Impact of the Paediatric Regulation on EU marketing authorisation holders: an EFPIA survey
This article was originally published in SRA
Angelika Joos, Judith Creba, Craig Johnson and the EFPIA Paediatrics Temporary Working Group describe an industry survey on the impact of the challenging regulation and propose recommendations for improvements.
The introduction of the Paediatric Regulation in Europe in 2007 has had a significant impact on the regulatory environment for medicines and its implementation has resulted in a steep learning curve for both industry and regulators. Much effort has been made by all stakeholders to implement the new requirements and to achieve a mindset change towards an early consideration and integration of paediatric development in the overall R&D process.
The European Federation of Pharmaceutical Industries and Associations conducted a survey of its members to identify opportunities and challenges of the paediatric rules, and to propose constructive ways to fully realise the intended aims of the regulation. These aims are to facilitate the development and accessibility of medicinal products for use in paediatric populations, to ensure that medicinal products used to treat paediatric populations are subject to ethical research of a high quality and are appropriately authorised for that use, and to improve the information available on the use of medicinal products in various paediatric populations. They should be achieved without subjecting the paediatric population to unnecessary clinical trials and without delaying the authorisation of medicinal products for other age groups.
The results from the EFPIA survey were presented at an InfoDay on Paediatric Medicines meeting, which EFPIA and the European Medicines Agency co-hosted on 23 May in London, UK. They are discussed in detail below.
Survey data and results
The EFPIA survey was conducted in the fourth quarter of 2010 and focused on the impact of the first three-and-a-half years of implementation of the Paediatric Regulation on the pharmaceutical industry. Respondents were asked to consider their company's experiences between January 2007 and June 2010. The survey comprised 61 questions covering all aspects relating to applications for a paediatric investigation plan (PIP) and their outcomes. The impact on company drug development and resources was also assessed.
Some 34 companies, including large and small firms, responded to the survey. In total, data from 316 PIP applications (including partial waiver requests) were analysed. This corresponds to 46% of the EMA-validated requests during the same period.
Most PIP applications were submitted under Article 7 of the Paediatric Regulation for new products under development (53%) and under Article 8 for line extensions for patented products (46%), while only 1% was submitted for off-patent medicines.
Some 12% of submitted PIP applications were for orphan product indications, 4% were for paediatric only indications and 96% covered paediatric development as part of ongoing adult development efforts.
During the survey period, companies submitted 98 applications for full product-specific waivers and 87 requests for confirmations of class waiver.
Article 16 of the Paediatric Regulation requires the submission of PIP applications "except in duly justified cases, no later than upon completion of human pharmacokinetic studies in adults". The interpretation of this time point has been left open to regulators and industry. While regulators push for early submission soon after completion of Phase I development in adults, industry strives to balance the timing of submitting the PIP application with the availability of adult development data, the probability of success for the overall project to complete the R&D cycle, and global development programme considerations.
According to the EFPIA survey, submission timings for Article 7 PIPs vary. The majority of applications were submitted following the proof of concept (PoC) or confirmation of the adult dose (see Figure 1). Submissions prior to the PoC resulted in a high rate of withdrawals. A high proportion of PIPs were agreed on with major modifications regardless of the submission timing. Even for PIPs submitted after PoC, companies received, in many instances, requests from the EMA's Paediatric Committee (PDCO) to return for later discussion on modifiying the PIP, based on the availability of further data (see Figure 2).
The experience of regulators with the respect to the overall procedural timeline, as foreseen in the regulation, was very positive. In 99.8% of cases, regulatory decisions were achieved within the legal timelines.
During the regulatory process, companies have the opportunity to respond to a "request for modification" of their application, which they receive from the PDCO after "Day 60". Generally, a three-month clock stop is suggested by PDCO to develop a response and re-start the procedure. However, this timeline can be extended by the applicant, depending on the specific nature of the PDCO request and the necessary time to develop a response.
