Is the regulatory world ready for 'nanosimilars'?
This article was originally published in SRA
In the beginning there were generics. Then came biosimilars. Now the regulatory world is preparing for the appearance of a new kind of follow-on product: "nanosimilars", or versions of the first generation of nanomedicines, whose patents are on the way to expiry.
It may come as some surprise that nanomedicines have been around for long enough to see the appearance of follow-on products, but the technology is now well established and there are a fair number of products either on the market or in advanced development.
In the EU, for example, eight nanomedicines have been authorized through the centralized procedure, and ten development products have been granted orphan status. Almost 50 nanomedicines and nano-imaging agents are currently in Phase I-III studies in Europe, with others further behind in development. Moreover, some 70 cancer trials involving nanomedicines are under way in the US, and the number of marketed drugs using nanotechnology is expected to grow, according to the European Medicines Agency.
This, the agency says, raises two distinct challenges: the imminent arrival of what it is calling "nanosimilars", products that are claimed to be similar to existing nanomedicines; and the likely need for new regulatory frameworks for the evaluation of new, increasingly complex hybrid structures that are paving the way for a wave of new pharmaceuticals, imaging agents and combination drugs.
Benefits of nanomedicines
Nanomedicines are purposed-designed drugs that may incorporate many components, and all have at least one of their dimensions in the nanosize range. Their potential benefits include improved drug delivery, more accurate organ- or cell-specific targeting, better solubility and stability, and improved transport across biological barriers.
The first generation of nanomedicines included liposomal formulations, nanoparticles and polymers/conjugates, mainly of drugs such anticancers, anti-infectives and immunomodulating agents. But future products will come in a whole new variety of shapes and sizes. Researchers at the University of Georgia, US, for example, are developing a nanoparticle-based technique that reprograms immune cells to enable them to recognize and attack breast cancer cells. Work at the University of Arizona has led to the creation of "Trojan horse-like" structures for improving drug delivery to cancerous cells, as well as DNA nanostructure-based vaccine complexes that resemble natural viral particles.
The development and regulatory evaluation of nanomedicines will require additional expertise from specialists in the area as the products become more complex. Robust methodology will be needed for evaluating them and ensuring long-term safety and risk management, while specific tools may be needed for adequate product characterization and manufacturing control, say experts from the EMA and other bodies in a paper published in Nanomedicine1. It will also be important to define the critical attributes that determine pharmacokinetics, body distribution, and non-clinical safety, and enable pharmacological proof of concept.
"Nanosimilars"
The agency, with the help of a multidisciplinary group set up in 2011, has been developing guidance on both novel nanomedicines – block copolymer-micelle medicines, and general issues relating to nanomedicine coatings2,3 – and "nanosimilars".
Like biosimilars, nanosimilars will bring their own challenges, the more so because of the complex structures they will embody. A reflection paper on similar versions of intravenous liposomal products was published in February4, while a draft paper on similar intravenous iron-based colloidal products will be put out for consultation later this year.
The February paper, says the EMA, is intended to help companies generate relevant quality, non-clinical and clinical data for the approval of similar intravenous liposomal drugs. It notes above all that liposomal products have specific distribution characteristics linked to manufacturing and formulation, and that similar plasma concentrations may not necessarily correlate with therapeutic performance. It looks at the pharmaceutical data needed to show comparable safety and efficacy of the test and reference products, or after changes to a liposomal product, and the extent to which pre-clinical and clinical studies will be needed.
The other paper, to be published later this year, will remind companies that existing first-generation nanosized colloidal intravenous iron-based preparations are complex and can induce hypersensitivity or other potentially severe reactions, as well as releasing free, unbound iron that can produce both short- and long-term toxic effects. Differences in the production processes or composition with reference to an innovator product may lead to diverse product characteristics that will impact on safety and therapeutic performance. These factors will all need to be taken into account when developing products that are claimed to be similar to the reference products.
Considerations such as these have dominated the debate over what evidence is needed to show comparability between originator and biosimilar medicines. And the debate is far from over, not only in the US, where final regulatory guidance is still awaited and no biosimilar products have yet been approved, but also in Europe, where 12 versions of biosimilars have been on the market for some years and approval recommendations have been made for two monoclonal antibody products.
How the situation will develop with respect to similar nanomedicines remains to be seen. The EMA seems to be the only regulator to have produced guidance on nanosimilars, and indeed to have coined the term: there is no mention of the concept on the US Food and Drug Administration's website, or anywhere else for that matter.
But with the first generation of nanomedicines nearing patent expiry, and researchers already working on cutting-edge technologies such as RNA nanoparticles, gold-coated nanoshells and inhalable nanocarriers, the prospect of nanosimilars is sure to bring a whole new dimension to the similarity debate.
References
1. Ehmann?? F et al, Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines, Nanomedicine, May 2013, www.futuremedicine.com/doi/abs/10.2217/nnm.13.68
2. EMA press release, 15 August 2013, www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/08/news_detail_001875.jsp&mid=WC0b01ac058004d5c1
3. EMA, Reflection paper on surface coatings: general issues for consideration regarding parenteral administration of coated nanomedicine products, 22 May 2013, posted online 15 August 2013, www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/08/WC500147874.pdf
4. EMA, Reflection paper on the data requirements for intravenous liposomal products developed with reference to an innovator liposomal product, 21 February 2013, www.ema.europa.eu/docs/en_B/document_library/Scientific_guideline/2013/03/WC500140351.pdf