Deana Ferreri, PhD

 critically evaluated the methodology used by Celltrion Healthcare and the FDA to determine whether Celltrion’s infliximab biosimilar CT-P13 (Remsima, Inflectra) was equivalent to the reference product Remicade for treating rheumatoid arthritis (RA) in the 2013 PLANETRA trial.

In 2016, CT-P13 became the first infliximab biosimilar approved by the FDA. By the second quarter of 2020, sales of CT-P13 achieved a 10.5% share of the US market for infliximab vs 84.1% for Remicade. In Europe, CT-P13 achieved a 57% market share vs 28% for the originator product.

The authors say their objective was to evaluate “if the equivalence margins chosen by Celltrion and the FDA for the first infliximab biosimilar CT-P13 were scientifically valid and clinically justifiable.”

They argued the appropriate equivalence margin for approval of infliximab biosimilars is 5.7 percentage points. Celltrion used an equivalence margin of 13 percentage points in their analysis, and the FDA used 12 percentage points in the approval process for CT-P13 and has recommended the same margin for the evaluation of other infliximab biosimilars.

The authors used the same method the FDA recommends to determine the equivalence margin; however, they contended the clinical trials of the originator drug used to calculate the equivalence margin did not meet the test for constancy, or comparability. The principal of constancy requires that clinical trials being used to estimate an equivalence margin must be similar enough to be pooled together.

In reviewing Celltrion's application for approval, the FDA evaluated data from 5 historical clinical trials involving infliximab to calculate an equivalence margin. However, according to the authors, only 2 of these trials met the constancy assumption. The remaining 3 trials were included in the pooled PLANETRA trial.

The FDA declined a request to comment, saying it does not comment on third-party research, but Celltrion responded with a point-by-point critique of the study.

The authors claim 1 clinical trial violated the constancy assumption because it evaluated efficacy approximately 8 weeks earlier than the others. However, according to Celltrion, which cited the summary of product characteristics for Remicade, “Available data suggest that the clinical response is usually achieved within 12 weeks of treatment and is maintained….Therefore, it is clinically acceptable to use the results of earlier time points.”

In another of the pooled PLANETRA trials, the authors noted, the methotrexate (MTX) dose was only about half that used in the other trials. However, Celltrion responded that this study was conducted in Japan: “It is general practice to use a lower dose of MTX in Asian countries (because of a relatively lower body weight).”  Furthermore, Celltrion noted a subgroup analysis of CT-P13 efficacy in the PLANETRA study “suggests no difference in efficacy by MTX dose.”

Celltrion also refuted the authors’ claim that this trial enrolled “milder” patients than the others, saying, “The average number of swollen joints in the Abe et al study [PLANETRA] was similar to the other trials and serum CRP [c-reactive protein] was the highest in the Abe et al study (4.2 vs 1.6-3.3). In addition, disease duration was the longest in the Abe et al study. Based on this, it is difficult to conclude that slightly milder patients were enrolled in the Abe et al study.”

For the third trial in the PLANETRA pooled trials, the authors reported that the severity of RA symptoms at baseline and the dose of MTX were unclear “solely based on the published information.” Celltrion responded that “the eligibility criteria were in line with other studies,” refuting the idea that this trial was different enough from the others to violate the standard of constancy.

The authors used 6 pooling scenarios to estimate what they considered an appropriate equivalence margin for CT-P13. Three of the 6 scenarios used all 5 trials, similar to the methodologies of Celltrion and the FDA. In these scenarios, equivalence margins ranged from 11.8 to 14.2 percentage points, similar to Celltrion’s 13 and the FDA’s 12 percentage point ranges.

In 3 scenarios, the equivalence margins were 10.5, 9.4, and 5.7 percentage points. The authors contend the equivalence margin of 5.7 percentage points is the most appropriate.

According to the authors, “The equivalence claim for CT-P13 to original infliximab in patients with rheumatoid arthritis did not appear to be supported when the constancy assumption was strictly assessed.”

They added, “The equivalence margin for biosimilars could be determined more conservatively.” The authors recommend the more conservative approach because of the complexity of biologic therapies and the novelty of biosimilars, saying, “This approach can guarantee that patients are protected from any remaining uncertainty or risks with the use of follow-on biological products.”

It is unclear based on the publication what prompted the authors to examine the FDA’s methodology for demonstrating equivalence of infliximab biosimilars. The authors claim no conflicts of interest and no specific funding from commercial or public sectors. The project was supported by the BK21 Plus Program of the National Research Foundation of Korea, which is a faculty-mentored talent development program. The article was peer reviewed.