The survey showed that in 65% of cases, companies needed a longer period to revise their PIP application and re-start the procedure. While the survey did not ask for the reasons for needing these longer periods, there are several possible explanations. These include the need for more time to: evaluate all potential options to address complex PDCO requests; assess clinical study feasibility with potential future investigators; or analyse the potential impact on the programme when further adult data become available during the development. Another reason for needing more time is to design the global paediatric development strategy and to integrate feedback received from other regulatory agencies, particularly from the US Food and Drug Administration, into the European proposal.
Outcomes and withdrawals
The survey revealed that 53% of submitted PIP/waivers and 71% of full waiver requests were agreed during the reporting period. However, 28% of PIP requests and 17% of waiver requests were withdrawn by applicants (see Figure 3).
The high number of withdrawals during the procedure is a concern for industry, as much effort and resources are invested in documentation preparation, submission, review and discussion.
The majority of the PIP or waiver request withdrawals occurred after Day 60 of the procedure, when applicants had received the PDCO requests for modification of their initial proposals. Some 39% of PIPs were withdrawn between Day 61 and 120 and an additional 33% were withdrawn during the clock-stop period (see Figure 4).
Respondents said that the most important reasons for initiating PIP application withdrawals concerned:
termination or reconsideration of the development that was unrelated to the PIP discussions (33%);
divergent positions between the applicant and the PDCO, including feasibility of the requested modifications (21%);
the need for additional time for applicants to consider requests by PDCO (11%);
studies or key binding elements requested by the PDCO being considered unfeasible (7%); and
the cost of the paediatric programme (6%) or the inability to achieve the reward in the remaining time (13%).
The main reason for withdrawing full product-specific waiver requests was because the PDCO had identified a medical need for a paediatric development programme and did not agree to grant a waiver (41%).
Applications for changes
During the development process, specific decisions on continuing and further developing the product are made based on the analysis and review of the generated data. Often, such data may also impact the paediatric development strategy. As a consequence, changes to agreed PIPs are necessary to ensure up-to-date strategies are included and compliance with agreed measures.
The survey showed that, although companies mostly submitted their initial applications after the PoC stage, almost half of the agreed PIPs (82/169) had subsequently been modified, and 20% had been modified at least twice (see Figure 5). The survey revealed that a high proportion of the requested changes had been accepted by the PDCO. Nevertheless, the maintenance of agreed PIPs is a resource intensive undertaking.
Interacting with the EMA and PDCO
The survey respondents were generally satisfied with their interactions with EMA staff. Interaction with the paediatric coordinator was said to be satisfactory and it was easy to obtain answers to specific questions from EMA staff. These answers were generally clear, consistent, useful and reliable. Respondents found the transparency on the position of reviewers in the summary report to be of use in helping them understand and follow the rationale of the regulators. The option for a clarification teleconference following the receipt of the PDCO request for modification on Day 60 was particularly valued, and the EMA was found to be very helpful in supporting the organisation of teleconferences.
On the other hand, companies called for improvement in their direct interactions with the PDCO rapporteur and peer reviewer during the procedure. They felt that the current system of providing an oral explanation to the PDCO at a late stage of the process did not help resolve issues in the ongoing procedure.
Consistency between the PDCO and EMA
The Paediatric Regulation allows applicants to request scientific advice on a specific paediatric study design free of charge at any time during the development process. Only 38% of survey respondents were found to have used this option. In most cases, this occurred before the submission of the PIP. Four companies reported that the PDCO had followed the scientific advice during the PIP assessment in all cases, while seven companies reported that the PDCO followed the advice only in some cases. However, we acknowledge that the EMA has made efforts during the past year to ensure a good collaboration between the PDCO and the agency's Scientific Advice Working Party, which might not be reflected in the early experiences reported in this survey.
During the survey period, national competent authorities or the EMA's scientific committee (the CHMP) raised questions for three new applications or variation procedures regarding the clinical relevance of the paediatric study, certain study design features, or the methodology of trials included in agreed PIPs. We note that the EMA now ensures that the PDCO is consulted during the CHMP's assessment of the paediatric data generated in accordance with an agreed PIP.
