Biologics have revolutionized the treatment of many disabling and life-threatening diseases, such as cancer, arthritis, psoriasis, kidney disease, irritable bowel disease, and growth disorders. Perhaps that is why seven of the top 10 molecules in the global pharmaceutical market and nearly 30 percent of the therapeutic pipeline (excepting vaccines) are biologics.1 Yet despite the growing presence and influence of biologics, access has become a significant global challenge. The reason for this, quite simply, is cost.

In addition to nearly one quarter of 46 European countries who do not provide access to biologics for arthritis,2 19 to 24 percent of dermatologists in key European and Canadian countries cite cost as a reason for not prescribing biologics.3 The burden of treatment costs is a growing problem worldwide (with new data showing that cancer patients are twice as likely as those in the general population to go bankrupt a year after their diagnosis4). Contributing to this problem are biologics, which in particular often prove too costly for patients most in need. On average, biologic treatment costs between $25,000 to 30,000 for patients.

Given the high cost associated with treatment, an impetus for more a more cost-effective means of delivering biologic therapy has driven much inquiry and research. In recent years, new agents known as biosimilars have shown promise in meeting this need. Biosimilars are approved biological medicines with compared quality, safety, and efficacy to a previously approved reference product whose exclusivity has expired. They are often considered the generic equivalent of biologics. Given the complex nature of these agents, however, the development and regulation of biosimilars is far more intricate and multifactorial.

In the European Union (EU), two biosimilar agents of infliximab (Sandoz biosimilars) were approved and have been in use since 2006, with safety profiles comparable to their respective reference product. Moreover, in 2013 the European Commission endorsed the role of biosimilars in enhancing competition and improving patient access.5 These developments likely represent the first steps in a much larger evolution of biosimilars in various therapeutic arenas—including psoriasis—that is to take place in the next several years.

DEVELOPMENT AND REGULATION OF BIOSIMILARS

Biosimilars are systematically developed and manufactured using the same quality standards as novel biologics. In highly regulated countries, all biosimilars are evaluated according to rigorous guidelines and must have highly comparable structural and functional attributes.6 They are approved via a stringent regulatory pathway requiring that there be no clinical relevant differences to the originals.6 Agents that do not meet these high standards are deemed non-comparable and not approved in highly regulated markets.7

The first step in the development of a biosimilar agent is the assessment quality of the reference products and defining of a target for development. According to the FDA, a highly similar molecule is key for biosimilar development8. A biosimilar must have a molecule profile match with the originator, both in terms of structure and function and in biological activity.9,10 It must also match the final dosage form to the originator. Thus, the independent design and development effort stage is a continuous feedback loop to the target profile.

Once the agent is developed, characterization and proof of comparability are required at all levels. To confirm biosimilarity, a biosimilar must demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence via tailored Phase III studies and support extrapolation to non-studied indications and interchangeability.9,10

“NON-IDENTICALITY” AND SIMILARITY

Despite strict control over the development and regulation of biosimilars, the variability of the reference product defines the target.11 While biologic products vary from batch to batch, non-identicality is a normal principle in glycosylate proteins.11 Thus, no batch of any biologic is “identitical” to other batches. Moreover, variability is natural and not problematic. Also worth noting is that manufacturing changes are frequent, with differences in attributes often larger than batch-to-batch variability.12 Examples of these changes include: change in the supplier of a cell culture media, new purification methods, and new manufacturing sites.11 However, such changes are not stringently controlled by regulators and do not lead to clinically meaningful differences.12

The most important aspect in the developing a biosimilar product that determines similarity is the biology.11 Beginning at the genetic stage, the variability of product quality attributes at the product start—including screening of host cell lines and transfection pools—is relatively wide. Then, from the screen of the clones and media development, the variability narrows further into the bioprocess development and DSP development.

In terms of clinical development, it's important to note that analytics and bioanalytics are highly sensitive in detecting differences,13 whereas traditional clinical endpoints are often not.14-18 Four stages of clinical development then confirm biosimilarity, including pre-clinical (tailored toxicology, efficacy and safety in relevant species models), PK/PD equivalence, efficacy/safety confirmation, and eventually post-approval collection of data to follow the product longterm. These stages help to confirm that a biosimilar must closely match the original product at all levels.19-22

THE FUTURE OF BIOSIMILARS

Today, biologics can be thoroughly characterized and understood both structurally and functionally, which has enabled the development of biosimilar agents. The target is set by the variability in the reference product and thorough understanding of the molecule. Knowledge of how process parameters influence product attributes is used to achieve matching quality. Clinical studies are designed to detect difference with the highest possible sensitivity. Thanks to modern science, even complex molecules can be developed as biosimilars today.