Celltrion responded, “This study does not reflect the FDA review procedure and the principles of the regulatory guidelines. The constancy assumptions have been evaluated improperly, and the disease is also misrepresented within the evaluation.” Celltrion also pointed out “In addition, the equivalence margin used for PLANETRA study was endorsed by EMA (European Medicines Agency).”

Celltrion has a growing influence on the biosimilar scene. In June, the World Health Organization 

 its rituxumab biosimilar (Truxima), promoting the use of this product among developing nations. In March, Celltrion and Teva Pharmaceuticals USA 

 a trastuzumab biosimilar (Herzuma) on the US market.

Kim S, Kim S, Lee H. A critical review of the United States regulatory pathways for determining the equivalence of efficacy between CT-P13 and original infliximab (Remicade). 

. 2020;14:2831-2840. doi:10.2147/DDDT.S254776

Articles

Celltrion finds fault with a critique of equivalence margins used to approve its infliximab biosimilar.

Celltrion Refutes Critique of CT-P13 Equivalence

Authors of a 1-year real-world study on anti—tumor necrosis factor (TNF) originator biologics and biosimilars for 

 (CD) and ulcerative colitis (UC) found anti-TNF therapy overall was more effective for achieving remission in patients with CD compared with those with UC.

Moderate to severe inflammatory bowel disease (IBD) may be treated with the anti-TNF biologics infliximab or adalimumab or their biosimilars, and the introduction of 

 has improved rates of remission and quality of life in IBD. However, the investigators identified a knowledge gap, noting that comparisons of effectiveness, safety, and tolerability of the anti-TNF agents between the 2 diseases have only been performed indirectly through meta-analysis.

The retrospective study included 179 patients, 89 with UC and 90 with CD. Approximately one-third of each group took the infliximab originator (Remicade), infliximab biosimilar (Remsima; CT-P13), or adalimumab (Humira).

Clinical activity and inflammatory markers were measured at baseline, after induction (14 weeks for infliximab, 8 weeks for adalimumab), at 30 weeks, and at 52 weeks. Endoscopic measures were assessed at baseline and 52 weeks.

After the induction period, there was a significant difference (

 = .05) in the percent of patients on any therapy who achieved clinical response between UC (84.3%) and CD (93.3%); the difference between diseases diminished by 30 weeks, and at 52 weeks, 82% of patients with UC and 80% with CD had achieved clinical response, although this finding was not significant (

The rate of steroid-free clinical remission after induction was higher in CD (58.8%) compared with UC (42.7%; 

 = .03). At 30 and 52 weeks, remission rates were higher in CD compared with UC, with 72.2% of patients with CD in steroid-free clinical remission at 52 weeks compared with 60.7% of patients with UC (

Among individual drugs, remission rate differences in the infliximab originator group became significant at 30 weeks between UC (56.7%) and CD (80%). At 52 weeks, remission rates were higher in CD for both the infliximab reference product and biosimilar groups, but the differences did not reach statistical significance (

 = .08). At 52 weeks, steroid-free clinical remission rates for the infliximab originator were 66.7% and 80% in UC and CD, respectively, and 57.1% and 76.7% for the biosimilar.

Differences in remission rates between diseases for patients taking adalimumab did not reach significance at any point in the study. In patients taking adalimumab, the steroid-free clinical remission rates at 52 weeks were 58.1% and 60% for UC and CD, respectively.

Regarding their finding of greater remission rates overall for CD compared with UC, the authors said the differences between the disease activity scoring methods are worth noting. In particular, the Harvey Bradshaw Index for CD takes into account “the intestinal manifestations of illness, present in 48.9% of our patients, and the subjective component of perception of the patients' health status,” which do not factor into the partial Mayo score for UC.

Overall, 13 patients discontinued therapy due to adverse events (AEs). The most frequent AEs were allergic reactions, dermatologic manifestations, and infections. The infliximab biosimilar group had both the greatest number of total discontinuations (3 in UC and 5 in CD) and the most AE-related discontinuations (1 in UC and 3 in CD). The adalimumab group had the greatest number of discontinuations for lack of efficacy.

The authors observed 3 cases of malignant disease during the study, which they say necessitates “careful and comprehensive follow-up of the patient in biological therapy.”

Endoscopic response was achieved by 51% of patients on adalimumab compared with 43.4% on the infliximab originator and 41.7% on the infliximab biosimilar. In the adalimumab group, endoscopic response was more common in UC compared with CD. The authors did note, however, endoscopic data were available for all patients with UC but only about half of patients with CD.

