La Princesa is a 564-bed public centre that serves, as per 2013 web report, an area of 310,464 inhabitants in a middle-upper class district of Madrid, Spain. It covers all specialties, except for paediatrics and obstetrics, in a teaching setting with a considerable trajectory of clinical and basic research.

Because one of the main goals of this article is to describe the unit, we include its description under the results section.

Prior to the development of the register, the unit members decided upon the conduct of a state analysis that would provide not only data on the use of biological agents at the centre, but also feed-back on the feasibility of merging databases from different departments. The state analysis was approached as an observational retrospective descriptive study. All patients treated at the centre with any biological treatment from January 2000 to December 2012, regardless diagnosis, were identified in the Clinical Pharmacy databases. Only patients followed at the participant departments were included—namely rheumatology, gastroenterology, dermatology, and neurology—as in other departments the biological treatments were anecdotal or related to complications in patients attended at the former ones. Although off-label—not listed as an indication in the summary of product characteristics—uses are included in the analyses, for the purpose of comparison across diseases, we studied the following indications: rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis, multiple sclerosis (MS), Crohn's disease (CD), ulcerative colitis (UC), and ankylosing spondylitis (AS). One must bear into account that an off-label use in any given year may become an accepted indication later on.

For the purpose of this study, we considered as BT the following: etanercept (ETN), infliximab (IFX), adalimumab (ADA), golimumab (GOL), certolizumab (CZL), abatacept (ABA), glatiramer acetate (GLA), anakinra (ANK), efalizumab (EFZ), fingolimod (FGL), interferon beta, 1a and 1b (IFN), natalizumab (NTZ), rituximab (RTX), tocilizumab (TCZ) and ustekinumab (UST).

The variables used for description were: (a) use patterns—indication or condition for which it was stated to be used, off-label or un-specified uses; (b) drug survival, based on dates of start and end of treatments, and whether treatment was maintained at the time of the last visit; (c) reasons for drug discontinuation, such as adverse events, ineffectiveness (discontinuation occurred within 6 months from start), loss of effectiveness (discontinuation occurred after 6 months from start), remission, or other; (d) patient variables, such as age at start of treatment, disease duration from symptoms onset; (e) and study periods, determined by the dispensation date at the beginning of biological treatment (2000–2005, 2006–2010, 2010–2012)—this year division was based on drug availability; of note, efalizumab was withdrawn from the market in 2009 due to the risk of progressive multifocal leukoencephalopathy. Three databases from the Pharmacy department related to drug dispensation, specialty, and cost—inpatient, ambulatory, and biological-specific—were merged with the centre's administrative database.

For the statistical analysis, we first carried out a description of the sample (patients and treatments), and by different time periods. Drugs survival was estimated by Kaplan–Meier curves. The retention time of biologic therapy was estimated for all compounds, despite one patient might have received different drugs or different treatments. Analyses were performed by specialty, biological agent, and study period using the appropriate statistical hypothesis contrast test depending on the variables analyzed (chi-square, log-rank, or analysis of variance). In addition, we carried out a multivariate analysis with Cox regression models to compare the influence of agent, disease, and first-line treatment versus successive treatments, in the discontinuation of treatment, either by any cause, by ineffectiveness or loss of effectiveness, or by adverse event. FGL and off-label uses were excluded in this analysis due to the small sample size. The analysis was performed with Stata v.12 (College Station, Texas).

The BTU was established in 2012 through a joint effort of professionals with extensive experience and interest in the use of BT from the departments of rheumatology, dermatology, gastroenterology, neurology, pharmacy, and hospital information and technology. The BTU aspires to contribute to the better use of BT, targeting the balance between sustainability and a favourable risk/benefit ratio for patients. Three major objectives were established: (1) Contribute to increasing the quality of use of biologics; (2) Contribute to sustainability of the use of BT; (3) Generate information for audits and publications. (1) The first objective includes issues like developing and updating protocols for the use of BT in different conditions, defining the therapeutic goal for our patients on BT, and defining quality indicators. These include: Percentage of patients with an indication for BT, patients with objective measures of disease activity recorded in clinical chart, patients meeting the therapeutic goal, and patients with BT withdrawn due to lack of efficacy. (2) The second objective includes initiatives to favour cost-effectivity. It includes measures like: favouring the use of drugs with lower cost, unless the existence of medical reasons for not doing so, regularly updating the information on the cost of BT to prescriptors, grouping patients under the same drug that is dosed by weight on the same day, in order to limit drug waste, or favouring the judicious use of biosimilars and innovative ways of optimization, like risk-sharing agreements. Indicators in this area include cost per patient, patients with dose of BT increased (intensifications), patients with dose of BT decreased (optimizations) or percent use of biosimilars. (3) The third objective includes two major goals: (a) an observational retrospective analysis of the use of BT in our hospital whose major results are included in this article and (b) the development of a prospective register enabling the conduct of clinical studies and practice audits.