Scope of PIP/waiver applications
The survey involved 414 proposed PIP or waiver applications and showed that companies usually aligned their PIP/waiver indications with the targeted adult indication (246). One respondent pointed out that it was "difficult to develop a detailed target indication at a point when this is not clear in the overall development path". Some 41 of the proposed PIP indications were consistent with the adult condition, while 32 were not covered by the intended adult condition.
The survey indicated that requests by the PDCO to include additional programmes and/or studies than initially proposed by the company were routinely received on PIP proposals (see Figure 6). A high proportion of these requests had an impact on study feasibility and resulted in unplanned cost in development. Companies reported that PDCO requests to include specific procedures in the protocol that present practical or logistical challenges, or to enroll additional patients or age groups, impacted the probability of successfully executing those studies (see Figure 7).
Figure 6. PDCO requests for additional development programmes
Additional paediatric subsets
Additional efficacy studies (including efficacy studies with safety as secondary endpoint)
Additional non-clinical studies
Additional PK/PD studies
Additional paediatric indications within the intended adult condition
Additional safety studies
Additional dosage forms
Others (eg juvenile tox studies, long-term maintenance therapy studies, long-term safety studies)
Additional paediatric indications outside the intended adult condition
Additional "dose finding" studies
Figure 7. PDCO request for changes to the study design impacting on feasibility
Request to include specific procedures in the protocol that presented practical or logistical challenges (eg specific monitoring or sample collection procedures)
Additional patients (leading to enrolment rates that would not allow meeting the agreed completion date or that would make the conduct of the study unfeasible)
Others (eg request for DSMB or request related to ethical aspects…)
Respondents raised concerns that for specific therapy areas where only a limited number of patients exist worldwide, the simultaneous execution of several PIPs may lead to significant competition and lower probability of generating enough data in a single study to enable proper scientific analysis and interpretation.
CTAs for clinical protocols
Clinical trial applications (CTAs) for paediatric studies are reviewed and approved by national competent authorities and/or ethics review committees in the participating countries before the trials can start. During the survey, seven companies observed that 14 CTAs that were consistent with an agreed PIP had been rejected or refused by the competent authorities or ethics committees during the CTA review process. The provision of the agreed PIP or full PDCO summary report made little difference during the approval discussion. Countries that were reported by more than one company to have rejected a CTA were France, Germany, the UK, Canada and India. Other countries that refused a CTA included Belgium, Denmark, Italy, Serbia, Tunisia, Russia and Argentina.
According to the companies, the main reasons for rejecting a CTA concerned:
push-back on the feasibility to conduct the studies;
safety concerns for the use of the compound in children;
refusal to include paediatric population or a part of it;
study design and/or inclusion/exclusion criteria;
ethical concerns regarding placebo;
ethical concerns regarding investigation in lower age groups; and
country regulation not allowing clinical trials in children (Tunisia).
In the above instances, the CTA was withdrawn, amended or approved after further discussions with the competent authority or ethics committee.
We believe that it is important that the PDCO and EMA continue to raise awareness on paediatric development questions. There is a need for close collaboration between PDCO members and the clinical trial assessors at the member state level to avoid delays or refusals of paediatric protocols. The rejection of protocols in countries outside the EU highlights the complexity in the management of global paediatric trials.
Interactions with agencies on global programmes
Given the global nature of drug development, the survey aimed to identify company strategies for agreeing on programmes with both the EU and US regulatory agencies.
It is not surprising that during the initial phase of implementing the Paediatric Regulation, 35% of 77 identical paediatric development plans were agreed first with the FDA and then submitted to the EMA, and only 23% of the 77 plans were agreed first with the EMA and then submitted to the FDA. Only 14% of identical plans were submitted to and discussed in parallel with both agencies.
In many instances, companies observed that the PDCO requested additional or different development than the company had agreed on with the FDA (see Figure 8). However, it is possible that this reflects early experience with the EU regulation and further monitoring is needed.
