CJ is a 62-year-old female beginning chemotherapy with doxorubicin and cyclophosphamide for stage III breast cancer. To minimize the risk of neutropenia-associated complications, it is planned for CJ to return to the clinic daily following chemotherapy for injections of a colony-stimulating factor (CSF) until her absolute neutrophil count exceeds 10,000 × 106/L. As the oncology pharmacist on the team, you are asked which CSF to recommend considering the recent development of biosimilar CSFs. Additionally, you are asked if biosimilar options are safe and efficacious for patient use. How would you answer?
Until recently, the selection of biological therapies for any indication was limited to the availability of the originator or reference product. For a patient like CJ, this would result in the prescribing of filgrastim (Neupogen) or pegfilgrastim (Neulasta) for prophylaxis of neutropenia and/or neutropenia-associated complications from chemotherapy. However, with patent expiration looming for many of these highly specialized medications, healthcare professionals are now facing the introduction of the biological therapy equivalent (referred to as biosimilars) of the chemical generic drug product. Because biologics are far more complex than their small molecule drug counterparts, often comprising large molecular weight proteins or peptides developed from living cells or organisms, minor differences in structural assembly or protein folding may theoretically translate into differences in activity not previously observed with the development of other generic drug products. As a result, many healthcare professionals have expressed concern and uncertainty regarding the similarity of clinical efficacy and safety between these new biosimilars and the corresponding reference biologics. Therefore, education of clinicians regarding biosimilars should address the major concerns/barriers to use of these drug products in clinical practice.
The paradigm that biosimilars are “similar but not identical” to the reference biologic is both what some clinicians find appealing from a pharmacoeconomic perspective and what other clinicians fear from a clinical utilization perspective. These concerns are what have led naysayers to erroneously conclude that biosimilars are of lower quality than the innovator drug and may not achieve therapeutic outcomes as effectively. To refute this notion, it is necessary to briefly address the development process of these drugs. First, because the manufacturing processes for biologics are proprietary, it is impossible to exactly replicate the structure of the innovator product. Small differences in amino acid sequence or protein folding will result in a new and unique biologic molecule.1 As such, biosimilars cannot be regarded as true generic versions of innovator compounds. It is also important to recognize that the concern related to the intrinsic variability in biologic systems often cited for biosimilars also results in minor variations from batch to batch in the production of innovator biologics so that no 2 batches will be identical. However, the quality controls imposed for both innovator biologics and biosimilars ensure the creation of a product that is within an acceptable range of variability and strives to eliminate any difference in clinical efficacy.2 Thus, the goal of biosimilar production becomes the desire to create a product that is highly similar to the innovator drug with regard to physicochemical and functional characteristics. If successful, clinical efficacy and safety must be addressed but is allowed by the FDA, to some degree, to be extrapolated from clinical trials and experiential utilization of the innovator drug. Some may find the FDA’s compressed approval pathway for biosimilars to be a cavalier approach for a unique drug molecule. However, Weise and colleagues address this directly by suggesting, “a repetition of the entire development program of the reference product is scientifically not necessary and could even be considered unethical.”2
Therefore, if we correctly conclude that an approved biosimilar product is structurally very similar to the innovator product, and the FDA allows the extrapolation of some clinical efficacy and safety data from clinical trials conducted for the innovator drug, are we ready to accept biosimilars for all patients and all indications? The answer should be...not yet, there’s more we must first consider!
Whereas products that share structural similarity should reasonably be expected to share adverse event profiles, concerns do still remain regarding immunogenicity. While major issues in product variation may be detected by ultrasensitive analytical methods, human immunogenicity data are required prior to approval of a biosimilar product. This is especially true for biologic compounds known to induce immune responses resulting in significant patient safety issues.2 Here, we may learn a lesson from our colleagues across the globe. The European Medicines Agency (EMA) was the first to develop guidelines for biosimilars in 2005 and followed with the first worldwide biosimilar approval in 2006. With 13 biosimilars approved by EMA to date, issues with immunogenicity have been observed and addressed for some products. In one example, EMA noted excessive immunogenicity with a biosimilar somatropin due to a high level of host cell proteins that could be removed through an additional purification step added to the manufacturing process.2,3 In the European model, pharmacovigilance and postmarketing studies for biosimilars are often recommended and tailored to the individual drug product and any perceived drug-specific issues that may exist.
