CRS Premeeting Workshop on the Regulatory Landscape for Therapeutic Biologics

Overview
While some biologics are intended to treat diseases and medical conditions, others are designed to prevent or diagnose diseases. The therapeutic biological products (TBPs) regulated by the Center for Drug Evaluation and Research (CDER) of the U.S. FDA typically refer to the following:

•  Monoclonal antibodies for in vivo use
•  Proteins intended for therapeutic use, including cytokines, growth factors, enzymes, thrombolytic proteins, and other novel proteins
•  Immunomodulators
•  Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease, or otherwise alter the production of hematopoietic cells in vivo.

Other biologics such as vaccines, blood, and gene and cell therapies are regulated by the Center for Biologics Evaluation and Research (CBER) of the U.S. FDA.

The workshop is aimed at providing a snapshot of the recent evolution in product development and regulatory evaluation of therapeutic biologics. In addition to therapeutic biologics, the workshop will also introduce the regulatory considerations for complex drug substances including peptides, which typically have no more than 40 amino acids, as well as related drug delivery systems such as implants and microspheres for parenteral administration.

Recognizing the challenges associated with developing and evaluating biological products, both governmental entities and industry in different regions of the world have made considerable efforts to do this right. This workshop will present several case studies covering both product development and regulatory evaluation of biological drug products. The goal of the workshop is to provide recent information related to global efforts on developing regulatory approaches to ensure smooth and efficient evaluation and approval of biological drug products. Contributors consist of current and past regulatory experts from both the United States and Europe.

The co-chairs, Hong Wen and Yan Wang, prepared this exciting workshop by assembling a great team of experts from around the world. The invited speakers include John Petricciani, Serge Beaucage, Liang Zhao, Mohan Sapru, Audrey Jia, Evangelos Kotzagiorgis, Xiaohui Jiang, Harsh Jain, Yan Wang, and Wen Qu. Below are synopses of a few presentations.

Complex Drug Substances Including Peptides
Drug products containing complex drug substances have unique therapeutic profiles that small molecular drugs cannot replicate. Complex drug substances can be a single molecule or a mixture of different components, and these include natural products, peptides and conjugated peptides, synthetic and biopolymers, and any other drug substance that presents a challenge in its characterization. Regulatory considerations differ slightly for drug products under a New Drug Application (NDA) and an Abbreviated New Drug Application (ANDA). Characterization including elucidation of structure and other characteristics is the main focus for complex drug substances in the NDA process. Although it still serves as the foundation in an ANDA containing a complex drug substance, the goal of characterization in an ANDA is to demonstrate the sameness of the active ingredient or pharmaceutical equivalence between a reference listed drug (RLD) and the proposed generic drug products. Nevertheless, having good characterization of a complex drug substance is a critical step to gain regulatory approval under either the NDA or ANDA path. In recent years, advances in analytical techniques contributed to the success of a number of NDA and ANDA products. The presentation will highlight regulatory considerations on characterization of complex drug substances including peptides using the advanced analytical techniques.

Therapeutic Biological Products
Different from structurally well-defined, low-molecular-weight chemical drugs, biologic products are complex molecules that are generated from live cells, such as bacteria, yeast, or mammalian cells. Most of them carry post-translational modifications (PTM) and have inherited heterogeneity. They often contain multiple units/domains and have multiple functions and a complicated mechanism of
action (MoA). Their manufacturing processes are also more complicated than synthetic small molecules. In addition, biological products often have immunogenicity issues when used in patients. Nowadays, the pharmaceutical and biotechnology industry has invested significantly in the development of “biosimilars.” However, in addition to the challenges listed above, the developers often need to use different cell expression systems, raw materials, processes, purification platforms, and different formulations during product development. The unpredictable manufacturing differences and limited knowledge on the variation of the reference products make development of successful biosimilars challenging. The presentation aims to provide a road map facilitating the development of biosimilars from an industry perspective.

Gene and Cell Therapies
There will be two presentations focusing on amphipathic trans-acting phosphorothioate DNA elements to deliver uncharged peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) as well as negatively charged DNA and RNA sequences in mammalian cells. Most human genes undergo alternative splicing events, which are triggered by intricate and highly regulated machinery requiring the sequence-specific binding of several proteins to nuclear pre-messenger RNAs (pre-mRNAs). Steric interference imparted by RNase H-incompetent oligonucleotide analogues, complementary to specific pre-mRNA splice sites, has been shown to be efficient at redirecting the splicing machinery during assembly of mature mRNAs.1 Indeed, skipping the mutated exons in dystrophin pre-mRNA, as an approach to the clinical treatment of Duchenne muscular dystrophy, highlights the biomedical significance of alternative splicing events.²

Nucleic acid–based drugs have been recognized as powerful tools for targeting therapeutically important mRNAs and eliciting their destruction or preventing their expression into protein-causing diseases. By virtue of their gene silencing properties, nucleic acid–based drugs have tremendous potential in the treatment of cancer, infectious diseases, and “undruggable” diseases in humans. However, a major impediment to the therapeutic application of nucleic acid–based drugs is in vivo delivery; a primary reason for this is the polyanionic nature of nucleic acids, limiting their cellular internalization. Nucleic acids can be divided into two categories on the basis of their sizes. DNA plasmids and mRNAs belong to the high-molecular-weight category, whereas siRNAs, antisense oligonucleotides, DNA or RNA aptamers, and DNA decoys (to name a few) belong to the low-molecular-weight category. Both categories present unique challenges, in terms of delivery, based on the number of negatively charged phosphodiester functions available for electrostatic interactions with cationic delivery reagents.³

Cell-based medicines (cell therapies, or CTs) are among the most recent new biologicals. They are complex in their structure, content, mode of action, and delivery. In addition, there is substantial diversity among CT products, and their nonclinical and clinical testing programs will depend on product-specific features and their clinical indications. All of these factors create significant challenges for regulators and developers of CTs. Nevertheless, the CT field has advanced rapidly during the past decade, and products already have been approved in several countries. It remains an emerging area of biomedical research and development in which there are many areas of regulatory uncertainty and differences among countries and regions. The presentation will focus on the recent advances in the international regulatory landscape for cell therapy.

Disclaimer
This article reflects the views of the author and should not be construed to represent the FDA’s views or policies.

References
1. Jaerver, P, O’Donovan, L, Gait, MJ. A chemical view of oligonucleotides for exon skipping and related drug applications. Nucleic Acid Ther. 24:37-47 (2014).
2. Moulton, HM, Moulton, JD. Morpholinos and their peptide conjugates: Therapeutic promise and challenge for Duchenne muscular dystrophy. Biochim. Biophys. Acta, Biomembr. 1798:2296-2303 (2010).
3. Scholz, C, Wagner, E. Therapeutic plasmid DNA versus siRNA delivery: Common and different tasks for synthetic carriers. J. Controlled Release 161:554-565 (2012). n