Protein Therapeutics and the Regulation of Quality: A Brief History

Steven Kozlowski

The history of the protein therapeutics over the past decades can be divided into five main periods. Each stage along the way has seen the development of new products, advances in science, and the evolution of quality regulations to adapt to those changes. A review of this history can be instructive as we advance in an era of new dosage forms, follow-on biologics, and unknown industry and regulatory challenges that have yet to arise.

Pre-1986: A Star Is Born

In the early 1950s, DNA was shown to transfer genetic information, and the double helix structure of DNA was resolved. By 1961, the genetic code was deciphered, paving the way to genetic engineering and biotechnology. These advances promised tremendous benefits but generated a great deal of fear. To deal with the potential risks of this new technology, the National Institutes of Health (NIH) issued guidelines on the use of recombinant DNA (now known as the NIH Guidelines for Research Involving Recombinant DNA Molecules) in 1976, and the following year, many bills were presented in Congress to limit the use of recombinant DNA technology. Between 1976 and 1986, however, fears about the use of DNA diminished, and genetic engineering allowed for the successful production and marketing of human insulin and growth hormone, both of which were manufactured using recombinant bacterial expression systems. These products were great successes. Although as a society we still worry about biotechnology, from genetically engineered foods to fictional recombinant velociraptors (thanks to Hollywood films such as Jurassic Park), we have seen the benefits of biotechnology-derived pharmaceuticals.

1986–1991: More Biotechnology Successes

Products: Interferon; The First Antibody; Hematopoetic Growth Factors
In 1986, interferon alfa was initially approved for the treatment of hairy cell leukemia, and other oncology and antiviral indications followed. Also in 1986, muromonab-CD3, the first marketed monoclonal antibody, was approved for the treatment of allograft rejection. This murine monoclonal antibody reversed acute renal rejection in greater than 90% of cases, and it was the first marketed product made from an immortalized mammalian cell fusion. In 1987, alteplase was approved for the treatment of acute myocardial infarctions; other therapeutic enzymes with cardiovascular indications followed. Alteplase production used immortalized Chinese hamster ovary cells (CHO), further advancing the role of mammalian cell lines in the manufacture of biotechnology products. From 1989 to 1991, the hematopoetic growth factors erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF, produced by recombinant yeast) were approved for marketing in the United States. These products treat anemia by reducing transfusions or treat neutropenia by reducing infections.

CLICK IMAGE TO ENLARGE Staff from the Office of Biotechnology Products at work. Far left: Mate Tolnay reviews monoclonal antibodies and runs a laboratory program. Center: Emanuela Lacana reviews therapeutic proteins. Above: Ashutosh Rao is an FDA-NCI fellow performing research and review side-by-side (review page obscured).

Science and Regulation: The Process is the Product
Biotechnology products are complex and have many structural attributes. Their source materials include bacterial, yeast, and mammalian cells, and contain a variety of potential impurities. Protein characterization used methods such as gel electrophoresis and chromatographic analysis. Peptide mapping was becoming a powerful tool for examining primary structure and modifications. Higher order structure was evaluated through biological activity. Because end-product testing is of very limited utility in assessing clinical performance of complex biological products, the manufacturing process was critical to assure consistent product quality. The strategy to deal with this process-dependence was to fix the commercial process to the process used for the manufacture of clinical lots. Thus, the product was linked to the labeled clinical outcomes through a highly defined manufacturing process. The biologics mantra of “the process is the product” applied. The importance of process for biologics already had been codified through separate license applications for products (product license applications or PLAs) and manufacturing facilities (establishment license applications or ELAs).

