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Youth Investment


Conducting a research study in a paediatric population requires an understanding of a number of unique considerations, with the biggest concern being the availability of sufficient patients. A thorough knowledge of current regional regulations can help address these challenges.

A few years have now passed since EU and US legislation intended to promote research of new and innovative drugs in paediatric populations. Both the US Pediatric Research Equity Act (PREA), introduced in 2003 and the European Medicinal Products for Paediatric Use regulation (EC 1901/2006) are aimed at ensuring paediatric populations would be included in the development plans of all new drugs. These requirements mean that the plans for paediatric studies must be taken into account in parallel to any adult plans, and should be submitted and approved early on in the development of medicines.

However, research conducted by a group of paediatric investigators shows that there remains a disparity between the proportion of research in adults and children compared to the disease burden of any given particular condition (1). The authors studied clinical trials implemented in the following conditions: asthma; migraine headaches; schizophrenia; depression; diarrhoeal illness; lower respiratory infection; malaria; bipolar disorder and HIV/AIDS. Despite 60 per cent of the disease burden of these conditions affecting children, it was found that only 12 per cent of the studies that were being performed were in a paediatric population.

The authors suggest that the geographical spread of disease, together with the funding from government or not-for-profit organisations, may partly explain the results. However, a survey may also suggest that companies are still coming to terms with the regulations and facing other barriers to complete studies (2).

Survey of Pharma and Biotech Companies

Pharma and biotech companies were surveyed to understand their current views and challenges in paediatric research. Appropriate R&D decision makers in targeted companies were identified and asked to complete an online questionnaire. Participants were asked a range of questions which focused on:
  • Their understanding of paediatric regulatory requirements in the US and Europe, and how these might be further improved
  • The impact that the paediatric regulations have had on their company and R&D resources
  • The main perceived barriers to implementation of paediatric research
  • Factors affecting their outsourcing decisions of paediatric development activities

Results

A total of 55 questionnaires from the surveyed companies were completed. Respondents were identified by pre-Results A total of 55 questionnaires from the surveyed companies were completed. Respondents were identified by prequestions as being decision makers in R&D spend in the company. The geographical distribution of the countries involved in the research and the size of the organisations represented in the survey are shown in Figure 1 and Table 1 (on page 62).

Understanding of Paediatric Regulations
While most had some, if not a complete, understanding of PREA regulations, 17 per cent admitted they had no understanding of PREA regulations and a further 10 per cent had never heard of PREA. A similar pattern emerged with the knowledge of European regulations and the requirement to submit a paediatric investigational plan (PIP), with 21 per cent admitting they had no understanding and a further six per cent not having heard of PIPs.

Impact of Regulations on R&D Resources
The requirement to prepare and perform paediatric studies has generally led to an increase in R&D budgets, with 50 per cent of responders stating that their budgets had increased to accommodate the PREA/PIP commitments. Surprisingly, 10 per cent felt that their investment into new products has decreased as a result of the regulations.

Barriers in Conducting Paediatric Research
When asked to identify the biggest challenges in conducting paediatric research, finding sufficient numbers of patients to complete study enrolment was overwhelmingly considered to be the most challenging part. Over 50 per cent felt that if all companies submitted PIP/PREA studies, there would be insufficient patients to complete these studies (see Figure 2).

Outsourcing Services in Paediatric Research
Based on the survey, there was a wide range of services for which the pharma and biotechnology companies would look for support to perform their paediatric research. Unsurprisingly given the previous responses, support in patient recruitment was the highest requested service.

Changes Desired to Paediatric Legislation
When asked to rank what changes could be made to PREA and PIP legislation, the highest area of importance for PREA was to extend the patent exclusivity period. While this was not relevant to PIP studies, the second highest area of importance for PREA – and the most important area for PIP regulation – was to simplify the rules in order to improve understanding.



Discussion
The introduction of legislation in Europe and the US to encourage paediatric research, by both carrot and stick approaches, has led to an increase in funding for, and performance of, programmes in children.

Since 2007, over 165,000 paediatric patients have been enrolled in PREA and Best Pharmaceuticals for Children Act (BPCA) studies that have been completed (see Table 2).

However, it is clear from the survey results that despite the regulations having been in existence for over five years, many R&D personnel still have not fully come to terms with the rules – with a surprising minority still unaware that these regulations exist.

