Deana Ferreri, PhD

Rituximab, a monoclonal antibody to the B lymphocyte surface receptor CD20, was originally approved in the United States in 1997 for treatment of non-Hodgkin lymphoma and has multiple additional approvals for orphan and nonorphan indications. But a recent study found off-label uses, particularly to treat demyelinating neurologic diseases, now account for more than half of patients receiving rituximab.

The study, conducted at Kaiser Permanente Colorado, included 1674 patients who received their first rituximab infusion between 2009 and 2017. Overall during that period, 1111 patients (66.4%) received rituximab for an approved indication and 563 (33.6%) received the drug for an off-label indication. However, off-label uses grew more common as the study went on, particularly in the latter half of the study period. By 2017, off-label indications were more common than approved indications; off-label use of rituximab rose from 1.2% of patients in 2009 to 55.6% by the end of the study in 2017. In contrast, use for approved orphan indications dropped from 92.8% of patients in 2009 to 38.8% in 2017.

Oncology indications comprised roughly three-fourths of the approved indications, most of which were non-Hodgkin lymphoma (66.4%), followed by autoimmune diseases, including both orphan-approved and orphan-designated indications, which accounted for 14.7%. The only approved nonorphan indication, rheumatoid arthritis, accounted for 11.3% of approved indications. Most off-label indications were neurologic diseases (72.7%), the vast majority of which were demyelinating diseases (91.4%), followed by hematologic diseases (7.3%).

Demyelinating Neurologic Conditions Driving Off-Label Use

The authors commented that the treatment of demyelinating neurologic conditions was “the primary driver of off-label use in our study,” and cited a recent Swedish study that found rituximab to be the disease-modifying therapy most commonly prescribed for patients with multiple sclerosis (MS). Furthermore, they noted that rituximab prescriptions in MS have risen following the publication of several small studies suggesting rituximab reduced inflammatory brain lesions in patients with MS. 

New Biosimilars Enter a Huge and Growing Market 

According to the authors, “Rituximab is considered a blockbuster specialty drug with nearly $4.2 billion in U.S. sales in 2017.” There are 2 FDA-approved rituximab 

, Celltrion’s Truxima, which was approved in 2018, and Pfizer’s Ruxience, which was approved in 2019.

In light of non-Hodgkin lymphoma, an orphan indication, making up two-thirds of approved indications, the authors noted the expense of orphan drugs, writing “In 2017, the average cost per patient per year for an orphan drug was $147,308, compared with $30,708 for a nonorphan specialty drug.” They added that biosimilars could reduce these costs and stressed the importance of their findings for health plan policy makers, writing “the launch of lower-cost rituximab biosimilars could lead to further increased use of the biosimilars for label and off-label indications.”

Delate T, Hansen ML, Gutierrez AC, Le KN. Indications for Rituximab Use in an Integrated Health Care Delivery System. 

. 2020;26(7):832-838. doi:10.18553/jmcp.2020.26.7.832

Articles

Rituximab was originally approved in the United States in 1997 for treatment of non-Hodgkin lymphoma and has multiple additional approvals for orphan and nonorphan indications. But a recent study found off-label uses now account for more than half of patients receiving rituximab.

Study Suggests Majority of Rituximab Use Is Off Label

The Orphan Drug Act of 1983 spurred research and development in 

, clearly benefiting these patient populations; however, the authors of a new 

 on the budget impact of multiple orphan approvals say the costs associated with additional exclusivity periods may outweigh those benefits.

The legislation allows filing for orphan status if the prevalence of the disease is less than 200,000 individuals, as well as for a manufacturer to seek an unlimited number of orphan approvals for a single drug, driving concern that approvals for multiple orphan indications could forestall competition by generics or biosimilars.

For each rare disease approval, the market exclusivity of the drug is extended by 7 years for that indication, which prevents the potential approval of a generic or biosimilar to treat the indication. The innovator company also receives tax credits on the cost of clinical trials associated with orphan approval.

The investigators suggest “certain drug manufacturers may be timing the filing of orphan designations to maximize the duration of exclusivity.” By analyzing FDA orphan drug approvals and claims data from 1983 to 2017, they sought to determine, for drugs with multiple orphan approvals, how many extra years of market exclusivity manufacturers gained and the associated costs.

During this study period, 432 branded drugs were approved for 615 orphan indications. The investigators found the rate of orphan approvals increased over time. On average, there were 1.47 approvals per drug, and market exclusivity was extended by 1.6 years. About 25% (108) of the drugs had 2 or more orphan approvals.

Drugs with a second orphan approval increased their market exclusivity by 4.7 years; for the third approval, 3.1 years; for the fourth,  2.7 years; and for the fifth, 2.9 years. Combined, orphan drugs with 5 approvals extended their market exclusivity by 13.4 years, “nearly tripling the initial market exclusivity period.”

Thirteen drugs had at least 10 additional years of market exclusivity stemming from multiple approvals for orphan indications; 7 of those 13 had market exclusivity for 20 years or longer, including 4 biologics: adalimumab, bevacizumab, coagulation factor VIIA, and filgrastim.

