Deana Ferreri, PhD

Analysis of a Korean health insurance database found the type of institution and physician specialty were the most important factors favoring the use of anti—tumor necrosis factor (anti-TNF) biosimilars in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Additionally, patients with RA who were taking glucocorticoids or who had comorbidities were less likely to receive biosimilars.

, aimed to provide insight into the real-world patterns of biosimilar initiation in patients with RA and AS in Korea by identifying patient characteristics and other factors associated with starting biosimilars using a logistic regression model.

Korea’s reimbursement guidelines for patients with rheumatic diseases recommend biosimilars as equivalent to their originators. However, in real-world clinical practice, a patient’s age or comorbidities may influence physicians’ willingness to prescribe a biosimilar. Furthermore, in the real-world, patients are not blinded. Patient concerns regarding biosimilars can contribute to reluctance to use biosimilars as well as a possible nocebo effect.

Using the Korean National Health Insurance Service (NHIS) database, researchers identified patients with RA or AS who had used anti-TNF agents from their initial approval of these biologics in 2004 through 2017. Between 2012, when the first biosimilar anti-TNF inhibitors were approved in Korea, to 2017, the rate of biosimilar use among patients prescribed TNF inhibitors increased to 16.5%.

To determine factors for initiating biosimilars, the researchers identified 4216 patients with RA and 2338 with AS who started anti-TNF inhibitors between 2013 and 2017.

Hospitals and clinics were factors for starting biosimilars, as opposed to tertiary or general hospitals. The authors hypothesize this could be due to simpler administrative procedures in hospitals or clinics.

Prescribing from internal medicine (including rheumatology), orthopedics, and other specialties was investigated, and internal medicine departments were a factor for starting biosimilars. The authors say this is perhaps due to differences in knowledge or acceptance of biosimilars by physicians in different specialties.

There was more biosimilar use in metropolitan areas and in other cities compared to Seoul. This could be due to regional differences in marketing by pharmaceutical companies as well as knowledge and opinions of clinicians, the researchers say.

Use of biosimilars in combination with other medications: 

Regarding the influence of use of other medications, in RA, patients who used methotrexate were more likely to initiate biosimilars, whereas those who used oral glucocorticoids were less likely to initiate biosimilars, possibly reflecting patient and physician uncertainty about the effectiveness of biosimilars used in combination with glucocorticoids.

Using an index measurement of comorbidities, patients with RA who had higher levels of comorbidities were less likely to initiate biosimilars, likely reflecting patient and physician concerns about the safety of biosimilars, according to the authors.

Registration with the Individual Copayment Beneficiaries Program (ICBP) for rare and intractable diseases was also a factor in RA; these patients were less likely to initiate biosimilars. ICBP was used as a marker of economic status, as patients registered with ICBP pay only 10% of their medical expenses as copayment. Household income, however, was not a significant factor. The authors say these findings suggest that lower cost sharing was associated with the selection of more expensive drugs.

Patient characteristics associated with biosimilar use in AS were unclear. The authors conclude that a general lack of knowledge about interchangeability of originators and biosimilars, and about switching to biosimilars, may inhibit the prescription of biosimilars. They recommend further observational and clinical research in a variety of patients to improve knowledge and potentially increase acceptance and prescription of biosimilars.

Sung YK, Jung SY, Kim H, et al. Factors for starting biosimilar TNF inhibitors in patients with rheumatic diseases in the real world. 

.  [published online January 24, 2020]. doi:10.1371/journal.pone.0227960.

Articles

The study aimed to provide insight into the real-world patterns of biosimilar initiation in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in Korea by identifying patient characteristics and other factors associated with starting biosimilars using a logistic regression model.

What Are the Factors for Starting Anti-TNF Inhibitor Biosimilars in RA and AS?

The nocebo effect may contribute to treatment failures upon nonmedical switching from an originator to a biosimilar, according to a review article, whose authors recommend rigorous studies to evaluate the 

, better patient education on biosimilars, and involving patients in the decision to switch.

Researchers reviewed randomized controlled trials (RCTs) and real-world evidence (RWE) studies on nonmedical switching, ie, switching patients who are doing well on their current originator therapy to a biosimilar.