It is good news for the outsourcing industry that the budget allocations for paediatric R&D in general have increased in addition to the range of expertise required by companies; however, there is still a great need for additional expertise in supporting companies to educate, prepare programmes and support their negotiations with regulatory bodies at an early stage in their drug development planning. The focus of the investment is clearly going to be on facilitating patient recruitment into their paediatric programmes.

For those companies who have planned their PREA/PIPs, there will be a potential bottleneck of patient availability for enrolment into their studies. In Europe alone there are more than 700 submitted PIPs (or waiver applications). The most leading therapeutic areas for PIP submissions are respiratory, endocrine and CV diseases. The spread of therapeutic areas will naturally be reflected in the adult drug applications. While some areas (such as asthma) will have a high burden of disease in children, many others will find recruitment very difficult. For example, the high study activity in oncology research in adults over the last decade means an over-emphasis of studies needed in a paediatric population, compared to the incidence of disease. Feedback from paediatric networks shows that diabetes and renal disease are two areas that have numerous ongoing paediatric research programmes nearing saturation.

So how can patient recruitment be supported in such a competitive environment? Best practice has to be to engage with industry experts, as well as investigators, as early as possible in the planning process. While the regulatory requirements of the US and EU may differ, the goal should be to have an aligned paediatric development programme that will reduce the need for duplicating studies. Engaging with regulatory and study design experts will avoid simple design flaws that can seriously affect the chances of recruiting into the planned studies. Performing feasibility already at the PIP/PREA planning stage will allow companies to go into negotiations with the regulators with the facts at hand about how realistic a programme could be. There is yet to be a precedent set for what would happen for a company’s market authorisation in the event of it failing to deliver its PIP obligations, yet no company will want to be the first to test the competent authorities.

Increasingly, co-operative groups have been formed in many countries to encourage and facilitate paediatric research. One such organisation in the UK is the Medicines for Children Research Network (MCRN), a government-funded group that proactively engage both industry and non-industry sponsored studies. Working with target timelines, the MCRN are able to support studies at all stages of planning and implementation, as well as all phases of studies.

The naturally protective instincts of parents, as well as the duties of safeguarding children by paediatricians, health workers and educators, make approaching families with children for the purpose of study involvement a delicate matter. Children themselves may also object to the rigours of clinical trials that require recurring medical visits, physical examinations, invasive tests and blood tests that may not be necessary in a real-world clinical situation. Scheduling visits after school hours/during school holidays, or organising follow-up visits that minimise disruptions to family routine and employment, will help.

Once studies are initiated, the importance of family education cannot be over-emphasised. Helping families understand that participation can have a noticeable effect on the health and well-being of both their own child participating in the study and millions of other children worldwide will support study entry.

Conclusion

The design and conduct of paediatric programmes has increased following the introduction of legislation to promote research in both the US and EU. However, there is still a long way to go before equity is reached with adult drug research. Roadblocks in the design and conduct of paediatric programmes show that a lack of understanding and knowledge could be causing delays in the submission of PREA/PIPs or submission of programmes that have not been designed with expert input after thorough discussion with the regulatory agencies. Time will tell the extent of the bottleneck in patient recruitment, as the outsourcing budgets and skill needs of pharma and biotechnology companies will continue to increase. Engaging expertise in paediatric research at the beginning of a molecule’s development programme is no longer a nice-to-have, but a must.

References
  1. Bourgeois FT et al, Clinical Drug Trials: A Paucity of Paediatric Representation Mismatched to Global Disease Burden, Abstract 1135.8 Paediatric Academic Societies Annual Meeting, 2012 2. Premier Research Survey 3. European Medicines Agency: visit: www.ema.europa.eu/ ema/index.jsp?curl=pages/ regulation/general/general_ content_000023.jsp&murl=menus/ regulations/regulations. jsp&mid=WC0b01ac05800240cd, accessed July 2012




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Colin Hayward is the Head of Medical Affairs at Premier Research. Colin is a Fellow of the Faculty of Pharmaceutical Medicine, with 13 years of international experience in pharmacovigilance, design and implementation of clinical programmes and medical affairs. He started his career in industry joining Roche pharmacovigilance and progressed through a series of positions to International Medical Leader before joining Prism Ideas as Executive VP in 2007. Colin joined Premier Research in January 2012 and in his current position is responsible for leading the company’s global medical affairs and pharmacovigilance teams. 
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