Abstract
Background:
In this analysis we aimed to describe Brazilian inflammatory bowel disease (IBD) patients’ knowledge and perceptions regarding biosimilars and compare with viewpoints from non-Brazilian patients.
Methods:
An online survey consisting of 19 questions was made available by the European Federation of Crohn’s and Ulcerative Colitis Associations between July 2018 and December 2018. Only respondents who had heard of biosimilars were asked to respond to all of the questions.
Results:
A total of 102 Brazilian IBD patients responded to the survey. The majority (78.4%) of patients had been exposed to anti-tumor-necrosis-factor drugs and 63.4% of them had heard of biosimilars. Brazilian respondents worried significantly more about biosimilars being less effective than the originator (62.5% versus 47.9%, p value 0.03) and molecular differences between biosimilars and originators (53.1% versus 31.8, p value 0.001) as compared with non-Brazilian IBD patients. The majority of Brazilian (75%) and non-Brazilian (64.1%) respondents thought that the lower cost of biosimilars should not come before their safety and efficacy (p value 0.09). In addition, 79.1% of Brazilian respondents believed that the arrival of biosimilars will have an impact on the management of IBD.
Conclusions:
Brazilian patients reported higher rates of misconceptions regarding biosimilars than non-Brazilian IBD patients. Although patients still worry about different aspects regarding biosimilars, they also tend to be confident that biosimilars will have an impact on the management of their disease. With the recent approval of many biosimilars in Brazil and the imminent widespread use of these drugs, our data raise awareness for the need of providing patient education to prevent negative expectations toward switching to biosimilars.
Introduction
Biological therapy has become the mainstay of treatment of inflammatory bowel disease (IBD) over the past 20 years. 1 The wide adoption of biologics in IBD care has led to an exponential increase in treatment-related costs. In this context, biosimilars, less expensive drugs, have been developed aiming greater access to biologic therapies.2,3
The European Medicines Agency (EMA) defines biosimilar as biological medicine highly similar to another already approved biological medicine (the ‘reference medicine’), with no clinically meaningful differences among them. 4 The regulatory process required for the market authorization of biosimilars relies mainly on the comparability exercise versus the reference product, but also includes the analysis of pharmacokinetic, pharmacodynamic, and efficacy studies. These drugs in general cost less than the original drugs, but they can only be marketed after data patent protection has expired. 5
Biosimilar uptake has greatly increased in Europe over the last few years, and many observational data have reassured safety and efficacy of these drugs in IBD. 5 However, experience with biosimilars in Brazil is still limited given the recent introduction of these drugs in the country. CT-P13, the first biosimilar approved for Crohn’s disease (CD) and ulcerative colitis (UC) was recently launched (2013 in Europe and 2015 in Brazil). In Brazil, biosimilars approved for IBD are CT-P13 (REMSIMA®), from the infliximab reference (REMICADE®, Janssen), and the adalimumab biosimilar (AMGEVITA® and HIRIMOZ®), from the adalimumab reference (HUMIRA®, Abbvie).6,7
Patients may have different perceptions toward these recently introduced drugs, which can create barriers to their uptake. 8 Moreover, improved patient understanding on the rationale for initiating or switching to biosimilars may encourage greater acceptance of biosimilars. 9 Therefore, the purpose of this study was to analyze the perception and knowledge from Brazilian IBD patients regarding biosimilars, through the sub-analysis of a European Federation of Crohn’s and Ulcerative Colitis Associations (EFCCA) web-based survey and highlight the main differences between the perceptions of biosimilars among Brazilian and non-Brazilian IBD patients.
Materials and methods
The questionnaire
The questionnaire was developed by the EFCCA in collaboration with IBD experts in the field, and it consisted of 19 questions. It was carried out as an online survey, available from July to December 2018 on the EFCCA website, and offered in another seven languages apart from English, including Portuguese. The national member associations of EFCCA were responsible for informing their membership about the survey. After basic demographic questions, only those respondents who had heard of biosimilars continued to the biosimilar-specific questions.
The participants
The participants of the survey were members of EFCCA associations or people following the communications of these associations.
Ethical consideration
The recruitment was self-selective, dispensing the requirement for consent form. In addition, data were de-identified and individual participant data were not published, which maintained confidentiality in all steps of study analysis. This study was conducted in compliance with regulations stated in the 1975 Declaration of Helsinki.
