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DDNC Position Statement on Biosimilars
August 2016

Biologics are therapeutic proteins including antibodies that are manufactured or derived from living sources. The technical definition from the US Code of Federal Regulations defines them as, “Any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of diseases or injuries of man.”

Biologics can be subdivided into general classes: Monoclonal antibodies, complex sugars, blood derivatives, vaccines, and recombinant proteins including cytokines, thrombolytic agents and enzymes.

Biologics are complex molecules that are derived from or manufactured using living cells or organisms. Thus it is currently impossible to make an identical copy; however, it is possible to make a highly similar product (hence the name biosimilar). This is different than chemical based drugs which are much smaller, less complex and generic copies are identical to the original product.

Analyzing data consisting of structural analyses and functional assays both in vitro and in vivo help ensure that biosimilars are, in fact, similar. If extensive structural and functional comparability testing does not reveal significant differences, it is thought highly unlikely that trials in patients would uncover any differences in safety and efficacy.

Biologics are complex therapies and cannot be duplicated. Biosimilars are thus similar to the originator product but not identical. The original biologic is referred to as the innovator product.

The FDA states, “The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change product are identical, but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any difference in quality attributes have no adverse impact upon safety or efficacy of the drug product.”

US statute defines two kinds of biosimilars: biosimilars and interchangeable biologics. According to the FDA, an approved biosimilar has demonstrated that it is highly similar to an FDA-approved biological product, and has no clinically meaningful differences in terms of safety and effectiveness from the innovator product. An interchangeable biological product is biosimilar to an FDA-approved innovator product and meets additional standards for interchangeability. For products that are administered more than once to a patient, the interchangeable biologic product must demonstrate that the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. Per the US statute, an interchangeable biological product may be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product.

Biosimilars have the potential to reduce costs, improve access to treatment nationally and globally, and thereby improve quality of life. Currently a variety of biologics are used to treat patients, including those with digestive disorders. They have revolutionized care particularly in immune mediated disorders such as inflammatory bowel disease (IBD). The cost of biologic therapy is significant and now felt to be the major driver of the cost of care in IBD (higher than hospitalization or surgery costs).

Safety and Effectiveness
DDNC believes that the FDA should take the necessary steps to ensure that all biologics and biosimilars undergo rigorous human testing to meet the highest safety standards.

One of the lessons learned with the use of biologics is that they can induce an antibody response that can affect efficacy (loss of response) and result in significant side effects (for example, infusion reactions or a delayed-type hypersensitivity). The ability to monitor both drug levels of a biologic and antibody to the biologic is thought to help optimize treatment and outcome. This approach, referred to as therapeutic drug monitoring (TDM), is gaining support in the literature and in clinical practice; however, the best and most cost effective approach to incorporate TDM is still under investigation.

Thus, when considering interchangeability with the biosimilar, there should be evidence that switching would not incur immunogenicity or loss of response to the innovator and vice-versa. Risk of cross reactivity of the anti-drug antibodies from the innovator agent to the interchangeable biologic should be studied, defined and listed on the label and prescribing information. Adverse events should be monitored for both biosimilars and interchangeable biologics in a post-FDA approval registry along with safety until enough experience with the product is gained to address whether there are any new safety concerns.

The risk of immunogenicity and ability (or lack of) to do therapeutic drug monitoring should be noted on the biosimilar label and prescribing information and should be updated periodically.

Each biosimilar should have a unique name and identification number to eliminate patient and provider confusion. Any substitution or change should be tracked by the pharmacy/pharmacist dispensing and this data made available to the treating provider upon request.

Shared Decision Making and Transparency
The prescribing provider and patient should be notified of the substitution of an innovator biologic with an interchangeable biologic and vice-versa. The prescriber should be able to prevent substitution by indicating “dispense as written” or “brand name necessary”. The decision of which biologic or non-interchangeable biologic should be one made jointly by the treating provider and patient in the best interest of the patient, not by an insurer, regulator or pharmacy. Arbitrary switching from one non-interchangeable product to another should be avoided given the potential for immunogenicity and compromised safety.

DDNC encourages Congress, Federal agencies and State legislatures to incorporate these principles and to enforce the provisions of the Biologics Price Competition and Innovation Act (BPCA).