Delaying or abandoning development
The Paediatric Regulation has increased industry focus on paediatric development. Many companies surveyed agreed that paediatric development is an integral part of the overall development of a product. As such, a major shift in mindset from the pre-legislation era has now been achieved by industry. Companies further agreed that the regulation's has led to earlier discussion of paediatric development not only within companies but also with regulators.
The availability of new paediatric indications and additional paediatric information to be added to product information was observed during the survey time period. Some 111 Article 45 procedures – which aim to assess previously existing paediatric data of medicinal products and to include information in the summary of product characteristics (SmPCs) – were reported to have been initiated. In 25 of 54 finalised assessments, this has resulted in the product information being revised to include paediatric data.
While the Paediatric Regulation stated that its goals should be achieved "without…delaying the authorisation of medicinal products for other age populations", the EFPIA survey showed seven cases in which the development in adults for new chemical entities or new biologic entities had been delayed or abandoned in expectation, or as a consequence, of additional cost and requirements associated with paediatric development. In addition, this also occurred in seven cases for new adult indications or line extensions to existing products.
Interestingly, of 159 new marketing authorisation applications or variations submitted, 19 applications experienced a delay due to requirements of the Paediatric Regulation. The reasons for delays are set out in Figure 9.
In summary, the Paediatric Regulation has increased awareness and early discussion of paediatric needs and development. Indeed, paediatric development has become more embedded into company development plans. However, there are concerns regarding the impact on R&D productivity and the demonstrated negative impact on some adult development programmes and submissions.
Impact on company resources
There may be a general public perception that companies can and should pay most of the paediatric R&D bill, as they generally have large resources, especially compared with academic sponsors. This perception does not, however, take into consideration the fact that companies operate under a resource-constrained business environment with a fixed R&D budget per operational year. Consequently, additional unanticipated costs occurring for one development programme will draw resources from other planned or ongoing programmes in adults, to balance the available budget. It should be noted that as a result of the recent global economic downturn, the global pharmaceutical R&D spend declined in 2009 for the first time in 40 years. As such, it is necessary to recognise that paediatric development must focus on a "real" existing need.
It is also worth noting that paediatric clinical development may be cost more than adult clinical development per clinical trial subject. This may be due to a need for: additional effort and resources; additional safety considerations for children; extensive interactions with ethics committees; additional forms for informed consent, assent and parental permission; and requirements to establish specific paediatric surrogate endpoints and to develop new formulations. Higher costs also relate to the need to overcome specific operational issues where there is a very low patient to site ratio for patient recruitment.
The EFPIA survey was designed to capture the impact of the regulation on company resources. For example, one company reported that juvenile animal studies, which are frequently requested by the PDCO, can cost about €200,000. Bioequivalence studies related to new formulations were estimated to cost around €300,000. Phase I studies cost up to €2 million and Phase III studies around €40 + million. Depending on the specific paediatric indication, the cost for additional clinical studies may be even higher.
A second company reported that expenditure of €50-100+ million can be expected for an entire paediatric programme. A third company said that the FDA-agreed programme for a compound ranged around $80 million, whilst the PDCO programme for the same compound added an additional $31 million due to a longer trial duration and additional active comparator requested by the PDCO.
A fourth company stated that €1 million was added to the R&D bill by an additional study required by the PDCO that was not requested by CHMP through the scientific advice process.
The survey also examined the additional resource cost to support the regulatory PIP process. Companies were asked to estimate the regulatory FTEs (full time equivalents) as well as the FTEs needed from supporting functions to develop, write, submit, discuss, and agree on the PIP. It was estimated that 0.1-4 FTEs (median 1 FTE) were required from the regulatory function to process one PIP, while 0.5-11 FTEs (median 3 FTEs) were required from other functions. Based on the 316 PIPs and 89 product-specific waiver requests that were assessed in the survey, and an assumption of the cost per FTE (= 220 working days/year * 8 h/day * €45/h1 = €79200) we can estimate that 3.2-131 million Euros (median €32.8 million) in regulatory resource and €16-360 million (median €98.4 million) in resource cost from other functions were invested across 34 companies during the surveyed time period.
