Biologics are highly complex polypeptide products that are derived from living organisms and are used in the prevention or treatment of disease. They have been approved for the treatment of a variety of serous illnesses including cancer (lung, breast, colorectal, etc.), heart disease, infection, multiple sclerosis, diabetes and anemia. Examples of approved biologics include insulin, hormones, monoclonal antibodies and some vaccines.

The relative newness and complexity of biologics has hindered the development of an abbreviated drug approval process like that which exists for chemical therapeutics. However, because of the increasing numbers of biologics entering the health care system and the expiration of patents covering these products, the demand for an abbreviated biosimilar approval process is increasing. With that, a familiar tug-of-war has emerged with generics advocating for greater competition and lower prices, and innovator pharmaceutical companies advocating patient safety and incentives for further innovation.

The following commentary addresses the differ-ences between chemical and biologic therapeutics and discusses some recently introduced legislation which attempts to address the concerns of both sides of the tug-of-war.

Unique Aspects of Biologics

Biologics are more complex than chemical therapeutics for a variety of reasons including their size, structural complexity, immunogenicity and the ways in which they are purified, and manufactured. A biologic is a large polypeptide often having more than one chain of amino acids. They can range in size from a few amino acids to several thousand amino acids and are often modified by cellular processes, including glycosylation, phosphorylation, etc., which render the proteins even more complex and difficult to characterize structurally. Current technology is unable to assess completely the structure of these molecules.

In addition to being more structurally complex, biologics are also more difficult to produce and purify. They require more complicated synthesis and purification procedures that are much less reliable than those used for chemical therapeutics. They are usually produced in the complex environments of living organisms. The biologic is just one protein among the many endogenous proteins present in the living organism. Thus, biologic production often results in an impure heterogeneous mixture containing the biologic, endogenous proteins and variants of the biologic (e.g., glycosylation changes, polypeptide fragments, etc.).

Further, the safety and efficacy of biologics, unlike chemical compounds, are highly dependent upon the process by which they have been manufactured and characterized. Minor variations in manufacturing conditions can greatly impact the structure of the biologic. Even small variations in structure such as a single amino acid alteration or a variation of a pattern of sugar residues have been shown to alter dramatically biologic activity.

Biologics are based on endogenous proteins and, therefore, are more likely than chemical compounds to induce immunogenicity. Small structural differences such as amino acid sequence, glycosylation, aggregate formation and formulation have also been shown to affect immunogenicity.

In order to provide a safe and effective biologic, any abbreviated biologic approval process must take into account the unique properties of biologics.

Abbreviated Approval Process for Biologics

The Abbreviated New Drug Application (ANDA) approval process for generics was established in 1984 by the Hatch-Waxman Act (Hatch-Waxman). Hatch-Waxman provides an abbreviated approval process for generic products (traditionally small chemical compounds), that relies on the data of the innovator product showing safety and efficacy. Under Hatch-Waxman, the generic drug must contain the same active agent and be bioequivalent. Because the innovator chemical therapeutic and the generic therapeutic are structurally identical, the FDA can rely on the innovator’s data to justify approval of the structurally identical generic. In order to balance the interests of the innovator pharmaceutical companies, Hatch-Waxman provides economic incentives in the form of data exclusivity for the innovator product and patent term restoration for time spent obtaining regulatory approval.

In contrast, biologics are generally approved under the Public Health Service Act (PHSA). Under the PHSA, there is no abbreviated approval process for biologics. A biosimilar product is unlikely to ever be structurally identical to the innovator product and thus cannot rely on the premise that structural identity equals the same safety and efficacy.

There is a push for an abbreviated biologic approval process. Thus, there are several pieces of legislation pending in Congress, which seek to provide an abbreviated approval process for biologics. The newest of these bills, the “Pathway for Biosimilars Act” (the Biosimilars Act), was introduced on March 13, 2008 and appears to offer the best balance between encouraging competition and creating market incentives all while maintaining patient safety.

