Biosimilar Uptake in Oncology Faces Many Hurdles

Carina Dolan, PharmD, BCOP

In 2015, the FDA approved the first biosimilar, filgrastim-sndz (Zarxio), under the Biologics Price Competition and Innovation Act of 2009. As of mid-July, 11 biosimilars have received agency approval, including 5 with an oncology indication.¹ By January 2018, at least 60 biosimilars were enrolled in the FDA’s biosimilar development program, with FDA commissioner Scott Gottlieb, MD, reporting that the agency had received requests for meetings to discuss biosimilars for 27 distinct reference biologics.²

Most recently, pegfilgrastim-jmdb (Fulphila) was approved by the FDA to decrease the incidence of infection with febrile neutropenia in patients receiving myelosuppressive chemotherapy similar to its reference product. Bevacizumab-awwb (Mvasi), for the treatment of adult patients with certain colorectal, lung, brain, kidney, and cervical cancers; and trastuzumab-dkst (Ogivri), for the treatment of certain breast and stomach cancers, are approved biosimilars that will have the greatest impact in the oncology arena. The expected lower costs of these drugs are likely to increase access to these therapies, which are among the most expensive drugs in the United States and are often out of reach for the patients who need them most.^3-5

Clinical and Patient Uptake of Biosimilars

Physician Barriers

The successful uptake of biosimilars in the practice of oncology, however, rests on numerous factors, involving clinicians, patients, payers, legislators, and manufacturers. These include the number and timing of entrants into the market; patient and provider acceptability; development costs; competition and litigation involving reference product manufacturers; market size and share; pricing; payer coverage and utilization policies; cost sharing; and regulatory policies around interchangeability (Figure 1).^6,7The most important and influential stakeholders for biosimilar acceptance and usage are physicians and patients. However, there is evidence of significant gaps in knowledge for both audiences.A survey of 376 US oncologists (part of a larger survey that included 1245 oncologists total from the United States, Europe, and Latin America) found that they lacked technical knowledge and understanding of the effects of biologics and biosimilars sharing the same nonproprietary name, and misunderstanding if biologics and biosimilars are structurally and therapeutically identical.⁸ Earlier surveys also found significant knowledge gaps regarding all aspects of biosimilars (chemical structure, difference from reference product, approval process, availability of biosimilars in the United States, etc) among clinicians of various specialties.^9-12

Gaining physician support for and confidence in biosimilars will require evidence demonstrating that the biosimilar provides similar efficacy and safety to the reference product. Still, some aspects of the biosimilar concept remain unclear to practitioners surrounding the biosimilar approval process, required clinical trials, and pharmacovigilance. A 2018 statement by the American Society of Clinical Oncology (ASCO) on the appropriate use of biosimilars in clinical practice highlighted the need for postmarketing evidence development to enhance physician and patient confidence in their use. The authors noted that this was particularly important because regulatory review of biosimilars relies less on clinical data and more on structural, functional, and pharmacologic data. ASCO also noted the challenges of such postmarketing evidence, given the fragmentation of the US healthcare system. It suggested that its CancerLinQ database, which provides data on millions of de-identified patients, and the pending FDA surveillance system, Sentinel, designed to monitor safety issues in clinical trials, could be used to collect these data.¹³

As with any biologic, physicians also have concerns about immunogenicity. Given that biosimilars will, by necessity, be manufactured in a slightly different manner from their reference product, there is concern that switching patients from a biologic to a biosimilar, or vice versa, could result in hypersensitivity reactions. To evaluate that possibility, some clinical trials have included product switching, although assessing immunogenicity often depends on the molecule and the indications studied.¹⁴

An important issue affecting physician uptake of biosimilars is interchangeability and substitution. To receive interchangeability designation, the manufacturer must demonstrate not only that the biosimilar has similar efficacy and safety to the biologic, but also that there is no greater risk in switching between the biologic and biosimilar than remaining on the reference product.¹⁵ The advantage to the manufacturer is some level of exclusivity.¹⁶ The FDA announced a pathway to interchangeability in January 2017 and is expected to designate the first interchangeable products within the next 2 years.¹⁷