Seven biologics (adalimumab, bevacizumab, botulinum toxin type A, canakinumab, coagulation factor VIIA, filgrastim, and ofatumumab) and 5 small molecule drugs (bortezomib, everolimus, ibrutinib, imatinib mesylate, and lenalidomide) whose multiple orphan approvals extended their exclusivity beyond the initial 7 years for the first approval. Assuming a 20% price drop after the seventh year for biologics due to biosimilar introduction and 75% for small molecules due to a generic introduction, the authors estimated the potential cost to the United States was an average $591 billion for the 7 years following the end of the extension from the first approval.

Questioning the Orphan Status of Drugs With Multiple Approvals

Although the Orphan Drug Act was intended to increase research and development into diseases affecting fewer than 200,000 people, the authors wrote, “Stacking multiple orphan drug approvals may result in total orphan populations of more than 200,000 individuals.” Although these drugs are treating rare diseases, “they are not orphan drugs since they are commonplace in the US health care sector and profitable to produce without government assistance.”

Furthermore, they said, several of the drugs with multiple orphan approvals were not initially developed for rare diseases. Nine of the 13 orphan drugs with more than 4 approvals “were introduced on the market for common diseases first before receiving an orphan approval several years into their availability.” The authors suggest this is incentivized partly because the research and development costs for a new drug are very high, whereas running a clinical trial on an existing approved drug in a new patient population costs much less. “Multiple indications and additional exclusivity can allow manufacturers to generate additional profits without considerable additional expense,” they wrote.

The authors concluded that limiting the number of rare disease approvals or years of market exclusivity from the Orphan Drug Act “could provide some savings in the billions of dollars with respect to the availability of generics or biosimilars at lower prices.” The authors acknowledged, “Doing so could impact future innovations and discovery of drugs for rare diseases.” However, they also questioned whether the $591 billion “for questionable exclusivity practices is worth the price of innovation across all orphan drugs.”

In a 2018 report, the Government Accountability Office found serious deficiencies with the ways in which the Orphan Drug Act is administered by the FDA. Read about that report 

Investigators found that manufacturers appear to be exploiting orphan drug exclusivities to extend market dominance and keep generics and biosimilars at bay.

Orphan Drug Exclusivity Keeps Biosimilars Off the Market, Study Says 

The currently available anti—vascular endothelial growth factor (anti-VEGF) therapies for wet age-related macular degeneration (AMD) are effective but problematic due to the cost, frequency of injections, and expertise required. Biosimilars in clinical development to compete on cost with these drugs will be arriving on the market, 

, the sister site of The Center for Biosimilars

In neovascular AMD, overexpression of VEGF-A drives the formation of abnormal, highly permeable blood vessels, leading to retinal edema and deterioration of retinal function. The introduction of anti-VEGF biologics, starting in 2004 with the approval of pegaptanib, improved treatment for neovascular AMD; rates of blindness due to the disease have fallen by 50% to 70%.

However, the treatment is costly, time consuming, and difficult to administer, plus it blocks neovascularization only temporarily. These drugs must be administered by retinal specialists via intravitreal injection every 4 to 12 weeks. In addition to the cost, the frequency of the injection regime makes adherence difficult. Many patients have difficulty arranging transportation or have comorbidities that take priority, which often result in missed appointments that reduce the effectiveness of treatment. The author noted that “In large-scale clinical trials, anti-VEGF utilization maintained visual acuity in more than 90% of patients,” but vision preservation results from real-world studies fall short compared with those from clinical trials because many patients are not getting the number of injections specified in their regimen.

Pegaptanib is no longer used because other anti-VEGF agents have demonstrated greater efficacy in clinical trials. Three anti-VEGF biologics are currently available: the VEGF-decoy aflibercept (Eylea), antibody fragments ranibizumab (Lucentis), and 

 has been prescribed off label since 2005, “because of its low cost and comparable efficacy.” Although clinical trials have, overall, shown these anti-VEGF agents are similarly effective, there may be individual differences between patients.

Emerging therapies aim to reduce the injection burden in neovascular AMD

To reduce the burden of regular injections, monitoring regimens to assess the individual patient’s disease activity and extend the dosing interval when appropriate are in use by many retinal specialists. There are several anti-VEGF agents in the pipeline designed to extend the interval between injections or change the delivery of the drug entirely. There is also promising data from a phase 1 clinical trial on gene therapy, in which the DNA sequence for an anti-VEGF agent was introduced via a viral vector into retinal cells “that then act like anti-VEGF factories.”

Abicipar pegol and faricimab are anti-VEGF agents in development, and clinical trial data suggest the dosing interval could be extended compared with existing agents. The FDA is expected to act on the application for abicipar pegol later this year, and an FDA filing for faricimab for use in neovascular AMD is expected as early as 2022. Conbercept, a new VEGF decoy, was approved for use in neovascular AMD in China in 2013 and is in phase 3 development in the United States with results expected in 2022. An FDA filing is expected in 2021 for the ranibizumab port delivery system (PDS), a device implanted into the eye supplying continuous release of the existing anti-VEGF biologic ranibizumab, as an alternative to injections.

, an intravitreal bevacizumab formulation is in phase 3 clinical trials with results expected later this year, and FDA approval is anticipated in 2021 or 2022.

 in July 2019. However, bevacizumab is not approved for neovascular AMD, and it is unclear whether antineoplastic bevacizumab biosimilars will be repackaged for intravitreal administration.

