Key Questions Surround Biosimilars, Generics in Specialty Pharmacy


Important considerations for pharmacists to concerning the switch from a brand name biologic to a new biosimilar.

Every pharmacist throughout their career will inevitably have a conversation with a patient about generic medications. The conversation will most often progress with the pharmacist touting the advantages of generic medications, explaining that the drug within the medication is identical to the brand.

Currently, more often than not, patients are happy about the cost savings and convinced enough to take the generic medication. With the success of generic drugs that treat relatively benign conditions (such as ibuprofen or common antibiotics), patients feel comfortable being treated with generics for more severe conditions (such as hypertension, hyperlipidemia, or diabetes).

With the combination of the confidence to ensure patients that generics are molecularly identical to brand name products along with a proven track record to support their efficacy, brand name drugs take a back seat to generics whenever they become available.

Enter biosimilars, which are being produced and manufactured to mimic current medications in the biologics medication class. Unlike traditional drug molecules, biologics are cultured and purified from living cells during their manufacturing process.

Their process to produce and replicate is significantly more complicated than that of traditional drugs. Biologics, often produced through the means of biotechnology, are combinations of multiple proteins and molecules to make a compound many times the size of traditional drugs.

Because of this complex process, biologics are traditionally very expensive and sensitive to storage and handling conditions. Nevertheless, throughout the last several years, these medications have become very popular and effective in treating many disease states.

Now let’s circle back to that pharmacist-patient conversation about generics and insert biosimilars instead. As previously mentioned, biosimilars are produced and manufactured to mimic biologics.

However, due to the complexity of the production process, biosimilars cannot claim to be molecularly identical. Established by the Biological Price Competition and Innovation Act and signed into law in 2010 as part of the Patient Protection and Affordable Care Act, the FDA has determined that biosimilars must be “highly similar to the reference product,” with no “clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product.”

A product deemed as a biosimilar, however, is not necessarily interchangeable. A second definition has been created for biosimilars that are interchangeable.

Interchangeability allows the product to be substituted at the pharmacy level without intervention from the prescriber. The definition of interchangeability is, “can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and reference product is no greater than the risk of using the reference product without such alternation or switch.”

Additional clinical evidence must be provided in order to earn this status. But here’s the rub: not a single drug has earned interchangeable status from the FDA to date.

Manufacturers have asked for clarity on the process, with the FDA expected to release final guidelines for interchangeability within the next 2 years.

Until then, and even after the release of certain interchangeable medications, how does a pharmacist confidently tell a patient that a non-interchangeable biosimilar is as good as the brand name product? When a patient pushes back, stating that their multiple sclerosis has been controlled for 10 years without relapse, how does a pharmacist ensure a patient that this biosimilar will effectively work for their treatment?

Before I try to answer these questions, let’s re-familiarize ourselves with the Orange Book and with the lesser known Purple Book.

The Orange Book

The Drug Price and Competition Act (also known as the Hatch-Waxman Act) was passed to require the FDA to produce a text named Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. The Orange Book identifies drug products that have been approved by the FDA based on safety and efficacy.

The Orange Book also contains therapeutic equivalence evaluations, meant to aid health care practitioners in proper product selection and health care cost containment. To lessen these costs, nearly every state has adopted laws to encourage the substation of generic products.

Therefore, the Orange Book continues to be a valuable publication to assist with this substation.

The Orange Book is broken into 4 sections:

  • approved prescription drug products and therapeutic equivalence evaluations
  • approved OTC drug products that are not covered in section 1 by an NDA or ANDA
  • certain drugs approved by the FD&C Act and administered by the Center for Biologics Evaluation and Research
  • a cumulative list of discontinued or exploratory drugs

The important section that most pharmacists are aware of is section 1. Before diving in, let’s first explain a couple of terms related to therapeutic equivalence.

First, pharmaceutical equivalent products are drugs that contain the same active ingredients with the same dosage form and route of administration, and are formulated to contain the same dosage. It may differ in shape, scoring, excipients, release mechanism, and packaging.

