EMA Explores How To Extrapolate Adult Data For Pediatric Drug Development
This article was originally published in SRA
The European Medicines Agency has proposed a more systematic way of extrapolating data from adult studies to support decision-making on the evaluation and approval of medicines for use in children.
In a draft reflection paper, the EMA says the aim of its proposals is to minimize the number of children subjected to clinical trials by maximizing the use of information derived from other sources without compromising the evidence base for regulatory decisions1.
Building on ideas laid out in a concept paper on extrapolation more generally that was published in 20122, the reflection paper suggests a structured approach that can be followed for each extrapolation exercise in order to improve interactions between the agency and industry sponsors and to standardize decision-making across the relevant EMA committees.
The reflection paper has been published in advance of a public workshop that the EMA is holding on May 17-18 to gather views from experts and stakeholders and agree on recommendations for clinicians, modelers and statisticians3. Discussions at the workshop will contribute to the further development of the paper, which will then be released for public consultation by the end of July this year.
Explaining the need for this initiative, the EMA says that accepting and implementing extrapolation for drug development is "challenging" for many reasons, such as the difficult of predicting age-related differences in pharmacokinetics, pharmacodynamics, efficacy and safety.
It is therefore necessary to look at the various extrapolation tools available (in vitro and animal models, biomarkers, analytical assays, better in silico tools, etc), define criteria to assess the quality of available data, standardize methods and decision criteria for extrapolation, and develop ways of managing the uncertainty and risk associated with reduced data requirements, according to the agency.
It says extrapolation can allow resources to be focused on areas where studies are most needed, for example age or disease subsets where least extrapolation is possible – mainly infants and neonates – because the differences between the populations are the largest.
The reflection paper is intended to be particularly useful in therapeutic areas where there are no specific guidelines on the rationale for extrapolation, where a case-by-case basis is foreseen or there is no clear guidance on the expected data requirements.
But the agency adds that there will always be a value judgment on the trade-off between the uncertainties of extrapolation and the additional patient resources needed to conduct further studies. "Extrapolation can only be justified when it is the result of a careful and explicit scientific process that eventually gives rise to knowledge gain, rather than an intuitive leap of faith that may undermine the possibility of further scientific knowledge generation," the reflection paper says.
Extrapolation Framework
It lays out the following framework for extrapolation:
The extrapolation concept: this consists of a systematic synthesis of all available data, including the use of modeling and simulation approaches, which aims to predict the differences with regard to pharmacokinetics/pharmacodynamics, disease progression, and clinical response to treatment between adults and children. The initial step in formulation of the concept should be to define the extrapolation target in terms of the population, drugs in the same class, and the condition, and to identify and review all possible source data.
The extrapolation plan: this aims to propose optimal studies in the pediatric population in line with predictions identified by the extrapolation concept. The extrapolation plan should clearly identify knowledge gaps, that is, data that cannot be extrapolated from adults, and if these are clinically relevant, it should identify any additional information or research that might be needed. This may not necessarily require new studies, but could involve new analyses of existing data or new modeling exercises.
Confirmation and extrapolation: this phase aims to confirm the extrapolation concept on the basis of the data collected in children and adults. "If the extrapolation concept cannot be fully confirmed, it should be updated and the extrapolation plan revised accordingly".
Mitigating uncertainty and risk: the limited data generated in the pediatric population may not be sufficient to resolve all uncertainties and assumptions of the extrapolation concept by the time of marketing authorization. Additional follow-up data may be necessary to address uncertainties and to further evaluate assumptions. Measures to generate these data need to be proposed.
In line with the growing emphasis on early engagement between drug sponsors and the agency, the EMA says that applicants should discuss extrapolation early on with the regulatory authorities, otherwise the "opportunity for extrapolation, with anticipated benefit of early market access, will be missed when not planned and discussed early."
Revision Of ICH Guideline
The EMA's extrapolation exercise is taking place at the same time as the ICH (International Council on Harmonization) guideline E11 on clinical investigation of medicines in the pediatric population is being revised, with extrapolation a key issue of focus.
The first stage of the E11 revision – a concept paper – was approved by the ICH steering committee in August 2014, with the aim of reaching step 4 of the ICH process (adoption of the harmonized guideline) by the fourth quarter of 2016. However, this timeline seems to have slipped back somewhat: an October 2015 update on progress from the ICH E11 efficacy working group said that finalization of the step 1 document had been postponed and would probably not now happen until June 2016, mainly because of the need to do more work on the subsections on extrapolation, modeling and simulation, and clinical trial methodology4.
References
- EMA draft reflection paper, April 1, 2016, www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/04/WC500204187.pdf
- EMA concept paper on extrapolation of efficacy and safety in medicine development, June 22, 2012, www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129285.pdf
- Workshop agenda, May 17-18, 2016, www.ema.europa.eu/docs/en_GB/document_library/Agenda/2016/01/WC500199753.pdf
- ICH EWG work plan, Oct. 2, 2015, www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/E11_EWG_Work_Plan_2Oct2015.pdf