Organizational Changes: The Separation of CBER and CDER
This period started with the creation of a combined FDA Center for Drugs and Biologics (CDB). In 1988, the CDB was divided into the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The responsibility for review was derived from the US Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. Responsibilities were further defined in the intercenter agreement of 1991. Under this agreement, review responsibility was based on product class in certain situations. For example, CBER reviewed immunoglobulins independent of their source or manufacturing methodology, and CDER reviewed hormone products (e.g., insulin or growth hormone) independent of their source and manufacturing methodology. Concerns over biotechnology, however, led to some methodology-based responsibilities. With exceptions as noted above, protein products produced in cell culture or through genetic alteration of an animal were reviewed by CBER, and proteins purified from natural tissues were reviewed by CDER. For methodology-based responsibility, once a protein class was assigned to a center, future proteins in that class remained in that center even if the manufacturing methodology changed (e.g., tissue-derived to recombinant-cell-culture-derived). Although this agreement had the potential for a complex distribution of biotechnology products (e.g., enzymes could reside in either center), in general, classical hormones were reviewed at CDER, and antibodies, growth factors, and cytokines were reviewed at CBER.

Summary of the Period: Biotech Products Become Real Players
The years 1986 through 1991 were a period of massive growth for biotechnology products. Estimates of biotech revenue were minimal in the early-to-mid-1980s, but by the beginning of the next period (1992), they had grown to approximately $8 billion. Recombinant products were being manufactured in mammalian and yeast cells as well as bacteria. The first recombinant enzyme and growth factors were approved. Monoclonal antibodies (MAbs), a technology anticipated since 1975, was realized in a licensed product. Biotechnology products were now real players in the pharmaceutical industry.

This success brought with it a number of issues that needed resolution. The uncertainty associated with developing pharmaceuticals, combined with the large investments for commercial biotechnology manufacturing, led to significant economic risk. Allowing for some flexibility in manufacturing scale or sites could reduce this risk and facilitate market responsiveness for approved products. Although MAbs were a big achievement, they were murine proteins and were limited by immunogenicity. As the interest in biotechnology expanded, it became clear that there was a need for agency and global biotechnology product standards.

1992–1997: A Biotechnology Industry

Products: Chimeric and Humanized Antibodies
In 1992, a monoclonal radiolabeled imaging agent, In-111 satumomab, was approved by the FDA. In 1993, the first interferon beta for use in treating multiple sclerosis was approved, and that same year dornase alfa was marketed to treat complications of cystic fibrosis. A second therapeutic antibody-related product, abciximab, was approved in 1994. Abciximab, an antibody fragment, was chimeric, with the constant regions having human instead of murine sequences. In 1997, the first whole chimeric antibody, rituximab, and the first humanized antibody, daclizumab, were approved. These genetically engineered modifications reduced the immunogenic murine sequences in MAbs; thus, they facilitated chronic use.

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 and biologics.

CLICK IMAGE TO ENLARGE

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 and Policy.

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 biotechnology industry.

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.

1998–2001: Biotechnology Improvements

Products: The Rise of Engineering
This period began with an expansion of indications for biotechnology products. In 1998, two humanized MAbs were approved: palivizumab, an antiviral antibody for a pediatric population, and trastuzumab, an antibody directed against a solid tumor. During this period, biotechnology products were modified in a variety of other ways to improve their performance. The first fusion protein, etanercept, linked a tumor necrosis factor receptor to an antibody Fc region and was approved in 1998. This dimerized the receptor and allowed for favorable pharmacokinetics. In 1999, denileukin difitox, a fusion of interleukin-2 and diphtheria toxin fragments, was approved.

In addition to these genetically engineered fusion proteins and prior radiolabeled antibody conjugates, a calicheamicin antibody conjugate was approved in 2000. Products linked to carefully controlled amounts of polyethylene glycol (PEG) were shown in many cases to have improved pharmacokinetics, and PEGylated versions of previously approved growth factors (G-CSF and GM-CSF) and interferons began to be marketed in 2001. Also, darbepoetin, a product with another strategy for improved pharmacokinetics, was approved in 2001. Darbepoetin is a variant of erythropoietin, genetically engineered to include two additional glycosylation sites.

Science and Regulation: Improved Methods for Characterization
Assays for both biotechnology product specifications and characterization continued to advance. Bioassays with lower variances were being developed. In 1999, ICH finalized Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (Q6B). Meanwhile, mass spectroscopy and nuclear magnetic resonance capabilities improved greatly. In 2002, at the start of the next period, the pioneers of these analytical techniques for biological macromolecules, Koichi Tanaka and John Fenn, shared a Nobel Prize for chemistry for the development of mass spectrometry in protein chemistry. Other advances included the use of orthogonal analytical methods, which allowed for improved characterization of variants, and the development of high-dose monoclonal antibody therapeutics, which led to advances in cell culture yields and high-concentration formulations. For chronically dosed products, pre-filled syringe dosage forms were now being used.