Although head-to-head trials in biologic-naive patients have generally found similar efficacy and safety of originator and biosimilar, discontinuation of biosimilar therapy due to loss of response or adverse events is somewhat common in switch studies. The authors noted the reasons for these treatment failures have not been investigated, and they explore the possibility that some of these failures are due to negative expectations of the patient who is aware they are switching from the originator to the biosimilar—the nocebo effect.

According to the authors, the currently available data does not allow for distinguishing between a true difference in pharmacologic activity and the nocebo effect as potential reasons for loss of efficacy or adverse events. They acknowledge that the clinical effects of subtle differences between originators and biosimilars are not fully known, and could cause certain individuals to respond differently; furthermore these subtle differences in the molecule potentially could trigger an immunogenic response to a biosimilar upon switching. The authors call for well-designed, blinded clinical trials on nonmedical switching with appropriate control groups and attention to the causes of therapeutic failure to accurately evaluate how much loss of response is attributable to the nocebo effect.

Nonmedical switching is most often motivated by cost. However, additional physician or hospital visits due to adverse effects or failure of treatment following nonmedical switching could negate the cost savings of switching to a biosimilar.

Negative views of biosimilars by physicians and patients remain a barrier to reducing costs. The authors cite a survey in which 84% of US physicians said they would not support switching a stable patient from an originator to a biosimilar,

 highlighting the need for more well-designed studies to improve physicians’ views of nonmedical switching. Also, since patients’ negative expectations are the driver of the nocebo effect, the authors suggest better patient education could help to reduce misconceptions about biosimilars, thereby reducing the potential for the nocebo effect.

The authors also recommend involving patients in the choice to switch. They note that in some countries and by some insurers, nonmedical switching is mandated for patients who are doing well on originator therapy. They recommend switching not be mandated, as involuntary switching may exacerbate patients’ negative expectations, leading to greater likelihood of the nocebo effect. In their review of the literature, they found the rate of discontinuation of biosimilars was lower in RWE studies in which patients were able to choose whether to switch.

1. Fleischmann R, Jairath V, Mysler E, Nicholls D, Declerck P. Nonmedical switching from originators to biosimilars: Does the nocebo effect explain treatment failures and adverse events in rheumatology and gastroenterology? [published online ahead of print, January 16, 2020]. 

. 2020;10.1007/s40744-019-00190-7. doi:10.1007/s40744-019-00190-7

2. Teeple A, Ellis LA, Huff L, et al. Physician attitudes about non-medical switching to biosimilars: results from an online physician survey in the United States. 

. 2019;35(4):611—617. doi:10.1080/03007995.2019.1571296.

Researchers reviewed randomized controlled trials and real-world evidence studies on nonmedical switching; that is, switching patients who are doing well on their current originator therapy to a biosimilar.

Nocebo Effect May Have Role in Some Treatment Failures, Adverse Events in Nonmedical Switching 

Researchers say biosimilar gene therapy could become a cost-effective, long-term treatment for autoimmune diseases, 

; their work looked at secukinumab biosimilar lentivirus-based gene therapy, which showed successful and prolonged expression of the recombinant antibody in rats.

Producing, transporting, storing, and administering monoclonal antibodies is time-consuming and costly. According to the researchers, if patients’ own cells could be used to manufacture a biosimilar, manufacturing, transportation, and storage steps could be eliminated, while providing a longer-lasting source of the drug potentially at a lower cost.

Secukinumab (Cosentyx) binds to IL-17A, inhibiting its interaction with the IL-17 receptor; secukinumab is prescribed for plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. The universality of IL-17’s involvement in autoimmune diseases made this particular drug attractive to the researchers.

Biosimilar gene therapy was tested in both ex vivo and in vivo experiments. Human chorionic villous mesenchymal stem cells (CMSCs) were isolated and transduced with a lentiviral vector containing the DNA sequences of the heavy and light chains of secukinumab, which were derived from the secukinumab protein sequence. In one group of rats, the transduced CMSCs were injected. In another group, the lentivirus was injected, and the rats were monitored for 60 days.

Expression of recombinant secukinumab at the mRNA and protein levels was confirmed in the transduced CMSCs, and the secreted antibody’s ability to inhibit IL-17 was confirmed in human fibroblasts. In both transduced CMSC and lentivirus injected rats, the presence of secukinumab in the bloodstream was confirmed at various points throughout the 60 day period.

