the researchers found that research’s main interests revolved around three main conditions, tumours, asthma and infections, which are already covered by abundant research compared to other acknowledged therapeutic priorities. In Europe, for now, children’s need for appropriate, effective medicines therefore seems to be neglected.

This use of a register’s data is a fitting example of how such data can be used to study research’s priorities, to identify the areas of need that are being left behind, and, more generally, to put ongoing research into context with available knowledge and provide policy makers with a tool for studying targeted interventions.

Scientific journal editors have recognised the importance of registering trials. The International Committee of Medical Journal Editors (ICMJE) has played a major role in trial registration among the scientific community with their decision25 not to publish trials that have not been registered at their inception, and many other medical journals that do not belong to the committee have adhered to this decision. The majority of scientists who carry out clinical trials also seems to generally support trial registration.26

EMEA regulations and EU database on clinical trials (EudraCT)

With the introduction in January 2007 of the new European legislation, EU Directive 2001/20/EC, referred to as the Paediatric Regulation,27 we should see an increase in the number of clinical trials performed in children in Europe. The legislation provides both a legislative framework to necessitate trials of medicines relevant to the childhood population and a financial incentive for companies to perform them, with a marketing authorisation extension. Similar legislative efforts within the USA have led to an increase in the numbers of trials in children.28

Part of this legislation includes the obligation to increase the availability of information on the medicinal products in the paediatric population. The information will comprise clinical trial protocol-related information and trial results covering trials of phases I, II, III and IV. This paediatric trial information will be collected and entered into a database, EudraCT (http://eudract.emea.europa.eu), and, following Article 41 of the Paediatric Regulation, which provides the legal basis for publication of information on paediatric clinical trials entered in this database, will be made accessible to the public. This information will be aimed at the public including lay persons, patients, families, health professionals and researchers as well as industry and the regulators. All trials with at least one investigator site in the EU and/or that are part of an agreed paediatric investigation plan (regardless of where they are conducted) will be included.

Specific guidance was laid out by the European Commission on 4 February 2009 on what information concerning paediatric clinical trials should be collected and what should be made public.29 The data fields are consistent with international initiatives that promote trial registration covering a predefined, minimum data set. The EudraCT database will represent a significant step for transparency in the development of drugs and their testing. The “legislative teeth” that the regulatory process gives the register, and its public nature, make it a large positive step forward.

In accordance with the Paediatric Regulation, an inventory of paediatric medicinal needs, based on the Paediatric Working Party (PEG) list, is being created. This list of paediatric needs (http://www.emea.europa.eu/htms/human/paediatrics/inventory.htm) concerns therapeutic areas and products identified as needing drug development or additional drug data. Another list, involving only off-patent medicines, identifies products with the highest need in children, and for which studies are required.24 This list will ensure that, under the Paediatric Regulation, funds will be directed towards areas of highest need.

The WHO portal

The WHO has also begun to focus on children’s medicines, and its involvement is welcome.30 Among its recent efforts is the creation of a list of essential medicines for children,31 based on a selection of priority paediatric conditions. The WHO also recently published a set of guidelines, entitled “Promoting safety of medicines for children”,32 aimed at raising awareness of medicine safety issues and providing guidance on effective systems for monitoring medicine safety. On more far-reaching terms the WHO launched an initiative called “Make medicines child size” (see http://www.who.int/childmedicines) in December 2007. The main goal of this programme is to raise awareness of, and address, the need for improved availability and access to safe and suitable child-specific medicines.

A large, important initiative that was set up by WHO is the International Clinical Trials Registry Platform (ICTRP; http://www.who.int/trialsearch). This platform was created following a call in 2004 for a network of international clinical trials registers, a single point of access and the unambiguous identification of trials. The primary objective is to facilitate the prospective registration of a minimum amount of information, defined by the ICMJE and the WHO,33 on all clinical trials, and the public accessibility of that information. It also advocates for the public availability of a minimal description of the results from clinical trials. The ICTRP is not itself a register, but is a search portal aimed to facilitate the searching of data provided by multiple registers. The registers that are currently contributing, and that have been accepted as data providers because they adhere to the WHO registry criteria (www.who.int/ictrp), are listed in table 1 along with their major characteristics. Since many trials registered in national registers are also registered in larger registers such as Clinicaltrials.gov or the ISRCTN, the WHO has implemented measures that will attempt to overcome the problem of duplicate records for the same trial. These are the use of a Universal Trial Reference Number (UTRN), specific criteria for WHO registries, and a system linking related records on the ICTRP Search Portal. Limiting trial registration to only a few, selected, multinational registers, as proposed by some authors, would decrease the problem of duplicate registration, but would undermine the significance and potential of national registers.34

Table 1

Registers currently contributing to the WHO’s International Clinical Trials Registry Platform (ICTRP)

In January 2009 the WHO launched its web-based portal “Clinical trials in children” (www.who.int/ictrp/child/en/index.html). The aim of the site is to improve awareness and make it easier to access accurate, up-to-date, understandable information relevant to the conduct of clinical trials in children. When searching for trials on the ICTRP a box can now be ticked that allows the search to be limited to include only clinical trials in children. The search filter has been designed to capture all trials that have children as participants. The information held on the Paediatric EudraCT database will be accessible via this portal in the future. The content of the site and the search filter will evolve over time in response to the feedback received from visitors to the site. Searching for paediatric trials can be difficult and having a central search portal dedicated to paediatrics will be a huge step forward.

Conclusions

It is evident, from the international initiatives described above, that research in children is becoming a priority worldwide and that the expectations of those involved in paediatric health are finally beginning to be met. An increase in paediatric research is expected given the recent Paediatric Regulation, and with the extensive use of registers on the part of researchers, regulators and the public, it is hoped that there will be more collaboration and less duplication of effort and waste of resources in carrying out unnecessary clinical trials. An important initiative such as that of the WHO portal, which will likely consolidate the effort made by all those who contribute to trial registers, will help to reduce duplication and waste of resources not only related to individual trials, but also to trial registers. Such an effort will, in the end and most importantly, contribute to improving children’s wellbeing.

REFERENCES

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Footnotes

  • Funding None.

  • Competing interests None.

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