The drugs started out at standard doses, but physicians were later allowed to optimize dosage for the individual patients. At week 30, 20% of patients with UC on the infliximab originator required optimization of therapy compared with none with CD. No other significant differences in optimization between diseases were reported. At week 52, 31.1% of patients taking adalimumab, 16.7% taking the infliximab originator, and 36.2% taking the infliximab biosimilar required treatment optimization.  

Given the real-world setting of the study, the authors found several baseline characteristics were significantly different between groups. They performed multivariate analysis adjusted for those factors, which included endoscopic disease activity, disease duration, percent of biologic-naive patients, extraintestinal manifestations, use of a concomitant steroid, and C-reactive protein level. Multivariate analyses suggested a 3-to-4—fold greater likelihood of clinical remission or steroid-free clinical remission at 30 and 52 weeks for patients with CD compared with those with UC.

The investigators consider their study a step toward greater understanding of anti-TNF agents in IBD and therapy tailored to the individual patient, as well as a starting point for future, larger prospective studies and randomized controlled trials comparing biologics use between UC and CD.

Barberio B, Zingone F, D&#700;Incà R, et al. Infliximab originator, infliximab biosimilar, and adalimumab are more effective in Crohn's disease than ulcerative colitis: a real-life cohort study. 

. 2020;11(5):e00177. doi:10.14309/ctg.0000000000000177

A real-world study on inflammatory bowel disease employing originator and biosimilar biologics suggests anti–tumor necrosis factor (TNF) therapy may be more effective for Crohn disease than for ulcerative colitis.
 

Anti-TNF Biologics Outperform in Crohn Disease 

This study has been updated to note that Avsola launched in July 2020.

The uptake of infliximab biosimilars in the United States is slow but tracks closely to the experience in Europe, where after 2 years infliximab biosimilars assumed a large share of the market, according to a new study.

Infliximab biosimilar uptake has lagged filgrastim biosimilar uptake, and investigators theorized providers find it easier to prescribe a change of medicine in the case of filgrastim, which is for blood cell regeneration following radiotherapy, than for infliximab, which is for rheumatoid arthritis and related conditions. They said physicians are naturally more cautious about changing medicines for chronic conditions that are well controlled with the initial medication.

Investigators analyzed uptake of infliximab biosimilars in the US Medicare population and reported that in the 2 years after the November 2016 launch of the first infliximab biosimilar (Inflectra), “biosimilars captured only 10% of the infliximab market and lowered reimbursements by 17%.” Renflexis was launched in July 2017.

These were the second and third biosimilars to be launched in the United States. The uptake of these biosimilars and the corresponding reduction in costs have not measured up, the authors commented, compared with results of the first biosimilar launch in the country (filgrastim, Zarxio). This biosimilar “had strong adoption after just 2 years, capturing 40% of the market and lowering unit prices by 25%.”

Trends in Infliximab Originator and Biosimilar Use

Using Medicare fee-for-service quarterly claims data, the researchers analyzed trends in use, reimbursement, and switching between the reference infliximab (Remicade) and its biosimilars from January 1, 2017, to December 31, 2018.

Total infliximab administrations decreased by 3.9% from Q1 of 2017 to Q4 of 2018. The proportion of biosimilar administrations increased over that time from 0.5% to 10.5% of the total. The authors noted this pattern was similar across approved infliximab indications.

In the first quarter of 2017, reimbursement per 10 mg for the newly launched biosimilar Inflectra was higher than for Remicade ($101.62 vs $86.87). After the second biosimilar (Renflexis) was introduced in May 2017, the relative biosimilar reimbursement began to fall, reaching $65.36 per 10 mg in the fourth quarter of 2018, 17.1% lower than the $78.86 reimbursement for the originator at that time.

The majority of both new and returning patients taking infliximab used the reference product. Among new patients,17.4% used a biosimilar, and 10.8% of returning patients used a biosimilar. Almost all new patients taking a biosimilar took only that biosimilar, and about half of returning patients using a biosimilar had switched from the reference product.

Most physicians (72.8%) prescribed only the reference product compared with just 3.5% who prescribed only biosimilars. Of those who prescribed both, 61.4% had switched some patients from the reference product to a biosimilar.

A “Considerable Minority” of Patients Switched to a Biosimilar

The authors said the reasons for the slower adoption of infliximab biosimilars compared with the previous filgrastim biosimilar are unknown. However, they speculated that “patients and physicians may be more reluctant to switch from a working biologic regimen in a chronic setting than an acute one.”

However, they acknowledged that “a considerable minority of patients did switch between biologic and biosimilar versions in 2018,” and suggested switching could have been the result of cost reductions, such as lower patient co-pays or physician rebates.

