Author byline as per print journal: Sandeep N Athalye, MBBS, MD; Shivani Mittra, MPharm, PhD; Ankitkumar M Ranpura, MD
Submitted: 2 November 2022; Revised: 21 December 2022; Accepted: 21 December 2022; Published online first: 30 December 2022
In the US healthcare system, of the 126 billion US dollar spent on biologicals in 2018, only 2% was spent on biosimilars . Biosimilars with a faster entry, higher volume share, and more robust price competition, can lead to substantially more savings (US$124.2 billion) between 2021 and 2025 . An analysis of more than one million patient-treatment years with biosimilars has raised no efficacy or safety concerns and this, in turn, should build confidence in the regulators, payers, physicians, and patients based on the substantial repertoire of the real-world data .
Biosimilar approvals require data from comprehensive analytical and clinical studies in ‘highly regulated’ jurisdictions such as the European Union, Japan and the US. These include non-clinical in-vitro studies of the molecular function; human pharmacokinetic (PK) and pharmacodynamic (PD) studies; a powered clinical efficacy study in the most sensitive indication of the reference product; and human immunogenicity studies, including ‘switch’ studies between the reference product and the proposed biosimilar for the US .
With the optimally regulated development of insulin biosimilars in place, the focus is now on the newer immuno-oncology biosimilars. Development for these is laden with challenges pertaining to the requirement of large efficacy equivalence trials, high costs of the reference products, and additional cost of concurrent chemotherapy drugs, amongst other challenges. The importance of harmonizing policies for biosimilar development, globally, cannot be emphasized more keeping in mind the inflection point where biosimilar developers are finding themselves to be.
The following suggestions can lead to leaner and faster development along with faster uptake of biosimilars in the regulated markets and, further, across the globe:
(1) Policies that encourage ‘totality of evidence’ but with an optimally customized trial design for each molecule, are required. For example, for denosumab biosimilar development, where the dosing is every 6 months, any additional switch requirement beyond one year increases the trial duration by 6 months, leading to a time and cost increase in the development. Single switch studies assess the effect of ‘switching’ to a biosimilar with regard to immunogenicity and related safety. Molecules such as denosumab, secukinumab and daratumumab have very low immunogenicity, <1%, <1% and <0.35%, respectively, and have not reported any efficacy or safety concerns even on long terms [5–7].
Previous studies have reported the anti-drug antibody incidence rate to be <1% with 8-year treatment with denosumab, and there is no evidence of PK differences, toxicity, or difference in the clinical response. This has been validated in several studies with denosumab and its biosimilars, see Table 1. In the case of secukinumab, of the <0.1% subjects that developed anti-drug antibodies, approximately one-half had neutralizing antibodies which were not observed to be associated with any loss of efficacy . Hence, single-switch studies for such molecules would not offer any additional information and should not apply to the development of their biosimilars.
Biosimilars approved to date by the US Food and Drug Administration (FDA) have not shown any major safety or immunogenicity concerns after single or multiple switches (if done), underscoring the importance of either completely waiving off the single-switch studies or only considering these for highly immunogenic drugs. Two systematic reviews by Cohen et al. (2018) and Barbier et al. (2020) consisting of 90 and 178 switch studies involving 14,225 and ~21,000 subjects, respectively, have shown no difference in the safety, efficacy and immunogenicity outcomes related to switching from the reference biological to the corresponding biosimilar [8, 9]. These results should assure regulators, prescribers, payors and patients that the risk of immunogenicity-related safety concerns or diminished efficacy remains unchanged after switching. Granting interchangeability claims for such low immunogenic molecules should be allowed based on the safety and efficacy trial data.
(2) The use of ‘one global reference product’ for biosimilar development trials can bring down the costs in a big way. The huge cost involved for reference drugs requirement is another deterrent to multiple players interested in developing biosimilars. The high cost of reference listed drugs (RLDs) for biologicals (Pembrolizumab, US$10,474 per vial: Daratumumab, US$6,500 per infusion; Nivolumab, US$7,436 per vial and Pertuzumab, US$6,216 per vial) makes one think why a single, most cost-effective amongst all available RLD’s cannot suffice for all developed regulatory markets [10–14]. PK bridging studies between the reference drugs (such as US-licensed and EU-approved reference products) are required considering the possibility of a drift in the quality attributes in the originator molecule across regions. This adds to the trial complexity and timelines, in addition to the cost, especially in the integrated patient trials in the oncology space. Based on past data on approved biosimilars, there is no evidence that such differences are observed. The two-arm clinical PK study instead of three arms, with either of the RLD, can substantially reduce the trial complexity, duration, and cost.
