Science and Regulation: MAb Guidance, Comparability, and other Critical Issues
In addition to establishing approaches for reducing antibody immunogenicity, MAb development was facilitated by agency guidance.
Under Katy Stein's direction, a substantially revised Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Usage was published by CBER in 1994 and further revised in 1997 to keep up with advances in manufacturing. The International Conference
on Harmonization (ICH) also produced many documents during this time period that serve as global standards for biotechnology
products. In 1995, two ICH guidelines—Analysis of the Expression Construct in Cells Used for the Production of r-DNA Derived Protein Products (Q5B) and Stability Testing for Biotechnology/Biological Products (Q5C) —were finalized. In 1997, ICH issued two more guidelines: Viral Safety Evaluation of Biotechnology Products Derived from Lines of Human or Animal Origin and Derivation (Q5A) and Derivation and Characterization of Cell Substrates Used for the Production of Biotechnology/Biological Products (Q5D).
Comparability, Manufacturing Changes, and the Creation of the BLA.
During this period, the manufacturing process remained a key determinant in defining the product. However, the need for efficient
product development, as well as the capacity to respond to variable market demands, drove the development of a regulatory
approach to changes in manufacturing processes. Also during this period, characterization of biotechnology products continued
to improve in areas such as oligosaccharide mapping. The concept that product characterization may allow for process changes
was integrated into documents on comparability. These ideas were incorporated in the FDA's 1995 Guidance Document Concerning
Use of Pilot Manufacturing Facilities for the Development and Manufacture of Biological Products and the FDA's 1996 Guidance
Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Bio-technology-Derived Products.
In 1997, a new approach to reporting manufacturing changes was established through the Food and Drug Administration Modernization
Act (FDAMA). These new reporting categories for biologics were laid out in 21 CFR 601.12. (Reporting categories for products
submitted under New Drug Applications [NDAs], appeared in 21 CFR 314.70). These regulations were fleshed out in the FDA's
1997 Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological
Products. The FDAMA removed the requirement of separate applications for product and establishment licenses, combining them
into a single biologics license application (BLA). This was intended to minimize differences between applications for drugs
Organizational Changes: PDUFA and OTRR— the Precursor to OBP.
This period began in 1992 with the first Prescription Drug User Fee Act (PDUFA), which allowed the FDA to collect application
fees from drug manufacturers to fund the new drug approval process. This act gave the agency the resources to meet timelines
and improve management of the review process. At CBER, by 1993 the Office of Therapeutics Research and Review (OTRR) was
formed by Kathy Zoon. Janet Woodcock was the first OTRR director, and the OTRR group included all review disciplines for
biological therapeutics, including the Division of Clinical Trials Design and Analysis, and the Division of Application Review
OTRR had four divisions that reviewed product quality in specific areas: MAbs, hematologic products, cytokine biology, and
cell and gene therapy. With the exception of cell and gene therapy, these divisions were the predecessors of the current Office
of Biotechnology Products (OBP). All these divisions had research laboratories and many laboratory-based reviewers. Under
Dr. Jay Siegel's direction, OTRR set up a research prioritization system to score research programs for quality and for relevance
to current and expected product classes.
In addition, OTRR research programs continued to undergo external peer review (site visits) for quality. This combination
of internal and external review continues in current OBP laboratories. These research programs helped OTRR support the growing
Summary of the Period: New Standards and Harmonization
Between 1992 and 1997, advances in biotechnology continued. Antibody chimerization and humanization opened the door for a
new class of products. The FDA underwent many changes, including PDUFA, the regulatory framework for biologics, the approach
to manufacturing changes, and the organizational structures for review of therapeutic biologics. During this period there
was a major shift in regulatory focus. Instead of regulating a group of successful individual biotechnology products, the
FDA was now regulating the biotechnology industry as a whole. Standards were developed for the industry and harmonized for
global marketing. Process changes across the industry became more manageable through regulatory approaches to comparability.