A biopharmaceutical, also known as a biologic medical product or more simply as a biologic or biological, is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein or living cells that are used as therapeutics to treat diseases. Biopharmaceuticals differ from other pharmaceutical products in that they are created using biological processes, rather than being chemically synthesized.
Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category. Some major regulatory agencies use the terms biological medicinal products or therapeutic biological product to specificly refer to engineered macromolecular products like protein-based and nucleic-acid-based drugs, distinguishing them from products like blood, blood components or vaccines, which are ususally directly extracted from a biological source.
Biologics can be composed of sugars, proteins or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources — human, animal or microorganism — and may be produced by biotechnology methods and other technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.
In some jurisdictions, biologics are regulated via different pathways than other small molecule drugs and medical devices.
Extracted from living systems
Some of the oldest forms of biologics are extracted from the bodies of animals, and other humans especially. Important biologics include:
- Whole blood and other blood components.
- Organs and tissue transplants.
- Stem cell therapy.
- Antibodies for passive immunization, e.g. to treat a virus infection.
Some biologics that were previously extracted from animals, such as insulin, are now more commonly produced by recombinant DNA.
Produced by recombinant DNA
As indicated the term "biologics" can be used to refer to a wide range of biological products in medicine. However, in most cases, the term "biologics" is used more restrictively for a class of therapeutics (either approved or in development) that are produced by means of biological processes involving recombinant DNA technology. These medications are usually one of three types:
- Substances that are (nearly) identical to the body's own key signalling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named (simply) "growth hormone" or biosynthetic human insulin and its analogues.
- Monoclonal antibodies. These are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are "custom-designed" (using hybridoma technology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type; examples of such monoclonal antibodies for use in various diseases are given in the table below.
- Receptor constructs (fusion proteins), usually based on a naturally-occurring receptor linked to the immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin-structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below.
Biologics as a class of medications in this narrower sense have had a profound impact on many medical fields, primarily rheumatology and oncology, but also cardiology, dermatology, gastroenterology, neurology, and others. In most of these disciplines, biologics have added major therapeutic options for the treatment of many diseases, including some for which no effective therapies were available, and others where previously existing therapies were clearly inadequate. However, the advent of biologic therapeutics has also raised complex regulatory issues (see below), and significant pharmacoeconomic concerns, because the cost for biologic therapies has been dramatically higher than for conventional (pharmacological) medications. This factor has been particularly relevant since many biological medications are used for the treatment of chronic diseases, such as rheumatoid arthritis or inflammatory bowel disease, or for the treatment of otherwise untreatable cancer during the remainder of life. The cost of treatment with a typical monoclonal antibody therapy for relatively common indications is generally in the range of € 7,000-14,000 per patient per year.
Older patients who receive biologic therapy for diseases such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis are at increased risk for life-threatening infection, adverse cardiovascular events, and malignancy. However, because other therapies are often ineffective, biologic therapy should be considered for some of these patients.
The first such substance approved for therapeutic use was biosynthetic 'human' insulin made via recombinant DNA technology. Sometimes referred to as rHI, under the trade name Humulin, was developed by Genentech, but licensed to Eli Lilly and Company, who manufactured and marketed the product starting in 1982.
Major kinds of biopharmaceuticals include:
- Blood factors (Factor VIII and Factor IX)
- Thrombolytic agents (tissue plasminogen activator)
- Hormones (insulin, glucagon, growth hormone, gonadotrophins)
- Haematopoietic growth factors (Erythropoietin, colony stimulating factors)
- Interferons (Interferons-α, -β, -γ)
- Interleukin-based products (Interleukin-2)
- Vaccines (Hepatitis B surface antigen)
- Monoclonal antibodies (Various)
- Additional products (tumour necrosis factor, therapeutic enzymes)
|USAN/INN||Trade Name||Indication||Technology||Mechanism of Action|
|abatacept||Orencia||rheumatoid arthritis||immunoglobin CTLA-4 fusion protein||T-cell deactivation|
|adalimumab||Humira||rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn's disease||monoclonal antibody||TNF antagonist|
|alefacept||Amevive||chronic plaque psoriasis||immunoglobin G1 fusion protein||incompletely characterized|
|erythropoietin||Epogen||anemia arising from cancer chemotherapy, chronic renal failure, etc.||recombinant protein||stimulation of red blood cell production|
|etanercept||Enbrel||rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis||recombinant human TNF-receptor fusion protein||TNF antagonist|
|infliximab||Remicade||rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Ulcerative Colitus, Crohn's disease||monoclonal antibody||TNF antagonist|
|trastuzumab||Herceptin||breast cancer||humanized monoclonal antibody||HER2/neu (erbB2) antagonist|
|ustekinumab||Stelara||psoriasis||humanized monoclonal antibody||IL-12 and IL-23 antagonist|
|denileukin diftitox||Ontak||cutaneous T-cell lymphoma (CTCL)||Diphtheria toxin engineered protein combining Interleukin-2 and Diphtheria toxin||Interleukin-2 receptor binder|
|golimumab||Simponi||rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease||monoclonal antibody||TNF antagonist|
Many vaccines are grown in tissue cultures.
