BSR Biologics Registry

I. Griffiths, A. Silman, D. Symmons1 and D. G. I. Scott2

BSR Biologics Registry Management Committee, 1 ARC Epidemiology Unit, Manchester University Medical School, Manchester and 2 British Society for Rheumatology, London, UK

Correspondence to: I. Griffiths. E-mail: ian.griffiths{at}nuth.northy.nhs.uk

The recognition of the pivotal role of inflammatory cytokines in the pathogenesis of rheumatoid arthritis, the development of specific antagonists, the demonstration of their clinical effectiveness and the subsequent commercial production and licensing of these agents have been the major achievements in rheumatology over the past decade. However, uncertainties remain regarding the short- and long-term safety of these agents, initially TNF-{alpha} inhibitors. Also, their significant cost, some tenfold greater than that of the previous most expensive agent, did impact on the use of these drugs in a cost-constrained health-care system such as the NHS. The British Society for Rheumatology (BSR) in April 2000 took the bold and imaginative step of producing clinical guidelines that recommended thresholds for both commencing therapy and continuing therapy in those who respond. It also suggested the establishment of a national registry of patients on biologic therapy to evaluate the safety of these agents [1]. The Registry was established at the ARC Epidemiology Unit, University of Manchester, and this, along with the explicit BSR guidelines, was probably influential in the National Institute for Clinical Excellence (NICE) Technology Appraisal Guidance No. 36, ‘Guidance on the Use of Etanercept and Infliximab for the Treatment of Rheumatoid Arthritis’ in March 2002, recommending the use of these drugs in keeping with the BSR guidelines and that ‘all clinicians prescribing etanercept and infliximab should register the patients with the Biologics Register established by the BSR’ [2]. The NICE guidelines on the use of biologic therapy are due for review in March 2005. In this editorial we review the aims, methods and organization of the Register and discuss how the emerging data will be managed.

The organization of the BSR Biologics Register (BSRBR) is centred on the BSR executive, which is advised by the BSRBR management committee, whose principal responsibilities are for the organization and implementation of the register and a data and monitoring board, who oversee the clinical safety and probity of the register; both receive regular updates from the Registry at the Epidemiology Unit at the University of Manchester.

The Registry has two unique functions beyond recording data on patients receiving biologic therapy. From the outset, the scientific question posed was whether biologic therapy was safe in both the short and longer term. Recognizing that documentation of the numbers of adverse events in biologic-treated patients would not be easy to interpret, we also planned to recruit a control population of rheumatoid arthritis patients treated with traditional DMARD therapies. Lymphoma was chosen as the driver for the power calculations, being the most infrequent of the potentially important adverse outcomes. The protocol was designed, therefore, to be able to detect a doubling of lymphoma rates in a 5-yr period in the biologic-treated compared with the DMARD-treated group. When the protocol was developed it was thought that the prescribing of the biologic agents would be rare and, therefore, to have sufficient power it would be necessary to recruit a high proportion (4:1) of comparison subjects. The initial sample size calculation suggested 1850 anti-TNF and 7600 comparison patients. Given that lymphoma is a rare event, the register would then be sufficiently large to detect important increases in other, more common adverse events. Since then, several new factors have emerged; the pattern of adverse events varies between different biologic therapies and so comparisons should be drug-specific, as opposed to class-specific. Also, the use of the drugs was considerably in excess of predicted and, by January 2004, more than 6000 patients had been commenced on anti-TNF therapy with current recruitment to the Register of approximately 450 biologic-treated patients per month. The initial 1850 patients were heavily skewed towards one agent, infliximab, because of the lack of availability of etanercept in the early stages. Further, since the Registry was established, two new agents, anakinra (an IL-1 antagonist) and adalimumab (an anti-TNF monoclonal antibody) have been licensed for the treatment of rheumatoid arthritis and the pragmatic view has been that the Register should recruit patients commencing on these new anti-cytokine therapies. Currently there are substantial numbers prescribed each of the three currently available anti-TNF agents recruited, though a more modest number of patients are treated with anakinra. Consequent to these factors, the initial protocol was reviewed during 2003 with the modification that 4000 patients should be recruited for each individual biologic agent, which would allow the control group to be reduced to 4000 patients. These figures would still allow the detection of a doubling of lymphoma rates over a 5-yr period for each biologic agent investigated.