An interchangeability designation allows the biosimilar to be substituted for the reference product at the pharmacy level similar to the way generic products are substituted for brand drugs today. The physician can still reserve the right to designate the drug by name. Substitution, however, is controlled at the state level. By March 2018, nearly all states, the District of Columbia, and Puerto Rico had passed some type of legislation allowing substitution of biosimilars, although the details vary by state.¹⁸

The aforementioned survey of 376 US oncologists found that 80% believed it is critically or very important that they be notified if a biosimilar is substituted for the prescribed reference drug. They were also more likely than their Latin American or European peers to believe that patients could switch biologics mid-treatment and expect the same results.⁸

Early experience with the filgrastim biosimilar showed that providers were slower to incorporate biosimilars into their practice until they gained experience and felt comfortable prescribing the biosimilar. One health plan in the United States reported that 30% of filgrastim prescriptions were for the biosimilar, while another reported that prescriptions for the biologic had dropped by a third since the biosimilars entered the market, disclosing initial hesitation from oncologists to prescribe them. Today, many payers are beginning to give biosimilars preferred status on their formularies.¹⁹

Figure 1. Parameters Influencing the Successful Uptake and Integration of Biosimilars Into US Oncology Practices⁷

Recreated from Seminars in Oncology, vol 41, suppl 3. Rak Tkaczuk KH, Jacobs IA. Biosimilars in oncology: from development to clinical practice, pages S3-S12, Copyright 2014, with permission from Elsevier.

Patient Knowledge Gaps

Oncologists also tend to be more comfortable with trying new therapies for patients and adding newly approved drugs to their armamentarium fairly quickly. Moreover, practitioners are feeling pressure from patients about high-cost biologic therapies, causing many physicians to speak out about the cost of therapies.²⁰Patients need to understand the concept of biosimilars and their place in the treatment continuum. To accomplish this level of awareness requires education, so patients can make an informed decision on their care. A 2015 American Autoimmune-Related Diseases Association survey of 362 of its members, 96% of whom have an autoimmune disease, found that more than 80% did not know what biosimilar medicines were, while about half understood the difference between biologics and biosimilars.²¹

In another consumer-focused survey from the consulting firm PricewaterhouseCoopers conducted in 2015, 67% of consumers did not know what a biosimilar was, while just 17% chose the correct definition from several choices.²²

Patients require education on the basic definition of biosimilars versus generic drugs; how they are tested and approved; costs; and availability of clinical trials.¹⁴ The ASCO recommendations call for healthcare professionals to educate patients, and for medical societies, government sources, and patient advocacy organizations to provide public awareness and education programs, as well as use standardized, publicly available materials.¹³

Payers and Reimbursement

Payers may also target patients directly with information about lower costs for biosimilars compared with the biologic medication. Medicare patients today pay a 20% co-payment for Part B drugs, which can be a significant cost for the higher priced biologics.²³ In addition, a growing percentage of commercially insured individuals have high-deductible health plans.²⁴ Thus, patients are becoming more aware of the cost of their healthcare.^25-27The majority of cancer biologics are administered in an outpatient setting and paid for under the medical rather than pharmacy benefit (Part B for Medicare). Medicare typically reimburses for medication administered in a physician office or infusion clinic at a rate of the average sales price (ASP) plus 6% as an administrative fee.²⁸ To incentivize the prescribing of biosimilars, CMS set the administrative fee for the biosimilar based on the ASP of the reference product plus 6% of the reference product’s ASP. How individual states will handle reimbursement under their Medicaid programs remains to be seen.²⁹ Moreover, in January 2018, CMS finalized a ruling on the hospital outpatient prospective payment system (OPPS) for 340b hospitals, adjusting reimbursement to ASP minus 22.5%.³⁰ This may impact the utilization of biosimilars in the ambulatory setting.

In the acute-care setting, biosimilars can be incorporated through the pharmacy and therapeutics (P&T) committee within the institution. This committee is primarily responsible for approving the pharmacy formulary system for the hospital and includes pharmacists, physicians, hospital administrators, nurses, and additional staff who support the medication use process. Many factors are taken into consideration when reviewing a drug to be placed on the formulary, including clinical effectiveness, operational objectives, cost, and product supply chain. Policies and procedures are approved that can include automatic substitution for medications to match the hospital formulary. Furthermore, the P&T committee can assist and direct staff educational programs that reflect changes to the formulary.