Organizational Changes: The Division of Therapeutic Proteins
In 1999, the OTRR’s Divisions of Hematologic Products and Cytokine Biology were combined into the Division of Therapeutic Proteins. This brought cytokines and growth factors together and left two divisions in OTRR for protein therapeutics: one for antibody-related products and the other for nonantibody therapeutic proteins.

Summary of the Period: Maturing Products and Processes
In the preceding eras, biotechnology products had succeeded and become an industry. During the 1998–2001 period, that industry matured and focused on improving its products and manufacturing processes. A variety of strategies, including fusion proteins, conjugation, PEGylation, and mutation were used and continue to be used to improve native proteins. The goal was no longer just to use biotechnology to manufacture a protein, but to tailor that protein to meet specific clinical performance needs. Improvements were not limited to product design but extended to the manufacturing process, allowing for improved yields and delivery of drug product. Advances in analytics allowed for better product characterization, and there was a broader appreciation for the potential clinical impact of structural variants. The intentional design of a glycoform variant to alter clinical performance highlighted this point. These improvements coincided with an increasing market for these products, representing approximately $30 billion of the $400 billion in yearly worldwide pharmaceutical sales for the beginning of the next period in 2002. As revenues grew, an interest in drug development costs also grew. In 2001, the Tufts Center for the Study of Drug Development estimated the cost of new drug development at over $800 million dollars.

2002 and beyond: Biotechnology for the 21st Century

Products: Fully Human Antibodies; Recombinant Enzymes
In 2002, adalimumab, a fully human antibody generated using phage display technology, was approved. In 2006, panitumumab, another fully human antibody generated using transgenic animals, was approved. Panitumumab is one of a number of biotechnology products that target epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) pathways. Between 2002 and 2006, a number of recombinant enzymes for lysosomal storage diseases, such as Fabry disease, some forms of mucopolysaccharoidoses, and Pompe disease, were approved for marketing. Also during this period, two fusion proteins and two antibodies that target adhesion and costimulatory molecules were approved.

Science and Regulation: Immunogenicity Concerns; Follow-on Biologics
Many issues of the previous periods continue to be relevant in this era. Manufacturing changes and comparability remain important issues for biotechnology products, and in 2004 ICH finalized its Q5E guidance, Comparability of Biotechnology/Biological Products Subject to Changes in Their Manufacturing Process.

Although the immunogenicity of protein products had been an issue throughout the history of biotechnology products, the publication in 2002 of information about transfusion-dependent pure red cell aplasia (PRCA) cases in patients receiving recombinant erythropoietin highlighted the risks of immunogenicity. Increases in the frequency of PRCA were associated with a manufacturing change of the product distributed in Europe. Immunogenicity is difficult to predict and can affect both safety and efficacy; thus, the potential for manufacturing changes to impact the immunogenicity of proteins needs to be considered. Hypersensitivity, immune suppression, and cytokine release syndrome are other potential immunologic adverse events of biotechnology products.

Many of the principles used in comparability for manufacturing changes may also apply to follow-on proteins or biosimilars, and there has been significant activity in this area. The FDA cosponsored meetings on the scientific considerations for developing follow-on protein products in September 2004 and February 2005, and in December 2005, the agency co-sponsored a New York Academy of Sciences Follow-On Biologics Workshop. Meanwhile, the European Agency for the Evaluation of Medicinal Products (EMEA) developed a pathway for biosimilar protein products; that agency’s Guideline on Similar Biological Medicinal Products was finalized in 2005. The FDA approved Omnitrope in 2006 under the 505(b)(2) pathway for products of the Food, Drug, and Cosmetics Act. The European Commission has also approved Omnitrope and recently approved an erythropoietin biosimilar product. There is yet no regulatory pathway in the US for follow-on or biosimilar protein products regulated under the Public Health Service Act. A number of draft bills are being debated regarding this issue, however, and the OBP scientific staff is ready to provide scientific input or review in whatever roles are dictated by future policies.