Infliximab biosimilars will gain much greater traction in next several years, based on results from Europe, they suggested.  “After 2 years, biosimilar infliximab garnered 13% of European market share, with subsequent uptake increasing steeply to 52% by 5 years.” In the United States, infliximab biosimilars have been available for less than 4 years. In December 2019, Amgen got FDA approval for its Avsola infliximab biosimilar, which launched in July 2020.

There are currently just 2 filgrastim biosimilars on the US market.

 on infliximab biosimilar use in Medicare beneficiaries similarly reported slow uptake but an increase in infliximab biosimilar use over time.

Chen AJ, Gascue L, Ribero R, Van Nuys K. Uptake of infliximab biosimilars among the Medicare population. 

. Published online July 20, 2020. doi:10.1001/jamainternmed.2020.3188

Investigators speculate on why infliximab biosimilars don’t have a larger market share by now.

Study: Slow Start for Infliximab Biosimilars

The authors of a new clinical review article combined evidence-based guidelines and clinical experience to create algorithms to guide decision making on the use of biosimilar anti—tumor necrosis factor (TNF) agents for moderate to severe Crohn disease (CD).

The authors, who see their work as a step toward standardizing care, noted that anti-TNF biologics, infliximab and adalimumab in particular, “constituted a quantum leap in efficacy” in CD treatment, and that access to these drugs “began to improve with the introduction of biosimilars for infliximab in 2013 and adalimumab in 2018.” However, standard procedures for initiating, monitoring, and managing anti-TNF therapy in CD have not yet been established.

The authors have presented their decision-making algorithm visually as a series of flowcharts, beginning with determining which patients are appropriate for anti-TNF therapy, followed by criteria favoring infliximab vs adalimumab and dosing regimens for each. A final set of flowcharts represents real-world scenarios physicians may encounter when monitoring a patient during treatment with infliximab or adalimumab biosimilars, along with recommendations for adjustment of therapy in those scenarios.

Identifying Patients Indicated for Anti-TNF Therapy

The authors started by providing criteria for establishing an indication for anti-TNF therapy, which includes assessment of disease activity scores, inflammatory biomarkers, and imaging.

Although disease activity scoring with the CD Activity Index (CDAI) has been used in clinical studies of anti-TNF agents in patients with CD, it is impractical for routine clinical practice because it must be calculated over a period of 7 days. The authors recommend an alternative assessment, the Harvey-Bradshaw Index (HBI), which they say correlates well with CDAI. An HBI of at least 8, they say, corresponds to moderate to severe disease.

Because HBI does not correlate well with inflammatory burden, the authors recommend measuring inflammatory markers and assessing the presence of mucosal lesions to corroborate the HBI score. Although there are no established cutoffs for C-reactive protein and fecal calprotectin, or established endoscopic criteria, the authors made recommendations supported by published research and clinical experience.

Before initiating therapy, they added, safety checks should be performed according to local and international guidelines and contraindications for anti-TNF therapy. They also advised setting patient-specific treatment goals.

Choosing Between Infliximab and Adalimumab Biosimilars

The authors note that although direct comparisons of infliximab and adalimumab in CD have not been published, the available evidence from observational studies suggests “no major differences in efficacy and safety between infliximab and adalimumab but a higher immunogenicity of the former.” They recommend weighing the preferred route and schedule of administration, dosing, combination therapy, and the patient’s inflammatory load.

Infliximab requires intravenous administration, whereas adalimumab is administered subcutaneously, allowing for self-administration by the patient at home. Subcutaneous infliximab is approved in Europe and is under review by the FDA. However, in the United States it will “ follow the [approval] pathway for novel products rather than biosimilars,” the authors state. Infliximab dosing is more easily tailored to the patient, whereas adalimumab dosing is limited by fixed-dose injections.

Because of the greater potential immunogenicity of infliximab, the authors say combination therapy with azathioprine should be considered, as it “has been shown to be superior to either treatment alone in patients with CD.” In contrast, combining immunomodulators with adalimumab is “potentially only marginally more effective” compared with adalimumab monotherapy.

The authors recommended infliximab in cases of perianal fistulizing disease, a requirement for flexible dosing, high systemic inflammatory load, or severe CD. They recommended adalimumab in cases of low inflammatory load or a preference for self-administration or monotherapy as opposed to combination therapy.

As of yet, most trials involving biosimilars in 

 bowel disease have been on infliximab. The first infliximab biosimilars were approved in 2013; adalimumab biosimilars became available in Europe in 2018, but these are not yet available in the United States owing to patent issues.

The authors cautioned that initiating biosimilars “may require a tailored approach beyond that used for reference biologics.” They advised using positive framing to avoid encouraging the 

 when addressing patients’ concerns regarding biosimilars.