Additional payer reimbursement and requirements may also affect biosimilar uptake. Germany, which has one of the strongest uptakes of biosimilars in the world, incentivizes its doctors to prescribe biosimilars through quotas, budgeting, and monitoring programs, while key opinion leaders and medical associations provide education and integrate the use of biosimilars into their guidelines.³⁰ Providing similar incentives for clinicians could drive uptake in the United States and, with the movement toward value-based reimbursement, may help drive the utilization of biosimilars. For instance, payers could offer higher in-office payments for clinicians who meet certain prescribing levels for biosimilars versus biologics.²⁵

Another potential barrier to the clinical integration of biosimilars may be the temporal and financial investment required to make the distribution change from the current biologic to a biosimilar. It is important to take into consideration the fine details that participants in the supply chain, such as manufacturers, pharmacy benefit managers, and specialty pharmacies, have in place to encourage continued prescribing of the reference product.¹⁴

Figure 2. Biologic Market Relationships⁶

Figure adapted from Mulcahy AW, Hlávka JP, Case SR. Biosimilar Cost Savings in the United States: Initial Experience and Future Potential. Santa Monica, CA: RAND Corporation; 2017. www.rand.org/pubs/perspectives/PE264.html.

The Economic Implications of Biosimilars in Cancer Therapy

Finally, although there are now 11 approved biosimilar drugs, only 3 are currently on the market. These delays in launching the biosimilar products are a result of pending litigation from the reference drug manufacturer. This presents a challenge for the ability of the biosimilars to penetrate the market in a timely fashion. Furthermore, brand suppliers are bringing new products to the market by enhancing the original biologic, otherwise known as follow-on biologics or “biobetters.”³¹ These new molecular entities are altered versions of approved biologics designed to improve their method of administration, safety, efficacy, or manufacturing.³² All of these issues may limit the potential cost savings from biosimilar use in the next several years, although their use will likely increase over time due to supply and demand factors.³³Historically, when a generic drug enters the market, the cost is less than that of the brand manufacturer. However, payers should not expect this level of price differential when it comes to biologics and biosimilars, nor even the 50% price differential they had hoped for.³¹ There are several reasons for this, including the higher cost of bringing a biosimilar to market. This can cost more than $100 million and take 5 years or more compared with the $2 million to $5 million and 2 years required for a generic.³³

Other barriers to lower pricing include complex, high-cost manufacturing processes; direct marketing to clinicians to share clinical data and highlight the efficacy and safety of the biosimilar compared with the original drug; development of a sales force in a new therapeutic arena; the need for phase IV studies to demonstrate real-world safety and efficacy; and the likelihood that there may be a limited number of biosimilars in a given category.³⁴

At the same time, rebates provided by pharmacy benefit managers and manufacturers that are tied to utilization of the reference drug may also mitigate any price reductions. Missing out on those rebates if patients are switched to biosimilars could make the reference drug much costlier, wiping out any savings from the biosimilar.³¹

A 2017 analysis from the RAND Corporation estimated that biosimilars would reduce direct spending on biologic drugs by $54 billion between 2017 and 2026, or about 3% of the total estimated biologic spending over the same period, with a range of $24 billion to $150 billion. The researchers cautioned, however, that the actual savings are dependent on industry, regulatory, prescriber, and insurer decisions, as well as potential future policy changes to strengthen the biosimilar market (Figure 2).⁶

As part of its analysis, RAND provided a case study on the uptake and cost savings of filgrastim-sndz and tbo-filgrastim. By the end of 2016, these 2 biosimilar-related products held a third of the total filgrastim market and were marketed at a 30% (tbo-filgrastim) and 45% (filgrastim-sndz) discount. RAND also noted that total spending on all 3 products (including filgrastim reference drug) dropped significantly between 2013 and 2016, suggesting the impact of the biosimilars. In addition, while the net price of filgrastim did not change during this time, both biosimilar-related drugs experienced large price decreases following their launch, likely due to competition in the marketplace, demonstrating that biosimilars could also increase access to more expensive drugs.^6,35,36

A 2017 simulation analysis of the cost savings resulting from the use of filgrastim-sndz versus filgrastim on 20,000 patients with follicular lymphoma found a per-cycle cost savings between $327 and $915, depending on the length of the cycle, yielding a savings between $6.54 million (5-day cycle) and $18.3 million (14-day cycle). The authors estimated that the savings would generate expanded access to the biologic obinutuzumab (Gazyva), approved for relapsed/refractory follicular lymphoma and previously untreated chronic lymphocytic leukemia, to between 60 and 169 patients in a budget-neutral manner.³⁷