A World Health Organization survey in 2019‒2020 in 20 countries has recognized the challenges related to the RLDs, which include limited access to information on the RLDs, financial constraints due to their price, and difficulty in obtaining RLD samples to assess comparability . While some countries accept RLDs that are foreign-licensed and -sourced, especially from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use countries , many others require a domestically licensed/marketed reference product or else require bridge studies for a foreign-sourced reference product that end up being costly and often unnecessary, see Table 2. To address these challenges and to bring about harmonization to have a single global reference product, exchanging information with other national regulatory authorities builds confidence in accepting foreign-sourced reference products, thus avoiding unnecessary bridge studies.
(3) There is also a strong need to have common statistical methods (currently, it is Risk Ratio for FDA versus Risk Difference for EMA) to assess biosimilarity and hence to calculate the sample size for the equivalence and efficacy trials . The difference between two-population means, for efficacy measures, is a widely used method as specified by European Medicines Agency (EMA)  for establishing margins for the calculation of the sample size. Differences in the statistical methods for assessing biosimilarity and sample-size estimation lead to huge differences in the sample-size requirement for confirmatory trials between FDA and EMA [18, 19]. The opportunity to use asymmetric margins is also a relevant consideration for future biosimilar development based on scientific reasoning. The large sample size and cost of reference products for such trials can become a barrier for companies developing biosimilars globally. Hence, having a uniform method to arrive at a trial size, with an intent to keep the totality of evidence approach, can be helpful in simplifying biosimilar development.
(4) Conducting a clinical trial for an orphan drug becomes costly due to recruitment challenges, and operational costs escalate due to the longer duration of the trial and the reference product cost. Procurement of reference products through tightly managed channels and access to patients is a challenge. No guidance exists for developing orphan drug biosimilars. Waiving off the clinical efficacy similarity trial for such orphan drugs can significantly reduce the cost of development with the burden of proof shifting to CMC (Chemistry, Manufacturing and Controls) similarity, sensitive functional assays, PK data. Innovative trial designs and statistics for smaller trials should be accepted if a waiver is not possible because of the non-availability of PD markers.
In conclusion, continued regulatory reforms for biosimilars, more affordability with competition brought through biosimilars, and a fair healthcare system that passes the savings to the patients can make biosimilar development more sustainable in the future. Greater savings may be feasible if managed care in the US and similar organizations across the globe increase biosimilar utilization and promote competition. The cost of developing biosimilars should be an important factor in the continued future growth of this sector. Initial apprehensions regarding biosimilars are already changing and in the future, a greater acceptance and faster adoption of biosimilars can be envisioned. A simple yet effective analogy that can make everyone realize the importance of biosimilars is that, just for a moment, we all close our eyes and think of a healthcare world without generics.
No financial support was received.
The opinions expressed in this article are personal views of the authors and should not be understood as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated.
Competing interests: SNA, SM and AMR are employees of Biocon Biologics Ltd. SNA and SM hold stocks in Biocon. AMR declares no conflict of interest.
Provenance and peer review: Not commissioned; peer reviewed.
Sandeep N Athalye, MBBS, MD
Shivani Mittra, MPharm, PhD
Ankitkumar M Ranpura, MD
Clinical Development and Medical Affairs
Biocon Biologics Ltd, Biocon House, Tower 3, Semicon Park, Plot No 29-P1 & 31-P, KIADB Industrial Area, Electronic City Phase – 2, Bangalore 560100, Karnataka, India
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Author for correspondence: Sandeep N Athalye, MBBS, MD, Chief Medical Offi cer, Biocon Biologics Ltd, Biocon House, Tower 3, Semicon Park, Plot No 29-P1 & 31-P, KIADB Industrial Area, Electronic City Phase – 2, Bangalore 560100, Karnataka, India
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