Submitted: 12 October 2020; Revised: 28 October 2020; Accepted: 29 October 2020; Published online first: 9 November 2020
While many sources claim that Europe is winning the race when it comes to biosimilars, a broader assessment of the landscape reveals a more encouraging story for the US. Although the European Medicines Agency (EMA) pioneered the framework for biosimilar regulation, the US Food and Drug Administration (FDA) is moving at approximately the same pace as EMA based on the number of approvals at the same time after implementation of its regulatory pathway .
The biosimilar regulatory framework in Europe was implemented in 2004. Within this framework, the Committee for Medicinal Products for Human Use (CHMP) provides initial assessments for marketing authorization of new medicines that are ultimately approved centrally by EMA . In the US, the Biologics Price Competition and Innovation Act of 2009 (BPCIA Act) created an abbreviated licensure pathway for biosimilars and granted FDA the authority to approve these near-identical biologicals . This legislation was implemented in 2010 as part of the Patient Protection and Affordable Care Act signed by President Barack Obama.
As of September 2020, approximately 10 years after implementation of the biosimilar approval pathway, 28 biosimilars have been approved by FDA, with 18 of those approvals granted in the last two years . In the 10-year time period following the creation of Europe’s biosimilar regulatory pathway, EMA approved 13 biosimilar products (some of which were marketed under several different brands) . From this perspective, the US appears to be on a faster pace than the EU in terms of biosimilar approvals. Currently, there are 45 biosimilars approved in Europe; however, these estimates fall to 35 when products approved in the US as follow-on biologicals via the 505(b)(2) pathway, e.g. somatropin, insulin, teriparatide, or abbreviated new drug application (ANDA) are excluded, see Table 1. Furthermore, Europe’s filgrastim biosimilar Tevagrastim®/Ratiograstim® was approved as Granix® (tbo-filgrastim) in the US via a Biologic License Application (BLA) prior to the implementation of a biosimilar approval pathway and is not included in the US biosimilar count.
Biosimilars have been developed in various therapeutic areas, including oncology and rheumatology, and are based on nine reference products. For some reference products, numerous biosimilars have been developed; for example, five biosimilars of Genentech’s Herceptin® (trastuzumab) and Amgen’s Neulasta® (pegfilgrastim) have been approved in the US and Europe. A summary of the biosimilars landscape in the US and EU is presented in Table 1.
Table 1 pending to upload
There are currently nine biosimilar applications under CHMP evaluation, including biosimilar candidates for adalimumab (2), bevacizumab (5), pegfilgrastim (1), and trastuzumab (1) . Unlike the transparency on biosimilar filings in Europe, FDA does not provide information on biosimilar candidates under review until they are approved.
Since the creation of a regulatory approval pathway, numerous guidance documents have been developed by both EMA and FDA to guide manufacturers in their development of biosimilar candidates. At least 10 documents have been released by FDA that provide guidance on scientific and quality considerations in the demonstration of biosimilarity and interchangeability . EMA has published three overarching guidelines and nine product-specific guidelines for biosimilars manufacturers that address both non‑clinical and clinical issues as well as quality-related issues .
Because EMA pioneered biosimilar regulations, the question has commonly been raised: To what extent does the European biosimilar experience translate to the US? Although the US and the EU are on a similar trajectory in terms of the number of biosimilar products approved, these markets differ in several respects. A critical point of divergence between the US and EU biosimilars terrain is the concept of interchangeability. Unique to the US, FDA may designate a product ‘interchangeable’ if it meets additional requirements beyond being biosimilar, which translates to more clinical development that includes switching studies and increased cost from a manufacturer’s perspective. To date, no biosimilar products have interchangeability status. Having a separate designation of interchangeability for an approved biological has been said to give the impression that interchangeable biosimilars are superior in quality to non-interchangeable biologicals – which is not the case. A major focus area for the Association for Accessible Medicines’ Biosimilars Council has been educating physicians and payers on interchangeability designations as they are ‘waiting for interchangeability to really get on board with biosimilars’ .
Perceptions of prescribing physicians about the safety of biosimilars is an ongoing issue. There is a need for increased confidence, particularly around switching from a reference product to a biosimilar. Concerns are particularly heightened in the oncology therapeutic area, where treatments can be curative and clinicians fear the loss of efficacy and increased immunogenicity . One of the key concerns around switching to a biosimilar is the negative counterpart of the placebo effect: the nocebo effect, a phenomenon in which negative expectations lead to worsening of symptoms . Some physicians continue to have doubts regarding the rigorous approval process for biosimilars and switching studies that have been performed thus far and transfer these negative concerns to patients through body language or tone of voice when discussing treatment options. Raising awareness about the nocebo effect by educating healthcare professionals on this phenomenon may mitigate its effect in patients receiving biosimilar products [12, 13].
