March 7, 2023 PAO-03-23-NI-01
A pathway for approval of biosimilars was first established in the European Union (EU), with one created in the Unites States several years later. The hope was that biosimilars, like generics, would reduce the cost of biologic drugs for patients, given that while large molecule therapeutics account for just 2% of prescriptions, they represent more than 40% of drug spending at the invoice level.1
Since 2015, the U.S. FDA has approved 39 biosimilars, with 22 of them actually launched.2 Approximately half target oncology indications, with slightly greater than 50% of those being therapeutics and the rest supportive care products. Market penetration ranges from 38% to 89%.1 Several biosimilars have been approved for rheumatology indications, but only two have reached the market (market share ~30%). Similarly, only one of the several biosimilars approved to treat inflammatory bowel disease has been commercially launched yet, and uptake has been slow.
Even so, it is estimated that the cumulative reduction in drug spending for classes of biologics with biosimilar competition totaled $21 billion over the past six years.3 Part of that success can be attributed to a significant increase in biosimilar launches from 2018 to 2020.2 The COVID-19 pandemic led to a slowdown in 2020 and 2021, but the rate of new approvals and launches is soon expected to return to pre-2020 levels based on the rising number of candidates in the FDA’s Biosimilar Development Program (77 in March 2019 vs. 96 in March 2022 — an increase of more than 70% since October 2015).4
The United States and Europe lead the market, and some countries have also established approval pathways, while many have yet to create regulations for biosimilars.5 Significant growth is expected as adoption of already known biosimilars increases, not only in the United States and Europe but in many other countries, and as new biosimilars for an increasing diversity of diseases are approved and commercialized.
Several factors have contributed to the slower commercial success of biosimilars in the United States compared with Europe. A key issue has been patent litigation instigated by branded biologic manufacturers fighting to hold on to their market share.1 These lawsuits have often delayed biosimilar launches for many years and are the main reason only just over half of FDA-approved biosimilars have reached the market. Another challenge has been the lack of awareness and understanding by both physicians and patients about biosimilars, which has led to concerns about their safety and efficacy. Physicians are also resistant to having the determination of interchangeability taken out of their hands (vide supra). Extensive authorizations and documentation by payers further exacerbate the problem, as the lack of significant price differentials for patients due to complex rebate and other programs for reference products creates confusion. Finally, the “nocebo effect” (negative expectations leading to negative outcomes) is a real concern with biosimilars and thought to play a significant role in otherwise unexplainably poorer clinical outcomes with biosimilars.
One way in which the FDA has attempted to overcome the hesitancy of physicians and patients is to create an interchangeable biosimilar designation. An interchangeable biological product is a biosimilar that meets additional requirements and may be substituted for the reference product at the pharmacy, depending on state pharmacy laws,” according to the FDA.6 The agency believes interchangeable biosimilars may help increase patient access to biologics.
To receive designation as an interchangeable biosimilar with the goal of allowing automatic substitution at the pharmacy level, a biologic product must meet all of the FDA’s regulatory requirements for biosimilars (clearly demonstrate comparability to the reference product) as well as be found in interchangeability studies to show no decrease in effectiveness or increase in safety risk associated with switching from the reference product and other marketed biosimilars to the proposed interchangeable biosimilar multiple times.7 Pharmacokinetics, efficacy, safety, and adverse events are considered in the evaluation. This designation would not, however, override state laws that require physician approval of biosimilar use, which vary widely.8
It is interesting to note all biosimilars approved in the EU are automatically considered to be interchangeable with the reference medicine and equivalent biosimilars.9 The same is true in Canada. It is also important to recognize that switching studies to prove interchangeability can involve hundreds of patients each and thus contribute to longer development timelines and more costly biosimilar products.10
Interchangeable biosimilars are not the only possible separate category of biosimilar products in the United States. Authorized biologics are nonbranded products developed by manufacturers of their own original reference products.11 The launch of authorized biologics to prevent loss of market share and revenue due to biosimilar competition could significantly impact the market. For instance, many biosimilars to AbbVie’s Humira (adalimumab) are expected to launch in 2023. While AbbVie has not announced any plans to launch its own authorized biologic of adalimumab, there is much speculation.
While the FDA proposes that the interchangeable biosimilar designation could increase patient access to biologics, there are different viewpoints regarding the benefits and negative effects that these products may have. One expert believes that the choice of a biosimilar will ultimately be driven by cost, but if two or more are comparable in price, interchangeability may influence the choice.11
Others argue that having a separate interchangeable designation suggests to patients that biosimilars without the designation are less safe and/or effective.12 Some biosimilar producers also contend that companies seeking the interchangeable designation are encouraging this perception and in their marketing campaigns are intimating that interchangeable biosimilars are “better.”
There is another argument that clinical data are insufficient for demonstrating comparability of biosimilars to reference products because they are not as precise.12 It is bioanalytical testing, including laboratory pharmacokinetic and pharmacodynamic studies, that best demonstrates comparability.
As of October 2022, the FDA had approved three interchangeable biosimilars. Several more, as well as some authorized biologics, are in development and could receive approval in the next 5–10 years.5 Interchangeable biosimilars have the potential to encourage more rapid and wider uptake of biosimilars.10 While these products offer financial savings, cost is not the only factor influencing the decision to use biosimilars or branded products. Physician and patient comfort is crucial. With many new biosimilars for a widening array of diseases expected to reach the market in the next several years, educating both groups will be essential.1,5
In addition, revision of regulatory requirements for biosimilar approval should be introduced to remove inefficiencies and decrease costs.10 In particular, it has been suggested that reducing the clinical requirements for biosimilars to aid switching with reference biologics (i.e., interchangeability studies) would be highly valuable. There is evidence to support this move: a review of 178 clinical switch studies found no evidence of switch-related adverse effects.13 In addition, evaluation of post-marketing data for biosimilar monoclonal antibodies for up to seven years following approval found no biosimilar-specific concerns with respect to safety or immunogenicity.14
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.