Date Published: April 17, 2019
Publisher: Springer International Publishing
Author(s): Jon S. B. de Vlieger, Daan J. A. Crommelin, Katherine Tyner, Daryl C. Drummond, Wenlei Jiang, Scott E. McNeil, Sesha Neervannan, Rachael M. Crist, Vinod P. Shah.
To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: “Drug Products, Including Biological Products, that Contain Nanomaterials” in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.
In Spring 2018, AAPS circulated a survey among its members asking (i) which FDA guidance(s) the community would most benefit from discussing in a workshop setting and (ii) what challenges should be discussed related to the guidance. The outcome suggested two draft guidance documents: the FDA draft guidance “Drug Products, Including Biological Products, that Contain Nanomaterials” (the nanomaterial guidance), published in December 2017 (1), and the FDA draft guidance on “Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products,” published in April 2016 (2). During two adjacent days, September 11–12, 2018, participants discussed the two draft guidance documents. Since the scope of the two guidance documents, as well as the composition of the audience, differed significantly, this report focuses only on the draft guidance on drug products containing nanomaterials. Discussions around the second draft guidance on immunogenicity testing are covered in a separate report.
Following a brief introduction by Dr. Vinod Shah, the chair of the workshop, speakers from the FDA and industry presented their thoughts about the background and content of the recently published draft guidance which covers various elements of the regulatory recommendations for drug products containing nanomaterials. Dr. Katherine Tyner from FDA (CDER Nanotechnology Working Group Lead) kicked off the presentations by describing her personal views regarding the history and reasoning behind the guidance document before discussing parts of the text in more detail.
A common denominator for these nanomaterials is their complexity. Two themes are prominent in the guidance: (1) characterization of the nanomaterial and (2) understanding how nanomaterial attributes relate to product quality, safety, and efficacy. A risk-based approach focused on a number of listed risk factors is proposed. Debates were held on the validity and practical meaning of the listed risk factors in the discussions during the workshop. For example, can one always fully characterize these complex structures, do we always know the mechanism by which the physico-chemical properties of the material impact its biological effect, or can in vitro release methods indeed predict in vivo release?
The guidance covers a large number of topics. Its position in the “pyramid” (Fig. 2) means that this is the basic guidance for a number of structurally quite different nanomedicine subgroups and therefore does not provide product-subgroup-related detailed instructions. In the limited time available during the meeting, a selection of topics from the guidance was highlighted by Dr. Daryl Drummond, Merrimack Pharmaceuticals, based on his experience developing nanomaterials for industry, more specifically, novel liposome products. The section identifiers noted in parentheses below refer to the corresponding section in the guidance where this topic is discussed.
Dr. Wenlei Jiang from the FDA (Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research) gave her personal views on regulatory research in nanomedicine with a focus on generics. FDA recognizes the complexity of nanotechnology products and strongly encourages regulatory research in this area. FDA has a strong program in place to support nanotechnology research and CDER’s nanotechnology research has focused on quality, safety, equivalence, and post-market surveillance of these products via internal projects and extramural grants/contracts. The outcomes of various studies become scientific bases for FDA general guidances and product-specific guidances for nanotechnology drug products, which are made available in the public domain (7,8). Results from industrial and academic studies related to these regulatory topics are also welcome.
In the guidance, CQA assessment is a major pillar for structuring the risk-based analysis. For example, it reads: “The CQAs need not be an exhaustive catalogue of quality attributes, but should capture attributes that potentially impact the quality, safety, or efficacy of the final product.” From an industrial perspective, certain well-established nanomaterial characteristics that are known to impact performance (e.g., clearance rates), such as particle size or surface charge, are provided for specifically in the guidance. However, many are product specific. Furthermore, it is beneficial to create a table at the onset of development for any new product candidate, listing the characteristic, the mechanism behind its theoretical impact on product performance, and the initial specifications. This should be updated during development as more data becomes available around the impact of ranges of characteristic parameters, or upon the identification of new attributes. Determining CQA’s and their related specifications is beyond a theoretical exercise and benefits from experimental data to establish the impact of meaningful changes to the CQAs, notably at the boundary of proposed specifications. Ultimately, the impact on clinical performance validates the approach taken to identify the attributes.
During the meeting and following the paper by Marden et al. (24), some participants made the point that the 505(j) route may not be appropriate in the case of drug products containing nanomaterials. Terminology-wise, the wording “complex generic” implies therapeutic equivalence and thus substitutability. In terms of complexity, complex nanomedicine products show resemblance to biologic products and therefore it was proposed to discuss a potential new regulatory pathway for nanomaterials that would be like the biosimilar pathway. The FDA staff participating in the meeting raised strong concerns that this topic was out of scope for a workshop intended to focus on the scientific issues related to nanomedicines.
Over time, differences in approval standards between different regions in the world have been observed, leading to additional efforts and increased costs (e.g., extra patient involvement) for both the innovative and generic industry. Examples are the different approval processes for complex generic drug products in the USA and the EU for LMWH (low molecular weight heparins), glatiramoids, iron-carbohydrate products, and doxorubicin HCl liposomes. Harmonization is critical for developers. When multiple new questions arise regarding nanomedicine development protocols in each and every new market, the approval of these much-needed candidate nanomedicines in these markets can be significantly delayed or even discontinued. Although not discussed in detail, the question was raised whether it is time for an ICH initiative, or to step up other initiatives to harmonize (parts of) the standards for approval of nanomedicines. During time of writing of this report, a statement of the FDA Commissioner Gottlieb was published in support of global harmonization of scientific and technical requirements for generic drugs. The ultimate goal of this global harmonization, as written in the statement, would be the attainment of a single global generic drug development program that can support simultaneous regulatory filings across multiple markets (25).
The AAPS Guidance Forum on the draft guidance, “Drug Products, Including Biological Products, that Contain Nanomaterials” proved to serve as an open discussion platform for scientists from industry, academia, and regulatory bodies. Such an open discussion provides relevant input for industry and regulatory authorities on how draft guidances are (to be) interpreted. For the particular draft guidance at hand, the formal commenting period was already closed at the time of the meeting. However, speakers from FDA invited participants to bring any questions to their attention to avoid any doubt on how to read and interpret guidances for the development of NDAs and ANDAs. Although aware of short timelines, the participants agreed that alignment of the release of guidance documents and the organization of public discussions such as in the AAPS Guidance Forum is of mutual benefit to both regulators and industry stakeholders. This would allow for in-depth, stakeholder-broad discussions of draft guidance documents, facilitating drug development and regulatory approval process for safe and effective nanomedicines—new or generic.