Register of Epoch-Making Biologics Hits 10 Years

BRIGHTON, ENGLAND – The arrival of biologic agents for the treatment of rheumatic disease has been hailed as a groundbreaking event, with their practical use undoubtedly aided by the setup and success of large-scale biologics registers in Europe.

“I think we've been very privileged in the past 10 years to have lived through an era where, rather similar to the introduction of steroids, a truly epoch-making set of drugs have come to the fore,” said Dr. David Isenberg. “They have really changed the way we practice in a way that was unimaginable 15 years ago.”

Dr. Isenberg, who recently stepped down as the chair of the BSRBR (British Society for Rheumatology Biologics Register) Steering Committee, added that “one very important aspect of the way in which these new drugs have been introduced is the growth of the biologics registers, which have been developed to monitor their use.”

Started in 2001, the BSRBR has now become the largest of the European biologics registers, with data still being collected on more than 20,000 participants with rheumatoid arthritis, of whom around 15,000 are receiving anti–tumor necrosis factor–alpha agents.

A year after the register started, the U.K. National Institute for Health and Clinical Excellence (NICE) published guidelines on the use of biologics and recommended that all patients who start treatment with the new agents should be included in the BSRBR.

“Almost immediately, the number of patients recruited per month increased – almost exponentially,” said Dr. Deborah Symmons, one of the two principal investigators for the BSRBR.

In fact, it was more difficult to recruit the comparison cohort of patients with active RA who were being treated with nonbiologic disease-modifying antirheumatic drugs (DMARDs) and were anti-TNF naive.

Dr. Symmons, professor of rheumatology and musculoskeletal epidemiology at the Arthritis Research UK Epidemiology Unit at the University of Manchester (England), noted, “It's the only study I've ever been involved with where we massively exceeded our sample size in less than the time that was estimated.”

With the recent call for clinicians to start registering patients who are being treated with certolizumab (the latest anti-TNF to gain NICE approval in the United Kingdom), the BSRBR continues to increase its patient numbers. The addition of tocilizumab and abatacept to the register is also planned in the near future.

In addition to the large patient numbers and power of the data that can be generated, the key to the success of the BSRBR is its ability to evolve and change with the times. When the register was started, the primary aim was to see if anti-TNF agents increased the risk of cancer (specifically non-Hodgkin's lymphoma) relative to nonbiologic DMARDs. Additional goals were added over the years, and – to enable long-term comparisons of all drugs in the register – an extended follow-up of all treatment arms was announced just last year.

The BSRBR is one of the few biologics registers to include a control arm of the standard therapy of the time (nonbiologic DMARDs). Because of changing baseline characteristics and anti-TNFs themselves becoming established therapy, however, recruitment into a second, anti-TNF cohort arm has just begun. Patients who start treatment with one of the older anti-TNF agents included in the register (infliximab, etanercept, or adalimumab) are eligible for inclusion into the new cohort. Newer agents entering the register will then be compared with the anti-TNF control cohort.

“Registers are epidemiologic cohort studies dedicated to pharmacovigilance and real-life effectiveness,” commented Dr. Angela Zink, one of the key people behind the 13,000-patient German biologics register RABBIT (Rheumatoid Arthritis Observation of Biologic Therapy), which also includes a control arm.

Dr. Zink, deputy director of the German Rheumatism Research Centre and professor of epidemiology of rheumatic diseases at the Charité Medical University Berlin, observed that biologics registers were “long-term enterprises,” with payback only many years after their initial setup.”

“In the end, registries allow you to answer questions that you couldn't answer with other types of studies,” Dr. Zink noted. Indeed, about one-third of patients in RABBIT would not have been eligible for clinical trials and, without the register, would not have been treated with anti-TNFs, she observed.

Without the buy-in of the large pharmaceutical companies that make biologic agents, however, the registers would be impossible to run. Although the BSRBR is funded through the BSR, which in turn has six separate contracts with the relevant manufacturers of biologics in the United Kingdom, the German register has managed to develop a single, seven-way contract with all manufacturers in Germany.

“At the end of the day it works because everyone benefits,” he said. The companies essentially get 5 years of follow-up data on their products while the researchers are able to publish their findings in the top rheumatology journals. In addition, “the BSR gets the kudos of running the world's largest biologics register.”