Therapeutic interchange also remains an important consideration in the use of biosimilar medications. For standard generic drug products, the FDA’s Orange Book provides guidance for substitution for an innovator product. Those products deemed identical are assigned an AB rating allowing a pharmacist to dispense, without medical authorization, a generic in place of a prescribed innovator drug. As established here, biosimilars are not identical to the reference product, thus resulting in issues with therapeutic interchange. The FDA has delineated a pathway by which a biosimilar may be labeled as interchangeable with an innovator compound. This pathway requires data in addition to what is expected for a product to simply be recognized by the FDA as biosimilar. Here, a manufacturer must demonstrate that a product may be expected to produce the same clinical outcomes in any patient as that observed for the innovator compound. Additionally, it must be demonstrated that the risk of switching therapy between the biosimilar and the innovator product is no greater than using the innovator product alone without changing therapies.4 Simply put, this process holds manufacturers to a higher standard of demonstrating biosimilarity, clinical efficacy, and human safety data than what would typically be required for FDA approval alone.
Even for products that have sought interchangeability, concerns still linger regarding traceability of biosimilar products in the clinical setting. This is perhaps the most compelling argument against automatic substitution rules for biosimilars. Here again we must point out the paradigm of “similar but not identical.” As such, for patients developing an adverse event or an immune-
mediated safety issue to a biosimilar, the exact product dispensed must be able to be appropriately and accurately identified. Root cause analysis and reporting to the FDA’s MedWatch program require specific drug information, including product name and lot number. To streamline this process, the FDA appears to have taken a proactive stance in biosimilar nomenclature that ties the manufacturer name to the drug product instead of using the chemical name alone as is done with small molecule generics. For example, Teva Pharmaceutical’s filgrastim biosimilar will be recognized as tbo-filgrastim rather than filgrastim alone. These higher standards of interchangeability and unique nomenclature may initially limit the market share for these new biosimilars as prescribers will be required to specify which drug product their patient will receive. Over time, the pharmacoeconomic benefits of using a less expensive biosimilar proven to have similar safety and efficacy profiles have been estimated to generate significant cost savings in an era where healthcare spending is spiraling out of control. In fact, some have estimated that the availability of a biosimilar product will replace 80% or more of prescriptions for some innovator products within 1 year of commercial availability.5
For those biosimilar products that meet the standards we have discussed, the FDA allows their use in the same treatment regimens at the same doses and using the same schedule as the innovator product. However, clinicians must be aware that commercial availability of a biosimilar does not automatically equate approval for all indications for which an innovator product is currently prescribed. Clinicians are encouraged to exercise appropriate judgment in choosing a biosimilar for an off-label use despite the fact that once clinical efficacy and safety have been demonstrated, substitution of a biosimilar will likely prove to be clinically appropriate in these scenarios.
As a cancer center, we have not yet been forced to make policy decisions regarding formulary inclusion of biosimilars, substitution of biosimilars in our treatment protocols, or in how we monitor patients for adverse reactions or immune-mediated complications following treatment with a biosimilar. I predict that we will observe characteristic patterns of early adopters eager to utilize a cheaper biologic to contain costs and late adopters determined to wait until additional data emerge for patients treated with biosimilars outside the highly controlled confines of a clinical trial. Ultimately, prescribers must feel comfortable that these new products are not jeopardizing the health, well-being, or prognosis of their patients with cancer.
In the case of CJ, we pondered the question of whether biosimilars were safe and efficacious for patient use. With the issues we have considered here, I believe the answer is yes, these FDA-approved drugs are safe and efficacious for our patients, and providers should give serious consideration to use of these products as an alternative to more costly innovator products. However, until we have more long-term safety data, patients should be monitored closely for tolerance, and providers should have a low threshold for converting patients back to the innovator drug if issues arise.
- Niederwieser D, Schmitz S. Biosimilar agents in oncology/haematology: from approval to practice. Eur J Haematol. 2011;86:277-288.
- Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood. 2012;120:5111-5117.
- European Medicines Agency. European Assessment Report on Omnitrope. www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000607/WC500043692.pdf. Accessed August 3, 2013.
- US Food and Drug Administration. Biologics Price Competition and Innovation Act of 2009. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ucm216146.pdf. Accessed August 3, 2013.
- Cornes P. The economic pressures of biosimilar drug use in cancer medicine. Target Oncol. 2012;7(suppl 1):S57-S67.