INTRODUCTION
Biologics are proteins and/or their derivatives that regulate the immune system or support tumor specific defense. They are also known as “biological” or “recombinant therapeutics” and there are multiple definitions to it, being a constant source of controversy amongst the semantic purists. Biologics do not represent one homogeneous drug group, rather includes unrelated molecules like monoclonal antibodies, growth factors, fusion proteins, interferons, and expression vectors generating proteins in situ.1
The first documented uses of the term “biologics” was in 1912 when the pharmacological editor of the California State Journal of Medicine, Fred Lackenbach, used it in connection with national health-care legislation and the control of vaccine production in the United States (US).2 For a long time, there was no equivalent expression in Europe, and terms like Naturstojfe, Wirkstoffe (biologische Arzneimittel) or medicaments biologiques were used; all of them had different meanings and connotations, but sharing a common reference to “natural products”. Over the past century, biologics are so ubiquitous that our bodies have increasingly become exposed to them without us realizing the same, e.g. the use of vitamins, vaccines, insulin, etc. In present context, however, the “natural products” of yesteryears cease to be recognized as biologics with new definitions excluding them. The aim of this chapter is not intended to go into the controversial semantics, but to introduce the reader to the history of this therapeutic revolution.
HISTORY OF BIOLOGICS
Under an Act of Congress in 1902, all viruses, sera and toxins used in the United States were required to conform to established standards. It was officially designated as “An Act to Regulate the Sale of Viruses, Serums, Toxins and Analogous Products in the District of Columbia, to Regulate Interstate Traffic in Said Articles, and for Other Purposes”.3 This law marked the beginning of a regime for licensing of drugs that ultimately evolved into the Food and Drug Administration (FDA), which today is responsible for the control of biologics in the US.4 When the FDA celebrated the 75th anniversary of the Food and Drugs Act of 1920 in 1995, it also celebrated the 2“Biologics Control Act” of 1902. Though in the original law of 1st July 1902, there was no mention of “biologics”, “biological” or “biological products”, which implicitly suggested the continuity in the regulation of biological products. It was with this new legislative framework in place, subsequent years witnessed the emergence of various labels to describe these products.
In 1917, the Biological Department of Eli Lilly (a pharmaceutical bigwig of his times) and Company published a small treatise on “Elements of Biologics” designed to provide the company's representatives with standard knowledge about biological or natural products like antitoxins and vaccines.5 By 1921, 41 establishments were licensed to sell more than 102 different sera, toxins and analogous products. Of these establishments, 32 were located in the US, one in Canada, one in England, three in France, one in Italy, two in Switzerland and one in Germany, posing a challenge to federal regulators. In 1923, Public Health Reports compiled a list of national agencies and organizations associated with the regulation of “biologics”.6
The isolation of the first-ever biologic was of the hormone insulin which was achieved by Frederick Banting and Charles Best in Toronto in 1921.7 The second biologic was erythropoietin, the existence of which was first proposed in 1906 by Paul Carnot based on his transfusion experiments in rabbits.8 From 1921 to 1934, other biological substances like vitamin D (1927), estrone (1929), androsterone (1931), ascorbic acid (1932) and progesterone (1934) were isolated and synthesized but it was in 1934, when the National Institute of Health (NIH) issued the first licenses to manufacturers for the production of a human blood product, which was a preparation of protein from human placental extract that was designed to immunize against measles.9,10 In 1937, work on biologics control was granted its own division within the NIH, the Division of Biologics Control. Institutionalizing the control of biologics involved expanding existing regulations on vaccines, sera and antitoxins to include arsenical drugs, blood and blood products. Meanwhile, in Europe, the physician and entrepreneur Gerhard Maclaus (1890–1942) published a famous three-volume textbook of biological remedies (Lehrbuch der biologischen Heilmittel); and in 1939, a research institute for biological remedies was founded at the Paracelsus.11
The decades after the Second World War, especially from the 1950s to the 1980s, there were dynamic years for biologics, as the quantity and quality of biologics and the challenges for regulators continued to grow. After the spectacular introduction of penicillin in the 1940s, the biotechnological exploitation of fungal metabolisms invigorated the search for magic bullets. Likewise, the invention of cortisone raised expectations and drove pharmaceutical industries in their search for “natural products” from exotic plants. Another advance in postwar research that significantly influenced the development of biologics was made in 1949 at Boston Children's Hospital, where scientists successfully grew a human virus, the Lansing 3type 2 poliovirus, in a human tissue cell culture.12 In the mid-1960s, pioneering work resulted in the first experimental live virus vaccine against German measles (rubella).