The potential approval and introduction of intravitreal bevacizumab ONS-5010 to the market would prevent bevacizumab biosimilars from use in neovascular AMD for the duration of ONS-5010 market exclusivity. In this case, “compounding facilities would be prohibited from repackaging antineoplastic bevacizumab into syringes.”

The patent for ranibizumab is set to expire in June 2020 and aflibercept in November 2023, and biosimilars are expected to enter the market as these patents expire. Multiple ranibizumab biosimilars are in late-stage clinical development, including FYB201 (Formycon and Bioeq), 

, and Xlucane (Xbrane Biopharma). There are also aflibercept biosimilars in phase 3 clinical development.

The author noted we can “anticipate that the therapeutic landscape in neovascular AMD will become much more crowded and complex over the next few years.”

Baumal CR. Wet age-related macular degeneration: treatment advances to reduce the injection burden. 

. 2020;26(5 Suppl):S103-S111. doi:10.37765/ajmc.2020.43435

The currently available anti–vascular endothelial growth factor (anti-VEGF) therapies for wet age-related macular degeneration (AMD) are costly, but biosimilars in clinical development may ease this problem.

Could New Therapies for Macular Degeneration Leave Anti-VEGF Biosimilars Behind?

 on biosimilars for the treatment of inflammatory bowel disease (IBD) issued by the Canadian Association of Gastroenterology and Crohn’s Colitis Canada

 drew backlash revealing the lack of consensus on this topic and highlighting ongoing controversies in the field.

The statement considered only the anti—tumor necrosis factor biologic infliximab (Remicade) and its biosimilar CT-P13 (Inflectra; Remsima). Following a full literature review, the statement suggested a biosimilar may be prescribed for biologic-naïve patients with Crohn disease (CD), but the authors called this a “weak recommendation based on low-quality evidence,” according to GRADE criteria. The authors, led by Paul Moayyedi, MB, ChB, PhD, of McMaster University, recommended using the originator if the price difference is “modest” and making decisions on a case-by-case basis between clinician and patient.

The statement cited insufficient evidence for recommending biosimilars to biologic-naïve patients with ulcerative colitis (UC). These conclusions are in contrast to the position statements of many other groups, such as the British Society of Gastroenterology, the Crohn's and Colitis Foundation, and the European Crohn’s and Colitis Organization regarding biologic-naïve patients. Of 15 statements issued since 2013 and detailed in the current publication, 12 recommend the use of biosimilars for biologic-naïve patients with IBD.

The statement recommended against nonmedical switching from infliximab to a biosimilar in patients with IBD who are doing well on the originator drug. Again, they described the recommendation as weak and based on low-quality evidence, adding “but data suggest that switching in this setting leads to an increased risk of worsening of disease, dose escalation and/or switching to an alternative therapy.”

 from Ken Bassett, MD, PhD, and Vijaya Musini, MD, MDs, DPH, both researchers at the University of British Columbia in Vancouver, cited “several serious flaws” in the methodology Moayyedi and his coauthors used to reach their conclusion regarding nonmedical switching.

First, Bassett and Musini criticized the inclusion of a conference abstract in the meta-analysis of switching data, saying the data “can’t be independently evaluated and verified.” A reliance on conference abstracts, rather than published trials, is a 

 of the existing evidence on biosimilars for IBD. However, 

 “it is important to include conference abstracts so that all available evidence can be evaluated,” and they pointed out that excluding the conference abstract would not have altered their conclusions.

Second, according to Bassett and Musini, the meta-analysis of nonmedical switching data “inappropriately” combined different end points from 2 trials, contending the data should not have been pooled. Moayyedi et al acknowledged this is a valid point for debate, saying it is “always a judgement call as to whether to synthesize such data.” However, they also claimed that analyzing the trials separately would have led them to the same conclusions.

Inherent in this debate are differing views among researchers on the primary published randomized control trial (RCT) on nonmedical switching in IBD (

), 1 of the 2 that Moayyedi et al considered in their analysis. NOR-SWITCH demonstrated similar efficacy and safety of nonmedical switching in patients across several inflammatory conditions including CD and UC; however, as Bassett and Musini acknowledged in their comments, the NOR-SWITCH trial lacked the statistical power to demonstrate noninferiority within individual disease groups. This limitation plus a nonsignificant trend toward disease worsening in the CD subgroup (pointed out by Moayyedi et al in their position statement) have caused disagreement regarding the safety of nonmedical switching from infliximab to CT-P13 in IBD.

The third criticism was the omission of a 

 on patients with CD, which “showed no differences in rates of clinical remission, loss of response or disease worsening.” Moayyedi et al included this trial in their analysis of biologic-naïve patients, but they say they excluded the nonmedical switching period of the study because the short follow-up duration and large proportion of patients not in clinical remission failed to meet their predefined inclusion criteria.

Finally, Bassett and Musini criticized the position statement for excluding uncontrolled studies, to which Moayyedi et al respond by calling their decision to include only RCTs and cohort studies with a control group “the main methodological strength of our approach.”

The position statement’s concern over the proportion of studies on nonmedical switching in IBD without a control group echoes those of a 

. Moayyedi et al argued uncontrolled studies provide only low-quality evidence, and the lack of a control group taking the originator drug makes it difficult to assess the safety of biosimilars, adding “Our goal was to evaluate the best-available evidence objectively, according to current best practice as a basis for our recommendation rather than to seek evidence that would support a predefined position.”