Manufacturing for the 21st Century
In August 2002, the FDA announced a significant new initiative, “Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century,”; to enhance and modernize the regulation of pharmaceutical manufacturing and product quality. This initiative stresses the following principles:

• Science-Based: An important component of this initiative is that it encourages the best science in manufacturing. It includes the use of new technologies, such as process analytical technology (PAT), and an overarching proactive approach to designing and controlling the manufacturing process (quality by design, or QbD). The FDA finalized a PAT guidance in 2004, PAT-A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. The ICH Q8 guidance, Pharmaceutical Development (Q8), focusing on the development of a manufacturing design space, was finalized in 2006. A pilot for application of QbD to small-molecule drugs by the Office of New Drug Quality Assessment (ONDQA) was very successful, and OBP plans to initiate a QbD pilot for biotechnology products. An important consideration for implementing these approaches is a strategy for risk management.

• Risk-Based: The ICH Q9 guidance, Quality Risk Management was also finalized in 2006. Where risk is concerned, the use of prior knowledge may play a critical role for biotechnology products. Platform approaches for manufacturing antibodies, for example, may be of great benefit. Even without modifications in pharmaceutical development, agency experience with manufacturing changes can be used to revise the risk assessments of manufacturing changes. Approaches to manufacturing changes may be altered based on discussions regarding significant revision of 21 CFR 314.70 for new drug approvals (NDAs). This revision may lead to risk-based changes in supplement classification and reduction of supplements. It has been suggested that 21 CFR 610.12 be further revised for BLAs. Risk-management principles also can be applied to internal agency review practices to ensure that decisions are consistent and that agency resource allocation is aligned with risk.

• Knowledge Coordination: To successfully use advances in pharmaceutical science and risk management, a large body of knowledge should be created. The biotechnology industry needs to coordinate all relevant experience, as well as developmental, manufacturing, preclinical, and clinical knowledge, and the FDA needs to coordinate prior decisions, outcomes, and relevant scientific findings. OBP is interested in using databases to analyze experiences with comparability and to evaluate the questions we pose to industry. One important approach to ensure agency access to experiences with related products is a unique nomenclature for proteins. Stephen Shaw, chief of NIH’s Human Immunology Section, has suggested using source gene identities (IDs) to link classes of related products. OBP is interested in using this strategy as part of protein identifiers for its databases. Gene IDs can also be used to identify antibody targets, and Enzyme Commission (EC) numbers can be used for enzymes. A more basic part of knowledge coordination, of course, is clear communication. CDER is implementing good review management practices to improve communication among review disciplines and with the industry. OBP has assigned umbrella contacts to each of five Offices of Drug Evaluation based on a model developed by ONDQA.

• Modern Management: The integration of current science, risk management, and knowledge requires modern quality-management techniques, including the implementation of quality systems approaches to all aspects of pharmaceutical production and quality assurance. The FDA issued its quality systems guidance, Quality Systems Approach to Pharmaceutical CGMP Regulations in 2006, and ICH released its draft Q10 guideline, Pharmaceutical Quality System for consultation in 2007.

The Critical Path and Biology
A key to the use of PAT, QbD, and risk management is defining critical product attributes and linking them to critical process parameters. Product complexity and heterogeneity suggest that critical product attributes can only be defined with a better knowledge of product–biology and structure–function relationships. Characterization of the in vivo structures of biotechnology products may be an important strategy to define critical product attributes. Although biological characterization is challenging, the benefits are not restricted to manufacturing and may play a role in other dimensions of the critical path for drug development. The FDA’s critical path initiative was launched in March 2004 with the release of an important report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. The Critical Path initiative includes industrialization as well as dimensions covering safety and medical utility. Biological characterization may enhance mechanistic understanding and inform decisions regarding product safety. This mechanistic understanding may also facilitate the appropriate selection of animal models. An understanding of molecular mechanisms using a variety of models can inform clinical trial design. Moreover, as the industry moves forward with the development of biomarkers and the use of systems biology (e.g., pharmacogenomics and proteomics), mechanistic understanding can provide plausibility for decisions based on complex data sets.

