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EMA responds to criticism of reflection paper on non-clinical studies for generic nano-particle iron medicinal product applications

This article was originally published in SRA

Executive Summary

The European Medicines Agency has responded to an article published in Scrip Regulatory Affairs, in which the author, David Snodin, criticises the agency's reflection paper on non-clinical studies for generic nano-particle iron medicinal product applications.

The EMA says…

The European Medicines Agency’s reflection paper on non-clinical studies for generic nano-particle iron medicinal product applications1 has been written to address the complex situation for coated nano-particle iron formulations where any variation in the nano-particle properties, structure, including coating or size distribution may result in different physicochemical properties leading to a different pharmacokinetic and biodistribution profile, with the potential of significantly impacting safety and efficacy of the medicinal product.

The reflection paper concludes that for the comparison of generic and reference nano-particle iron medicinal products, physicochemical characteristics comparison as well as classical bioequivalence evaluation in humans based on plasma concentrations may not be sufficient to ensure a comparable safety and efficacy profile, in which case measurements of non-clinical target tissue distribution studies will generally be needed.

As indicated also by Dr Snodin in his article (see also, 21 July 2011), reflection papers are issued by the EMA in cases where it is too premature to develop a full guideline or when the scientific knowledge is rapidly evolving.

A reflection paper is not a guideline and is not intended to set scientific, technical or regulatory requirements, in accordance with the scope of reflection papers as set out in the current regulatory framework2.

The purpose of this reflection paper is to communicate in an open and transparent manner the current status of discussions in the non-clinical area for generic nano-particle iron medicinal products where scientific knowledge is evolving and experience is limited: therefore a conservative approach is taken at this point in time. This is also in line with a recent reflection paper published by EMA on the generation of relevant data to support generic liposomal products, another nano-particle formulation3.

The scope of this reflection paper is limited to the non-clinical studies which may be needed in support of generic applications and it is not intended to discuss in detail other scientific areas such as quality comparability or clinical studies; the latter being outside the scope of the paper should not be considered “omissions”.

With reference to Dr Snodin’s criticism that important evidence has been omitted in the discussion of the potential differences between generic versions of nano-particle iron products and the innovator, and that only a subset of potentially biased references has been quoted in the paper, we underline that all experience gained with actual regulatory submissions has been taken into account.

Several publications on iron safety non-clinical studies refer to nano-particle iron as seen in regulatory submissions (ie iron core covered by a carbohydrate coat) but many others to “naked iron”, the latter not being the focus of the discussions in this reflection paper: a complete overview of the literature was not intended.

The reflection paper discusses the principles for assessing generic nanoparticles iron and it does not aim to prescribe any particular strategy. Non-clinical requirements are assessed in the context of the full package provided by the applicant including quality, safety and efficacy data, which is unique for each application. It is the applicant’s decision to choose the intended development programme for their product, which should be properly justified. In the case were applicants have specific questions on the data requirements for the demonstration of comparability, they are advised to seek product-specific scientific advice according to the EMA procedure4. Any data that fail to support comparability between an originator and a generic medicine will be of regulatory concern.

Wherever possible, the EMA is, as indicated by Dr Snodin, committed to supporting approaches in the area of replacing, reducing or refining animal studies (the 3Rs), supporting the recently adopted EU animal welfare directive on the protection of animals used for scientific purposes5. For nano-particle formulations, differences in tissue distribution and toxicological profiles have been described and a classical generic approach might not be sufficient to ensure a safe and efficacious use of the medicinal product. It is one of the EMA’s responsibilities to ensure patient safety and keeping this in mind has also preserved the 3Rs principles by encouraging the use of cell or tissue culture systems for mechanistic purposes.

In conclusion, the intention of the reflection paper was to communicate in an open and transparent manner the current state of regulatory thinking in relation to the non-clinical studies necessary to support nano-particle iron generic applications in the EU. In this regard, the EMA continuously supervises the quality, safety and efficacy of authorised medicines to ensure that their benefits outweigh their risks, being strongly committed to communication and maintaining an open dialogue with all our stakeholders. The principles spelled out in this reflection paper will be reviewed in the future in light of the experience gained with further regulatory submissions and contributions from stakeholders.

Beatriz Silva Lima


Safety Working Party

Committee for Medicinal Products for Human Use

European Medicines Agency


1. Reflection paper on non-clinical studies for generic nanoparticle iron medicinal product applications (EMA/CHMP/SWP/100094/2011), published April 2011,

2. Procedure for European Union guidelines and related documents within the pharmaceutical legislative framework,

3. Reflection paper on liposomal formulations (EMA/CHMP/806058/2009), published July 2011,

4. EMA Scientific Advice procedure,

5. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes, OJ, 20 October 2010, L276, 33-79

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