The serum concentration of the antibody was higher in lentivirus treated rats compared to CMSC treated rats. However, the authors noted these concentrations were substantially lower than those currently approved for administration of secukinumab, and that improved serum concentrations would be necessary for human application of this therapy. 

Fallah A, Estiri H, Parrish E, Soleimani M, Zeinali S, Zadeh-Vakili A. Biosimilar gene therapy: Investigational assessment of secukinumab gene therapy. 

. 2020;21(4):433—443. doi:10.22074/cellj.2020.6309

The study examined secukinumab biosimilar lentivirus-based gene therapy, which showed successful and prolonged expression of the recombinant antibody in rats.

Animal Study of Secukinumab Biosimilar Gene Therapy Yields Promising Results 

Improving access to fairly priced, quality-assured generics and biosimilars is essential to realizing the potential public health and cost-saving benefits of these drugs, according to an editorial published in 

, which also lays out strategies to achieve this goal.

In the publication, the authors point out that achieving universal health coverage requires universal access to safe, effective, quality-assured, and affordable drugs and vaccines, and they highlight the role of generics and biosimilars. The authors cite increasing trust in generics and biosimilars, as well as incentivizing the use of these lower-cost options, as needed improvements. However, they also acknowledge biosimilars have not realized the cost advantages currently associated with generics, at least in part due to the complex production processes and more extensive regulatory requirements biosimilars need for approval compared with generics.

The authors review the research on how policies used by health authorities aimed at reducing prices have worked thus far:

: Establishing groups of interchangeable drugs, each with a single reimbursement price, was found to decrease spending by leading patients to options at or below the reimbursement price. However, after the reimbursement price has been set, there is little incentive for manufacturers to drive prices below that point, which could limit potential cost savings.

Basing generic/biosimilar price on a percentage of the originator price

: Similar to internal reference pricing, a fixed discount could discourage price competition. Plus, the price of the originator has a large influence on how well this policy works, the authors say.

Nonproprietary prescribing and generic substitution

: The authors note that countries with mandatory generic prescribing or a high prevalence of generic prescriptions see substantial cost savings and that generics entered the market earlier in countries with mandatory generic prescribing.

Where nonproprietary prescribing is not mandatory, prescriber or patient perceptions about the quality of the generic compared with the originator may limit the utilization of generics. The authors suggest, at minimum, voluntary implementation of these policies where it is not feasible to make them mandatory.

For biosimilars, the situation is more complex since they are, by definition, “highly similar” as opposed to identical. Although biosimilars must establish no clinically meaningful differences from the originator before approval, the authors note the issue of switching patients to a biosimilar from their current reference product remains “the subject of debate.”

 Generic prices can be reduced by pooling procurement. Tendering, in which suppliers must compete for contracts, has also been widely and successfully used to reduce prices; however, this can also drive small suppliers from the market, leading to decreased competition.

The authors conclude by stating that increasing trust in generics and biosimilars, and assuring their timely entry into the market, will yield greater benefit from these lower-cost options. Further, they note that efforts from all stakeholders are necessary ,as no single policy will achieve this goal.

For example, the authors recommend that governments carefully review pricing policies and grant priority review to the first generic, that payers provide incentives for pharmacists to dispense generics and biosimilars, that pharmaceutical companies either grant or take advantage of voluntary licensing, that physicians seek out evidence-based and independent information and prescribe the most cost-effective treatment, that physicians be involved in “switch studies,” and that government, physicians, and prescribers all help to educate patients about the safety and efficacy of generics and biosimilars.

Ferrario A, Dedet G, Humbert T, Vogler S, Suleman F, Pedersen HB. Strategies to achieve fairer prices for generic and biosimilar medicines. 

Increasing trust in generics and biosimilars, and assuring their timely entry into the market, will yield greater benefit from these lower-cost options, according to a recent review.

Achieving Cost Savings With Biosimilars Will Require New Strategies, Authors Say

An observational study found health-related quality of life and disease activity in Finnish patients on maintenance therapy for inflammatory bowel disease (IBD) were comparable before and after switching from 

The biosimilar CPT-13 (Remsima) is currently approved in Europe for all uses for which the originator infliximab (Remicade) is approved, including Crohn disease (CD) and ulcerative colitis (UC), which are often referred to collectively as IBD. 

