We conducted between June and November 2020, a nationwide, noninterventional, anonymised, self-administered, one-time web-based survey among dermatologists, rheumatologists, gastroenterologists and hospital pharmacists. These three medical specialties were selected because they treat patients with chronic inmmunomediated diseases and use similar biologic medicines (currently four biosimilars in Spain). We decided not to include other specialties because their context could be different. We also included hospital pharmacists because they play a relevant role in the use of biosimilars as patient education or taking part in the biological medicines (including biosimilars) committees (BMC).

A multidisciplinary steering committee composed by one dermatologist, one rheumatologist, one gastroenterologist and one hospital pharmacist was stablished. The selection criteria were: 1) Specialized in the use of biosimilars with demonstrated experience; 2) clinical experience ≥ 8 years and/or ≥ 5 publications; 3) members of relevant health professionals associations.

Then, a comprehensive literature review in PubMed was performed to analyse articles that reported the variability in the use of biosimilars (rates, type of biosimilars, etc.), knowledge, perceptions, attitudes, barriers and facilitators on the use of biosimilars, irrespectively of the drug. We used PubMed's Clinical Queries, and individual searches with Mesh (like Biosimilar Pharmaceuticals) and free text terms (as biosimilar or variability) up to March 2020. The results and other information including the methodology of the studies (most of them surveys) was discussed in a nominal group meeting of the steering committee. In this meeting, an expert methodologist guided the discussion and assisted decisions. The committee agreed to collect data of Spanish health professionals due to the lack of studies. Then, they selected the main points to be explored and decided to design a national survey. For each main point an objective was established and a set of questions proposed. To select the questions, the committee discussed the wording and questions reported in other articles or proposed different ones. The methodologist commented the implications of formulating questions in different ways. Some of the final questions are the same questions of other surveys (adapted to the Spanish context if necessary), others are original (the survey is available by request to the corresponding author).

This resulted in two structured and closed surveys that were generated using the Survey-Monkey online platform and administered by an independent third party. One for the physicians and another for hospital pharmacists. Both shared 55 questions. Physicians answered 6 more specific questions whereas hospital pharmacist another 2. For example, physicians were asked about patients’ reaction when a switch was proposed and hospital pharmacists about physicians’ reaction when a switch was proposed.

Afterwards, an invitation to participate in this survey was emailed to the survey sample. Reminder emails were sent at 4-6 weeks after the initial mailing. The survey front page included information about the survey, the objectives of the project, and asked for their voluntary participation. By reading and responding, the health professionals gave their consent. All the respondents were able to review and change their responses by scrolling up and down the page before definitive submission. The surveys were first piloted on a small number of health professionals.

We selected a purposive convenience sampling of 73 health professionals (41 physicians including dermatologists, rheumatologists, gastroenterologists and 32 hospital pharmacists). We looked for health professionals from all Spanish regions that worked in National Health Hospitals with different characteristics (e.g., general hospitals, county hospitals). We did not apply any criteria regarding to previous knowledge, experience with the use of biosimilars, participation in BMC or other criteria related to the use of biosimilars. To select them, we analysed the type of hospitals in each Spanish region and the steering committee proposed a list of colleagues (using their personal contacts or asking other colleagues).

The survey was organized in six main sections that included different questions: 1) Sociodemographic and practice related questions, like the presence of a multidisciplinar BMC (a committee in which ≥ 2 different health professionals are involved, e.g. hospital pharmacists, dermatologists, rheumatologists, and gastroenterologists). An active involvement in the BMC was defined as an active participation in relevant decisions regarding to biologics such as suggesting which ones can be approved in the hospital; 2) biosimilars knowledge and importance (development, biosimilarity, sensitive indication, approval requirements and processes, efficacy, safety, switching, extrapolation, interchangeability, etc.); 3) access, attitude and perceptions [number and type of biosimilars available in each hospital (all commercial brands of biosimilars available in Spain were included), local policies and coordination, clinical protocols, educational issues, prescription, pharmacy-level substitution, adherence, impact, satisfaction, incentives, etc.]; 4) barriers to biosimilars uptake; 5) facilitators to biosimilars uptake; 6) future with the use of biosimilars and other questions. The survey contained a mixture of checkbox answers and questions asking responders to rank their level of agreement, knowledge, comfort or importance of each statement from 1 to 5 or 10. At the end of most of questions (n = 31) a space for comments was provided.

We performed a descriptive analysis. We used the distribution of frequencies, the mean and standard deviation, or the median and interquartile range, depending on the distribution. The survey responses to individual questions were summarized as number and percentage of responding health professionals. Comparisons were performed using the Student's t-test or the Chi-square test. The comments are described in the results section in in double quotes in italics.