In July 1972, both the authority to administer the drug provisions of the Federal Food, Drug, and Cosmetic (FD&C) Act for all biological products and the responsibility for implementing the Biologics Act was delegated to the FDA. The Division of Biologics Standards was then transferred from the NIH to the FDA and renamed the Bureau of Biologics (BoB). Insulin was inarguably the first protein that embodied the aspirations of the new biology. A team at the University of California, San Francisco, associated with Herbert Boyer, who in April l976 founded the small company GeneTech (Genetic Engineering Technology), used the bacterium Escherichia coli to produce insulin and claimed success in September 1978. The FDA finally approved the drug in 1982. By 1988, live proteins like insulin, human growth hormone, hepatitis B vaccine, alpha-interferon and tissue plasminogen activator had been approved as drugs by the FDA.
The discovery that revolutionized the antibody therapy came after decoding of the human genome which revealed that there are 30,000 different genes encoding possibly 50,000 different proteins and that disease may result when one of these proteins is defective or present in abnormally high or low concentration. This ability to identify the cause of disease has presented a number of targets for possible therapies. The first monoclonal antibodies (mAb), Ortho Biotech's muromonab-CD3 (Orthoclone), was approved by the FDA in 1986.13 The original concept of antibodies as molecules that bind to specific targets emerged through the pioneering work of Paul Ehrlich, Emil von Behring, Shibasaburo Kitasato, and Karl Landsteiner.14 Further, recombinant deoxyribonucleic acid technology has allowed a new generation of protein-based medicines and in Cambridge, the United Kingdom, scientists developed a relatively simple method for custom-producing antibodies in the laboratory.15 More recent advances led to the development of part-mouse, part-human mAbs called chimeras [e.g. rituximab (Rituxan) and cetuximab (Erbitux)], as well as humanized antibodies [e.g. trastuzumab (Herceptin) and bevacizumab (Avastin)] that contain a bare minimum of nonhuman amino acid sequences. In 2002, the first completely human therapeutic mAb, Abbott's adalimumab (Humira), received market approval. Today, there are over a dozen mAbs, with collective oncology market sales in 2006 of over US $7.8 billion and sharp growth predicted over the next decade.16
In 1988, the FDA had again split biologics from the more general drug review process. Since then, the FDA has been busy distributing and redistributing the responsibility for an ever-growing number of biological products. The FDA Center for Biologics Evaluation and Research (CBER) became responsible for some therapeutic proteins, such as monoclonal 4antibodies, but control of these was later transferred to the Center for Drug Evaluation and Research (CDER).17
DEVELOPMENT OF BIOSIMILARS
The realm of biologics has evolved throughout the 20th century. With the advent of biosimilars, there is a big competition to challenge the parent molecules.18 Biologics and their biosimilars are large complex molecules and require a different regulatory framework to produce constant quality. Most regulations in the 21st century have addressed this by recognizing an intermediate ground of testing for biosimilars which require more testing than for small-molecule generics, but less testing than for registering completely new therapeutics.19 In 2003, the European Medicines Agency introduced an approval pathway for biosimilars, termed similar biological medicinal products, that is based on a thorough demonstration of “comparability” of the “similar” product to an existing approved product.20 Within the United States, the Patient Protection and Affordable Care Act of 2010 is developed for biosimilars for comparison with the FDA-licensed reference biological product.21
PRESENT DAY BIOLOGICS
Necessity is the mother of invention and new clinical situations where the conventional treatment options fail and/or are contraindicated, newer drugs are being developed and the already existing ones are being tried as a hope rather an expectation. Results are giving rise to research, eventually handling the clinicians a new set of arsenal. Diseases like psoriasis, where target-specific drugs are now universally being used with a more favorable side-effect profile, thus providing an effective and safe alternative choice for treatment. Alefacept (Amevive) was the first biologic approved by the FDA in 2003 for the treatment of moderate-to-severe chronic plaque psoriasis. However, in November 2011, Astellas Pharma US, manufacturer of alefacept, announced its decision to cease sales of the drug. There are currently five other FDA-approved biologics for psoriasis and psoriatic arthritis––adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®) and ustekinumab (Stelara®). If there is one biologic in dermatology which is closest to challenging the conventional immunosuppressants as the first choice drug, it would be the use of rituximab in pemphigus. Treatment of hidradenitis suppurativa, pyoderma gangrenosum, skin cancers, collagen vascular dermatoses, severe cutaneous adverse reactions, alopecia areata, chronic urticarial and atopic dermatitis have been a challenge over the years and this “therapeutic revolution” with biologics and biosimilars is expected to make life easier for patients as well as clinicians.5
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- Questions and answers on biosimilar medicines (similar biological medicinal products). European Medicines Agency. 2014.
- United States Food and Drug Administration. Approval Pathway for Biosimilar and Interchangeable Biological Products. Maryland: USFDA; 2010.