OBP Research Activities
The OBP staff reviews regulatory submissions for investigational new drugs (INDs), BLAs, NDAs, and supplements. The staff participates in meetings, pre-approval inspections, and some postapproval inspections. Many OBP reviewers are laboratory-based and involved in research programs. This gives OBP research programs direct access to emerging regulatory challenges. Areas of OBP research include: the development of bioactivity assay cell lines for products such as anthrax toxin therapeutics; the role of aggregates and residual host cell molecules in immunogenicity; viral clearance and inactivation studies; and the development of standards for virus retention filters. The research programs have internal and external reviews, as indicated earlier, and result in guidance and other publications, and facilitate effective sponsor interactions. Research on topics such as cytokine biology relate to the products the office currently regulates, however, an internal knowledge base in immunology, biology, and biochemistry also prepares the staff to deal with new developments.

FDA Commissioner Andrew von Eschenbach has highlighted the FDA as a bridge from discovery to delivery. To function as this bridge, the FDA must be a science-led agency. He instituted the Interagency Oncology Taskforce (IOTF) while still director of the National Cancer Institute to forge such a bridge. OBP has had multiple IOTF fellows in its research programs and intends to continue to strengthen the discovery-to-delivery bridge in whatever ways needed.

Organizational Changes: The Evolving Role of OBP
In 2002, the Division of Cell and Gene Therapy was made a separate office in anticipation of growth in these areas. In 2003, OTRR was transferred to CDER, and this move to the CDER was a partial return to the combined Center for Drugs and Biologics of 20 years ago. Although biologics still present many unique issues, improvements in product characterization and the facilitation of consistent clinical endpoints for therapeutics were among the rationales for the consolidation.

When oversight of therapeutic biologics initially transferred to CDER, review responsibilities were divided between the Office of New Drugs and the Office of Pharmaceutical Science (OPS). OTRR was split into the Office of Drug Evaluation 6 (ODE6) and the Office of Biotechnology Products (OBP). ODE6 was made responsible for clinical and preclinical issues, and ODE6 personnel and products were distributed to other Offices of Drug Evaluation (ODEs) throughout the Office of New Drugs as of October 2005. OBP has primary review responsibility for chemistry, manufacturing controls, and product quality. It also has expertise in immunology and other aspects of biology that contribute to product review. Moreover, OBP has regulated the quality of a number of nonrecombinant proteins, and from 2002 to the present, many others have been transferred to OBP. Botulinium toxins were transferred to the office from CBER. Botulinium toxins are licensed therapeutics in which the active ingredient also appears on the CDC’s category A list of biological agents; despite this notoriety, the licensed products are used safely and effectively. In addition, pegademase, an enzyme approved for treatment of a form of severe combined immunodeficiency (bubble child syndrome), has been transferred to OBP. Enzymes (recombinant and nonrecombinant) to treat Type I Gaucher’s disease, along with other enzymes, such as pancrealipase, sacrosidase, hyaluronidase, and chymotrypsin, were transferred to OBP between May and August of 2006.

With the move of many enzymes to OBP, more than 85 approved products are now regulated by OBP for quality. This represents a one-third increase since 2005. More than a fifth of these products are regulated under the NDA pathway, and this fact gives OBP reviewers experience with both the NDA and BLA pathways. (The pathway by which a protein product is regulated depends on the Food, Drug, and Cosmetics Act, the Public Health Services Act, and related regulations.)

Current Situation and Projections for the Future

The last two decades have established biologcis in the pharmaceutical marketplace. In addition to products now in OBP, recombinant versions of insulins, somatropin, gonadotropins, and other recombinant products have been marketed during the past 20 years. In 2006, an inhaled form of insulin (Exubera) was approved, expanding protein products into a new dosage form. Many complex hematologic factors regulated by CBER have also been marketed as recombinant products. Some estimates of biotechnology sales for 2004 exceed $40 billion dollars, and estimates approach $60 billion dollars for 2010.