The surveys response and sample main characteristics are depicted in table 1.

The responder's level of knowledge/understanding of biosimilars is exposed in table 2. We found a medium level of knowledge (scale of 1-5) in key aspects of biosimilars development (means around 3). The reported level of importance (scale of 1-10) of these key aspects and of real-life data was in general high (means around 8). Safety was considered the most important aspect of biosimilars development. Just few differences were observed between hospital pharmacists and physicians.

A total of 23% of hospital pharmacists and 28% of physicians knew what a sensitive indication is. We found that 20-30% of participants did not know the definition of extrapolation, and more than 50% of responders (61% of hospital pharmacists and 54% of physicians), did not have clear understanding of interchangeability, switch or substitution.

There was a great variability in the number, types and brands of biosimilars depending on the hospital. Many participants agreed that there should be more than one brand for two main reasons. First, in order not to run out of stock, and, second, to stimulate competition in the biologicals medicine market. We observed several organization preferences, policies, and practices regarding biosimilars. But most of participants consider economic/efficiency reasons as the main drivers for incorporating biosimilars to the organization. We highlight that 28% of physicians were unaware of procedures and criteria behind the incorporation of biosimilars.

Most participants (85%) were content to initiate biosimilars in biologic treatment-naïve patients. Although 55% of participants have experience with extrapolation, hospital pharmacists were significantly more comfortable than physicians with extrapolation, 74% vs 38% (p = 0.039). In this regard, many stated that “Biosimilars might present different results depending on the disease. Therefore, data on each indication should be provided”. Around 10% of responders considered appropriate to switch from the reference biological medicine to a biosimilar. Most of participants were reluctant to switch between biosimilars. Some participants commented: “There is little evidence about switching”, “I have observed efficacy reductions that cannot be explained solely by nocebo effect”, “I would need more time in clinical practice to explain switching to a patient”. Finally, compared with hospital pharmacists, significant more number of physicians appeared to have a negative opinion towards the automatic substitution of the reference biological medicine with a biosimilar at the pharmacy level, 16% vs 67% (p < 0.001). Besides, 22% of participants indicated this practice in their organizations.

Separate questions assessing details of switching revealed that switching does not modify patients clinical monitoring, at least for 72% of participants. When explaining and proposing a biosimilar to patients, 36% of physicians indicated that in general patients are quite reluctant/mistrustful, though they approve it in the end. When hospital pharmacists were asked about the reaction of physicians if a switch was proposed, 32% stated that they understand and approve the switch, 32% that appear to be quite reluctant /mistrustful, even if they approve in the end and 16% that physicians directly do not accept the switch. A large rate of respondents (more than 90%) believe that adherence to biosimilars is similar to that of reference biologic medicines. Several comments suggested a possible negative influence of pharmaceutical industry and patient associations on biosimilars confidence.

A total of 23% of hospital pharmacists and 34% of physicians indicated their organizations have pre-defined criteria on the use of biosimilars. Some organizations follow regional objectives and criteria others have established some (“mandatory”) criteria to start a biosimilar in biologic treatment-naïve patients or to switch all patients on infliximab. We gathered some comments suggesting some kind of pressure to prescribe biosimilars especially in biologic treatment-naïve patients. Others considered that specific or pre-defined criteria on the use of biosimilars are not needed. Almost 60% of participants reported that in their organizations, medical directors or other managers have proposed recommendations to prioritize biosimilars in biologic treatment-naïve patients, and to promote switches.

Finally, 81% of physicians answered that they were quite or very satisfied with the use of biosimilars. Most of responders also considered that the use of biosimilars has a positive impact on costs. Nevertheless, they did not find a clear different impact on efficacy, effectiveness, safety, immunogenicity, adherence, or patient satisfaction.

Tables 3 and 4 depict main barriers and facilitators to biosimilars uptake.

When asked if biosimilars might be the first line of treatment, and even replace traditional medicines, the majority answered positively.

We included a specific question for the hospital pharmacists about the importance of different activities related to biosimilars. They graded them form 1 (not important) to 10 (very important) as follows (means): Patients support programs 7.0 ± 2.7; Home-Delivery service 6.4 ± 2.8; Telepharmacy/telemedicine 7.2 ± 2.5; Hospital management educational support 7.2 ± 2.4.

Finally, we provided the possibility to declare other concerns with the use of biosimilars. Apart from those related to long-term or real-life data, others like the lack of biosimilars traceability or the risk of biologic reference medicines stock shortages due to the line is no longer profitable for the pharmaceutical company emerged.