EMA reflection paper on generic nanoparticle iron products: a case of bias by omission?
This article was originally published in SRA
Nanoparticle iron (NPI) products are used as diagnostic MRI contrast agents and as therapies for iron-deficiency anaemia. David Snodin argues that a European Medicines Agency working party should reconsider its position in its reflection paper that recommends comparative non-clinical studies for generic NPI products.
A reflection paper prepared for the European Medicines Agency's scientific committee, the CHMP, appears, at a superficial level, to present a plausible rationale for requiring comparative non-clinical studies on generic parenteral nanoparticle iron (NPI) products1. However, a more detailed and critical assessment of the data in the document, and of important evidence omitted, suggests otherwise.
The one-sided and cursory narrative presented in the paper raises fundamental issues in relation to fairness and balance in regulatory decision making and animal welfare.
NPI products are many and varied, falling into two broad categories: diagnostics (MRI contrast agents)2-5 and treatments for iron-deficiency anaemia6. At least seven of the latter category are approved – or close to being approved – in the EU/US7 and generic versions are becoming available in some cases, particularly for iron sucrose (originator trade name Venofer)8-10.
NPI preparations for treating iron-deficiency anaemia contain iron oxide/hydroxide nanoparticles surrounded by a carbohydrate shell that isolates bioactive iron from plasma components until the complex enters macrophages of the reticuloendothelial system mainly in the liver, spleen and bone marrow. Breakdown of the complex within macrophages slowly releases iron that enters the intracellular pool (eg as ferritin) or the iron is transported via plasma transferrin to erythroid precursor cells for incorporation into haemoglobin11. Some NPIs contain small amounts of free and/or “labile” iron that may be incorporated directly into transferrin12, 13.
Reflection papers are issued by the EMA in cases where it is too premature to develop a full guideline. The reflection paper in question, prepared by the CHMP’s Safety Working Party (SWP), states that physicochemical characterisation and human pharmacokinetic data are insufficient to evaluate the safety and efficacy of generic NPIs, citing published evidence on tissue distribution in vitro for different NPIs14 and on different toxicological profiles (in vivo) for several iron sucrose generic NPIs15.
The cited tissue distribution studies used cultured cells and the authors emphasise that their results do not reflect the in vivo situation. In addition, iron oxide nanoparticles (? 100nm) have been shown to be no more toxic in vitro than micrometer particles16. Published results of comparative rat toxicity studies, sponsored by the originator company, on Venofer and three different generic iron sucrose products (Generis, Ferriv and Hematin) appear to indicate potential differences in relation to markers of oxidative stress17-19. However, these findings should be interpreted with great caution for a number of reasons: all of the generic iron sucrose products failed to meet the US Pharmacopeia (USP) specification for iron sucrose injection for at least two parameters20; the dose used (40 mg/kg IV bolus) was at least ten times the maximum recommended clinical dose; healthy iron-replete rats were employed (thus exaggerating any iron-overload toxicity); and the rat studies appeared to be non-compliant with good laboratory practice, none of which was mentioned by the SWP.
One would have expected the SWP to be extra vigilant in its review of sponsored studies, possibly to the extent of undertaking a raw data audit. A recent report21 suggests that iron-overload phenomena found in young rats treated with supratherapeutic doses of iron sucrose are unlikely to be representative of effects in anaemic patients. A further sponsored study compared the clinical safety and efficacy of Venofer and a generic iron sucrose (Fer Mylan)22. The latter product received special approval in France23, 24. The study results showed that the generic iron sucrose may be less effective than the originator product (in terms of the 12.6% increase in the dose of Fer Mylan required to produce the same haemoglobin level) but no differences in clinical safety were observed. However, the extent of compliance of the generic iron sucrose with USP requirements is unknown and potential confounding factors, such as plasma ascorbate status, which has been shown to be positively correlated with increased iron bioavailability from iron sucrose25, and time-related changes in iron excretion, were not evaluated.
The possibility of toxicity mediated by oxidative stress and formation of reactive oxygen species (ROS) is a long-standing concern for iron-containing pharmaceuticals in general and, in particular, for parenteral NPI products. Originator iron sucrose has been associated with a variety of potential ROS-mediated adverse effects26-29 including increased susceptibility to infections30, 31 and renal toxicity in patients32, 33 and in rats34 but not reported in sponsored rat studies using a similar dose.
There is little doubt that iron causes oxidative stress and the clinical literature is substantial, differing reports and opinions regarding its clinical significance still being commonplace35-40. However, several investigators have pointed out that the clinical impact of experimental findings is largely hypothetical and speculative since patient safety data for NPI products are generally reassuring provided that the recommended dosing regimen is not exceeded and overdose avoided41-43. NPI products that contain free or labile iron, or release iron by rapid degradation of the carbohydrate coating, are considered more likely to produce adverse effects (by transferrin supersaturation and/or ROS generation)44,45; the maximum safe clinical doses of different NPI products seem to be governed by this phenomenon. By contrast, a recent report46 suggests that “naked” iron in the form of IV ferric chloride has a similar clinical safety profile to iron sucrose but is not quite as effective. Overall, ROS generation appears to be not associated with adverse outcomes47, 48, although caution in some situations, such as in patients with sepsis and chronic kidney disease patients receiving haemodialysis, may be appropriate.