On the other hand, pharmaceutical alternatives contain the same therapeutic moiety, but are formulated using different salts or complexes, or are different dosage forms and strengths. Therapeutic equivalents are pharmaceutical equivalents that have also demonstrated bioequivalence. Bioequivalent products show comparable bioavailability.

Now that the big words have been defined, we can take a closer look at section 1, in which drug products are evaluated for therapeutic equivalence. Each drug listed in the Orange Book is provided with a 2-letter code.

The first letter A or B determines whether the product is therapeutically equivalent to other pharmaceutically equivalent products. When the first letter designation is an A, the FDA considers the drug to be therapeutically equivalent to another product.

In contrast, if the first letter is a B, the FDA has determined actual or potential differences in bioequivalence, therefore the drug is not therapeutically equivalent (though it may be pharmaceutically equivalent). The second letter (A, B, C, D, E, N, O, P, R, S, T, X) of the designation will tell the story of either the dosage form of the medication, or in some cases, the FDA’s evaluation of bioequivalence.

For example, an A-rated drug that has a designation of AA indicates a product that has no bioequivalence problems when in conventional dosage forms. On the other hand, an AB-rated medication has resolved any actual or potential bioequivalence problems through in vitro/in vivo testing.

Most generic medications are considered AB-rated drugs. Furthermore, AB designations can be broken down into subcategories, such as AB1, AB2, etc. This occurs when other drugs of the same strength or dosage forms have not proven bioequivalent to each other.

B-rated designations indicate drugs that have not been proven to be bioequivalent to other commercially available products of the same drug. This designation is often provided to drugs that have shown certain pharmacokinetic differences, such as differing dissolution or absorption rates.

The Orange Book is a comprehensive resource that provides excellent therapeutic equivalency data for traditional drugs and their generics.

The Purple Book

The Purple Book is considered to be an analog to the Orange Book for biologics and biosimilars. Similar to the development of biologics and the approval of biosimilars, the Purple Book is still being developed.

Licensed by the FDA under the Public Health Services Act, the Purple Book provides a list of all biological products that have been approved by the FDA. Included in this publication is the date a biologic product was licensed, any reviews and allowances for reference product exclusivity, and the date that an approved biologic will lose exclusivity.

Furthermore, there is a listing of biological products that have filed to earn biosimilar or interchangeable status, along with the accompanying reference product. The Purple Book is still early in development though, and is currently being created by 2 separate agencies.

The first agency is the Center for Drug Evaluation and Research and the second is the Center for Biologics Evaluation and Research. Both agencies have a slightly different take on the Purple Book, publishing much of the same information in differing formats.

Although the naming of such agencies may lead to some confusion, the Purple Book is presently less complicated than its counterpart the Orange Book. Nevertheless, as interchangeable biosimilars start to become available and biologic products continue to proliferate, there will likely be additions in the future.

Back to the Patient

So how does a pharmacist answer the patient who has concerns about the switch from a brand name biologic to a new biosimilar? The comparable question with brand named drug molecules and their generics is relatively easy to answer.

The FDA has gone to great and detailed lengths developing the Orange Book; however, this question for biosimilars is very difficult to answer. Once the FDA begins to approve interchangeable products, the pharmacist can be confident in the process that the FDA has undergone to ensure clinical efficacy.

In the gray area of biosimilars, as health care professionals, is it appropriate to encourage our patients to use the less expensive alternatives? Pharmaceutical companies, pharmacy benefits managers, and pharmacies alike will spin the benefits of biosimilars and may even provide talk tracks for pharmacists.

Nevertheless, as more biosimilars come to market, this question and answer will lay heavily on my mind.

About the Author

Alex Toman attended Duquesne University, earning his Doctor of Pharmacy degree in 2011. Alex worked as a retail Pharmacist until 2015, at which time he transitioned into a clinical Pharmacist role within the specialty pharmacy industry. He is currently enrolled in the Masters of Science in Pharmacy Business Administration (MSPBA) program at the University of Pittsburgh, a 12-month, executive-style graduate education program designed for working professionals striving to be tomorrow’s leaders in the business of medicines.

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