The biosimilars marketplace
While the European biosimilars market has been credited with higher uptake compared to the US market, rates of uptake differ from country to country in Europe and can vary significantly by product class. A report by KPMG commissioned by Medicines for Europe to analyse the procurement of medicines in hospitals in eight European countries highlighted the variability in biosimilar sales against originator in these different Member States . An average of hospital biosimilar volume in March 2019 showed that Denmark achieved 63% overall biosimilar volume, with the UK coming in second at 45%. Germany had 40% biosimilar volume, France had 34%, and Belgium tied with Switzerland for last place among the countries studied at 14%. In a recent assessment of the impact of biosimilar competition in Europe, 16 European countries were reported to have achieved > 90% biosimilar utilization for filgrastim and pegfilgrastim in 2018, while utilization in Ireland was just 27%. Among antitumor necrosis factor biosimilars (adalimumab, etanercept and infliximab), Norway and Denmark had 81% and 96% biosimilar uptake, respectively, while every other country’s utilization was less than 50% . Variations in adoption rates among individual European countries as well as across therapeutic areas are influenced by government involvement, reimbursement structures and tender procurement policies.
In the US, biosimilars have gained significant share in the majority of therapeutic areas in which they have been introduced, ranging on average from 20% to 25% within the first year of launch, with some projected to reach greater than 50% within the first two years [16, 17]. As expected, first-to-market biosimilars tend to capture a greater portion of the segment compared to later entrants. Filgrastim biosimilars have been on the market the longest at five years and have achieved a 72% share, while bevacizumab and trastuzumab biosimilars have approximately 40% share. Rituximab and infliximab have had the most limited adoption, with approximately 20% market share .
Biosimilar competition has a significant potential to impact overall drug spending, with the amount of savings per country based on the volume and list price of products prior to biosimilar entry [15, 17]. Manufacturers are reducing healthcare costs by launching biosimilars at a wholesale acquisition cost (WAC) that is generally 15% to 37% lower than the reference product WAC and 3% to 40% below the reference product average sales price (ASP). Manufacturers of originator products have had to adapt their strategies in order to stay competitive, whether it be launching a second-generation product, or a new formulation aimed at reducing side effects. Biosimilar competition and originator manufacturer responses are translating into significant savings. The annualized savings reached US$6.5 billion in the second quarter of 2020, where reference molecules sold US$20.8 billion (annualized) pre-biosimilar . Savings over the next five years as a result of biosimilar alternatives are projected to exceed US$100 billion .
Biosimilars include both self-administered drugs obtained at retail pharmacies as well as provider-administrated drugs in inpatient and outpatient settings. In the US, the balance of cost savings to healthcare payers, providers and patients is different for each of these due to differences in payment and cost-sharing arrangements . Most self-administered pharmacy-dispensed biologicals are paid for on a fee-for-service basis and the final amount paid by insurers reflects several transactions, including a confidential rebate payment. On the other hand, the costs associated with provider-administered biologicals are purchased directly from manufacturers and wholesalers or through group purchasing organizations either incorporated into prospective, bundled payments or under fee-for-service arrangements. Access to these biologicals (reference or biosimilar) is determined by formularies that may reflect the highest price concession rather than the lowest list price.
To date, there have been no self-administered biosimilars launched in the US. This is in stark contrast to Europe, where biosimilars administered via self-injection at home are available, including a recently approved subcutaneous form of infliximab . It remains to be seen how self-administered biosimilars will fare in the US system where higher list price drugs may be ‘preferred’ on the formulary based on their profitability for those constructing the formulary.
Overcoming the hurdles
Despite having approved 28 biosimilars in 10 years, the US faces one of its biggest biosimilar hurdles when it comes to launching these products. So far, 18 of 28 biosimilars have been made available to patients, while the others have not been commercialized due to patent-related issues. In an effort to protect their originator products, brand manufacturers block competition by filing numerous follow-on patents. The expense of challenging these patents can serve as a deterrent to potential biosimilar competitors . Brand manufacturers also disincentivize biosimilar utilization by leveraging a ‘rebate trap’ wherein brand manufacturers offer significant rebates for their products that disable competition from biosimilars coming on the market .
While there is work to be done to accelerate commercialization of biosimilars, FDA has taken active steps to mitigate some of these barriers to biosimilar utilization. In July 2018, Health and Human Services Secretary Alex Azar announced a Biosimilars Action Plan (BAP) to advance policies that facilitate the development of the biosimilars market and increase competition for biological drugs .
Key strategies of FDA’s BAP of 2018:
- Improve the efficiency of the biosimilar and interchangeable product development and approval process
- Maximize scientific and regulatory clarity for the biosimilar product development community
- Develop effective communications to improve understanding of biosimilars among patients, healthcare providers and payers
- Support competition by addressing attempts to ‘game’ FDA requirements to ‘unfairly delay market competition’ to follow-on product
FDA said these actions are meant to prevent companies from blocking new biosimilars from entering the market and to stop manufacturers of reference products from manipulating the exclusivity provision to fend off biosimilar entry to the marketplace. Each of the four key elements of the BAP was associated with a number of priority deliverables, and since then FDA has been taking steps to meet those.
