Is “Biologics Versus Biosimilars” A Different Story Than Brand Names Versus Generics?
In 1984, the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) created a shortened new drug application pathway for generics by eliminating the need for preclinical and clinical studies if bioequivalence—i.e., the rate and extent of absorption—could be demonstrated. The FDA defines a generic drug as follows: “A generic drug is identical–or bioequivalent—to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.” For many drugs, the process was straightforward and payers hoped to reduce expense by purchasing generics.
Although the FDA frequently uses the term “biologic drug,” we have been unable to find an official FDA definition for “biologic drug.” The FDA instead separately defines “biological product” and “therapeutic biological product.” These are the current FDA definitions—Biological Product: “Biological products include a wide range of 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 cutting-edge 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.” The FDA then defines a therapeutic biological product as follows: “A therapeutic biological product is a protein derived from living material (such as cells or tissues) used to treat or cure disease.” Thus, biologics are large-molecule medications produced by living cells. They are produced by using recombinant DNA technology to direct protein synthesis within cells which can then be used to produce medications.
The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product.  Biosimilars, also called “follow-on biologics,” are in many ways analogous to generics, but are not generic drugs. In Canada they are aptly labeled “subsequent entry biologics (SEBs).”  We like the clarity of the Canadian term, but Americans will hear the terms “biologics” and “biosimilars.”
Biologics and biosimilars are large protein molecules. Manufacturing a biosimilar drug poses numerous complexities not seen in the manufacturing of “small molecules” created as generic drugs. A company wishing to manufacture a biosimilar does have access to the commercial biologic product, but does not have access to the biologic cell line used by manufacturerof the reference biologic or details of the manufacturing process such as how fermentation and purification were carried out. This lack of information (and therefore the lack of identical manufactured cellular material), together with the molecular and structural complexity of large biologic proteins makes for immense complexity for the companies who will be creating biosimilars. The bottom line is that even though a biosimilar has the same recombinant DNA sequencing, small differences in structure or chemistry due to the processes and chemicals used in the culture, purification, storage, etc. may result in differences in efficacy, safety and immunological outcomes.
The Health Care Reform Act has outlined a process for abbreviated approval for biosimilars. The FDA has conducted public meetings and published requirements for a drug to be considered biosimilar, emphasizing clinical studies demonstrating that the product is “highly similar” to the reference product, although minor differences are allowed if the differences do not result in clinically meaningful safety, purity and potency differences. In addition, interchangeable biological products may be substituted at the pharmacy level without the intervention of a healthcare provider. 
The strength of evidence necessary to result in a decision of biosimilarity and interchangeability remains unclear. It is also currently unclear if separate evidence for each indication will be required. Currently The European Medicines Agency (EMA) has outlined important elements and considerations required to support the designation of biosimilarity in comparison with existing biologics along with fairly detailed scientific guidance documents on biosimilar medicines. Key requirements include similar pharmacokinetics and pharmacodynamics in humans and the demonstration of similar clinical efficacy and safety of the biosimilar compared to that of the reference biologic. Several biosimilar agents have already been licensed in Europe. The American College of Rheumatology has developed a concise position paper which takes a patient-centered approach to biosimilars. The paper is available online.  Key points are—
- Biologics are proteins produced by living cells, including monoclonal antibodies, soluble receptors, receptor antagonists, novel molecules derived by genetic engineering and other types of proteins that can be used to treat human diseases.
- Biosimilars may represent a cost-saving alternative to reference biologics.
- Currently the FDA has not provided details of the kind of testing required to demonstrate sufficient similarity in efficacy and safety for approval.
- A similar production process does not ensure that the biosimilar is functionally equivalent to a reference biologic. Extensive human testing will be required.
- Even though the FDA has been establishing standards for licensure to ensure the safety and effectiveness of biosimilars and issued a guidance in February 2012 , the FDA has not approved a biological product as biosimilar or interchangeable.
- Several companies are developing biosimilar products and will almost certainly submit applications for licensure under the new law. It is not yet known when the first biosimilar will be on the U.S. market.
2. FDA definitions.
4. Subsequent Entry Biologics (SEBs).
6. American College of Rheumatology. http://www.rheumatology.org/practice/clinical/position/biosimilars.pdf
7. Biosimilars FDA Guidance. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259797.htm
8. Colbert RA, Cronstein BN. Biosimilars: the debate continues. Arthritis Rheum. 2011 Oct;63(10):2848-50. doi: 10.1002/art.30505. PubMed PMID: 21702015.
9. Reichert JM, Beck A, Iyer H. European Medicines Agency workshop on biosimilar monoclonal antibodies: July 2, 2009, London, UK. MAbs. 2009 Sep-Oct;1(5):394-416. Epub 2009 Sep 25. PubMed PMID: 20065643.
10. Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation’s biosimilars program. N Engl J Med. 2011 Aug 4;365(5):385-8. PubMed PMID: 21812668.