Statistical considerations
The response variables were categorical. Explanatory variables were integer age and binary disease. A binary logit model was used for the response variables that had only two possible values and a generalized logit model for the variables that had more than two possible values. In some questions, some observations were deleted as a result of missing values for the response or explanatory values. Students’ t test and chi-square were used to analyze the data, accordingly. A two-tailed p value of 0.05 was used for statistical significance.
Results
Respondent demographics
A total of 106 Brazilian patients responded to the survey. Out of them, 81.1% (n = 86) had CD, 15.1% (n = 16) had UC, 1.9% (n = 2) had gluten sensitivity, and 1.9% (n = 2) a rheumatic disease. Only respondents with IBD (n = 102) were included in the analysis. The respondents (37.5%) were 31–45-years old, and 1.9% had been diagnosed in 1990 or before, 6.7% between 1991 and 2000, 29.8% between 2001 and 2010, and 60.6% in 2010 or later (Table 1).
Demographic characteristics of Brazilian and non-Brazilian respondents.
IBD, inflammatory bowel disease.
Exposure to biologics and biosimilars
Regarding current and previous exposure to anti-tumor-necrosis-factor (anti-TNF) therapy, 67.6% of Brazilian IBD patients were currently being treated with anti-TNF; 4.9% had been treated with anti-TNF in the past, but the therapy had been discontinued due to inefficacy, and 5.9% had received anti-TNF in the past, but the therapy was discontinued due to side effects. Only those patients who had heard of biosimilars (63.4%) continued to the biosimilar-specific questions (Table 2).
Results of questions 1–15 and comparison with non-Brazilian IBD patients.
IBD, inflammatory bowel disease; TNF, tumor necrosis factor.
Concerns about biosimilars
In reference to general aspects of biosimilars, Brazilian respondents were more likely to express concerns regarding the efficacy of biosimilars (62.5% versus 47.9%, p value 0.03) and molecular differences between biosimilars and originators (53.1% versus 31.8, p value 0.001) as compared with non-Brazilian IBD patients. Only 12.5% of Brazilian respondents had no specific concerns about biosimilars (Table 2).
Lower price of biosimilars
Most Brazilian IBD patients (53.1%) believed that cost sparing provided by biosimilars will expand access to biologic agents to more patients, which is in line with the conceptions of non-Brazilian IBD patients (48.1%, p value 0.5). In addition, 75.0% of Brazilian and 64.1% of non-Brazilian patients think cost savings should not come before the efficacy and safety of the treatment (p value 0.09). The vast majority (92.2%) of patients believed that this savings will not impact economic status and 6.2% believe that it will not make any difference to the economy (Table 2).
Extrapolating data
The respondents were told that the biosimilar of Remicade® was approved for the treatment of IBD by extrapolating data from rheumatoid arthritis and were asked how they felt about this. The majority of Brazilian IBD patients (57.8%) would prefer if it could be tested for inflammatory bowel diseases before extrapolating the data from rheumatologic disorders, while 51.6% would wait for more data in IBD before accepting a biosimilar for either CD or UC, as compared with 31.2% (p value 0.05) of non-Brazilian IBD patients. Just 6.2% of the Brazilian respondents would trust the decisions made by regulatory agencies and would not wait for IBD-specific data. Moreover, 34.4% of the Brazilian respondents would trust their treating physician, who would make the decision to use biosimilars in their treatment and just 7.8% would trust their pharmacist to make the decision to use biosimilars in their treatment (Table 2).
Biosimilars coming onto the market
The vast majority of Brazilian IBD patients (78.1%) reported that patients should systematically be given information about biosimilars and 65.6% thought that patient associations should be informed, and able to give their opinion regarding biosimilar issues. Furthermore, 45.3% of the Brazilian respondents thought that many more patients should receive biosimilars in a real-life setting before recommending its use in a large population of IBD patients, and 48.4% thought that the country in which the biosimilar drug had been tested or created should be known before the biosimilar was used in their own country (Table 2).
Interchangeability with reference drug
Respondents were surveyed on their views on interchangeability (Table 2). Among Brazilian respondents, 27.0% would accept the exchange if their treating physician approved it, 38.1% if evidence-based data were available, and 34.9% of the respondents would be opposed to the idea if they were not aware of the exchange. None of them would agree with the drug exchange by the pharmacist. There was no significant statistical difference between Brazilian and non-Brazilian IBD patients on this topic.
