Safety and Scientific Standards First: Why Biosimilars Require Clinical Testing

Biologic medicines have revolutionized treatment and profoundly impacted the lives of millions of Americans.^1,2,3 Amgen has played a critical role in this treatment revolution. We have more than a dozen originator biologics and 2 biosimilars on the market in the United States, with more biosimilars in our development pipeline. Because of our long history of innovation, not everyone recognizes that we have made a multi—billion-dollar investment in our pipeline of 10 biosimilars, and rightfully consider ourselves one of the global leaders in the marketplace.

History tells us that regulatory approval pathways for medicines need 2 key elements: solid, replicable scientific evidence and patient and prescriber confidence that the FDA has applied appropriate standards in evaluating that evidence. In the case of biosimilars, both elements are met by scientifically appropriate and globally accepted regulatory standards, including the requirement for comparative clinical studies. Comparative analytical studies are not by themselves a sufficient demonstration that there are no clinically meaningful differences in efficacy, safety, and immunogenicity between a biosimilar and its reference product, but are essential to supporting that demonstration.

In recent years, some have advocated that analytical data alone (eg, in silico or in vitro testing) are sufficient to demonstrate biosimilarity, arguing that a comparative clinical study is an unnecessary burden that may discourage manufacturers from entering the biosimilars arena. However, several factors strongly weigh against this line of reasoning and favor maintaining clinical testing to fully evaluate potential biosimilars.⁴

One factor is the complexity of biologics, including biosimilars.

The US biosimilars regulatory pathway, established by Congress in 2010 in the Biologics Price Competition and Innovation Act (BPCIA), defines a biosimilar product as one that is highly similar to, and has no clinically meaningful differences from, its biologic reference product.

There will always be some analytical differences between a biosimilar and its reference product given the complexity and inherent variability of biological products. Biologic structural factors, such as molecular folding and glycosylation, can introduce the potential for functional variations. Analytical methodologies alone cannot definitively evaluate the potential impact of such differences between products on clinical outcomes, including efficacy and immunogenicity.⁵

As a result, there is a need to demonstrate clinical equivalence between the biosimilar and biologic reference product with respect to pharmacokinetics, safety, efficacy, and immunogenicity through comparative clinical testing. The importance of comparative clinical testing is supported by early experience with biosimilar equivalence testing in the European Union, where clinical trials exposed immunogenicity issues with biosimilar versions of biologic molecules (eg, human growth factor and erythropoietin).^6,7

Further, a comparability assessment conducted by Amgen of a biologic before and after a proposed manufacturing process change found that the nonclinical assessments of structure—function relationships were insufficiently sensitive to identify clinically relevant differences resulting from differences in the glycosylation profile.⁸

In addition, in silico testing (analytical testing) alone cannot definitively evaluate the potential impact of subtle structural and functional differences between a proposed biosimilar and a reference product on clinical outcomes.

For example, software can recognize that 2 biosimilar agents have an identical amino acid sequence, but it will not necessarily capture functional variations. As another example, in vitro testing of biologics addresses only T-cell epitope content, which is sequence-based and therefore expected to be identical between a reference product and biosimilar.

In contrast, currently available in vitro and in silico tools, as well as those anticipated in the foreseeable future, are not able to reliably predict differences in B-cell epitopes, which might be enhanced in a biosimilar due to differences in glycosylation patterns.

Further, these analytical tools cannot assess potential immunogenicity based on how biological products are recognized in patients, which can vary substantially due to the vast diversity of T-cell and B-cell receptors across the population. The current state of science means these types of analytical tools cannot substitute for clinical testing, but they can provide essential data as part of a biosimilar’s comprehensive data package to demonstrate biosimilarity.⁴

Furthermore, biosimilar manufacturers do not have knowledge of the exact manufacturing process used to create a reference biologic; therefore, there will inevitably be differences in how reference and biosimilar products are produced.

Comparative animal (when relevant) and clinical analyses are necessary to comprehensively evaluate that such differences have no meaningful effect on clinical outcomes, including efficacy and immunogenicity.

Finally, claims that clinical testing slows the pace of innovation and discourages introduction of new biosimilars into the marketplace are unfounded.

Since the BPCIA’s enactment in 2010, the FDA has approved 23 biosimilar products (with 9 having reached the market thus far) and 80 biosimilars are currently in FDA’s development program. This robust pipeline of biosimilars argues against the notion that clinical standards need to be lowered to encourage companies to throw their hats into the market. The biosimilars market is continuing to grow in the United States; in fact, short-acting granulocyte colony-stimulating factor (G-CSF) biosimilars achieved nearly half of the market share in a little over 3-and-one-half years, long-acting G-CSF biosimilars achieved 20% market share in just 9 months, and a single epoetin alfa biosimilar achieved 12% market share in just 6 months.⁹

As a company with a 4-decade legacy of delivering innovative biologics to patients, and an equally fervent commitment in biosimilars (3 approved and 2 launched in the United States, with many more in our pipeline), Amgen understands that patient, physician, pharmacist, and payer confidence in the regulatory approval process is a critical factor to the long-term success of the US marketplace with biosimilars. We strongly believe appropriate clinical testing must be included in the regulatory approval process for biosimilars.

References

1. Odes S, Greenberg D. A medicoeconomic review of early intervention with biologic agents in the treatment of inflammatory bowel diseases. Clinicoecon Outcomes Res. 2014;8(6):431-43. doi: 10.2147/CEOR.S39212.

2. Holdam ASK, Bager P, Dahlerup JF. Biological therapy increases the health-related quality of life in patients with inflammatory bowel disease in a clinical setting. Scand J Gastroenterol. 2016;51(6):706-11. doi: 10.3109/00365521.2015.1136352.

3. Frieder J, Kivelevitch D, Fiore CT, Saad S, Menter A. The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis. Exert Rev Clin Immunol. 2018;14(1)1-19. doi: 10.1080/1744666X.2018.1401468.

4. Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: preclinical assessment and mitigation. Clin Immunol. 2013;149(3):534-55. doi: 10.1016/j.clim.2013.09.006.

5. Sekhon B, Saluja V. Biosimilars: an overview. Biosimilars. 2011;1:1-11. doi: 10.2147/BS.S16120.

6. Romer T, Saenger P, Peter F, et al. Seven years of safety and efficacy of the recombinant human growth hormone Omnitrope in the treatment of growth hormone deficient children: results of a phase III study. Horm Res. 2009;72(6):359-69. doi: 10.1159/000249164.

7. Seidl A, Hainzl O, Richter M, et al. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29:1454-1467. doi: 10.1007/s11095-011-0621-4.

8. Grampp G, McElroy P L, Camblin G, Pollock A. Structure-function relationships for recombinant erythropoietins: a case study from a proposed manufacturing change with implications for erythropoietin biosimilar study designs. J Pharm Sci. 2018;107(6):1512-1520. doi: 10.1016/j.xphs.2018.01.018.

9. Amgen data on file. OBU Customer Datapack, week ending May 3, 2019 (Extract date May 24, 2019), unsmoothed data.