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Policy Review Cites Need for Regulatory Clampdown on Pay-for-Delay Tactics


An international group of physicians, surgeons, lawyers, scientists, and pharmacists weighs in on biosimilar policy differences and deficiencies in the United States, Europe, and Japan.

In a fresh policy review, authors call for stronger regulatory action to frustrate tactics used to delay the market entry of biosimilar products in the United States. They call for policy improvements on substitution of biosimilars for reference products, and they argue the case for greater extrapolation of indications for biosimilars so that they automatically cover orphan drug designations of the originator brands.

The review was conducted by members of the Southern Network on Adverse Drug Reactions, an international collaboration of physicians, surgeons, lawyers, scientists, and pharmacists, who who examined various aspects of the biosimilar landscape in the United States, European Union, and Japan—3 of the world’s largest biologics marketplaces.

The authors noted that 27% of new cancer drug approvals in the European Union, United States, and Japan are for biologics. Biosimilars have become available as patents have expired for the trastuzumab, bevacizumab, and rituximab originator products.

The first therapeutic oncology biosimilar candidates were submitted for European Medicines Agency (EMA) and FDA approval in 2016 and to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) in 2017. These regions “account for the majority of biological pharmacotherapy use worldwide” and invest the most in research and development for biologics, according to the authors.

The EU, which has the longest history with biosimilars, accounts for 90% of global biosimilar sales. In total, 33 biosimilars for oncology have been approved by the EMA, 16 by the FDA, and 10 by Japan’s PMDA. Between 2017 and 2019 the European Union approved 13 biosimilars to bevacizumab, rituximab, and trastuzumab; the United States approved 9; and Japan approved 7. The EMA and FDA have also approved supportive care oncology biosimilars to filgrastim, pegfilgrastim, and epoetin alfa.

The policy review examined variations in approval policies, interchangeability, pricing, and barriers to competition among the 3 regions. The potential cost savings for oncology biosimilars are immense, according to the authors. “Medical spending savings of more than $110 billion by 2029 are projected among the European Union, the United States, and Japan, with the use of oncology biosimilars in place of reference biologics accounting for most of these savings.”

Extrapolation, Interchangeability, and Substitution

The authors noted that the United States approaches extrapolation distinctly differently from how the European Union and Japan regard it. EU and Japanese regulators allow biosimilar manufacturers to “ask for oncology biosimilar approvals to be extrapolated to indications that in the USA had been designated as an orphan drug setting.”

The authors recommended the United States adopt “full extrapolation for each clinical indication approved for the reference biologic” to encourage a competitive market for therapeutic oncology biosimilars.

Regulatory approaches to interchangeability also differ among the 3 regions. In the European Union, interchangeability and substitution policies are decided by individual countries, many of which allow substitution of a reference biologic with a biosimilar at the pharmacy. Biosimilar substitution is not permitted in Japan. In the United States, substitution is not permitted unless the biosimilar has met the requirements to be designated as interchangeable, which no biosimilar has yet.

The authors recommended the PMDA “consider liberalizing its policies on substitution.” In the United States, they recommended the FDA modify its requirements on interchangeability “to help achieve this designation for an increasing number of therapeutic oncology biosimilars.” They also called for US states to reconsider prohibitions on biosimilar substitution, “as it creates an undue burden on providers and raises patient concerns with little safety benefit.”

Pricing and Pay-for-Delay Agreements

In the European Union, biosimilar price discounts average 30%, and in Japan, discounts are 30% or, if the biosimilar has at least 10 approved indications, 40%. In the United States, discounts range from 10% to 33%; however, rebates and “preferred positions on formularies often result in reference biologics being the least expensive option.”

The authors said pay-for-delay agreements, in which the biosimilar manufacturer is paid by the reference biologic manufacturer to delay entry of the biosimilar to the market, are common in the United States and Europe. In the United States, they noted, pay-for-delay agreements were entered into by manufacturers of 4 FDA-approved trastuzumab biosimilars. They commented that this practice delays patient access to more affordable treatment.

The reviewers recommended the US Federal Trade Commission (FTC) review nontransparent rebates and pay-for-delay agreements “for their potentially anticompetitive nature,” noting that there are “similar concerns” in the United Kingdom.

Patent Challenges and Anticompetitive Practices

The authors reported that oncology biosimilar launches in the United States have been more adversely affected by patent challenges than in the European Union and Japan. Patent challenges, they wrote, are rare in the European Union and are made only occasionally in Japan, whereas patent challenges have occurred for 56% of approved oncology biosimilars in the United States, and “many” therapeutic and supportive oncology biosimilars were not launched after winning FDA approval, “because patent litigations or administrative patent challenges were ongoing.”

In addition to patent litigation, the authors discussed delays due to inter partes reviews (patent legitimacy reviews), which they described as “narrower in scope and less expensive than litigation,” but still able to delay market launches for years, “thereby negatively affecting patient access to health care products.”

The reviewers recommended sweeping changes in the United States to preclude makers of reference biologics from delaying the introduction of biosimilars. In the United States, they wrote, “large changes [are] needed to the so-called patent dance and to the frequent filing of administrative challenges (inter partes reviews).”

The reviewers did note that the FDA and FTC have recently agreed to strengthen their efforts to reduce and discourage anticompetitive behavior. “This agreement is key to facilitating robust competition within the biologics marketplace by decreasing health care costs of oncology biologics,” they wrote.

Overall, the authors advocated encouraging competition by minimizing pay-for-delay agreements and patent challenges, while supporting physician and patient education on biosimilars. They also cited a need for long-term pharmacovigilance, “particularly with respect to immunogenicity.”

The authors closed by arguing that addressing their identified barriers to oncology biosimilar launch, “would improve the regulatory approval process, improve access to therapeutic biologics and biosimilars, and potentially lead to cost savings that have been anticipated since 2015.”


Bennett CL, Schoen MW, Hoque S, et al. Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated policy review from the Southern Network on Adverse Reactions. Lancet Oncol. 2020;21(12):575-588. doi:10.1016/S1470-2045(20)30485-X

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