Biologics

Biologics include a wide range of medicinal products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. 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.

Biologics

As indicated above, 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 medications (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:

• 1) 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".
• 2) 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.
• 3) 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.

Biosimilars

See also biosimilars

Unlike the more common "small-molecule" drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to manufacturing process changes. The follow-on manufacturer does not have access to the originator's molecular clone and original cell bank, nor to the exact fermention and purification process. Finally, nearly undetectable differences in impurities and/or breakdown products are known to have serious health implications. This has created a concern that generic versions of biologics might perform differently than the original branded version of the drug. So, unlike most drugs, generic versions of biologics are not authorized in the US or the European Union through the simplified procedures allowed for small molecule generics. Notable exceptions include several of the earliest biopharmaceuticals made via recombinant DNA technology, including biosynthetic 'human' insulin and human growth hormone, which are grandfathered under the U.S. Federal Food, Drug & Cosmetic Act which addresses mainly small-molecule chemical drugs. By comparison, vaccines and most other biotech drugs are governed under the Public Health Services Act, which would need to be amended by U.S. Congress and signed into law by the President to allow for generics.

In the EU 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. In the US the FDA has taken the position that new legislation will be required to address these concerns. Additional Congressional hearings have been held, but no legislation had been approved as of June 2008. Due to a lack of FDA manufacturing guidelines for generic versions of synthetic insulin and human growth hormone, generics manufacturers are caught in a bind.

The FDA announced in 2001 that it was working on guidelines for pharmaceutical companies to produce generic versions of synthetic insulin and human growth hormone. The Agency had long had suggested the guidelines were forthcoming, but in April 2006, the FDA suddenly announced it would not be releasing the long-delayed guidelines for the production of generic versions of insulin and human growth hormone as anticipated In a March 17, 2006 letter obtained by the Associated Press, which was written in response to a Feb. 10, 2006 letter from Sen. Orrin Hatch (R-UT), and Rep. Henry Waxman (D-CA), the FDA associate commissioner for legislation Patrick Ronan said that the FDA instead intended to publish broader guidelines that applied to ALL generic versions of protein-based drugs, also known as follow-on protein products, therefore the FDA would not be outlining specific guidelines for insulin or human growth hormone.

In response, Rep. Waxman said in a statement that the Agency's action was "a misguided step that will only result in further delay" of rules for low-cost generics. The regulatory hiatus regarding generic versions has effectively extended the patents for the past few years at the expense of consumers and their healthcare providers.

In August 2006, four state governors, looking to ease drug costs under state programs, petitioned the FDA to provide guidelines for generic versions of insulin and human growth hormone. In their petition, the governors joined other critics in accusing the Agency of dragging its feet

"The FDA's delay in informing manufacturers of the requirements for obtaining approval of therapeutically equivalent versions of insulin and human growth hormone has cost the states and other health-care providers hundreds of millions of dollars," the petition said. Democratic Governors Kathleen Sebelius of Kansas and Jim Doyle of Wisconsin joined Republicans Tim Pawlenty of Minnesota and James Douglas of Vermont in signing the petition. Since then, the governors of New Mexico, Virginia and West Virginia have also signed the petition.

"We have been informed that there are no scientific reasons for delaying the issuance of the guidance documents FDA already has drafted," the bipartisan group of governors wrote the FDA. "There is no legal or regulatory obstacle to the immediate issuance of these guidance documents," they added.

The governors said that insulin and human growth hormone are a breed apart from other biotech medicines and should therefore be considered distinct from other biotech drugs. Insulin and human growth hormone both have relatively simple structures and a long history of safe use, they said.

Examples

A few examples of biologics made with recombinant DNA technology include:

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	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, Crohn's disease	monoclonal antibody	TNF antagonist
trastuzumab	Herceptin	breast cancer	humanized monoclonal antibody	HER2/neu (erbB2) antagonist

See also

• Biopharmaceuticals
• Biosimilars

References

External links

• Yali Friedman Why are biogenerics so hard to regulate?. BiotechBlog.com. Retrieved on 2007-12-17..
• Debbie Strickland Guide to Biotechnology. Biotechnology Industry Organization (BIO). Retrieved on 2007-12-17..
• Timothy B. Coan and Ron Ellis Report for USA Specialty Pharmaceuticals: Generic Biologics: The Next Frontier. Consumer Project on Technology. Retrieved on 2007-12-17..
• About biologics. National Psoriasis Foundation. Retrieved on 2007-12-17..