Table. Selected Late-Stage Investigational Oncology Biosimilars^38-51

CHOP indicates cyclophosphamide, hydroxydaunomycin, vincristine, prednisolone; DLBCL, di use large B-cell lymphoma; FEC, 5- uorouracil, epirubicin, and cyclophosphamide; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PCR, pathological complete response; PD, pharmacodynamics; PFS, progression-free survival; PK, pharmacokinetics; TTP, time to progression.

New and Emerging Cancer Biosimilar Agents

Trastuzumab

Rituximab

Bevacizumab

Cetuximab

Conclusions

The same analysis showed that switching patients from pegfilgrastim to filgrastim-sndz yielded savings of between $55.9 million for 5 days of treatment and $16.7 million for a 14-day cycle. The savings would expand access to obinutuzumab treatment for patients in a budget-neutral manner.³⁷Several oncologic biosimilars to trastuzumab, rituximab, cetuximab, and bevacizumab are in late-stage clinical trials (Table^38-51).The trastuzumab biosimilar CT-P6 demonstrated similar efficacy and safety in a head-to-head trial with trastuzumab (both combined with paclitaxel) in HER2-positive metastatic breast cancer (MBC) as well as in the neoadjuvant setting in women with early-stage breast cancer.^38,39 The biosimilar BCD-022 also demonstrated similar efficacy and safety in the MBC setting.⁴⁰ Another trastuzumab biosimilar candidate, SB3, was also studied in the neoadjuvant setting in patients with early-stage breast cancer. It demonstrated equivalence based on pathologic clinical response rate, safety, pharmacokinetics, and immunogenicity.⁴¹Several biosimilars are under investigation for rituximab, including CT-P10 in patients with follicular lymphoma. Early results from an ongoing randomized clinical trial in patients with late-stage disease demonstrated CT-P10’s similar efficacy, safety, and pharmacokinetic equivalence to rituximab.⁴² Meanwhile, the biosimilar BCD-020 demonstrated significant difference in overall relapse rate and safety compared with rituximab in 92 patients with follicular or marginal zone non-Hodgkin lymphoma.⁴³ A third rituximab biosimilar, RTXM83, demonstrated comparable ef cacy to rituximab in terms of tumor response, pharmacokinetic profile, pharmacodynamic activity, safety, and immunogenicity in patients with previously untreated CD20-positive diffuse large B-cell lymphoma.⁴⁴Bevacizumab biosimilar candidates include BCD-021, studied in patients with advanced nonsquamous non—small cell lung cancer (NSCLC) in combination with paclitaxel plus carboplatin. There were no significant differences in efficacy or safety between the biosimilar and the reference product.⁴⁵ At least 5 other bevacizumab biosimilars are in late-stage clinical trials.⁴⁶One of the first biosimilars to be studied against a drug other than the reference biologic, STI-001, was investigated in patients with EGFR-expressing metastatic colorectal cancer in combination with irinotecan versus irinotecan alone. The combination therapy showed significant improvement compared with chemotherapy alone with an overall response rate of 32.9% versus 12.8%, a progression-free survival rate of 5.6 versus 3.2 months, and overall survival of 14.1 versus 13.4 months.⁴⁷ The manufacturer also reported significantly fewer adverse events than in studies of the reference product, with no hypersensitive reaction compared with more than 10% of patients in the cetuximab trials. The manufacturer attributed the difference to a different production method. However, the results have not yet been published, only announced in a 2016 press release. Several other cetuximab biosimilars are in early development.⁴⁸As more patents begin to expire on oncologic biologics, the pace of biosimilar development in this therapeutic arena will pick up speed. At least 16 biosimilars are now in late-stage development and 2 are already approved (albeit not on the market as of March 2018). Their uptake in the oncology community, however, remains unclear. Challenges include physician and patient understanding of biosimilars versus biologics, particularly in terms of approval process; concerns over immunogenicity; pricing; interchangeability and substitution; cost; and supply chain issues. The option biosimilars offer, even at a 15% discount, will likely overcome these barriers as they move into the market and offer some promise for future treatments

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