The debate around the official statement from the Canadian Association of Gastroenterology and Crohn's Colitis Canada makes it clear that as of yet there is no broad consensus on nonmedical switching from infliximab to CT-P13 in IBD, and the statement itself and raises doubts about the use of CT-P13 in biologic-naive patients with UC.

For now, some official statements and reviews of the literature are in favor of  biosimilars, saying they are 

 in IBD, while others advise more caution regarding the 

, arguing more research is needed before policy decisions—and individual physician—patient decisions&mdash;can be made with confidence.

1. Moayyedi P, Benchimol EI, Armstrong D, Yuan C, Fernandes A, Leontiadis GI. Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease. 

. 2020;3(1):e1&#8208;e9. doi:10.1093/jcag/gwz035

2. Bassett K, Musini V. Response to the Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease. 

. 2020;3(2):96&#8208;97. doi:10.1093/jcag/gwz046

3. Moayyedi P, Benchimol EI, Armstrong D, Yuan C, Fernandes A, Leontiadis GI. Response to Comments on the CAG/CCC Position Statement on Biosimilars for Inflammatory Bowel Disease. 

. 2020;3(2):98&#8208;99. doi:10.1093/jcag/gwaa004

A joint position statement on biosimilars for the treatment of inflammatory bowel disease (IBD) sparked backlash and criticism over the recommendation against nonmedical switching from reference infliximab to a biosimilar.

Researchers Take Issue With Methods Used to Arrive at Recommendation Against IBD Nonmedical Switching

In just 2 weeks, the final version of the trade agreement known as the United States—Mexico–Canada Agreement (USMCA) goes into effect.

Although it has been amended to remove provisions researchers argued would limit patient access to generics and biosimilars in the 3 countries, this update to the North American Free Trade Agreement (NAFTA) is dogged by criticism that it fails to improve patient access to vital and affordable drugs.

The new agreement significantly strengthens labor rights in Mexico, opens the Canadian dairy market to US dairy farmers, and increases the amount of North American—sourced parts required in cars manufactured in the 3 countries, but it will not improve access to generics and biosimilars, according to Tolulope Anthony Adekoa, PhD, whose 

 of the agreement was published recently in 

NAFTA has governed trade between Canada, the United States, and Mexico since 1994. As a candidate for president, Donald Trump was sharply critical of NAFTA and vowed to negotiate a new agreement if elected. Negotiations between the 3 countries wrapped up late in 2019, and the agreement is scheduled to take effect on July 1.

The final version has engendered mixed reviews. Prior to the removal of intellectual property provisions that would have dramatically curtailed access to biosimilars and generics in Mexico and Canada, the Association for Accessible Medicines was 

“The revised text creates greater opportunities for patients in Mexico, Canada, and the United States to access less-expensive medicines and promotes a competitive pharmaceutical market across the 3 countries,” the group wrote in its final analysis.

BIO, a pharmaceutical industry group, contended the removal of product exclusivity extensions left American innovator companies exposed to intellectual property theft. “By removing enhanced IP protections for biologic medicines, [Trump’s] administration just surrendered one of the most important tools that would help stop it,” BIO President and CEO Jim Greenwood said in a 

In May 2019, prior to ratification of the USMCA, an extensive 

 discussed in detail the chapters of the agreement with implications on public health. Regarding pharmaceutical prices and access, the authors concluded that the draft agreement would have expanded “intellectual property rights and regulatory constraints that will lead to increased drug costs, particularly in Canada and Mexico.”

Two provisions of concern to the authors regarding intellectual property were 

 in the final version of the agreement. One would have allowed patents for “new uses” of a known product, which the authors predicted would facilitate “evergreening” of pharmaceutical patents. The second provision would have imposed 

 for biologics, which the authors noted would have been “the longest period of market protection for such drugs negotiated in a trade agreement to date.”

The latter draft provision would have extended market exclusivity in Canada from the current 8 years, while in the United States it would have undermined legislation in Congress to shorten the 12&thinsp;years of market exclusivity biologics have now to 7&thinsp;years. In Mexico, which does not grant exclusivity for biologics, such product protections would have significantly altered the patient access landscape.

In a letter published on June 5, Adekola, a research assistant specializing in intellectual property law at the School of Law at City University of Hong Kong, revisited the 

 review in light of the final version of the USMCA . According to Adekola, the authors’ concerns regarding the effect of the USMCA on public health remain valid despite the removal of the 2 provisions. The final agreement, Adekola argued, “has done little to enhance access to generic medicines and biosimilars” and “has done little to enhance public health.”

Indeed, several other provisions the authors argued would “serve to delay the market entry of less-expensive generic and biosimilar medicines” remain in the final trade agreement, These include a provision allowing for extension of a patent term for “unreasonable” delays in the market approval process, protection of undisclosed data from regulatory submissions, and a provision linking a drug’s patent status to its marketing approval process, which the authors of the review claimed could delay the market entry of a generic “while disputes over possible patent infringement are resolved.”

In addition to intellectual property, the authors warned that provisions elsewhere in the agreement “may lower standards for assessing drug safety and efficacy, increase pressure to speed up regulatory processes (with concomitant safety risks), and place constraints on the public release of information about pharmaceutical inspections.”