The survey revealed that 90 PIPs and 17 waiver requests were withdrawn and 18 development programmes with agreed PIPs were completely stopped during later development phases due to reasons unrelated to the PIP. This means that an estimated resource cost of €5.8-136 million (median €39 million) was invested by companies in support of submissions from which there was no obvious paediatric benefit.
In summary, the Paediatric Regulation has had a significant impact on R&D strategies and the need for additional regulatory resources. The management of regulatory procedures related to initial PIP submissions and subsequent modifications is a resource intensive undertaking. In addition, the high number of withdrawals and the attrition of programmes during later stages of development results in use of resources that could be allocated to other activities. This impact must, of course, be considered in the context of the overall paediatric clinical development cost and the uncertainty inherent in the R&D process.
In order to balance and compensate industry for the additional investment into paediatric R&D, the regulation offers incentives and rewards (ie a six-month extension of the Supplementary Protection Certificate (SPC); two years of additional marketing exclusivity for orphan drugs). Industry experience in this area is currently quite limited as the rewards can only be obtained after the successful completion of paediatric programmes. Nevertheless, seven products in the survey were found to have already benefitted from a six-month SPC extension, However, concerns regarding the rewards remains. In 22 of 169 programmes surveyed, companies did not expect to be able to apply for rewards due either to timing constraints or because the product in question is not protected by a SPC.
In addition to uncertainties concerning timelines on completing paediatric clinical research, the regulatory procedures to include the generated data in the product information and the availability of all documents from all member states are also of concern. We found that companies generally needed to complete their PIP programmes (last patient, last visit of the last study) 3.5 years in advance of patent expiry. This is based on the deadline for submission of the extension request to national patent offices, which is defined as two years before SPC expiry, and the survey data reporting that the median time to submit and complete a type II variation to update the marketing authorisations in all member states is 1.5 years.
Figure 10 illustrates the delay per product between the closure of the type II variation by the reference member state agreeing the scientific assessment or the European Commission decision subsequent to an Article 29 paediatric referral procedure and the issuance of the national marketing authorisations in all 27 member states. According to Article 28(5) and Article 34(3) of Directive 2001/83/EC on medicinal products for human use, the national decision implementing the EU agreement should be adopted within one month.
In summary, companies are beginning to receive the rewards offered under the Paediatric Regulation, and applications to national patent offices are being made and granted. The timeline to complete PIP programmes is crucial to retain the right for the reward and there is a significant risk that companies may not achieve rewards in compensation for their additional research investment. To ensure that companies have a fair chance of obtaining the rewards, there is a need for more flexibility on the timing of completing PIP commitments, while avoiding unnecessary administrative hurdles or delays during regulatory procedures.
Compliance checks are essential for the successful validation of new applications and variations, as well as for the entitlement to receive rewards for paediatric development efforts.
Some 34 partial compliance checks and 20 full compliance checks were performed during the survey period. Of these, two negative compliance checks were reported due to discrepancies or lack of clarity of some key binding elements and wording in study protocols and clinical study reports. One company reported an initial negative opinion that was converted to a positive opinion after clarification.
The survey preceded a recent clarification2 by the EMA on its compliance check policy, and this is an area that should be monitored further.
Industry experience with Article 46
Article 46 of the Paediatric Regulation requires marketing authorisation holders to submit to competent authorities any study they sponsor and which involves the paediatric population within six months of the study's completion. This is irrespective of whether the study is conducted under a PIP or not.
During the survey, companies submitted 122 studies in compliance with article 46. For 13 submissions, the assessment by the competent authority was deferred because of planned future regulatory procedures such as line extensions or variations.