Another distinctive feature of the Registry is its formal pharmacovigilance role in complying with the Sponsored Safety Assessment of Marketing Medicines (SAMM) requirements, whereby suspected adverse events are promptly reported to the pharmaceutical companies, who in their turn need to inform the Medicines and Healthcare Products Regulatory Authority (previously MCA). This scheme runs in parallel to the ‘yellow card’ reporting scheme, which clinicians should comply with in the standard manner. The sponsoring companies have therefore delegated to the Register this pharmacovigilance task, and to this end a unique collaboration exists at European level between the four manufacturers/European marketers (Abbott Laboratories, Amgen, Schering Plough and Wyeth Laboratories) and three European registries (Sweden, Professor Lars Klareskog; Germany, Professor Angela Zink; and the UK Register). With input from the European Medicines Evaluation Agency (EMEA), we have an agreed protocol for adverse event data capture and reporting. Meetings of this group are held twice yearly, recognizing that some questions, particularly in regard to rare events, might require pooling of experience between registers.

The data set requested from clinicians at the time of patient recruitment includes information on demography, diagnostic criteria, extra-articular features and co-morbidities, as well as data on clinical activity (DAS28), HAQ and SF36 functional measures. We believe these items are important, both to allow appropriate adjustment for comparison with the conventionally treated group and also to permit a within-cohort analysis to compare adverse event rates by disease severity. Follow-up of response using these outcomes will also allow us to evaluate any adverse events against benefits. A fourfold follow-up strategy is in place. All patients are flagged with both the National Cancer Registry, to identify incident cancers with information obtained on site and type, and the National Health Service Central Register, to identify all patient deaths by cause. In addition there is follow-up of patients both via their clinicians and directly to patients 6-monthly for 3 yr from onset of treatment. The direct patient data collection requests details of intercurrent illness and complications occurring during the preceding 6 months. Clinicians are asked for information on disease activity, changes in therapy, and adverse events or intercurrent illnesses occurring during the preceding 6-month period. Central Registry data on cancer and mortality will be collected indefinitely.

It was rapidly apparent that the collection of these data placed considerable strain on clinical units, and in general there has been a need to increase both the nursing and administrative staff to cope with this additional burden. Securing these additional resources is no easy task but varying examples of the ‘case of need’ are available on the BSR website. However, with the evolving changes in the NHS, it is apparent that this type of data is necessary for clinical governance purposes at a local level, independent of a National Registry.

The licensed indications for anti-cytokine therapies are also expanding and, for some agents, now include ankylosing spondylitis and psoriatic arthritis. It is not known if the frequency and nature of adverse events in these other diseases will be the same as in rheumatoid arthritis. Our advice, therefore, is to recommend the registration of all patients but to analyse the non-rheumatoid arthritis group as a separate cohort, though currently 95% of patients on the Register have rheumatoid arthritis as their primary diagnosis.

There will be several challenges in interpreting the data. Increasingly, patients will be switched from one agent to another and allocating a long-term outcome to one agent will be problematic. Whereas those submitting data would like early feedback on what has been achieved, the nature and size of the task necessitates taking a long-term view to permit robust estimates of the actual increased risk, if any, from these agents. The position is somewhat analogous to a clinical trial in which interim analyses should only be undertaken after careful consideration. On the other hand, the Register needs to be mindful not to delay detailed analysis if early indications suggest a high risk of an unforeseen, yet serious problem. The establishment of an independent data monitoring board, whose remit is to advise on such matters on receipt of regular reports together with the pharmacovigilance tasks undertaken on behalf of the companies, should minimize this risk.

The success of the registry is primarily a reflection of British rheumatologists’ commitment to and belief in the underlying logic of the Register. We estimate that 80% of patients commencing therapy are entered onto the registry, and this level of compliance is probably only achievable through a cohesive professional body functioning within a national health service. Emerging information will tell us about the safety in both the short and the long term and about the efficacy of these agents in the real clinical world, and will also show responsible governance of expensive therapies. Emerging data certainly suggest that the drugs are both efficacious and well tolerated, 86% of patients remaining on therapy at 6 months and 80% at 1 yr.

IG has received grants/research support in the form of part support (0.5 WTE) of a departmental research nurse for data collection for 2 yr from Schering Plough. DS has stated that the British Society for Rheumatology Biologics Register is funded by grants from Abbott Laboratories, Amgen, Schering Plough and Wyeth to the BSR. The other authors have declared no conflicts of interest.

References

  1. British Society for Rheumatology. New treatments in arthritis: the use of TNF-{alpha} blockers in adults with rheumatoid arthritis. Report of a Working Party of the British Society for Rheumatology. London: British Society for Rheumatology, 2000.
  2. National Institute for Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis. Health Technology Guidance. No. 36. London, National Institute for Clinical Excellence, 2002.




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