Pathway for Biosimilars Act

The Biosimilars Act provides a licensure pathway for the approval of biological products that gives the FDA flexibility to apply current scientific knowledge and determine which tests and data are necessary to support a finding of biosimilarity / interchangeability, without sacrificing patient safety. The Act also maintains economic incentives for further investment in new drugs by innovator pharmaceuticals.

Data Required for Application

The Biosimilars Act requires the applicant to provide data in the form of analytical studies, animal studies and clinical studies. The studies must demonstrate that the biological product is structurally “highly similar” to the reference product. Further, the clinical studies must demonstrate the safety, purity and potency for each condition for which the reference product is approved.

The application process gives the FDA the authority to determine whether the current scientific knowledge supports a determination of biosimilarity for a particular product and, if so, to determine what assays and criteria should be used in this assessment. Based on the FDA’s past guidance, it is likely that the FDA will examine a variety of factors in determining what studies are necessary to assess biosimilarity, including the complexity of the molecule, the degree of similarity between the reference product and the biosimilar, the complexity of the manufacturing and purification processes and the FDA’s past experience with the reference product.


The Biosimilars Act requires that the biologic be assessed for biosimilarity and interchangeability at the same time. A biosimilar is considered interchangeable (e.g., a true generic) when it is so similar to the reference product that it can be substituted for the reference product without the consent of the prescribing physician (e.g., substituted by pharmacist). The FDA will hold the biologic interchangeable if the information contained in the application shows that the biologic is (1) biosimilar to the product and (2) is expected to produce the same clinical results as the reference product in any given patient for each condition of use prescribed, recommended or suggested in the labeling of the reference product. If the biological product is to be administered more than once to an individual, the risk in terms of safety or diminished efficacy of switching between the biologic and the reference product can be no greater than the risk of using the reference product without switching.

Some concern with allowing for an inter-changeable designation for biologics is inevitable given that biologics are not generics in the true sense. However, it is likely the FDA will apply this designation conservatively.

Guidance Documents

The Biosimilars Act requires that the FDA issue guidelines for determining whether a product is biosimilar and interchangeable. In fact, the FDA may not accept an application until the Agency has initiated a proceeding for the issuance of guidance documents for the product or product class, nor make a determination that a biologic is interchangeable with a reference product unless the FDA has issued final guidance documents. These final guidance documents can only be issued following receipt and consideration of public comments to published draft guidelines.

The guidance documents must (1) indicate that given the current state of scientific knowledge it is feasible to make a determination of biosimilarity / interchangeability with respect to a product or product class; and (2) provide an explanation of the data that is necessary to make this determination. Further, the documents will include a description of the criteria the FDA will use to determine whether the biologic is biosimilar and, if appropriate, interchangeable with the reference product. Importantly, the Biosimilars Act gives the FDA the ability to publish guidance documents which state that the FDA will not currently license a product or product class because the current science and experience does not support the licensure of a biosimilar.

Data Exclusivity

The Biosimilars Act provides for a period of regulatory data exclusivity, aimed at protecting the data supplied by an innovator from being used by another party seeking approval through reliance on that data, for a particular amount of time. Specifically, the Biosimilars Act calls for a period of 12 years of data protection to the reference product being used by a sponsor seeking a biosimilar product. An extra 2 years of protection is possible if the innovator product is approved for a medically significant new indication within the first 8 years of data exclusivity. An extra 6 months of protection is also possible if approved for use in a pediatric population. Thus, the Biosimilars Act protects innovator exclusivity for a good period of time all while encouraging further innovation and testing by the innovator drug for new uses.

With respect to the generic, the Biosimilars Act prohibits a second biosimilar from being determined interchangeable for 2 years after the first biosimilar is found interchangeable with the reference product.

Looking Ahead

Although biologics are new to the ANDA approval process, with the emergence of biologic therapeutics, there is every reason to expect that the tug-of-war which has long existed in the chemical therapeutic arena will take on new dimensions. Progress of pending legislation will be interesting to watch.