The BTU is formed by one coordinator, one or two members of the different services involved and one full time data analyst. They hold periodic meetings to define objectives, share the results of analyses, discuss studies in their respective fields that can be of interest to others, as well as difficulties or challenges. It is important to clarify that the BTU does not decide at the individual level which biologic will be used for each patient. This decision still corresponds to the practicing specialist and each of the departments establishes its own way of deciding. In the case of rheumatology, two weekly sessions are organized for making these decisions.

The databases contained information on 1465 patients and 2238 treatments through the study period. Table 1 shows a description of the patients included, by specialty. The mean age of the patients as of first biological treatment was 48±16 (SD), and 61% were women. The patients treated with biologics in the four specialties were different in age, percentage of sex, and, of course in diseases, with RA (35.9%) as most frequent disease, followed by MS (16.5%), and psoriasis (14.6%).

By specialty, the number of treatments analyzed was: dermatology n=378 (16.9%), gastroenterology n=216 (9.7%), neurology n=317 (14.2%), and rheumatology n=1324 (59.2%). In relation to the number of biological treatments per patient, 65% of the treatments analyzed correspond to a first-line treatment, and 22% to a second-line biological; a patient received a maximum of 8 different biologic treatment lines. Table 2 shows the distribution of biological drugs for all lines of treatment by specialty and time-period. The biological agents most frequently used were ETN, ADA, IFX, IFN β-1a, and RTX, and varied within specialty across time-periods.

The agents were used off-label in 271 cases (12.1%). Rheumatology was the specialty with more off-label uses (16.6%) and neurology showed the lowest rate (2.2%). The compounds with the highest percentage of off-label use were ANK (55%), GOL and RTX (both 31%), UST (21%), and IFX (19%), while the proportion did not reach 10% in ETN, ADA, EFZ, or GLA, and it was null for IFN, FGL, and NTZ. Finally, the period with the highest off-label use was 2011–2012 (16%) compared to 2000–2005 (12%).

The 2238 treatments corresponded to 5309 treatment-years, with a maximum follow-up of 13 years; 1086 treatments were discontinued. The retention rate of all biological treatments was 41% at 5 years, 23% at 10 years and 19% at 12 years.

Prior to any adjustment, the highest median survival was observed in dermatology (3.7 years) and the lowest in rheumatology (3.2 years) (see Fig. 1A). At 10 years of treatment, the retention rate was 29% in gastroenterology, 22% in neurology, 17% in rheumatology, and 0% in dermatology, but there were no significant differences between specialties in overall survival (p=0.370).

Fig. 1.

Survival function of biological therapies by specialty (A), disease (B), and period of treatment (C).

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The median survival differed depending on the underlying disease (p<0.001), the highest being for PsA (7.0 years) and AS (5.3 years), and the lowest for RA (3.0 years) and UC (0.9 years); the median drug survival for psoriasis, MS, and Crohn's disease were 3.2, 3.6, and 4.5 years, respectively (Fig. 1B). After 2 years of treatment start, survival was, in order of frequency, 71% for PsA, 69 for AS, 66% for psoriasis, 62% for CD, 61% for MS, 57% for RA, and 39% for UC.

The analysis of the retention time of the biological compound according to the number of treatment cycles was carried out for the first cycle versus the second and subsequent cycles. The median survival rate goes from 3.85 years for the first cycle to 2.75 years for the second and subsequent cycles (p<0.001). Finally, survival seemed to differ in relation to the time period, but not statistically (p=0.071). Retention rate reached 50% at 4.23 years in 2000–2005 and 3.16 years in 2006–2010—the last period did not reach the median. The retention rate at 1 year was 78%, 67%, and 75% for the period 2000–2005, 2006–2010, and 2011–2012, respectively (Fig. 1C).

The most common reason for discontinuation was ineffectiveness (26%), followed by loss of effectiveness (19%), and adverse reactions (18%). The reasons for discontinuation were significantly different by specialty (Table 3). In dermatology, the most common reason was loss of effectiveness (20.5%), while in gastroenterology and rheumatology this was ineffectiveness (29.6% and 29.1%, respectively), and in neurology, adverse reactions and ineffectiveness showed similar percentages (22% and 22.6%). In relation to drugs, adverse reactions were the most common cause of discontinuation for RTX (24.6%) and IFX (24%), ineffectiveness for ADA (31.8%) and IFN β-1a (25.6%), and loss of effectiveness for IFX (28.6%). Finally, loss of effectiveness was the most common reason for discontinuation in 2000–2005 (27%), while ineffectiveness was the most frequent reason in the other two periods (Table 3).

A table in supplementary material shows the results for the three models for discontinuation. The probability of discontinuation by any cause increased significantly with ANK (HR=1.85), UC (HR=2.15) and second-line treatment (HR=1.34), and decreased with UST (HR=0.40) and in PsA (HR=0.64) and AS (HR=0.77). As for the discontinuation for ineffectiveness or loss of effectiveness, the probability was lower in PsA (HR=0.53), AS (HR=0.56), and psoriasis (HR=0.61), and with RTX (HR=0.49), while the risk increased significantly with second-line treatment (HR=1.72). Finally, the probability of discontinuation due to adverse reaction was associated with the use of ANK (HR=2.96) and it was significantly lower in PsA than in RA. The treatment line does not seem to have an effect on the discontinuation rate due to adverse reactions.