With the more common small-molecule drugs, an exactly identical generic drug can be reliably produced and marketed. Because biologics are vastly more complex, other manufacturers cannot guarantee that their version is exactly identical to the original manufacturer's version, although it is similar to the original biologic. The subsequent manufacturer may use a slightly different manufacturing process, which can occasionally produce significantly different effects. The follow-on manufacturer does not have access to the originator's molecular clone bank and original cell bank. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications.
Because different manufacturers may produce slightly different products, they consequently cannot guarantee that their version is exactly as safe and effective as the original manufacturer's version. So, unlike most drugs, generic versions of biologics were not authorized in the United States or the European Union through the simplified procedures allowed for small-molecule generics. As a result, nearly all biologics have been brand-name therapeutics and required very extensive testing. Notable exceptions to this rule include several of the earliest biopharmaceuticals made via recombinant DNA technology, including biosynthetic 'human' insulin and human growth hormone.
Legislation in the 21st century has attempted to address this by recognizing an intermediate ground of testing, which is more testing than for small-molecule drugs proven to be identical to each other, but less testing than for completely new therapeutics.
In the European Union a specially adapted approval procedure has been authorized for certain protein drugs, termed similar biological medicinal products. This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product.
Within the U.S., the Patient Protection and Affordable Care Act of 2010 created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA licensed reference biological product.
The acceptance of biosimilars may reduce the profitability of biologics and the cost to the patients and healthcare systems. This acceptance may, in turn, be driven by lobbying with public institutions and opinion leaders, particularly during the upcoming 2012-2019 biologics patent cliff.
When a new biopharmaceutical is developed, the company will typically apply for a patent, which is a grant for exclusive manufacturing rights. This is the primary means by which the developer of the drug can recover the investment cost for development of the biopharmaceutical. The patent laws in the United States and Europe differ somewhat on the requirements for a patent, with the European requirements are perceived as more difficult to satisfy. The total number of patents granted for biopharmaceuticals has risen significantly since the 1970s. In 1978 the total patents granted was 30. This had climbed to 15,600 in 1995, and by 2001 there were 34,527 patent applications.
Large scale production
Biopharmaceuticals may be produced from microbial cells (e.g. recombinant E. coli or yeast cultures), mammalian cell lines (see cell culture) and plant cell cultures (see plant tissue culture) and moss plants in bioreactors of various configurations, including photo-bioreactors. Important issues of concern are cost of production (a low volume, high purity product is desirable) and microbial contamination (by bacteria, viruses, mycoplasma, etc.). Alternative platforms of production which are being tested include whole plants (plant-made pharmaceuticals).
A potentially controversial method of producing biopharmaceuticals involves transgenic organisms, particularly plants and animals that have been genetically modified to produce drugs. The production of these organisms represents a significant risk on the part of the investor, both in terms of the risk of failure to produce the required organism, and in the risk of non-acceptance by government bodies due to the perceived risks and from ethical issues. Biopharmaceutical crops also represent a risk of cross-contamination with non-engineered crops, or crops engineered for non-medical purposes.
One potential approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk (or blood or urine). Once an animal is produced, typically using the pronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome. The first such drug manufactured from the milk of a genetically-modified goat was ATryn, but marketing permission was blocked by the European Medicines Agency in February 2006. This decision was reversed in June 2006 and approval was given August 2006.
In the European Union, a biological medicinal product is one of the active substance(s) produced from or extracted from a biological (living) system, and requires, in addition to physico-chemical testing, biological testing for full characterisation. The characterisation of a biological medicinal product is a combination of testing the active substance and the final medicinal product together with the production process and its control.
- With regard to the production process, a biological medicinal product can be derived from biotechnology or derived from other new technologies. It may be prepared using more conventional techniques, as well, as is the case for blood or plasma-derived products and a number of vaccines.
- With regard to the nature of its active substance, a biological medicinal product can consist of entire microorganisms or mammalian cells or of nucleic acids or proteinaceous or polysaccharide component(s) originating from a microbial, animal, human or plant source.