Same pharmacological name
When told that the biosimilars would have the same pharmacological name as the reference drug, so that when prescribed, there would be no way to distinguish it from the reference drug, 33.3% of the Brazilian and 48.5% of non-Brazilian respondents said they would want to know whether they were receiving the biosimilar or the reference drug, while 42.9% of the Brazilian and 24.8% of non-Brazilian patients would want to have all the necessary information before the drug was administered, and obtain written information (Table 2).
Biosimilars’ impact on the management of IBD
Among Brazilian respondents, 24.2% believed that biosimilars would completely impact the management of IBD, 45.2% believed that the impact would be just probable, 9.7% believed that biosimilars might impact the management of IBD a little and 4.8% of the respondents believed that biosimilars would not impact the management of IBD at all. There was no significant statistical difference between Brazilian and non-Brazilian IBD patients (Table 2).
Biosimilar prescribed and explained by the treating physician
If biosimilars were prescribed and explained by their treating physician, 30.6% of the Brazilian respondents would be fully confident; 37.1% of them would be worried, but would accept the treatment; 11.3% would probably not accept the biosimilar and 11.3% would ask another physician. There was no significant statistical difference between Brazilian and non-Brazilian IBD patients (Table 2).
Pharmacist handing out the biosimilar
If the pharmacist handed out the biosimilar and changed the initial prescription without the consent of the prescribing physician, 82.3% of the Brazilian and 64.6% of the non-Brazilian respondents (p value 0.03) would try to obtain the reference drug (Table 2).
After starting biosimilar treatment
After starting a treatment with biosimilars, 50.0% of the Brazilian respondents would carefully follow the treatment, 22.6% would be worried and probably would stop treatment at the first doubt or adverse event, and 27.4% would be worried, but the fact that treatment was approved by the EMA would reassure them. There was no significant statistical difference between Brazilian and non-Brazilian IBD patients (Table 2).
Biosimilars and generic drugs
After receiving a definition of what generic drugs are, 17.7% of Brazilian IBD patients believed that biosimilars are like generic drugs, 12.9% of the respondents believed that biosimilars are close to generic drugs, 50.0% of the respondents believed that biosimilars are not at all like generics, and 19.4% did not know. Finally, 37.1% of the respondents reported that they take generic drugs without worries; 41.9% of the respondents accept generic drugs, but have some doubts, and 11.3% of the respondents reported that they refuse generic treatments whenever they can (Table 2).
Quality of information and communication on biosimilars
A question was added in the current survey about how the respondents would grade, on a scale from 0 (very poor) to 10 (excellent), the quality of information/communication that they received so far on biosimilars. Results are shown in Figure 1. In another new question, the respondents receiving biosimilars were asked whether they have been systematically informed by their doctors. Some of the respondents (18.2%) said they had, and 33.3% said they had not; for 42.4%, the question was not applicable (Figure 1).
Quality of information and communication on biosimilars (%).
Biosimilar efficacy and side effects in patients who have been switched
In two more questions, respondents were asked about their experiences on efficacy and side effects if they had been switched from Remicade to a biosimilar. Only 6.1% of the respondents reported to be experiencing the same efficacy, and 12.1% reported not. For 75.6% of the respondents, the question was not applicable. In addition, 4.5% of the respondents reported experiencing more side effects than before. For 78.8% of the respondents, the question was not applicable.
Discussion
Our study assessed Brazilian IBD patients’ perceptions regarding biosimilars through a sub-analysis of a previous survey 10 performed by EFCCA. Our findings highlight that concerns about use of biosimilars still remain among Brazilian IBD patients, which may reflect the lack of reassuring information about these drugs in the current scenario.
As in the non-Brazilian population, the majority (78.4%) of Brazilian patients had been exposed to anti-TNF drugs, and 67.6% of Brazilian respondents were being treated with that class of biologic at the time of the survey, while just 49.8% of non-Brazilian patients were currently using it. That significant statistical difference could be explained by the fact that anti-TNF drugs are the only biologic class available for IBD treatment in the Brazilian public health system.
Given that biosimilars for IBD were just recently introduced in Brazil (2015), 7 it was unexpected that 63.4% of Brazilians had been told about biosimilars as compared with 44.0% of the overall IBD population. 10 This information could reflect different educational strategies regarding biosimilars in each country. In addition, Brazilian patients reported higher rates of misconceptions regarding biosimilars, demonstrating that they probably have superficial knowledge on the topic. For instance, many concerns regarding biosimilars were shown, especially about their efficacy (62.5%), but also about non-similar molecular structure, safety and tolerability. Accordingly, only 14.3% of Brazilian IBD patients had been exposed to infliximab (IFX) biosimilar. We speculate that the low uptake of biosimilars in the Brazilian population may have contributed to their uncertainties.
