Biosimilars used for supportive care in cancer have been available in the U.S. since 2015.

As patents expire on therapeutic biologics used for cancer treatment, biosimilars of these medicines will begin to emerge, and are expected to play an increasingly prominent role in healthcare.

Amgen is developing biosimilars of some of the most complex and important oncology therapeutics. Gary Fanjiang, MD, vice president of Biosimilars Global Development, Amgen, discusses the development of biosimilars and some of the clinical considerations related to their use.

What does it take to develop a biosimilar?

A biosimilar is approved based on showing that it is highly similar to, and has no clinically meaningful differences from, an FDA-approved originator biological product, known as a reference product.

 The goal of a biosimilar development program is to demonstrate biosimilarity between the proposed biosimilar product and the reference product, not to independently establish the safety and effectiveness of the proposed product.

The process starts with evaluating the reference product, and importantly, understanding the key function/activity and structural characteristics that drive its activity.

Then a cell line must be created that produces a protein with the same amino acid sequence, and with post-translational modifications that are similar to that of the reference product. After creating a cell line, significant process development is done to further refine how that cell system produces the protein, underscoring the importance of an iterative process in establishing similarity in structure and function to the reference product, especially with respect to the critical attributes.

This is done until the protein demonstrates similar binding to its target, among other demonstrations such as maintaining structural and functional similarity. This process of refinement to achieve a specific outcome requires skill and experience with developing and manufacturing complex proteins. Then a clinical pharmacokinetics (PK) study and if necessary, a pharmacodynamics (PD) study is done to demonstrate similar PK.

Finally, at least one comparative clinical study typically is conducted to reduce residual uncertainty about the potential for clinically meaningful differences in efficacy, safety and immunogenicity between the biosimilar and its reference product. It is important that this study is conducted in a sensitive population and with sensitive endpoints. In this context, “sensitive” means one with which you are likely to detect a difference in efficacy, safety or immunogenicity due to differences in the products, if such a difference exists.5 A biosimilar program is based on the totality of evidence approach, in which these studies are necessary to demonstrate biosimilarity.

Compared to a generic drug, which takes an average of three years to develop, a biosimilar takes approximately seven to eight years to develop.

What are some of the aspects of biosimilar clinical trials that are unique as compared to the development of new originator therapeutics?

For novel therapeutics, the goal of clinical trials is to prove safety and efficacy of the product versus standard of care. For biosimilars, the goal is to demonstrate that the biosimilar is highly similar to the reference product structurally and functionally, and that there are no clinically meaningful differences between the two products, and not to independently re-establish efficacy and safety.

The FDA evaluates this using a “totality of evidence” approach. This means that it will look at all the data generated, including analytical, nonclinical and clinical data, with each piece of evidence contributing to the FDA’s evaluation of similarity.

 The clinical trial data plays a different role in the overall data package than in trials for new therapeutics. Within this data, the analytical characterization is an important step that has the highest level of sensitivity to identify any structural or functional differences, should they exist and that further clinical studies reduce any remaining residual uncertainty.

Is it true that biosimilars can be approved for indications beyond those that are directly studied clinically?

This concept is different from innovator product development where in some cases data may be extrapolated to a very similar population, such as adults to pediatrics, within the same indication.

For biosimilars, extrapolation is the approval of a biosimilar for use in an indication held by the originator (reference) biologic not directly studied in a comparative clinical trial with the biosimilar.

There needs to be scientific justification to support extrapolation, which includes the assessment of certain scientific factors, the totality of the data generated, and FDA’s previous finding that the reference product is safe and effective in the indications being considered.

 The ability to not directly study every indication sought is one way in which development costs can be reduced, while still making important biologic medicines available to patients.

What is your view on interchangeability in oncology?

In the U.S., an “interchangeability” designation means that FDA has evaluated additional evidence showing that the biosimilar can be expected to produce the same clinical result as the reference product in any given patient and, if the product is administered more than once, the risk of switching between the biosimilar and the reference product is not greater than the risk of using the reference product without such switch. If a biosimilar is designated as “interchangeable,” then it allows for pharmacy substitution without the intervention of the physician, in accordance with state pharmacy laws.

In oncology, I don’t think this designation will be particularly meaningful, since biosimilars are generally infused products, and typically are not distributed through an out-patient pharmacy.

How do you think biosimilars may change cancer care?

The cost of cancer care is a barrier to many patients having access to cutting edge therapies.

 I welcome the addition of biosimilars to the portfolio of treatment options, as they have the potential to provide additional therapeutic options and contribute to a more sustainable healthcare system.

 By introducing greater competition, they also may have the indirect effect of lowering the cost of innovator drugs.

To learn more about biosimilars, visit www.AmgenBiosimilars.com.

U.S. Food & Drug Information. Biosimilar Product Information. https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm580432.htm. Accessed June 13, 2019.

National Cancer Institute. Biosimilars for Cancer Emerge as Patents on Widely Used Biological Drugs Expire. https://www.cancer.gov/news-events/cancer-currents-blog/2018/biosimilars-cancer-treatment. Accessed June 13, 2019.

U.S. Food and Drug Administration. FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM428732.pdf. Accessed June 13, 2019.

U.S. Food and Drug Administration. Biosimilar Development, Review, and Approval. https://www.fda.gov/drugs/biosimilars/biosimilar-development-review-and-approval. Accessed June 13, 2019.

U.S. Food and Drug Administration. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed June 13, 2019.

Camacho LH, et al. Biosimilars 101: considerations for U.S. oncologists in clinical practice. 

Blackstone EA, Fuhr JP. The Economics of Biosimilars. 

U.S. Food & Drug Administration. Biosimilar and Interchangeable Products. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580419.htm#interchange. Accessed June 13, 2019.

The impact of Biosimilar Competition in Europe. https://www.medicinesforeurope.com/wp-content/uploads/2017/05/IMS-Biosimilar-2017_V9.pdf. Accessed June 13, 2019.

The impact of Biosimilar Competition in Europe. https://ec.europa.eu/docsroom/documents/31642/attachments/1/translations/en/renditions/native. Accessed June 13, 2019.

Articles

Gary Fanjiang, MD, vice president of Biosimilars Global Development, Amgen, discusses the development of biosimilars and some of the clinical considerations related to their use.

Sponsored Content by Amgen

Articles

Biosimilars in Cancer Care: Potentially Improving Patient Access to Essential Therapies9,10