Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

The Regulatory Environment in Nanomedicine: A Comparison between US, EU, Canada and Australia in Assessment of Anticancer-Therapies ***

Dr. Alexandra Schubert (Abschlußjahr: 2014)

Summary
When comparing the definitions of “nanoscale” the size range varies from the atomic level at around 0,2 nm to smaller than 1.000 nm but most definitions in the EU and elsewhere indicate a range from 1 nm to 100 nm. The FDA has not adopted a formal size definition but will ask for the same value range of approximately 1 to 100 nm. It is important, whether the nanomaterial exhibits special properties or phenomena, including physical or chemical properties or biological effects, that are attributable to its size. Other important features could be size distribution, surface modification, persistence and other physical-chemical characteristics. Most of them are very useful to predict how reactive a nanomaterial would be in humans or in terms of a risk assessment but the problem for most of all is the fact, that they can’t be applied in general for all nanomaterial. Until now it is also unknown at what size these properties can be expected or even if they don’t appear.
The parameter of nanoscale should be enforceable through agreed measurement techniques, but it appears to be difficult, when validated methods still need to be developed and results strongly differ depending on the applied method.
Early requests of consumer advocate groups e.g. to declare that products with engineered nanoparticles are an imminent hazard to the public and that nanosunscreen products should be recalled from the market were rejected by showing with scientific research and laboratory work, that there was no significant dermal penetration of nano-sunscreen products.
Nanomedicine in general shouldn’t be categorized as “safe” or “unsafe”. Nanomedicine may be more toxic but also less toxic than its conventional counterparts. As an example Abraxane is less toxic than Paclitaxel with Cremophor.
Nanotheranostics with encapsulated or attached imaging agents or contrast agents have advantages to conventional methods of tumor detection. It is the number of agents and the possibility to combine different agents on or in nanocarrier systems. Hence with the improved imaging resolution it is possible to detect small metastatic lesions, which are undetectable using conventional methods.
The lesson learnt from personalized anticancer therapy is the fact that cancer shouldn’t be understood as a single disease. Instead it is a group of several subtypes, each of them having its own biologic features. It is assumed that personalized therapy schemes will increase in future. With the personalized medicine the clinical trial design will change. Statistically significant results can be obtained with smaller patient groups due to the fact that specific subtypes of patients enter a trial.
Regarding the regulatory assessment of nanomedicine there is consensus of all authorities in question that the current guidelines, which are not nano-specific, are sufficient, robust and efficient. Anyhow some draft guidelines and reflection papers have been published to help companies regarding the specialties of nanomaterial. For example a draft guideline of FDA advices that unique properties and behaviors of nanomaterial, that are attributed to its dimensions, should be considered. These new properties need further evaluation, because they can affect safety, effectiveness, performance, quality and health. Similarly an EU reflection paper states that changes of particle size or shape can lead to different physiochemical properties and different biodistribution and pharmacokinetics. This may have an influence on efficacy and safety, thus additional data or non -clinical studies are needed for the approval of nano-generics.
The existing framework can possibly be adapted in case of new experience gained in the field of nanopharmaceuticals. For the future several experts concluded in about 5 to 10 years either major changes of the current regulatory frameworks and/or specific regulations for  nanomedicines are necessary in particular. Common goals of all federal agencies are the increasing scientific understanding of nanomaterials and related products, the identification of regulatory gaps, and consequently the "preparedness" for the evaluation of future nanomedicines.
Due to the often missing labeling of nanomaterial, the "nano-specific" oversight at federal level in the USA as well as on EU level is questioned. Therefore there are intentions to dispatch the lack of oversight with the implementation of reporting and tracking mechanisms.

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