Protein Therapeutics and the Regulation of Quality: A Brief History - As the biotechnology industry has matured through various stages of growth, regulatory agencies have evolved in response to the ne

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Protein Therapeutics and the Regulation of Quality: A Brief History
As the biotechnology industry has matured through various stages of growth, regulatory agencies have evolved in response to the need to define quality standards.


BioPharm International
Volume 20, Issue 10

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.


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