The development of biologic medicines has revolutionized the pharmaceutical industry treatment landscape across a wide spectrum of diseases . In cancer care , biologics in the form of monoclonal antibodies ( mAbs ) and hematopoietic agents are now commonly recommended in oncology guidelines for the treatment of underlying disease as well as for the management of sideeffects . 1 While the efficacy of biologics remains undisputed , the drugs have had a considerable budgetary impact on cancer care such that the annual growth rate in cancer drug spending in the US is 12 – 15 % and estimated to reach $ 100 billion by 2022 . 2 This is hardly surprising given the size of the international biologics market , which in 2018 was worth approximately US $ 276 billion , with seven of the top ten best-selling drugs being biologics . 3
The increasing cost of cancer therapy had prompted a global and concerted effort to identify cost-containment strategies , while simultaneously increasing access to safe and effective therapies . One approach as many of the biologics face patent expiration is through greater use of biosimilars . Enhanced use of biosimilars therefore represents a major opportunity not only to reduce overall cancer drug expenditure , but also to provide fiscal room to treat a larger number of patients . Data from the EU suggests that countries where biosimilars ’ market penetration is highest has resulted in a 30 – 45 % cost saving . 4
Several European countries have achieved significant cost savings through greater use of biosimilars but this has yet to be fully realized in the US . Achieving satisfactory market penetration in the US has been an uphill struggle for biosimilar manufacturers , who face a complex web of barriers which conspire to make it more difficult to achieve greater market penetration . An understanding of the origin of these barriers and potential solutions would ultimately lead to more equitable cancer care for patients in the US .
Barriers to biosimilar adoption Regulatory hurdles The European Medicines Agency ( EMA ) took the lead in developing the regulatory approval process for biosimilars with the first agent , Omnitrope ® ( a recombinant human growth hormone ) being launched in 2006 . 5 The regulatory framework for biosimilar evaluation was much slower in the US and it was not until 2010 , with the creation of the Biologic Price Competition and Innovation Act ( BPCIA ), that a comparable framework was introduced . Although the FDA approval process is broadly similar to the method used by the EMA , there are several important differences that have hindered the introduction of more biosimilars into the US market . As of August 2020 , there have been 28 biosimilars approved by the FDA ( compared with 59 by the EMA ) yet only 17 have reached the market . 6
In addition to patent protection , the FDA also affords the reference product a 12-year exclusivity period from when the product was first licensed 7 and will not officially approve a biosimilar before this date , thus providing an effective monopoly for the reference product . A provision in the BPCIA is the requirement for information exchange between the biosimilar and reference product manufacturers . As the manufacture of a biologic requires several different technological processes , these are invariably patented by the manufacturer of the reference product . By allowing information exchange , the originator company can assess whether any of their patents have been breached by the biosimilar manufacturer , potentially causing a further delay to market entry . The two companies engage in what has become commonly referred to as the ‘ patent dance ’, which further delays approval of the biosimilar . As an example , the anti-inflammatory biologic Humira ® ( adalimumab ), has over 100 patents covering production process techniques , making it extremely hard for biosimilar manufacturers to obtain approval . 8 Although biosimilar manufacturers can legally skip this dance , they still run the risk of patent infringement lawsuits in open court , especially as the BPCIA Act itself has created many possible uncertainties that might lead to litigation 9 and have become a major disincentive for many biosimilar manufacturers seeking approval . Although there are only a small number of players in the biologics / biosimilar market , the outcome of a judicial review has often led to a confidential agreement between the two parties and effectively a ‘ pay-for-delay ’ settlement , in which the reference manufacturer pays the biosimilar company to stay out of the market .
Payer perspectives In most European countries , there is a single payer system and biosimilar uptake in Europe was successful where payers were given the right incentives . A problem for biosimilar market penetration in the US is the absence of an equivalent single market and the system is much more complex , encompassing both government and private payers . Each organization will have its own reimbursement rules and varying degrees of negotiating power , which makes it difficult for individual biosimilar manufacturers to gain a share of the market . Although it is still early days for the US biosimilar market , historically , several reimbursement complications limited biosimilar adoption . For example , the Medicare part D benefit originally led to higher outof-pocket expenses for patients in the coverage gap , despite the lower acquisition cost of the biosimilar because the manufacturer discount scheme ( applied during the coverage gap ) did not apply to biosimilars . Fortunately , this has been rectified by the Bipartisan Budget Act ( 2018 ) so that biosimilars are now treated in the same way as reference products , with discounts of up to 70 %, and thereby creating a level playing field . However , this may still serve as a deterrent to marketing biosimilars because the drug manufacturer previously had no obligation to pay the coverage gap discount .
Another financial barrier is the rebate system , which is agreed upon between the reference product manufacturer and pharmacy benefit managers and other payers , which incentivizes the use of the reference product over biosimilars . Most pharmaceutical companies offer a rebate to payers for having their drug on a formulary , which can reach up to 50 % of the drug ’ s list price . 10 Payers can therefore fall into a ‘ rebate trap ’ if they decide to use a biosimilar instead of the reference product because the manufacturer withdraws the rebate . In fact , as illustrated in a theoretical analysis by Hakim et al , 10 even if the biosimilar is 60 % cheaper than the reference product and the payer can switch 50 % of patients onto the biosimilar , it will still be more expensive than using the reference product .
Physician / pharmacist perspectives An important component to biosimilar adoption is confidence among prescribing physicians . Nevertheless , while most physicians have
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