FDA’s most recent actions addressed biosimilar market competition in a joint statement issued by FDA and the Federal Trade Commission (FTC) that identified four goals to help combat anti-competitive practices . In particular, the agencies noted their concern with false or misleading statements comparing biological reference products and biosimilars, which may be hampering biosimilar uptake by creating negative misperceptions about the safety and efficacy of biosimilar therapies. To further clarify how data and information about biosimilars should be presented in a truthful and non-misleading manner in regulated promotional materials, FDA announced the release of the ‘Draft guidance for industry: promotional labeling and advertising considerations for prescription biological reference and biosimilar products – questions and answers’ and invited comment by stakeholders in the docket. As part of their efforts to promote greater competition, FDA and FTC held a public workshop in March 2020 to discuss their ‘collaborative efforts to support appropriate adoption of biosimilars, discourage false or misleading communications about biosimilars, and deter anticompetitive behaviors in the biological product marketplace’.
Targeting faster reviews, FDA issued new draft guidance in February 2020 detailing how it will speed its review of biosimilar or interchangeable application supplements, which can be used to update the initial biosimilar approval when it is for fewer than all the reference product’s licensed conditions of use . At the time of submission, applicants may decide not to seek licensure of a proposed biosimilar for conditions of use that are protected by patent for the innovator. FDA had previously committed to reviewing and acting on original 351(k) BLA supplements with clinical data within 10 months of receipt; however, the agency now says such supplements will be reviewed and acted upon in a 6-month timeframe.
The US Centers for Medicare and Medicaid Services (CMS) have also revised a number of their payment policies in an effort to promote biosimilar competition. Three policy changes made under Medicare Part B to incentivize biosimilar uptake were: 1) BPCIA required Medicare Part B to pay for biosimilars at the ASP of the biosimilar plus 6% of the innovator product’s ASP ; 2) unique payment codes were provided for each biosimilar (reversing policy that grouped drugs under single codes) ; and 3) biosimilars were allowed ‘pass-through’ status under the 340B Drug Pricing Program, which meant they could be paid at ASP plus 6% rather than being heavily discounted (–22.5%) . Furthermore, under Medicare Part D, the Bipartisan Budget Act of 2018 changed the treatment of biosimilars in the coverage gap (doughnut hole) discount programme, requiring manufacturers to give discounts for biosimilars . Furthermore, in 2019, there was a lowering of the maximum copay amount on biosimilars to rates commensurate with generic copay amounts for lower income beneficiaries.
In parallel with updated regulatory policies that encourage development of the biosimilars market, a growing body of evidence has amassed to support the clinical safety of biosimilars. In a systematic review of primary data from 90 studies that enrolled 14,225 unique individuals, the nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference biological . Similar results were observed in a systematic review of 57 switching studies evaluating the efficacy, safety and immunogenicity risk of transitioning between an originator biological and a biosimilar . These results should increase confidence of patients, healthcare professionals and the public in biosimilars, leading to increased acceptance of these safe and effective medicines.
Although it has been suggested that biosimilars are not living up to their promise in the US, the current landscape suggests otherwise. FDA has approved 18 biosimilars in the past two years alone and a total of 28 since the implementation of a regulatory pathway just 10 years ago. Although getting these drugs into the hands of patients has hit some stumbling blocks due to anti-competitive behaviours from brand manufacturers, FDA has been proactive in addressing these ‘shenanigans’ and has created a BAP as well as additional guidances to mitigate such barriers to uptake and ensure the biosimilars market is poised for success. Clinical studies on the impact of switching between reference medicines and biosimilars have underscored the safety of biosimilars and impart confidence in their utilization for both physicians and patients.
In short, the overall outlook on biosimilars is positive. Pharmaceutical Research and Manufacturers of America (PhRMA), an organization representing biopharmaceutical manufacturers, believes that biosimilars are helping to bring down the cost of drugs in the US market and are positioned to achieve further savings. Katie Verb, Director of Policy and Research for PhRMA, says that federal policies are having a positive effect. These sentiments were echoed by Dr Leah Christl, Amgen’s Executive Director for Global Regulatory and Research and Development Policy, who believes the US biosimilars market is showing healthy vital signs.
This paper is funded by the Alliance for Safe Biologic Medicines (ASBM).
The ASBM is an organization composed of diverse healthcare groups and individuals – from patients to physicians, innovative medical biotechnology companies and others – who are working together to ensure patient safety is at the forefront of the biosimilars policy discussion. The activities of ASBM are funded by its member partners who contribute to ASBM’s activities. Visit www.SafeBiologics.org for more information.
Competing interests: Dr Madelaine Feldman is the Chairperson of the Alliance for Safe Biologic Medicines. She has participated in advisory boards for Gilead, Lilly, Pfizer and Samsung. Mr Michael S Reilly, Esq is the Executive Director and employed by Alliance for Safe Biologic Medicines. Mr Reilly served in the US Department of Health and Human Services from 2002 to 2008.
Provenance and peer review: Not commissioned; externally peer reviewed.
Madelaine Feldman, MD, FACR
Michael S Reilly, Esq
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Author for correspondence: Michael S Reilly, Esq, Executive Director, Alliance for Safe Biologic Medicines, PO Box 3691, Arlington, VA 22203, USA
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