Adekola echoed these concerns from the 2019 review and concluded that, although 2 of the problematic provisions have been deleted, the final trade agreement perpetuates a problematic status quo by failing to “ameliorate the existing effect of intellectual property protection on access to generic medicines and biosimilars.”

The United States–Mexico–Canada Agreement came to a rocky impasse over drug exclusivity protections, and July 1 is the day this agreement takes effect.

Criticism Dogs Launch of Trade Agreement

an adalimumab biosimilar (Idacio), an arthritis product, in Germany a year ago, has demonstrated that its proposed pegfilgrastim biosimilar (MSB11455) has similar safety and immunogenicity profiles to the reference product (Neulasta).

Pegfilgrastim is the long-acting form of filgrastim, a recombinant human granulocyte colony&#8208;stimulating factor (G&#8208;CSF). It is administered to patients undergoing myelosuppressive chemotherapy to reduce the risk of developing febrile neutropenia, a serious adverse effect of chemotherapy characterized by a high body temperature and low neutrophil count. Additionally, this condition can force patients to reduce the dose of chemotherapy or discontinue it entirely. 

G-CSF is a hematopoietic growth factor that stimulates proliferation, differentiation, and activation of neutrophils. The use of filgrastim or pegfilgrastim reduces the risk of febrile neutropenia, which improves the likelihood of patients completing chemotherapy.

Fresenius Kabi is headquartered in Germany and last year announced the 

 of its biosimilar activities in a new center in Eysins, Switzerland, where the company hopes to conduct biosimilar research in immunology and oncology. The company also has a tocilizumab biosimilar, for rheumatoid arthritis, in its development pipeline.

Biosimilars to pegfilgrastim have previously been approved and launched, such as Sandoz’s Ziextenzo in the 

. According to a recent conference abstract from Sandoz, the use of pegfilgrastim biosimilars has the potential to prevent more cases of febrile neutropenia by 

 to patients who are not generally treated (those at intermediate risk for febrile neutropenia) because of the high cost of the reference product.

There is potential for any biologic drug to provoke an immunogenic response, and immunogenicity is a major concern regarding biosimilars, because the “ability to stimulate antibody formation can differ between structurally closely related molecules, with even minor changes affecting immunogenicity,” as stated by the authors. The development of antidrug antibodies (ADAs) can negatively affect the therapeutic action of the drug or predispose the patient to adverse reactions.

Because pegfilgrastim is a recombinant human protein, immunogenicity is particularly concerning, because ADAs could cross-react with the endogenous human protein and interfere with the function of that protein in the body.

Analytical similarity and pharmacokinetic and pharmacodynamic 

 have previously been demonstrated for the proposed pegfilgrastim biosimilar, and the current study was designed to evaluate immunogenicity and safety in healthy volunteers compared with the reference product.

Safety and Immunogenicity of the Proposed Biosimilar 

The immunogenicity results demonstrated noninferiority of MSB11455 based on the prespecified margins. Treatment-induced ADA-positive rates were 8.9% in the MSB11455 group and 9.5% in the reference product group.

Most ADAs were specific to the polyethylene glycol (PEG) portion of pegfilgrastim rather than filgrastim. No filgrastim-specific neutralizing antibodies were reported, but 3 patients in the MSB11455 group and 1 in the reference product group had at least 1 sample with pegfilgrastim-neutralizing activity. The authors noted that “no relevant differences in ADA characteristics such as onset, titer, and specificity were found between the treatment groups.”

Safety and tolerability were similar between groups. Most patients (99.4%) in each group experienced some treatment-emergent adverse event (TEAE); the most common were headache and bone pain, which are known adverse effects of pegfilgrastim. Just 1 patient of the 168 in the MSB11455 group and 2 of 168 in the Neulasta group experienced a serious TEAE.

There were no significant differences in the pattern of TEAEs reported for ADA-positive subjects compared with ADA-negative patients, and similar TEAE frequency was found in anti-PEG positive patients between groups. The results provide support for the biosimilarity of the proposed biosimilar MSB11455 to pegfilgrastim, investigators concluded.

Fresenius Kabi’s pegfilgrastim biosimilar candidate has demonstrated a similar safety and immunogenicity profile to the reference product (Neulasta).

Fresenius Kabi Pegfilgrastim Shows Matching Safety, Immunogenicity

Choosing appropriate clinical end points and analysis procedures is essential to both establish clinical equivalence of biosimilars and convince physicians and patients that the agents are worthy of use. In a recent study, investigators use the HERITAGE study to argue for a more accurate system for measuring biosimilar equivalence.

There has been much discussion of moving away from hazard ratios (HRs), which measure risk of disease progression or death events between regimens or drugs, toward an analysis known as restricted mean survival time (RMST), which directly compares the number of these events over specified time intervals.

The authors of the study propose that RMST would provide more meaningful and interpretable information than HR.

The authors noted that studies of anticancer drugs typically use a time-to-event indicator, such as progression-free survival (PFS) or overall survival (OS), as the primary measure of efficacy. However, studies assessing clinical equivalence of biosimilars to those reference products instead use the overall response rate (ORR) at a specific time point, an HR-based measure.

