Complex Medicines: Science, Regulation, and Accelerating Development

Complex drugs enable promising therapeutic breakthroughs, but also pose challenges for characterization and regulatory evaluation. The formulations being developed to treat cancer and other diseases have been specifically designed such that their physicochemical characteristics can curtail off-target toxicities and optimize pharmacokinetics. As these products increase in complexity, so too must the technologies and methods for characterization and evaluation. The Nanotechnology Characterization Laboratory has been helping developers for more than a decade by providing state of the art characterization services to help advance these products into clinical trials. This talk aims to highlight the emerging trends in complex drug characterization as well as the scientific challenges they face. Challenges in identifying critical quality attributes, defining bioequivalence for generic products, as well as strategies aimed at addressing regulatory questions and commercialization will be discussed.

Since more than one decade,nanoparticle-based formulations are emerging with multiple objectives, raising challenges on their development, characterization and standardization related to quality and biological activity. These so designated “complex drugs/medicines”raise specific questions needing regulatory support, related to eg the relationships between their quality attributes and the biological activity, including target interaction, dose-response, biodistribution patterns. Some of the referred components are the basis for the development of these “complex drugs/formulations”. The complexity is often driven by the difficulties behind a thorough characterization and analytical measuring of nanoparticles and the drug-particle complexes, and the incomplete knowledge on how changes (even small) in attributes of the particles or drug-particle conjugates impacts on the bioactivity of the product, related to target access as well as target interaction. Of particular relevance for the activity of any nanoparticle-based medicine is the understanding on how some changes in the attributes can impact on the pattern of tissue distribution, and the potential for changing the pattern of activity, efficacy and safety. These aspects and the science behind have been considered by Regulators in Europe and abroad, eg the United States FDA.Several guidance documents have been issued to help Companies and Researchers on developing innovative or follow on “Complex drug formulations”. The thinking behind the produced documents,by the European Regulators and some practical examples will be discussed. Key words: nanomedicine, nanoparticle, liposome, bioequivalence, generics, CHMP and FDA regulatory guidance.

Over the last 30 years, new drug development in pharmaceutical industries has shifted significantly, moving towards more complex formulation design, for better disease management, adherence to patients, adoption of new technology as well as in part for better patent protection. As a result, it is becoming challenging for generic companies to come up with viable option for these products to be available in the market at an affordable price. Therefore, the generic industry is becoming smarter in its approach, increasingly pursuing more paragraph III/IV type applications and, in some cases, taking regulatory paths such as 505(b)(2). In recent years, the FDA has received generic applications for drug device combinations (e.g. pulmonary and nasal delivery), nano technology-based products (e.g. generic Rapamune/sirolimus), biosimilars (e.g. filgrastim, Inflectra), complex transdermal patches, implants, ophthalmic, long acting injectables, soft gels and many other products that did not exist in the past in generic market. This presentation will focus on the key scientific and regulatory issues with respect to complex generic drug development.

Health Canada is a department within the Canadian Federal Heath Portfolio (which comprises Health Canada, the Public Health Agency of Canada, the Canadian Institutes of Health Research, the Patented Medicine Prices Review Board and the Canadian Food Inspection Agency) and is responsible for the regulation of consumer products, environmental and workplace health, food and nutrition, cannabis as well as drugs and medical devices. This presentation will outline Health Canada’s current perspective on complex drugs (specifically non-biological complex drugs) as well as follow-on complex drug products. Additionally, an overview of the activities of the International Pharmaceutical Regulators Programme Nanomedicines Working Group, currently co-chaired by Health Canada, will be provided.

Very different medicinal products are allocated to the group of non-biological complex drugs (NBCDs), such as solutions for injection containing glatiramer acetate, iron sucrose complexes, or low molecular heparins as well as liposomal parenterals with encapsulated drugs like doxorubicin.

Due to their complex structure and composition approval procedures well established for generic drugs (i.e. abridged application/ANDA) are not appropriate here as long as the essential condition of identical active ingredients cannot be confirmed. Therefore, comprehensive comparability exercise is needed between the innovator product and its follow-on versions in order to conclude on their similarity in qualitative and quantitative composition. Considering the obvious differences in structure and complexity between the various NBCDs identical regulations cannot be applied to all these products. Thus, one consistent NBCD guideline including requirements for all these products cannot be adequate, but product-specific guidances should be more appropriate.

During the last couple of years such guidances have been developed for the European Union and the United States of America. There are, however, certain differences in the requirements between both legislations. Bridging the gap between deviating viewpoints and harmonization of the regulations should be the intention of regulatory agencies and industry. Essential condition for such initiative is the availability of experimental findings in order to establish science-driven regulations.

A detailed comparison of the current requirements suggested by the existing guidances indicates more consistency between the recommendations than expected considering the international debate on the most adequate approach for this heterogeneous group of products. However, reports published on experimental comparisons between generic alternatives which received the marketing authorization based on these regulations and their innovator reference products showed differences in certain quality attributes or, in some cases, also in clinical efficacy/safety outcomes.

It will be the mission for scientists from academia, industry and regulatory agencies to reconsider the current regulations in the light of the published findings in order to find out which quality attributes are clinically relevant and, thus, may be considered "critical" for the therapeutic effects. The most appropriate way to achieve this goal needs to be defined case-by-case considering the significant deviations between products of the NBCD group. Aspects relevant in this context will be highlighted.