Once treatment is initiated, monitoring and adjusting therapy may improve outcomes for patients with CD treated with anti-TNF agents, the authors suggested, because a large proportion of patients experience loss of response within 1 year of treatment initiation.

Recommendations for clinical monitoring, biomarker analysis, imaging, and 

and options for adjustment of therapy were provided for different clinical scenarios: primary remission, primary response without remission, primary nonresponse, and loss of remission/response. As a whole, the authors’ algorithm aims to standardize anti-TNF therapy for CD while also personalizing therapy to the individual patient.

Reinisch W, Gecse K, Halfvarson J, et al. Clinical practice of adalimumab and infliximab biosimilar treatment in adult patients with Crohn's disease.

. Published online July 7, 2020. doi:10.1093/ibd/izaa078

Wide variation in treatment patterns for Crohn disease is attributable to failures to translate evidence uniformly and cost barriers. Authors of a new report have formulated algorithms to help reduce heterogeneity in treatment of patients.

In Search of Better Algorithms for Treatment of Crohn Disease

A recent study comparing usage of the infliximab biosimilar Inflectra (infliximab-dyyb; CT-P13) with that of the originator biologic (Remicade) among Medicare beneficiaries found that use of the biosimilar is increasing even though it accounted for less than 10% of total monthly administrations.

Study data also suggest some beneficiaries are switching from the reference product to the biosimilar. However, analyses by indication and prescribing clinician suggest that patients and physicians may still have concerns about extrapolation to gastrointestinal indications, according to the authors.

, examined the demographics, usage, and uptake patterns of Remicade and Inflectra in the infliximab-eligible Medicare fee-for-service population in the United States from July 2016 to December 2018. “The overall uptake of biosimilar infliximab has been much slower than that of the biosimilar filgrastim, the first biosimilar product to enter the US market,” the authors noted.

The demographics for the populations treated with the reference product and biosimilar were “broadly similar,” with differences by geographical region. Greater percentages of biosimilar-treated patients were found in the Midwest and West, as opposed to greater percentages for the originator in the Northeast and South.

A breakdown of the biosimilar and originator-treated populations by indication determined the biosimilar was administered somewhat less for 

, which encompasses ulcerative colitis (UC) and Crohn disease (CD). Gastrointestinal indications accounted for 22.5% and 25.9% of treatments with the biosimilar and originator, respectively.

The authors said 17.4% and 15.3% of patients treated for CD received the reference drug and biosimilar, respectively. UC accounted for 8.5% and 7.2% of patients on the originator versus the biosimilar.

Analyzing by prescribing clinician, the authors found that gastroenterologists prescribed the biosimilar less often (14%) compared with the reference product (17%), whereas oncologists prescribed the biosimilar more commonly (10.5%) than the reference product (5.5%). 

 prescribed the biosimilar and reference product in the same proportions (58.2% and 59.9%, respectively).

The authors observed a relative reluctance to prescribe biosimilars for gastrointestinal indications. “There may still be some reservations among certain patients or providers regarding usage of the product for indications extrapolated from the overall conclusion of biosimilarity” between the reference and biosimilar agents, they wrote.

The use of the infliximab biosimilar in CD and UC was originally 

 from the demonstration of similarity to the reference product in clinical studies on patients with rheumatoid arthritis (RA). Notably, 55.02% of patients being treated for RA received the biosimilar. The percentage receiving the reference product was 52.24%.

Patients taking the reference product and those taking the biosimilar were more likely to have prior use of the reference product,“which indicates that some beneficiaries are switching from the reference product to the biosimilar,” according to the authors.

The dose patterns across different indications were similar for those using the originator versus the biosimilar. This was notable in CD, where “the label for each product specifies that increasing the dose to 10 mg/kg may benefit patients who have lost their response.” The authors said the similar dose distributions in CD suggest that the “biosimilar has not required more dose escalation than the reference product.”

The authors recommended further study of infliximab biosimilars in IBD, attention to clinicians’ rationale for their prescribing choices, and more effort to educate patients and physicians about biosimilars.

Kozlowski S, Flowers N, Birger N, et al. Uptake and usage patterns of biosimilar infliximab in the Medicare population. 

. Published online June 23, 2020. doi:10.1007/s11606-020-05957-1

Slow growth of use of biosimilar infliximab in a Medicare fee-for-service population suggests lingering hesitancy on the part of gastroenterologists and patients, particularly when it comes to extrapolation to off-label uses, according to a new study.  
 

Use of Infliximab Biosimilar in Medicare Population Is Low but Growing

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

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 

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.