Some 39 Article 46 procedures were commenced and 23 of those have now been finalised. Based on these 23 finalised procedures, relatively few have resulted in revised product information (see Figure 11). For us, this raises the following two questions. Should the start of more procedures be deferred until additional data from ongoing developments are available? Or is there a need to rethink the requirement to submit paediatric trial results within six months of study completion?
Conclusion and recommendations
The EFPIA survey collected extensive data from 34 companies based on their experience with the Paediatric Regulation between January 2007 and June 2010. It shows that companies have embedded paediatric development in their development processes and this has had significant impact on R&D resources. Certain benefits of the regulation for paediatric patients have also been realised for paediatric patients: 22 SmPCs have been updated with paediatric information generated under agreed PIPs; of these, ten have included new paediatric indications. In addition, 25 SmPCs have been updated to reflect existing paediatric information reviewed under Article 45. Companies have also begun to realise the rewards offered by the regulation.
However, the survey highlights some critical areas of the regulation in need of urgent improvements. For example, the ideal timing, content and scope of the PIP application as well as measures to reduce the high number of current withdrawals must be considered. These areas should be addressed immediately, without waiting for a formal revision of the legislation. Industry generally embraces paediatric development, and would like to move constructively forward on this matter together with other stakeholders
Below we propose a set of short-, medium- and long-term improvements that are required for the Paediatric Regulation to fully achieve its objectives.
Short-term improvements for the PIP process:
allow for a clock-stop at Day 90 of the PIP procedure to facilitate the discussion during the procedure;
allow for optional interactive discussion meeting with PDCO at Day 90 to finalise the PIP opinion;
allow for a clock-stop during the PIP modification procedure to enable more time for discussions and agreement; and
facilitate more direct discussions between PDCO Rapporteur(s) and sponsors, where required, as these are extremely valuable to find acceptable solutions
Short-term improvements for regulatory guidance:
clarify the definition of condition versus indication for the scope of PIPs to remove uncertainty;
facilitate early joint discussions between regulatory experts, academia, learned societies and the pharmaceutical industry;
build consensus on the most appropriate paediatric plan per indication, balancing unmet or critical paediatric needs with current practical/feasibility limitations
build paediatric requirements into regulatory therapeutic guidance as soon as possible; and
publish available data and regulatory guidance related to epidemiology for known disease areas in order to avoid duplication of efforts in researching and preparing PIPs.
Medium-term improvements for the commission guideline3:
submit and discuss an initial PIP with regulators once proof of concept in adults is established/reached;
limit the initial PIP to "high-level" information and agree paediatric needs, target indication, target population, formulation and projected timeline depending on development milestones; and
include commitment to return to the PDCO with detailed study design proposals before paediatric studies are started.
Long-term improvements for the Paediatric Regulation:
limit the scope of mandatory paediatric development to the corresponding adult indication and defined critical unmet medical needs.
align the submission to authorities of paediatric clinical trials with the general 12 months submission deadline for clinical trials; and
initiate a reflection on the adequacy of rewards and incentives.
The authors would like to thank Vera Berchten and Anthony Razafimbazaha (Novartis) for their help in the organisation and analysis of the survey data.
1. Revision of the Clinical Trials Directive (2001/20/EC), Concept Paper Submitted for Public Consultation, 9 February 2011, http://ec.europa.eu/health/files/clinicaltrials/concept_paper_02-2011.pdf
2. Questions and answers on the procedure of PIP compliance verification at EMA, 3 March 2011, www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/09/WC500003916.pdf
3. Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers or deferrals and concerning the operation of the compliance check and on criteria for assessing significant studies, OJ, 24 September 2008, C243, 1-12, http://ec.europa.eu/health/files/eudralex/vol-1/com_2008_jo243/com_2008_243_en.pdf
Angelika Joos is head, regulatory policy Europe & Most of world at Merck Sharp & Dohme (Brussels, Belgium). Judith Creba is head EU liaison & policy, regulatory affairs at Novartis (Basel, Switzerland) and Craig Johnson is principal regulatory consultant, Lilly (Surrey, UK). Contact email: firstname.lastname@example.org.