These products have provided benefits to patients across a wide range of medical needs, from rare enzyme deficiencies to far-too-common malignancies. Current OBP products are distributed across many clinical indications. Approximately 30% of the office’s marketed products are in the oncology, hematology, and medical imaging clinical divisions. The gastroenterology, anti-infective, and ophthalmology divisions each make up more than 10% of the marketed products reviewed by OBP for quality. Divisions covering anti-virals, rheumatologic, dermatologic, neurologic, cardiovascular, and transplant indications each have approximately 5–10% of OBP’s approved products. This distribution is based on primary responsibility, and many biotechnology products have multiple indications.

These products improve survival times or quality of life in a variety of diseases, and hundreds of new products are under development. Despite an overall slowdown in the development of new molecular entities in the pharmaceutical industry, many biotechnology product classes have an increasing product pipeline. There also has been an increase in meeting requests at early stages of product development. These meetings help companies ensure, early on, that they understand the information FDA needs to evaluate their filings. The future may have many follow-on or biosimilar products. New indications for biotechnology products, such as the treatment of psychiatric illnesses, may develop as disease understanding and product design advance. Current development strategies will be used, along with more sophisticated approaches such as evolutionary technologies to tailor protein biochemical attributes, immunogenicity, and clinical performance. Novel and more convenient protein dosage forms may be much more common. In addition to current uses, proteins are likely to play important future roles in combination therapies and in conjunction with cellular and nanotechnologies. Strategies for mining the now-sequenced human genome may provide a new generation of biotechnology-based therapeutics. We may also see therapeutic advances from combining the target specificity of protein products with the population-specific target selection of systems biology.

Over the last two decades, biotechnology has moved from a source of fear to a source of benefit, even outside the pharmaceutical arena. Despite a 1978 Hollywood depiction of killer tomatoes, in 1993 a genetically engineered tomato was approved-and life went on. However, some uncertainties in biotechnology still exist, and both the industry and the agency must be ready to take advantage of new opportunities and to respond to new challenges. OBP and its staff, both as regulators and consumers, look forward to the next two decades of biotechnology.

Disclaimer

Products mentioned in this article were chosen to illustrate developments in product design, manufacturing, or dosage form. In some cases, clinical indication or other attributes were noted. No endorsement or judgment beyond product labeling on these or other products should be inferred.

Acknowledgements

Keith Webber, Elizabeth (Wendy) Shores, and Patrick Swann provided valuable comments on this manuscript.

Sources

Sources for information in this article include the following:
1. FDA and OBP staff.
2. FDA’s web site, www.fda.gov
3. US Food and Drug Administration. Science and the regulation of biological products, 2002. Rockville, MD.
4. Walsh G. Biopharmaceutical benchmarks 2006. Nat Biotechnol. 2006 Jul;24(7):769 –76.
5. Product package inserts.
6. BIO web site, www.bio.org

About the author

Steven Kozlowski, MD, is the director of the Office of Biotechnology Products in the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, 301.796.2390, steven.kozlowski@fda.hhs.gov.

The Evolution of Protein Therapeutics and the Regulation of Quality: A Timeline

1953

First accurate model of DNA suggested.

1961

Genetic code deciphered, paving the way to genetic engineering and biotechnology.

1976

DNA technology guidelines (now known as NIH Guidelines for Research Involving Recombinant DNA Molecules) issued by the National Institutes of Health.

1982

Human insulin, created using recombinant DNA technology, introduced.

1985

Growth hormone first manufactured using recombinant DNA technology.

1986

Interferon alfa and muromonab-CD3 approved.

1987

Alteplase, produced using Chinese hamster ovaries, approved.

1988

FDA’s Center for Drugs and Biologics divided into two organizations: Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER).

1989

Erythropoietin, granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF) approved.

1992

In111 satumomab, a monoclonal radiolabeled imaging agent, approved.

1992

Prescription Drug User Fee Act (PDUFA) allows FDA to collect application fees, providing resources to meet timelines and improve management of review process.

1993

First interferon beta approved for use in treating multiple sclerosis; dornase alfa marketed to treat complications of cystic fibrosis.