The study details the authors’ analysis of reconstructed OS and PFS data from the HERITAGE trial using RMST.

 assessed equivalence of a trastuzumab biosimilar plus taxane compared with the reference product plus taxane in 458 patients with metastatic breast cancer. The primary end point was 24-week ORR, and disease events and deaths were recorded through 48 weeks. The authors reanalyzed the data on disease progression events and deaths as PFS and OS using RMST.

In the original study, there were nonsignificant differences in disease progression events and deaths between groups. However, the CIs, according to the authors of the new study, were quite wide, leading them to doubt that there were no true differences between groups. “For PFS, the hazard from the biosimilar group might be 28% higher than that from the reference product,” they wrote. “Consequently, even if the biosimilar product is approved by the regulatory agencies, clinicians and patients may not be convinced to adopt the biosimilar as an alternative to the reference product.”

Reanalyzing using RMST, the time to disease progression or death was 38.8 weeks in the biosimilar group compared with 37.5 weeks for the reference product, a difference of 1.3 (95% CI, −1.3 to 3.8) weeks. The RMST difference for OS between the biosimilar and reference product was 0.7&thinsp;(95% CI, −0.7 to 2.1) weeks. For the biosimilar, these findings demonstrate maximum differences in PFS and OS of just 10.1% and 5%, respectively, both reasonably-sized CIs, according to the authors.

“Unlike the results from the hazard ratio, these time-scaled small differences in OS and PFS…provide a clinically meaningful way to evaluate whether the biosimilar is clinically equivalent to trastuzumab over a 48-week time window,” the authors wrote.

The authors asserted that expressing the results as the number of weeks before a progression event in each group is more easily interpretable than describing the percent difference in events as a function of time using HR.

The authors explained that the use of HR requires an assumption that each group being compared has a constant rate of events over time.

However, in oncology biosimilar equivalence trials, the rate is not necessarily constant; the number of disease progression events or deaths during the study period is often limited. RMST, on the other hand, requires no assumption of a constant rate.

Furthermore, the precision of HRs, the authors said, depends on the number of events rather than the duration of the study, meaning that sufficiently precise HRs to determine clinical equivalence in many cases will require an unreasonably large sample size, and a longer study does not necessarily mean more precision.

RMST requires no assumption of proportional hazards (constant rates of events). With a time-to-event measure such as RMST, a change in the rate of events over time will not violate the underlying assumptions of the model.

The authors concluded that RMST-based methods “provide a clinically interpretable between-group difference with feasible study size and study duration compared with the HR-based approach.”

Finally, they suggest the use of RMST-based methods for postmarket surveillance, because “for most current biosimilar trials, one may argue that the patients’ exposure times might be too short to assess PFS and OS and long-term safety.”

Uno H, Schrag D, Kim DH, et al. Assessing clinical equivalence in oncology biosimilar trials with time-to-event outcomes. 

. 2019;3(4):pkz058. doi:10.1093/jncics/pkz058

Investigators use the HERITAGE trial findings to argue for a more precise way of measuring clinical equivalence for biosimilars.

Investigators Propose Different Measures for Biosimilar Equivalence

Gastroenterologists generally are accepting of biosimilars for initiating therapy in patients who are biologics-naïve. However, they remain skeptical of switching patients to biosimilars if their disease is successfully managed with an originator biologic.This practice is called nonmedical switching, and it may be done to get patients on a less expensive form of the same therapy.

 of nonmedical-switching studies of patients with inflammatory bowel disease (IBD) has detailed the knowledge gaps and study limitations responsible for this hesitation by gastroenterologists.

The majority of studies thus far have suggested nonmedical switching from infliximab to its biosimilar CT-P13 (Inflectra; Remsima) is safe. Previous reviews have 

The systematic review identified 44 studies on switching patients from infliximab (Remicade), the first biologic marketed for use in IBD, to the biosimilar CT-P13; however, only 3 were randomized controlled trials (RCTs), only 1 of which has been published. Approximately half of the studies reviewed by the authors, most of which were observational and not intended to change treatment patterns, were not yet published.

The authors of the current review concede that “safety and efficacy of biosimilar use in infliximab-naïve patients is generally accepted,” but they advise caution on nonmedical switching because of study limitations that include the small number of RCTs compared with observational studies, lack of controls in observational studies, lack of long-term data, and a reliance on studies published at conferences for which key study design details are missing.

 by Frank I. Scott of the Crohn’s and Colitis Center at the University of Colorado Anschutz Medical Campus agrees that more research is needed before nonmedical switching can be widely adopted.

The review authors found shortcomings with the single published RCT, the 

, which studied a switch from originator infliximab to the biosimilar in 6 inflammatory diseases, including IBD. The study included the use of a composite measure of disease worsening across the same 6 heterogeneous inflammatory diseases, with different dosing regimens and concomitant therapies.

The authors also criticized the inclusion criteria for the trial as having “ill-defined disease-specific criteria,” which they said “introduces the potential for bias and limits the inferences that can be extrapolated to IBD.” Furthermore, they criticized the noninferiority margin, which they say could have demonstrated noninferiority even if up to 50% of the patients switched to CT-P13 experienced disease worsening, based on enrollment numbers.

