Innovating Biologics Regulation: Insights from the Founding Director of the US FDA’s Division of Monoclonal Antibodies

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Biopharmaceutical researchers, manufacturers, and regulators converged on Washington, DC, in January 2023 to attend CASSS’s 26th annual Well-Characterized Biological Products (WCBP) meeting. Among the opening festivities at each such event is conferral of the prestigious William S. Hancock Award for Outstanding Achievements in Chemistry, Manufacturing, and Controls (CMC) Regulatory Science. The prize honors people who have spurred on significant advances in scientific principles, applied technologies, and science-based regulations for biomanufacturing process development, characterization, analysis, and quality assessment. The 2023 recipient of the prize is Kathryn Stein, who served as founding director of the Division of Monoclonal Antibodies (DMA) in the US Food and Drug Administration Center for Biologics Evaluation and Research (FDA CBER).

Stein joined CBER in 1980 and assumed leadership over the DMA in 1992. She received the CBER Outstanding Service Award in 2002 for spearheading policy related to science-based regulation of monoclonal antibodies (MAbs), thus helping to bring novel therapies to the public. After retiring from the agency, she served as senior vice president of product development and regulatory affairs at MacroGenics. Following a second retirement in 2016, she spent several years as an industry consultant.

During a virtual presentation of the Hancock Award, Marjorie A. Shapiro (chief of the FDA Laboratory of Molecular and Developmental Immunology) highlighted milestones in Stein’s illustrious career, then asked her to reflect on her experiences with shaping regulatory policy in the earliest days of MAb development and manufacturing. Below are Stein’s edited responses, which provide valuable insight into the development of science-driven review of biological products.

Early Experiences with MAbs
Vaccine Research: Before joining FDA CBER, I was a postdoctoral researcher and then a staff scientist at the National Institutes of Health (NIH), where I studied immune responses to polysaccharide antigens. At that time, researchers were trying to conjugate polysaccharides and proteins for use in routine childhood vaccines. I was interested in why infants didn’t respond to “pure polysaccharide” vaccines but did respond to polysaccharide–protein conjugates. My group produced many MAbs against the meningococcal group C polysaccharide, which was appropriate for vaccines in development for that pathogen. We used those MAbs to detect polysaccharide antigens, study immunologic mechanisms, and characterize vaccine products. We generated MAbs of different isotypes and immunoglobulin G (IgG) subclasses, enabling us to study the function of the antibodies’ crystallizable fragment (Fc) regions and their role in protecting against meningococcal group C.

I believed that my research experience could be put to good use in evaluating products at CBER. The agency was beginning to receive applications for polysaccharide vaccines, and clinical development of conjugate vaccines was on the horizon. I had used basic research in mouse models to understand immune responses to polysaccharide and conjugate vaccines, so I applied that knowledge to review of applications to the FDA. My team approved first polysaccharide vaccines and later conjugate vaccines for routine use in toddlers and then in infants. Although my research focused on meningococcal group C polysaccharides, I also reviewed submissions for conjugate vaccines against type B Haemophilus influenzae. The most gratifying aspects of my career were seeing such vaccines approved for use in toddlers and infants and witnessing a decline in invasive Haemophilus disease.

Establishing the DMA: Because of my experience with making hybridomas and purifying MAbs, I was tasked with reviewing investigational new drug (IND) applications for such products. Subsequently, when CBER was reorganized into three offices — for blood and blood products, vaccines, and therapeutic products — I was asked to head the new MAbs division (DMA) in the Office of Therapeutics when it opened in 1992. I was interested in MAbs for several reasons. Most important, I believed that monoclonals could be generated against almost any antigen and, therefore, could become a major product class.

However, it took a while for MAbs to get off the ground. Although murine MAbs were relatively easy to produce and could be effective against diseases in mice, they were ineffective for human use. They caused immunogenic reactions, exhibited short in vivo half-lives, and bound human Fc receptors poorly, reducing their effector functions. Development of chimeric and humanized antibodies enabled the field to succeed. We subsequently witnessed the advent of human MAbs derived from a variety of expression systems.

Our office soon reviewed applications for antibody–drug conjugates (ADCs), radiolabeled MAbs for diagnostic and therapeutic applications, and bispecific antibodies (bsAbs). Biopharmaceutical developers needed more time to clear the engineering and manufacturing hurdles associated with murine monoclonals. But solving those problems has led to many innovations in Fc engineering. Today, many product types exist, with large increases in numbers of bispecific constructs and, for ADCs, linkers and payloads. More than 100 MAbs now have been approved for use in the United States, including some bsAbs and ADCs.

Regulation of Novel Products
Our division’s early endeavors included publication of a “Points To Consider” (PTC) document for MAbs in 1994 (1), which we updated in 1997 (2). The FDA had issued a PTC document for monoclonals in the 1980s (3), so it was out of date by the time that the DMA was formed. Because MAbs represented a new product class, I determined that we needed an updated guidance. Rule-making takes a long time, but guidance documents provide suggestions. Thus, they do not take as long to publish as regulations do, and they can be updated more easily.

The 1994 PTC document ultimately served as a global model for regulation of MAb products. I received requests from Europe, Canada, Japan, and Australia for copies of it. Because the technology was changing so rapidly and because many new product types were being developed (including antibody fragments, ADCs, and radiolabeled antibodies), it was important to update the 1994 guidance.

The 1997 PTC document was comprehensive in covering both CMC and preclinical/clinical aspects of drug development. Sponsors often approached us to ask whether they could develop products that were different from those on the market. We considered what the sponsors were asking and told them, “Show us the data.” Basically, we took a scientific approach to biologics regulation. When industry wanted to do something new, we asked for data to show that a product would be useful and safe.

The same was true for processes. For example, one sponsor requested to apply the same viral-clearance studies performed on one product to another. The company provided data showing that the approach was appropriate, and we determined that the data indeed supported the request. That is how the agency developed its policies for generic and modular viral clearance, which our team presented at the first WCBP event in 1997.

Another policy outlined in the 1997 document was to allow reduced safety testing during phase 1 clinical studies of MAbs for serious or life-threatening conditions — provided that sponsors applied two robust, orthogonal steps during a purification process. My understanding is that such policies and experiences helped early in the SARS-CoV-2 pandemic with decisions about advancing MAb therapeutics quickly into clinical studies.

Enabling Progress
Considering how rapidly technologies change, I felt that it was important for our office to maintain a research laboratory, enabling us to stay current with analytical methods and manufacturing technologies. To that end, it is critical to continue building adequate staffing.

I am grateful to all of my technicians, graduate students, and postdoctoral researchers for their contributions to the research in my laboratory, which provided me with time to work on regulating vaccines and MAbs. Although I believed that monoclonals could be directed against any antigen, in my wildest dream, I didn’t think that I could turn on the television and see them and conjugate vaccines advertised every day.

1 94D-0259. Draft: Points To Consider in the Manufacture and Testing Of Monoclonal Antibody Products For Human Use. US Food and Drug Administration: Rockville, MD, August 1993;

2 FDA-1994-D-0318. Points To Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use. US Food and Drug Administration: Rockville, MD, February 1997;

3 Points To Consider in the Characterization of Cell Lines Used To Produce Biologicals. US Food and Drug Administration: Rockville, MD, 1987.

S. Anne Montgomery is cofounder and editor in chief, and Brian Gazaille is managing editor of BioProcess International;

Learn more about CASSS and the Hancock Award online at’-2023-hancock-award-winner.