In this observational study, health-related quality of life (HRQoL) and disease activity were assessed in adult patients on maintenance therapy for IBD at the time of switching to the biosimilar and then twice more, at 3 and 12 months. The study included 54 patients with IBD: 26 with CD, 27 with UC, and 1 with unclassified IBD.

Health-related quality of life (HRQoL) was evaluated by a survey assessing 15 dimensions of health with possible scores ranging from 0 (death) to 1 (full health). Mean scores at 3 and 12 months did not significantly differ from time of switching in patients with CD or UC. However, in patients with CD, there was a significant decrease in 2 dimensions, breathing and excretion, from time of switching to 12 months. There were no significant differences in any dimension in UC. Of the entire study group, 40% of patients experienced a clinically important improvement, and 31% experienced a clinically important deterioration at 12 months.

Disease activity was assessed by questionnaires (Inflammatory Bowel Disease Questionnaire; IBDQ), clinical evaluation (Crohn Disease Activity Index; CDAI, or Partial Mayo Score; pMayo), and an objective laboratory measurement (fecal calprotectin; FC).  In the whole study group, there were no statistically significant changes in these disease activity indicators between the time of switching and 3 months or 12 months.

At 3 months there was an improvement in IBDQ scores in patients with CD compared to time of switching, but the difference was no longer statistically significant at 12 months. A change in IBDQ score indicating a clinically meaningful improvement occurred in 1/26 patients with CD and 4/27 patients with UC at 12 months. One patient with UC experienced an IBDQ score change indicating relapse.

The authors concluded infliximab and biosimilar CPT-13 performed comparably for maintenance therapy of IBD during the 12 months of follow-up. Cost of the therapy, however, did differ. When comparing 1 year on infliximab and 1 year on the biosimilar, the number of drug administration visits and doses were not significantly different, but the cost of the biosimilar was 35% that of the originator. Costs related to secondary health care were not significantly different in the year on infliximab and the year on the biosimilar.

Huoponen S, Eberl A, Räsänen P, et al. Health-related quality of life and costs of switching originator infliximab to biosimilar one in treatment of inflammatory bowel disease. 

 (Baltimore). 2020;99(2):e18723. doi:10.1097/MD.0000000000018723.

The biosimilar CPT-13 (Remsima) is currently approved in Europe for all uses for which the originator infliximab (Remicade) is approved, including Crohn disease (CD) and ulcerative colitis (UC), which are often referred to collectively as IBD. 
 

Study Suggests CPT-13 Comparable to Infliximab at Lower Cost in Patients With IBD

raises concerns that special and accelerated drug approval programs at the FDA in recent decades may have resulted in a process that approves drugs based on weaker data, without reducing overall drug development time.

An accompanying editorial describes the current regulatory process as “a thicket of special programs, flexible review criteria, and generous incentives,” and suggests starting points for reforms, including improving access to biosimilars.

, Darrow et al. describe the evolution of FDA’s approach to drug approval from 1983 to 2018 based on federal laws, FDA regulations, drug approval records, and user fee records. 

FDA must balance rigorous testing of new drugs to clearly define benefits and risks against timely approval for drug makers and access for patients. Special development, protection from generic competition, and expedited approval programs, such as Orphan Drug, Fast-Track, Accelerated Approval, Priority Review, and Breakthrough Therapy, were instituted by FDA to support drug development, especially for rare and serious diseases. However, in 2018, 81% of all new drugs won regulatory approval through one or more of  the expedited programs, the article noted.

Special approval programs have increased administrative costs at FDA (paid for mostly by user fees), and postponements of generic competition have been costly to the US healthcare system, the authors noted.

Over the time period analyzed by the authors, FDA has accepted more surrogate measures, and as a result harder and more relevant clinical endpoints are studied less often. In 1995-1997, 80.6% of drug approvals were supported by at least 2 pivotal trials, compared to 52.8% in 2015-2017. The authors caution that reliance on surrogate measures may accelerate the approval of drugs that pose significant risk but have little clinical value.