1993

CBER’s Office of Therapeutics Research and Review (OTRR) formed.

1994

Abciximab, an antibody fragment that is chimeric (with the constant regions having human instead of murine sequences), approved.

1994

Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Usage published by CBER.

1995

ICH finalizes Analysis of the Expression Construct in Cells Used for the Production of rDNA Derived Protein Products (Q5B) and Stability Testing for Biotechnology/Biological Products (Q5C).

1995

FDA issues Guidance Document Concerning Use of Pilot Manufacturing Facilities for the Development and Manufacture of Biological Products.

1996

FDA issues Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology Derived Products.

1997

First whole chimeric antibody, rituximab, and first humanized antibody, daclizumab, approved.

1997

To keep up with advances in manufacturing, CBER revises Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Usage.

1997

ICH issues 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).

1997

Food and Drug Administration Modernization Act (FDAMA) establishes a new approach to reporting manufacturing changes.

1997

FDA Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products fleshes out the regulations for reporting manufacturing changes.

1998

Etanercept, the first fusion protein, approved.

1999

Denileukin difitox, a fusion of interleukin2 and diphtheria toxin fragments, approved.  

1999

ICH finalizes Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (Q6B).

1999

OTRR’s Divisions of Hematologic Products and Cytokine Biology are combined into the Division of Therapeutic Proteins.

2000

A calicheamicin antibody conjugate approved.

2001

Marketing began for PEGylated versions of previously approved growth factors (G-CSF and GM-CSF) and interferons.

2001

The Tufts Center for the Study of Drug Development estimates the cost of new drug development at over $800 million dollars. </paragraph1>

2001

Darbepoetin, a variant of erythropoietin genetically engineered to include two additional glycosylation sites, approved.

2002

Koichi Tanaka and John Fenn shared Nobel Prize for chemistry for the development of mass spectrometry in protein chemistry.

2002

Market for biotechnology products represents approximately $30 billion of $400 billion in yearly worldwide pharmaceutical sales.

2002

Adalimumab, a fully human antibody generated using phage display technology, approved.

2002

Publication of information about transfusion-dependent pure red cell aplasia (PRCA) cases in patients receiving recombinant erythropoietin highlighted risks of immunogenicity.

2002

FDA announces its “Pharmaceutical Current Good Manufacturing Practices for the 21st Century;” initiative.

2002

OTRR’s Division of Cell and Gene Therapy is made a separate office.

2002

A number of recombinant enzymes for lysosomal storage diseases (such as Fabry disease, some forms of mucopolysaccharoidoses, and Pompe disease) approved. Two fusion proteins and two antibodies that target adhesion and costimulatory molecules also approved.

2003

OTRR is transferred to CDER. Review responsibilities were divided between the Office of New Drugs and the Office of Pharmaceutical Science (OPS). OTRR is split into the Office of Drug Evaluation 6 (ODE6) and the Office of Biotechnology Products (OBP).

2004

ICH finalizes Guidance for Industry: Comparability of Biotechnology/Biological Products Subject to Changes in Their Manufacturing Process (Q5E).

2004

FDA’s Critical Path initiative launched with release of Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.

2004

FDA cosponsors meetings on scientific considerations for developing follow-on protein products and cosponsors a New York Academy of Sciences follow-on biologics workshop.

2004

FDA finalizes Guidance for Industry: PATA Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.

2005

EMEA’s Guideline on Similar Biological Medicinal Products finalized.

2006

Panitumumab, a fully human antibody generated using transgenic animals and one of a number of biotechnology products that target epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) pathways, approved.

2006

FDA approves Omnitrope under the 505(b)(2) (generic) pathway of the Food, Drug, and Cosmetic Act.

2006

ICH finalizes Guidance for Industry: Pharmaceutical Development (Q8), focusing on the development of a manufacturing design space, and Guidance for Industry: Quality Risk Management (Q9).

2006

An inhaled form of insulin (Exubera) approved, expanding protein products into a new dosage form.

2006

FDA issues Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations.

2007

ICH releases the draft Guideline for Industry: Pharmaceutical Quality System (Q10) for consultation.