- With regard to its mode of action, a biological medicinal product can be a therapeutic medicinal product, an immunological medicinal product, gene transfer materials, or cell therapy materials.
Within the United States, biologics are regulated by the FDA's Center for Biologics Evaluation and Research (CBER). Drugs, by contrast, are regulated by the Center for Drug Evaluation and Research (CDER). Approval can require several years of clinical trials, including trials with human volunteers. Even after the drug is released, it will still be monitored for performance and safety risks. The manufacture of the drug must satisfy the "current Good Manufacturing Practices" regulations of the FDA. They are typically manufactured in a clean room environment with set standards for the amount of airborne particles.
- antibody-drug conjugate
- Center for Biologics Evaluation and Research (CBER)
- Genetic engineering
- List of recombinant proteins
- List of pharmaceutical companies
- Center for Biologics Evaluation and Research (2010-04-01). "What is a biological product?". U.S. Food and Drug Administration. Retrieved 2014-02-09.
- Rader RA (2008). "(Re)defining biopharmaceutical". Nat. Biotechnol. 26 (7): 743–51. doi:10.1038/nbt0708-743. PMID 18612293.
- "Drugs@FDA Glossary of Terms". Food and Drug Administration. 2 Feb 2012. Retrieved 8 April 2014.
- Walsh, Gary. Biopharmaceuticals: Biochemistry and Biotechnology, Second Edition. John Wiley & Sons Ltd. ISBN 978-0-470-84326-0.
- United States Food and Drug Administration (August 2008). "Supplemental applications proposing labeling changes for approved drugs, biologics, and medical devices. Final rule". Fed Regist 73 (164): 49603–10. PMID 18958946.
- Kerr LD (2010). "The use of biologic agents in the geriatric population". J Musculoskel Med 27: 175–180.
- BriskFox Financial. "Biopharmaceutical sector sees rising R&D despite credit crunch, finds analysis". Retrieved 2009-03-11.
- Roger SD, Mikhail A (2007). "Biosimilars: opportunity or cause for concern?". J Pharm Pharm Sci 10 (3): 405–10. PMID 17727803.
- Nick C (2012). "The US Biosimilars Act: Challenges Facing Regulatory Approval". Pharm Med 26 (3): 145–152.
- Committee for Medicinal Products for Human Use (CHMP) (2005-10-30). "Guideline on Similar Biological Medicinal Products". European Medicines Agency. Retrieved 2007-12-17.
- 75 F.R. 61497; United States Food and Drug Administration (2010-10-05). "Approval Pathway for Biosimilar and Interchangeable Biological Products". Public Hearing; Request for Comments.
- Calo-Fernández B, Martínez-Hurtado J (December 2012). "Biosimilars: Company Strategies to Capture Value from the Biologics Market". Pharmaceuticals 5 (12): 1393–1408. doi:10.3390/ph5121393.
- Luke Foster. "Patenting in the Biopharmaceutical Industry—comparing the US with Europe". Archived from the original on 2006-03-16. Retrieved 2006-06-23.
- Decker EL, Reski R (2008). "Current achievements in the production of complex biopharmaceuticals with moss bioreactors". Bioprocess Biosyst Eng 31 (1): 3–9. doi:10.1007/s00449-007-0151-y. PMID 17701058.
- Dove A (2000). "Milking the genome for profit". Nat. Biotechnol. 18 (10): 1045–8. doi:10.1038/80231. PMID 11017040.
- Phillip B. C. Jones. "European Regulators Curdle Plans for Goat Milk Human Antithrombin". Retrieved 2006-06-23.
- "Go-ahead for 'pharmed' goat drug". BBC News. 2006-06-02. Retrieved 2006-10-25.
- The Commission of the European Communities (2003-06-25). "Commission Directive 2003/63/EC amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use". Official Journal of the European Union. p. L 159/62.
- Biological Products at the US National Library of Medicine Medical Subject Headings (MeSH)
- Yali Friedman (2007). "Why are biogenerics so hard to regulate?". BiotechBlog.com. Retrieved 2007-12-17.
- Debbie Strickland (2007). "Guide to Biotechnology". Biotechnology Industry Organization (BIO). Retrieved 2007-12-17.
- Timothy B. Coan and Ron Ellis (2001-06-01). "Report for USA Specialty Pharmaceuticals: Generic Biologics: The Next Frontier". Consumer Project on Technology. Retrieved 2007-12-17.
- "About biologics". National Psoriasis Foundation. 2006-11-01. Retrieved 2007-12-17.