Seeking Harmonization in Nanomedicines Regulatory Framework

Planned launches of generic versions of first-generation nanomedicines and the emergence of a second generation of more-complex nanotechnologies in healthcare are now becoming a big challenge for licensing agencies. Unsurprisingly, the pharmaceutical industry has its doubts about the exact regulatory requirements for approval of innovative nanosubstances in medicinal products. The uncertainties are not only confined to Europe but also other developed regions such as North America, mainly due to the gaps in knowledge about the safety of nanomedicines derived from recent advances in nanotechnologies.

Sean Milmo

"The industry wants greater clarity among regulators, more uniform standards, and more harmonization," Beat Loeffler, chief executive of the European Foundation for Clinical Nanomedicine (CLINAM), Basel, Switzerland, told BioPharm International. "There is a feeling that the regulators do not know what they want." An annual international conference on clinical nanomedicines, organized jointly at Basel in June 2013 by CLINAM and the European Technology Platform on Nanomedicine (ETPN), called for greater consistency among regulators in dealing with new nanopharmaceutical products.

Safety Requirements

In Europe, the safety rules on nanosubstances in medicinal products can be particularly perplexing because in many cases, the nanotechnologies are applied to drug-delivery systems, carriers, and imaging agents. As a result, the products have been categorized as combination products or medical devices rather than medicines. In the European Union (EU), this categorization has given much more scope for the regulatory authorities of the 28 EU member states to approve nanomedicines rather than the European Medicines Agency (EMA), whose main responsibility is the approval of pharmaceuticals.

Some national governments have been taking their own regulatory initiatives on the management of nanosubstances in medicines and other products because of the reluctance of the European Commission (EC) to tighten up EU rules in the area. Last year, after a regulatory review on controls of nanomaterials, the EC decided to leave EU legislation on nanotechnology unchanged. Instead, the EC stated that the safety of nanomaterials should be assessed on a case-by-case basis on the grounds that they are similar to normal substances in that some may be toxic and some may not.

In an earlier recommendation, made in October 2011, the EC provided leeway for national governments to apply their own controls on nanomaterials by recommending a broad definition of "nanomaterial." A material was defined as "nano" when it contained 50% or more particles in the size range of 1–100 nm. The EC also acknowledged that because of "special circumstances" in the pharmaceutical sector, the recommendation of an upper limit of 100 nm should "not prejudice the use of the term nano when defining certain pharmaceuticals and medical devices."

France has been among the most ambitious EU member states in introducing a new nanotechnology legislation, which came into effect in May this year, but which has, so far, not raised any significant opposition among French pharmaceutical companies. Its main requirement is that manufacturers, importers, and distributors of engineered nanosubstances make annual declarations to the French government of the amounts they are placing on the national market with details of their uses.

"This legislation is not a hurdle and the provision for annual declaration encourages transparency, which is a desirable objective," explains Laurent Levy, chief executive of Nanobiotix, Paris, a nanomedicine company and a member of the biotechnology committee of the French Pharmaceutical Companies Association. The increase in new nanomaterial legislation at the national level in Europe is, however, causing some nanomedicine companies to see regulation as being an obstacle to innovation.

"Small and medium enterprises (SMEs), in particular, are regarding regulation in nanotechnology as a barrier," Levy, who is also vice-chairman of the ETPN, an EU-funded research organization, said in an interview with BioPharm International. "But once they start interacting with the regulatory authorities about their new products, they become much less concerned because they are in a dialogue with the authorities during the development of their nanoproducts, and therefore, will know what is expected of them."

Nanobiotix has been keeping in close contact with the French National Agency for the Safety of Medicines and Healthcare Products (ANMS) in the development of a nanoparticle-enhanced radiotherapy technology. In June 2013, ANMS authorized the company to start a clinical trial of the technology for the treatment of head and neck cancer.

The Nanobiotix technology, however, is an example of disparities outside Europe in the international classification of nanomedicines. In Europe, it has been categorized as a medical device, while in the US, FDA considers it to be a drug. As a result, Nanobiotix reckons its first products will reach the market more quickly in Europe than in the US because European national authorities responsible for licensing medical devices require fewer clinical trials than with pharmaceuticals.

"There may be a bit of a difference in the time to market between Europe and the US, but in the end, you have to meet the same regulatory requirements of demonstrating an acceptable benefit-to-risk ratio," explained Levy.

EMA Takes Charge

Meanwhile, EMA has been stepping up its efforts to ensure a consistent EU-wide approach to nanomedicines in the two areas for which it has responsibilities—pharmaceuticals and combination products, defined as devices with a predominant pharmaceutical application. So far, EMA has only evaluated 11 marketing-authorization applications for nanomedicines, of which eight have been approved and three withdrawn. This number is fewer than in some of the larger EU countries. In France, for example, 36 nanomedicines, 21 of them being drug-delivery products, have been licensed.

EMA has recently drafted reflection papers (i.e., discussion documents on the principles underlining the risk assessment of groups of products that may provide a basis for later guidelines) on generic nanomedicines or nanosimilars. The agency is also planning reflection papers on new second-generation nanotechnologies, on which it has already published discussion documents on block-copolymer micelles and nanomedicine coatings. As a coordinator of evaluation strategies throughout the EU's network of national licensing authorities, EMA believes it is in a strong position to boost assessment standards in areas such as nanomedicines.

"The agency has access to the best available scientific expertise in Europe, which it can consult during the evaluation of the quality, safety, and efficacy of all new compounds, including nanomedicines," an EMA official told BioPharm International. "EU-wide harmonization is one goal of EMA. However, the agency's main intention is to ensure that only safe and efficacious medicines enter the EU market."

EMA's Committee for Medicinal Products for Human Use (CHMP) has a multidisciplinary expert group on nanomedicines, which can tap into the evaluation experience among member states. The agency has also been extending its regular contacts with non-European agencies on nanomedicines. CHMP chairs regular meetings on the matter with FDA and the licensing authorities of Japan, Canada, and Australia. "There are no official recommendations from these meetings," said the EMA official. "The focus is on knowledge-sharing and finding common areas for collaboration."

The reflective paper on block-copolymer micelles, written jointly by the agency and Japan's Ministry of Health, Labor, and Welfare (MHLW), was an idea that came out of one of the international meetings. The EMA's investigations of nanomedicines have highlighted the need for more public-sector assistance in Europe on the characterization of nanoparticles in medicinal products. The micelles reflective paper pinpointed the importance of characterization of approximately 15 properties of block-copolymer micelles and properties related to the manufacturing process and in-vivo behavior, as well as of the chemical structure and nature of the polymer raw materials.

The ETPN is currently exploring the idea of setting up a European Nano-Characterization Laboratory that would act as the centre of a network of characterization facilities across Europe. It would be modeled on the US National Cancer Institute's (NCI) Nanotechnology Characterization Laboratory (NCL), which has close links with FDA.

Europe is gradually putting together an evaluation structure that should accelerate the development and commercialization of the next generation of nanomedicines. "Like with all new technologies, there have inevitably been areas of uncertainty with nanomedicines," said Levy. "But ultimately, as knowledge of the technology increases, there will be a high level of consistency and clarity in the way it is regulated across Europe."

Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.