Biosimilars and originator biologics are complementary to each other, much in the same way as generics and their reference products (saving money both directly and by freeing up funds for further innovation). However, though the comparison of biosimilars to generics makes sense as a broad comparison, there are several key distinctions to note. Most importantly, biosimilar development is far more complex than standard generic development and therefore requires more time and budget. The total costs to research and develop a biosimilar can range between $100 million to $250 million, with a time to market estimate of seven to eight years, including Phase III pivotal studies required in patients, and further Phase IV studies post-approval. The same complex manufacturing process that has been used for the original biologic agents will be essential for biosimilars.

Despite the high costs of development, however, it remains inevitable that biosimilars, once developed and more integrated into the global health system, will help reduce the cost and improve access to appropriate treatment for patients with various debilitating diseases. With patents ending on a number of biologic agents, we will see the continued development of several biosimilars, leading to a substantial decrease in price of drugs and hopefully opening up the market for patients who don't have access at the present time. With a “level playing field” for all biologics, genuine competition will purportedly lead to increased innovation and decreased prices for patients.

Article based on Dr. Menter's scientific presentation at the 2014 American Academy of Dermatology Meeting in Denver, CO.

Alan Menter, MD, is Chief of Dermatology at Psoriasis Research Institute at Baylor University Medical Center, Dallas, TX . He is also a Clinical Professor at the University of Texas Southwestern Medical School.

  1. Evaluate Pharma, Feb 2013; Sandoz analysis
  2. Putrik P1, Ramiro S, Kvien TK, et al. Inequities in access to biologic and synthetic DMARDs across 46 European countries. Ann Rheum Dis. 2014;73(1):198-206.
  3. Nast A, Mrowietz U, Kragballe K, et al. Barriers to the prescription of systemic therapies for moderate-to-severe psoriasis--a multinational cross-sectional study. Arch Dermatol Res. 2013;305(10):899-907.
  4. Cancer diagnosis as a risk factor for personal bankruptcy, ASCO 2011
  5. Consensus Information Paper 2013. What you need to know about Biosimilar Medicinal Products.
  6. Brockmeyer C, Seidl A. Binocrit: assessment of quality, safety and efficacy of biopharmaceuticals. Eur J Hosp Pharm Prac. 2009; 15(2): 34–40.
  7. Schellekens H. Biosimilar epoetins: How similar are they? Eur J Hosp Pharm 2004;3:43–47.
  8. Steven Kozlowski, Director, FDA Office of Biotechnology Products, Biosimilar Workshop, APEC, Seoul, April 4, 2012
  9. McCamish et al, ClinPharmacol & Ther 2012;
  10. Visser J, Feuerstein I, Stangler T, et al. Physicochemical and Functional Comparability Between the Proposed Biosimilar Rituximab GP2013 and Originator Rituximab. BioDrugs. 2013; 27: 495–507.
  11. Schneider, C. K.: Biosimilarity: A better definition of terms and concepts. 25th Annual DIA EuroMeeting, 04- 06/03/2013, Amsterdam
  12. Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310-312.
  13. Kaymakcalan Z1, Sakorafas P, Bose S, et al. Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clin Immunol. 2009;131(2):308-316.
  14. Weinblatt ME1, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999 Jan 28;340(4):253-9.
  15. Weinblatt ME1, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35-45.
  16. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354:1932-39
  17. Keystone E, Heijde Dv, Mason D Jr, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319-29.
  18. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis. 2009 Jun;68(6):789-96.
  19. McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3):405-417.
  20. Visser J1, Feuerstein I, Stangler T, et al. Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab. BioDrugs. 2013;27(5):495-507.
  21. Gascon P1, Fuhr U, Sörgel F, et al. Development of a new G-CSF product based on biosimilarity assessment. Ann Oncol. 2010 ;21(7):1419-29.
  22. .Weigang-Köhler K, Vetter A, Thyroff-Friesinger U, et al. HX575, recombinant human epoetin alfa, for the treatment of chemotherapy-associated symptomatic anaemia in patients with solid tumours. Onkologie. 2009;32(4):168-74.
  23. Strober BE, Armour K, Romiti R, et al. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know. J Am Acad Dermatol. 2012 Feb;66(2):317-22