Although the NOR-SWITCH trial demonstrated noninferiority and included patients with IBD, the data presented on ulcerative colitis and Crohn disease (CD) “did not allay” the concerns of gastroenterologists regarding switching their patients on infliximab to a biosimilar, according to the editorial. The review authors noted “the trend toward increased disease worsening in CD patients has caused some concern in the gastrointestinal community and a desire for more robust data in IBD patients.”

In an IBD subgroup open-label extension of NOR-SWITCH, stable switched patients stayed on CT-P13, and stable patients on infliximab switched to CT-P13. Efficacy, safety, and immunogenicity were similar between the groups; however, the authors of the systematic review said that “low enrollment numbers precluded conclusive implications to be drawn.”

The other 2 RCTs on nonmedical switching were conducted wholly on patients with IBD. In these trials, similar efficacy, safety, and immunogenicity were reported between groups. However, the authors of the systematic review caution that our understanding of the details of these studies is incomplete because they were presented at conferences and have yet to be published, a concern Scott echoes in his editorial.

The authors of the review acknowledge that, overall, the 21 published observational studies suggest that nonmedical switching from the infliximab originator to the biosimilar is safe, but they also note that study designs were heterogeneous and many lacked a control group. Loss of response and discontinuation rates also varied widely between studies. This variability in observational study design and results make it “difficult for broad generalizations regarding the safety and effectiveness of nonmedical [switching] to be made,” the authors noted, adding that observational studies have not had robust assessments for antidrug antibodies, leading to knowledge gaps regarding immunogenicity.

Mandatory switching to biosimilars to reduce health care costs and expand access to biologic therapies has been criticized by gastroenterologists, “who cite a lack of high-quality controlled trials to support such decisions in stable patients,” according to the review article. Several countries have instituted some measure of mandated switching to biosimilars, such as 

, and these policies have drawn criticism from 

. According to the editorial, “While nonmedical switching policies have been enacted, there has been incomplete pharmacovigilance reporting.”

Both the systematic review and accompanying editorial stress the need to ensure patient safety before cost reduction, as well as that future studies should address the knowledge gaps regarding long-term effectiveness and immunogenicity. They also recommend a greater reliance on published RCTs as opposed to those only available as conference abstracts.

Although the totality of the evidence is reassuring, the jury is still out on nonmedical switching to biosimilars, according to new study results.
 

Gastroenterologists Want More Evidence on Nonmedical Switching

The main hurdle preventing biosimilars from coming to market is the primary patent on the originator product, not supplementary patents, according to a European 

. Investigators also found that product exclusivity extensions, which are customary in Europe, delay the market entry of competitor products.

A patent protects the intellectual property of pharmaceutical manufacturers, guaranteeing them market exclusivity for a set number of years to recoup their drug development costs. Pharmaceutical corporations routinely get secondary patents for tweaks to those drugs to extend their exclusivity, but the study of biosimilar litigation in Europe found that secondary patents were not sufficient to delay the market entry of biosimilars for 9 top-selling monoclonal antibodies.

“Except for 1 patent on trastuzumab where the decision to reject the patent was overturned in appeal, biosimilar developers have won all identified opposition and national patent litigation cases. This indicates that some patents on trastuzumab were seen as a real hurdle for biosimilar entry, but that biosimilar developers can challenge these patents and win,” the authors wrote.

In the United States, patents are often considered 

 barriers to biosimilar market entry, and the multiple patent filings over individual products are known as patent thickets. 

 on patent litigation have been sought to improve access to these lower-cost medicines. In Europe, the authors of this new study suggest, some patent barriers may be more illusory than real.

The drugs in the study received the standard 20-year European patent protection, and much of that time elapsed before development and approval stages were complete and the products could be brought to market. Many of the drugs received 5-year exclusivity extensions through the award of a supplementary protection certificate (SPC); in some cases, extensions were awarded to encourage the development of pediatric medicine.

In total, the drugs studied had market exclusivity for between 10 and 17 years, which the study authors described as “rather large” but consistent with European guidance that innovators “should be able to enjoy an overall maximum of 15 years of exclusivity” after marketing authorization is received.

Innovators sought to extend that exclusivity by patenting variations on the formulation, new dosage regimens, routes of administration, and combination therapies. They also sought to protect their markets by developing next-generation products related to the patented antibody.

The study authors analyzed patent filings and legal challenges from biosimilar developers to determine how basic patents, patent extensions, and secondary patents affected market entry for biosimilars. They provided detailed case studies of 3 monoclonal antibodies used for to treat cancer: trastuzumab (Herceptin), bevacizumab (Avastin), and cetuximab (Erbitux).

They found that the developers of each reference product filed for multiple patents after receipt of their original product patent; however, in most cases, the secondary patents were either not upheld by the European Patent Office or successfully challenged by competitors in court.

The European Medicines Agency has approved more than 50 biosimilars since 2005, with the first monoclonal antibody biosimilars approved in 2013. The study authors noted biosimilar developers face “substantial hurdles arising from patents taken after the basic patent,” but they said those hurdles are “surmountable, given that many cases were observed to have been won by biosimilar developers and agreements were made to settle ongoing cases.” In some cases, rather than litigate, the biosimilar developers were able to “invent around” a patent.

The authors also found patents on new formulations were not an effective protection strategy; they noted that these secondary patents often are ruled invalid because they are not “inventive.” They noted that AbbVie filed a patent for a formulation of Humira with less injection pain but that this patent was later revoked.