The toxicological evaluation recommended by SWP for all NPI products, irrespective of whether appropriate physicochemical standards are met, is essentially a comparative iron-distribution study with timed sampling of plasma, the reticuloendothelial system and target tissues for iron content. No results from such a testing paradigm were cited in the reflection paper and no data could be found in the literature on generic iron sucrose preparations. Thus, it appears that the recommended approach is entirely hypothesis-based, unvalidated and with no established correlation to clinical safety. Moreover, critical information is lacking on dosing regimen, interpretation criteria and inherent variability (in respect of distinguishing between different batches of originator iron sucrose and USP-compliant and non-USP-compliant iron sucrose). On the other hand, a generic iron sucrose product, Iron Sucrose Azad, that meets the USP specification in all respects, is reported to have a closely similar toxicological profile to that of originator iron sucrose49.
The proposed testing regimen is somewhat analogous to the comparative toxicity assessment of biosimilar products50, but the latter are much more difficult, if not impossible, to characterise using physicochemical data alone and there are sufficient checks and balances in the overall safety programme to evaluate the clinical relevance of any apparent toxicological differences. A generic iron sucrose is included as a candidate for in vivo assessment in a publication on the therapeutic equivalence of complex drugs51. Because only sponsored publications are used as support for this approach and since one of the co-authors is an employee of the originator company, the justification presented on generic iron sucrose is considered to be highly compromised.
The reflection paper fails to include two significant regulatory precedents. A generic iron sucrose product, Ferrologic, was awarded EU approval in 2007/8 based solely on comparative physiochemical data/USP requirements52 and an entirely new NPI product, Monofer, was approved in 2009 in the absence of drug-specific toxicological data (using “read-across” from data on iron dextran)53. Thus, the SWP is requesting a significant toxicological evaluation of generic NPIs whereas two precedents suggest comparative physicochemical data or read-across have in the past been considered sufficient. This insistence on a toxicological evaluation is contrary to the spirit of the existing animal welfare provisions of EU legislation54, which are soon to be strengthened by Directive 2010/63/EU on the protection of animals used for scientific purposes. Article 4.1 of this directive indicates that member states should ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used instead of a procedure55.
Regulatory omissions
The content, recommendations and the status of the reflection paper raise a number of critically important regulatory questions.
Firstly, when preparing “guidance” documents, should the SWP be entitled to ignore requirements applied to applicants in Directive 2001/83/EC56 on medicines for human use in terms of including all relevant information, whether favourable or unfavourable (Annex 1, General Principles), and preparing an overview that contains an integrated and critical assessment of the non-clinical data and a discussion and justification of the testing strategy (Annex 1, 2001/83, PI, 2.4)?
Why did the SWP fail to mention the provisions of Annex 1, PI, section 3.2 (6) indicating that if no relevant monograph is available in the European Pharmacopoeia nor in the pharmacopoeia of a member state, “compliance with the monograph of a third country pharmacopoeia can be accepted”?
Why, when such a reflection paper amounts to de facto regulatory guidance, was there no inbuilt public consultation? (It would be somewhat disingenuous for the SWP to argue that individual applicants can challenge the provisions of the reflection paper since only the bravest and most confident assessor would be willing to contradict an opinion from the working party.)
Is it justified to dismiss largely by assertion rather than detailed scientific justification an approach based on physicochemical data, the latter being supported by published data and precedents, thereby apparently ignoring existing and additional impending requirements on minimisation of procedures employing experimental animals?
Is the recommendation to employ a completely untested and unvalidated toxicological paradigm with no proven correlation to clinical safety justified?
If no significant differences were detected between the originator NPI product and a generic NPI using the recommended testing paradigm, would this overrule any potential quality deficiencies related to drug substance specification criteria? (If not, this is considered to further undermine the rationale for in vivo testing.)
Finally, is it acceptable to require toxicological studies on a generic version of an originator product that gained approval without any compound-specific non-clinical evaluation? The latter situation, a complete inversion of the normal legal requirements on generic products, could arise in the future in relation to generic versions of Monofer.
In view of these numerous concerns, the SWP may wish to reconsider its position on the reflection paper. Otherwise, it could be inferred that the working party is not averse to setting a general regulatory precedent in relation to the omission of key evidence on drug quality and safety and to the acceptability of assessments that are incomplete and potentially misleading.
References
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7. Ibid
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56. Directive 2001/83/EC, http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_cons2009/2001_83_cons2009_en.pdf
Dr David Snodin is the principal of Xiphora Biopharma Consulting, a UK-based consultancy offering nonclinical services to the pharmaceutical sector. Dr Snodin is also a former expert preclinical assessor at the UK Medicines Control Agency (now the Medicines and Healthcare products Regulatory Agency) and a former UK representative on the EMA/CHMP safety working party. Website: http://xiphora.com/. Email: