Navigating Biosimilars in Dermatology

Biologics are emerging as key agents for the treatment of a spectrum of disorders, from cancers to autoinflammatory diseases, including psoriasis. As in other disease states, biologic agents have revolutionized the treatment of psoriasis, and several tumor necrosis factor inhibitors are approved for its treatment.

With demonstrated superior efficacy and safety profiles compared with previously used conventional treatment options, the expectation of outcomes with biologic agents is at worst a well-controlled disease, and at best, disease remission.

However, the prohibitive cost of biologics has limited patient access to treatment, with the consequence of undertreatment of moderate to severe psoriasis.¹

The goal of affordable and accessible treatment for all, together with the looming patent expiration of many biologic agents, has fueled interest in the development of biosimilars. Biosimilars of the originator tumor necrosis factor inhibitors that were approved for the treatment of psoriasis — including adalimumab, etanercept, and infliximab — are now licensed in several countries.² As biosimilars are increasingly used globally, new challenges are exposed that can have an impact on their clinical use.

By definition, a biosimilar is not a “generic version” of the reference biologic agent. The size, complexity, manufacturing process, and potential immunogenicity differentiate biosimilars from small-molecule generics.³ Whereas biologic agents such as monoclonal antibodies are derived from living organisms and consist of relatively large and often highly complex molecular entities, biosimilars are the chemical copy of the reference biologic. The amino acid sequence of the biosimilar and the reference biologic is expected to be the same, and the functional characteristics with regard to safety, efficacy, and purity are expected to have no clinically meaningful differences.^2,4,5 In most cases, approval of a biosimilar is based on equivalence trials in which the biosimilar should demonstrate neither inferiority nor superiority to the reference biologic agent within an acceptable margin of error. However, a universally acceptable margin of error has not been defined. Indeed, the margin of error can be influenced by study design, study population, and sample size, as demonstrated by Wan and colleagues, who found a range from ±14% to ±18% among different studies that compared a biosimilar with its reference biologic agent.⁵ In general, clinical studies of biosimilars are less robust than studies on the originator biologic, and in some cases, the clinical data and indications of the originator biologic are extrapolated to the biosimilar product.

The basic requirements of a biosimilar compared with its originator biologic agent has resulted in variations in the interpretation of ‘biosimilarity’ in different countries. This has resulted in variations in manufacturing, requirements for approval, and use of biosimilars for the treatment of psoriasis at the clinic and pharmacy level.⁶ Among the 13 countries reviewed by Cohen and colleagues, significant differences exist in their recommendations on how biosimilars are manufactured and used for the treatment of psoriasis.⁶ For example, although regulatory pathways and guidelines for the use of biosimilars are available in some countries, with variations in details and requirements, they are lacking in others.⁶ The lack of clarity and consistency in the naming of biosimilars adds to the confusion over their use. For example, Amjeviat^©, Amgevita^©, Solymbic^©, and Exemptia^© are the biosimilar names for the reference biologic adalimumab, and Flixabi^©, Inflectra^© and Remsima^© are the biosimilar names for the reference biologic infliximab.⁴ The cost differentials between a biosimilar and the reference biologic also vary by country, ranging from 70% in Norway and 30% in India to 15% in the United States,⁶ as do recommendations for interchangeability and substitution and requirements for postmarketing surveillance and reporting of adverse events.⁶ 

Although there is currently a lack of robust data to support a recommendation for biosimilar interchangeability and switching, in some countries, substitution at the pharmacy level is allowed with or without consultation with the prescribing physician, while in other countries, physicians are mandated to use a biosimilar product over the reference biologic.⁶ Moots and colleagues concluded from their evaluation of 53 switching studies that there are insufficient data from postmarketing pharmacovigilance and a lack of evidence from comparative clinical trials to fully conclude the safety of substitution or switching between a biosimilar and its reference biologic with respect to long-term efficacy, safety, and immunogenicity.⁷

“It’s important to avoid biosimilar substitution for a number of reasons,” said lead author Robert J. Moots, MD, PhD, professor of rheumatology at the University of Liverpool in England and head of the European League Against Rheumatism Centre of Excellence, adding, “the two most important in my mind are that repeated substitutions run the risk of generating anti-drug antibodies, and pharmacovigilance is difficult, if not impossible, unless the correct brand/type of drug is fully traceable.” Based on the findings from their study, Moots and colleagues suggest using caution when switching between the biosimilar and the reference biologic, recommending that it should be a decision made primarily by the treating physician on a case-by-case basis and supported by sound scientific data. 

Given the demonstrated efficacy and safety of biologic agents for improved treatment and outcomes in patients with moderate to severe psoriasis, and the potential of biosimilar products for improved access, there is need to address the current global confusion over prescribing policies and appropriate use of biosimilars at the clinic and pharmacy levels. The International Psoriasis Council has recognized the need to address these challenges and has advocated that dermatologists take an active role in the development of biosimilar prescribing policies worldwide. Because the progression to psoriatic arthritis among some patients with psoriasis often necessitates a multidisciplinary treatment approach that may involve primary care practitioners, rheumatologists, and dermatologists, a more collaborative approach may be a better to address the challenges that are common to these healthcare providers, who may, in fact, be treating the same patient. “I agree that a collaborative approach is essential in all aspects of patient care, including biosimilar prescribing policies,” said Professor Arnon D. Cohen, MD, MPH, PhD, director in the department of quality measures and research and chief physician at the Clalit Health Services in Tel Aviv, Israel.

From a physician perspective, irrespective of the country, challenges to clinical decision-making emerge from different angles, including the variation in manufacturing, regulatory practices, and pharmacovigilance, together with limited data from comparative clinical studies. There is lack of clarity on naming convention and differences in the recommendations for their use by regulatory agencies. These challenges are heightened by differences in the cost differential between the biosimilar and the reference biologic agent, as well as the lack of robust data to provide guidance on interchangeability or substitution, resulting in variations in practices and challenges with traceability, monitoring, and accurate adverse event reporting. On interchangeability or substitution of a biosimilar with its reference biologic agent, the International Psoriasis Council recommends that the treating dermatologist should be notified prior to any originator or biosimilar drug substitution being made, and the choice of therapy — biosimilar or originator biologic agent — is a decision made primarily by the patient and the dermatologist after consideration of safety, efficacy, and cost.

References

1. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Are patients with psoriasis undertreated? Results of National Psoriasis Foundation survey.  J Am Acad Dermatol. 2007;57:957-962.
2. Gerdes S, Mrowietz U, Augustin M, et al. Biosimilars in dermatology – theory becomes reality.  J Dtsch Dermatol Ges. 2018;16(2):150-160.
3. Li E, Ramanan S, Green L. Pharmacist substitution of biological products: issues and considerations. J Manag Care Spec Pharm. 2015;21(7):532-539.
4. Müller R, Renner C, Gabay C, Cassata G, Lohri A, Hasler P. The advent of biosimilars: challenges and risks.  Swiss Med Wkly. 2014;144:w13980.
5. Wan MT, Strober BE, Wu JJ, Shin DB, Gelfand JM. How similar are the treatment responses to biosimilars in patients with psoriasis? A systematic review of statistical margins in comparative clinical trials.  J Am Acad Dermatol. 2017;77(3):569-572.
6. Cohen AD, Wu JJ, Puig L, et al. Biosimilars for psoriasis: worldwide overview of regulatory guidelines, uptake and implications for dermatology clinical practice. Br J Dermatol. 2017;177(6):1495-1502.
7. Moots R, Azevedo V, Coindreau JL, et al. Switching between reference biologics and biosimilars for the treatment of rheumatology, gastroenterology, and dermatology inflammatory conditions: considerations for the clinician.  Curr Rheumatol Rep. 2017;19(6):37.