The article reports that although FDA shortened its review times from more than 3 years in 1983 to less than 1 year in 2017, overall drug development time (from beginning human studies to approval) has not changed: approximately 8 years. The rate of new drug approvals (other than generics and biologics) has not increased substantially since 1983.

On the other hand, the authors acknowledge some positive outcomes. The median number of generics has increased following legislation to incentivize and accelerate generic drug development.  Plus, biologic approvals are increasing over time, reflecting technological advancement. Although drugs are now supported by fewer studies before approval, the number of patients in these studies has not declined.

In the accompanying editorial, Joshua M. Sharfstein, MD, the former principal deputy commissioner of the FDA, suggests 4 starting points for reforms:

Rationalize and update programs to preclude unintended consequences (such as reducing competition) and to limit fast-track and breakthrough status to increase the likelihood that these treatments will offer major advances.

Strengthen postmarket safety oversight for drugs with the potential for both major benefits and serious risks, and take advantage of Risk Evaluation and Management Strategies programs.

Recalibrate those programs that provide drug makers with special marketing protections to reduce costs and improve access to biosimilars.

Promote the generation of definitive evidence via use of clinically relevant end points with patent and pricing incentives.

1. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. 

. 2020;323(2):164-176. doi:10.1001/jama.2019.20288.

2. Sharfstein JM. Reform at the FDA—In need of reform. 

. 2020;323(2):123-124. doi:10.1001/jama.2019.20288.

Faster Drug Approvals, Weaker Data? Study Raises Concerns About FDA Process

The Institute for Clinical and Economic Review (ICER), an independent research institute that assesses drugs, tests, and other healthcare technologies, recently released its final report and policy recommendations on the clinical effectiveness and economic value of Janus kinase (JAK) inhibitors for treating rheumatoid arthritis (RA).

ICER reviewed clinical data comparing JAK inhibitors tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq) to conventional disease-modifying antirheumatic drugs (DMARDs) or to the TNF inhibitor adalimumab (Humira).

The final report includes voting results from a December 2019 meeting of one of ICER’s independent evidence appraisal panels, the California Technology Assessment Forum (CTAF), plus policy recommendations from an expert roundtable.

With regard to clinical effectiveness and safety, CTAF votes supported the conclusions of the draft evidence report originally issued in October 2019:

CTAF members voted there was sufficient evidence DMARD plus upadacitinib, tofacitinib, or baricitinib was superior to DMARD alone in patients who have had an inadequate response to DMARD.

There was sufficient evidence upadacitinib plus DMARD provided net health benefit compared to adalimumab plus DMARD.

There was insufficient evidence tofacitinib plus DMARD provided net health benefit compared to adalimumab plus DMARD.

There was insufficient evidence available to compare net health benefit of upadacitinib and tofacitinib.

Short-term (6-month) adverse events rates were comparable among all treatments; the most common adverse events were infections, such as upper respiratory infections, bronchitis, and nasopharyngitis. The 3 JAK inhibitors had similar safety profiles in trials lasting 1 year or longer.

, ICER’s review of long-term economic value concluded upadacitinib provided “marginal clinical benefit” compared to adalimumab at higher costs, however, meeting commonly cited cost-effectiveness thresholds.

The value-based price benchmark for upadacitinib (vs. adalimumab) to treat the entire eligible population across all prices did not exceed the threshold of $819 million. Discounts of 25% to 26% from the list price of upadacitinib would be required to reach the $100,000 to $150,000 per QALY threshold prices. The estimated cost of upadacitinib vs. adalimumab was $600 per month while in remission; the incremental cost-effectiveness ratio was $92,000 per quality-adjusted life-year (QALY).

Despite meeting cost-effectiveness thresholds, CTAF member votes were split between “low” and “intermediate” long-term economic value for upadacitinib, citing a potential lack of generalizability to the real-world patient population, as the exclusion criteria for the only phase 3 clinical trial on this JAK inhibitor would have excluded “a significant portion” of patients with RA. Insufficient data were available to compare tofacitinib or baricitinib to adalimumab in terms of cost-effectiveness.

ICER cautioned that its economic value model may be complicated by the price of adalimumab, which previous assessments by the organization suggested may be above commonly cited cost-effectiveness thresholds.