Patenting of a new administration route is a desirable strategy for an innovator seeking to retain market share, they wrote. For example, an agent becomes more convenient for patients if a subcutaneous route for a previously intravenously delivered drug becomes available. The authors add that this path is also open to developers of biosimilars. Celltrion received European market authorization for a subcutaneous formulation of its infliximab biosimilar (Remsima) in 2019. Biosimilars developers may also take advantage of new techniques for production of the antibody, which may be patentable.

A new dosage regimen may be patentable if it provides “unexpected advantages” over previous regimens. Biosimilar developers may have the option to leave the patented dosage regimen out of the label of the biosimilar, but they prefer to use a dosage regimen consistent with that of the reference product, according to the authors. At the basic patent expiration of adalimumab (Humira) in 2017, there were still 2 dose regimen patents active. However, biosimilar developers eventually gained market entry in 2018 following litigation.

The authors concluded that in Europe, secondary patents have not been the major barrier for biosimilars; instead, “the key protection instruments are the basic patent and the additional protection provided by the award of an SPC with possible pediatric extension, which provide for an average effective market protection of the innovator product of 15 years.”

Additionally, in cases where biosimilars were not available until several years after patent expiration, the authors attributed some of this delay to the complexity of development and manufacturing, not the patent strategies of the developers of the originator biologics.

Moorkens E, Vulto AG, Huys I. An overview of patents on therapeutic monoclonal antibodies in Europe: are they a hurdle to biosimilar market entry? 

. 2020;12(1):1743517. doi: 10.1080/19420862.2020.1743517.

European investigators say their analysis of court cases involving innovator monoclonal antibodies suggests secondary patents have generally failed to stop biosimilar competition.

In Europe, Secondary Patents Can't Stop Biosimilars, Study Says

When it comes to product launches and approvals, Australia and the United States are roughly equal in terms of the maturity of their biosimilars markets. A recent study revealed another similarity: Despite a national initiative to make the Australian public more aware of biosimilars, Australian patients may have very low familiarity with biosimilar therapy.  

Investigators did a single-clinic study (N = 132) of patients with rheumatoid arthritis (RA) during the 2017 period when the etanercept biosimilar (SB4, Brenzys) became the first biosimilar medicine for RA in Australia.

“The proportion of our cohort who were familiar with biosimilar therapy was very low (6%); this result matched the 9% to 11% biosimilar awareness levels among patients with inflammatory conditions in the United States and Europe,” the investigators wrote.

However, the same study revealed that more than three-quarters of patients with RA were open to using biosimilars if recommended by their rheumatologist.

The authors noted that Australia’s national, single payer system spends approximately US $1.4 billion yearly on biologics and it has been estimated that widespread use of biosimilars could potentially reduce that by up to 24%. The Australian Department of Health launched a 

in 2015 to educate prescribers, pharmacists, and patients on the benefits of biosimilars. Australia is encouraging the use of biosimilars, aiming to expand patient access to biologics.

In May 2019, Australia's Generic Biosimilar Medicines Association furthered this effort by launching an educational 

 on biosimilars for prescribers, pharmacists, and patients.

The etanercept biosimilar became available for dispensing through community pharmacies in 

. The investigators conducted the study “prior to any significant prescribing of biosimilars” with the goal of understanding the perception of biosimilars by patients not yet familiar with these drugs. Patients with RA who visited a clinic in an Australian tertiary hospital between August 2017 and February 2018 were invited to participate.

Although there has been much investigation into physician awareness, knowledge, and attitudes regarding biosimilars, the authors say the patient perspective has been less studied, particularly in Australia. They noted patient acceptance is important for widespread adoption of biosimilars, citing inadequate patient acceptance as a leading factor inhibiting switching from originator to biosimilar in European rheumatology studies.

Each patient in the Australian study was asked about their awareness and potential acceptance of biosimilars before being shown a visual aid explaining the concept of biosimilars, after which biosimilar acceptance was assessed again.

Although just 6% of patients surveyed were familiar with biosimilars, prior to education, 77% reported they would accept a biosimilar if it were recommended by their rheumatologist.

Other international studies have shown high acceptance rates (Germany, 70%; France, 89%) when biosimilars were first introduced in those countries. Just 5% of patients in the Australian study said they would refuse a biosimilar. Another 18% were unsure, but 50% said they wanted to know more about biosimilars after seeing the visual aid.

The investigators also found that patients who routinely refuse generics were significantly more likely to refuse biosimilars.

Among those who said they would refuse a biosimilar, 57% were concerned about efficacy, and 14% were concerned about safety. Among those who would accept biosimilars, approximately 12% to 15% reported concerns about efficacy, safety, operating a new injection device or changing medicines.

Overall, only 25% of patients were concerned about pharmacy-level substitution without consulting the prescriber. In Australia, pharmacists are allowed to substitute a biosimilar for the reference biologic unless the prescriber explicitly 

 it. Some Canadian provinces have implemented automatic 

 of biosimilars for reference biologics. In the United States, many states have considered or implemented policies allowing pharmacists to switch to biosimilars unless the physician has indicated otherwise.  

The investigators said the low awareness in Australia “identifies a need to improve Australian patient awareness of biosimilars.”

Patients in an Australian clinic were generally open to using biosimilars but knew little about them, according to a recent study.
 