These findings raise awareness regarding the possible nocebo effect, defined as a negative effect of a medical treatment that is related to patients’ expectations and unrelated to the drugs’ physiological action, that may be induced as a result of a negative attitude toward an intervention. 11 Experiences shared by patients as well as media information may influence perceptions of biosimilars, contributing to nocebo effects. 12 Our data reinforce the need for proper patient education concerning the biosimilars in order to decrease hesitation, clarify doubts and to provide greater adherence to biosimilars. Interestingly, although the worries remain, respondents were significantly more likely to believe that biosimilars would have an impact on the management of IBD (69.2%).
Although the results reinforce that patients have a basic knowledge on biosimilars, they do want to be involved when the physician chooses their treatment. They emphasized the desire to be informed when starting a biosimilar; however, some patients still disclosed they would probably not accept the biosimilar (13.3%) or they would ask for another expert opinion (13.3%). Informing patients during the medical appointment or via patient’s organizations could be a way to provide a better understanding and to build confidence on biosimilars. It is also important to inform patients on immunogenicity and other safety issues.
In a hypothetical situation in which treatment with biosimilars was started, just half of the patients committed to follow the treatment, and 22.6% of the Brazilians said that they would stop the treatment at the first doubt or adverse event. These results emphasize data from a recently published meta-analysis that included 3594 IBD patients who switched from originator to biosimilars in real-world cohorts that had discontinuation rates of 8%, 14%, and 21% at 6, 12, and 24 months, respectively. The most common causes of discontinuation were loss of response (5%) and adverse events (7%). 13
This survey had several limitations. It was self-selective, only available online in a European website in eight languages (including Portuguese), which may have contributed to the low access of Brazilians to the questionnaire. Moreover, the results of this study might not be representative for the population who lives in Brazil, due to the small sample and the lack of information regarding the region where the patients live.
In conclusion, despite rigorous approval processes by regulatory entities, Brazilian IBD patients’ knowledge regarding biosimilars is more limited than that observed for non-Brazilian IBD patients, and some concerns about their use persist. Increasing knowledge of patients and professionals on safety and efficacy of biosimilars could minimize negative expectations about these drugs as treatment options.8,14 Moreover, we believe that the widespread use and experience with biosimilars from now on in Brazil will pave the way for increased confidence with these drugs. Our study reinforces European Crohn’s and Colitis Organization recommendations 15 that a switch should be based on collaborative decision making, benefiting individual patients, rather than systematic non-medical decisions that can compromise safety and treatment adherence.
Footnotes
Acknowledgements
The authors would like to acknowledge EFCCA for invitation to participate in the analysis of the Brazilian patients in the survey.
Conflict of interest statement
KSG reports no potential conflict of interest relevant to this manuscript. BPF reports no potential conflict of interest relevant to this manuscript. MBM has received fees for serving as a speaker and/or an advisory board member for Janssen, Abbvie, UCB, and Takeda. FVT has received fees for serving as a speaker and/or an advisory board member for Abbvie, Janssen, and Takeda. LA has received financial support from Biogen for lectures; grants have been awarded to the EFCCA (for projects, advocacy activities, surveys) from Atlantic, AbbVie, Biogen, Celgene, Celltrion, Merck-MSD, Ferring, Janssen, Mundipharma, Otsuka, Pfzer, Shire, Takeda, Vifor, and Philips Morris International Foundation. SL has received consulting fees from Pfizer. RSH has served as a speaker of Janssen, Takeda, and Abbvie, and an advisory board member of Janssen and Pfizer. LPB has served as a speaker, consultant, and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC Pharma – Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, and Theravance. NSFQ has served as a speaker and advisory board member of Janssen, Takeda, and Abbvie.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical statements
The participants of the survey were members of EFCCA member associations or persons following the communications of these associations. Informed consent was waived since the survey recruitment was self-selective. In addition, data were de-identified and individual participant data were not published, which maintained confidentiality in all steps of study analysis. This study was conducted in compliance with regulations stated in the 1975 Declaration of Helsinki.
