It is well known to any newly-minted pharmacy school graduate that minute changes in atomic structures of molecules making up synthesized medicines can have a significant impact on the final product. A good illustration of this concept can be found in the chemical differences between erythromycin, an antibiotic discovered and developed in the 1970’s, and azithromycin, an antibiotic introduced in the 1990’s. Azithromycin is derived from erythromycin when a single nitrogen atom is introduced to the lactone ring of the molecule. This small atomic change in the molecular structure results in significant differences in the potency and administration of azithromycin.
While the development of synthesized drugs made by combining specific chemical ingredients in an “ordered process” in a controlled laboratory environment has its challenges, the complexity of medicines derived from living cell lines is significantly more profound.
According to Biotechnology Innovation Organization (BIO), synthesized medicines most often have well-defined chemical structures, and a finished drug can usually be analyzed in a laboratory to determine all its various components. By contrast it is difficult, and sometimes impossible, to characterize a complex biologic by testing methods available in the laboratory.
For Biologics, “the product is the process.” Because the finished product cannot be fully characterized in the laboratory, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time. This suggests that biosimilars are highly similar but are not identical to the originator product. Hence policies that govern synthesized small molecule development and use are not appropriate for biologics and biosimilars. Evolving policy decisions that are being made in the United States are reflecting this reality.
The debate on the role of biosimilars in the U.S. healthcare system began in earnest in 2010 with the passage of the Affordable Care Act (ACA), as the legislation provided a pathway for these new types of medicines. Biosimilars are thought to have the potential to increase patient access to lifesaving biopharmaceuticals while reducing healthcare costs. For example, according to the IMS Institute for Health Informatics, after the introduction of the erythropoetin biosimilar in the European Union there was an increase of 16 percent in usage accompanied by a decrease of 27 percent in price per treatment day.
Biosimilars, by definition, are intended to be “similar” to the reference originator molecules but are not exact copies; thus they are not considered generic versions of the original product. The Food and Drug Administration (FDA) designates generic versions of synthetic small molecules as AB since the generic drug has proven to meet the necessary bioequivalence requirements through human or laboratory testing compared to a brand name standard.
Subsequently, the generic version may be “interchanged” with the originator drug if it reaches an 80 percent to 120 percent bio-equivalency threshold to the originator drug. For these types of generic drugs, the FDA does not require a company to conduct clinical trials to evaluate the safety and efficacy of the compound compared to the brand name product before the company can bring the generic to market.
In the biosimilar space, however, policies on interchangeability are still being evaluated. In 2014, the FDA released the Purple Book which lists biological products, including any biosimilar and interchangeable biological products licensed by the FDA under the Public Health Service Act. Many observers believe that the FDA will evaluate each biosimilar on an individual basis as the science of biosimilars evolves, and provide a designation as applicable.
One thing we do know is that the FDA requirements for approval of a biosimilar are significantly different than what is required for small molecule generics. The FDA requires not only pharmacokinetic analytic studies for biosimilars but also directs companies to conduct clinical trials comparing the biosimilar to the originator medicine.
In other words, not only do biopharmaceutical companies need to provide data to support the bioequivalency attributes of a biosimilar, but they must also demonstrate comparable safety and efficacy data through clinical trials which could give a additional evidentiary level of comfort to providers and patients. Unfortunately, to the dismay of patients and providers, the FDA announced in March that it has decided that the prescribing label of a biosimilar will not include the comparative safety and efficacy data. This decision deprives the interested stakeholders easy access to the comparative data and forces patients and providers to explore convoluted regulatory records in order to find this important information.
Even if the designation of interchangeability is granted it doesn’t mean that payers have the green light to automatically substitute an originator biopharmaceutical with a biosimilar. Since the practice of medicine and pharmacy are governed by state licensure boards, it will be up to each state board of pharmacy to update their pharmacy practice substitution laws as the class of biosimilars is an undefined entity in the regulations. In the end, if prescribers are adamant about avoiding substitution they have the authority to write “DNS” (Do Not Substitute) on the prescription pad so that the prescription cannot be filled with a different product.
The other missing piece needed to complete the policy puzzle for biosimilars is the naming debate currently managed by the World Health Organization (WHO). International Nonproprietary Names (INNs) is a global system of assigning unique names for drug substances. INNs are designations used throughout the world for a product. Currently, biosimilars can have the same INNs as their reference product which can potentially impact traceability of adverse drug reactions for pharmacovigilance.
The WHO has adopted a policy that recommends adding a 4-letter biologics qualifier random suffix to the INN for biologics or biosimilars. Distinguishable biosimilar names improve tracking; facilitate post marketing surveillance and aid in appropriate prescribing and dispensing. This policy has been adopted by the FDA, although as with any other policy for this class of medicine it will be evaluated on an ongoing basis.
In the United States, so far only two biosimilars have been approved by the FDA. This provides us a golden opportunity to learn a great deal about the potential applicability, success, and failures of biosimilar policies here and markets outside of the U.S. In Europe, for instance, the pathway for biosimilar approvals was created in 2003. The European Medicines Agency (EMA) approved the first biosimilar in 2006 and there are 20 biosimilars that are currently available in various European countries. Notably, the EMA recently stated that questions related to switching from one biological medicine to another should be discussed by patients with their physician and pharmacist. Now that is one policy I believe everyone can agree upon that should immediately be adopted for all types of medicines.