To the Editor: The tumour necrosis factor (TNFα) inhibitors etanercept, infliximab and adalimumab are new treatments for rheumatoid arthritis (RA) subsidised by the Pharmaceutical Benefits Scheme (PBS) under strict criteria. These are based on data supplied by the sponsors and protracted discussions between the stakeholders: the Pharmaceutical Benefits Advisory Committee (PBAC), the sponsors, rheumatologists and consumer representatives.1 One eligibility criterion is that adult patients must be or have been rheumatoid-factor positive. This requirement raises particular concerns.

Rheumatoid factor is not exclusively associated with RA. It is found in a number of other autoimmune and infectious diseases, and has been detected in healthy people. Rheumatoid factor is a serological criterion in the American College of Rheumatology classification for RA. However, its presence is not definitive for a clinical diagnosis of RA, with rheumatoid factor being absent in about 30% of patients with RA. Studies suggest that patients who test positive for rheumatoid factor at baseline are more susceptible to relatively severe expression of RA, with development of erosions and functional disability.2 As the PBS already limits access to TNFα inhibitors to patients with severe active RA, the predictive value of rheumatoid factor for severity is redundant.

We systematically reviewed 23 clinical trials of TNFα inhibitors available in the public domain (references available on request). The review showed that only the Early Rheumatoid Arthritis trial restricted recruitment to patients who tested positive for rheumatoid factor.3 The aim of this study was to examine the effect of etanercept on the rate of development of erosions in patients with early RA, not whether rheumatoid-factor status affected response.

We conclude that the evidence for an association between rheumatoid-factor status and response to TNFα inhibitors in patients with severe RA is inadequate to justify rheumatoid-factor status as a criterion for PBS subsidisation. Similarly, no evidence for an association between rheumatoid factor and response to disease-modifying anti-rheumatic drugs has been reported.4 Nevertheless, potential predictors of response to TNFα inhibitors and such drugs are emerging (eg, polymorphisms of HLA-DRB1, TNFα, and interleukin-10).5 Further analysis of the unpublished individual patient data held by the sponsors is needed to shed light on this question. Clinical studies specifically designed to evaluate the influence of rheumatoid-factor status on response would be helpful.

The PBAC may have been provided with these data, but patients and clinicians operating in the public domain have not. This gives rise to an ethical dilemma whereby prescribers cannot provide a plausible explanation for why rheumatoid-factor status is an access criterion. For example, if rheumatoid-factor-positive status was selected to exclude patients with rheumatoid-factor-negative psoriatic arthritis, then the rationale would not appear to be ethically sound. Greater transparency with respect to the rationale and the evidence for the criteria selected for targeting subsidised access to important high-cost pharmaceuticals will enhance confidence in the PBS process.

Comment: I am grateful for the opportunity to put the perspective of the Pharmaceutical Benefits Advisory Committee (PBAC) on this important issue for patients and prescribers using TNFα inhibitors for rheumatoid arthritis.

I can confirm that the PBAC based its recommendation to exclude patients who test rheumatoid-factor negative on a meta-analysis of the data presented to it in the sponsor’s reports of two published randomised trials.1,2 The sponsor of etanercept requested a restriction that limited use to patients with rheumatoid-factor-positive status — a proposition that was queried by the PBAC in its evaluation. The sponsor indicated in its response that rheumatoid-factor status was a treatment-effect modifier. As anticipated by Lu and colleagues, the reason for the recommendation was neither to confirm the diagnosis of rheumatoid arthritis nor an attempt to identify patients with more severe disease. The main reason is that there was some statistical support for the contention that, in patients with rheumatoid arthritis, being rheumatoid-factor positive is associated with a better response to treatment with these drugs. Unfortunately, my request to the sponsor to be able to release in this letter the information on which the decision was based was refused.

The statistical analysis relied on by the PBAC was based on individual patient data, stratifying trial participants into two groups (rheumatoid-factor positive and rheumatoid-factor negative), and then formally applying a test for interaction against the reported treatment effect compared with placebo. Although a post-hoc analysis, this approach has the advantage of relying on the entire trial dataset rather than increasing the likelihood of detecting spurious differences by conducting a series of post-hoc sub-group analyses. It also differs from the systematic review reported by Lu and colleagues, which sought to examine the question based on the reported eligibility criteria of the trials, and therefore could only be conducted at the level of the overall trial, not the level of the individual patient in the trials. The interpretation of the data available to the PBAC at the time was supported by rheumatologists advising the PBAC about actual restrictions for the subsidy of these expensive agents.

It is perhaps noteworthy that many decisions that guide treatment are made purely on the basis of biological plausibility. On this occasion, there was some statistical support, albeit from a post-hoc analysis, to support any biological arguments. There is inevitably an element of judgement about these decisions, as is clear in the letter from Lu et al, who describe “accumulating evidence” in relation to whether gene polymorphisms “may be predictive of clinical responsiveness”.

The current situation, as exemplified in this letter, in which the PBAC is unable to give detailed reasons for its decisions, clearly demonstrates the urgent and critical need for greater transparency of the PBAC processes, and underscores the fundamental right of Australian consumers and prescribers to information relevant to decisions about the subsidy of medicines in this country. The PBAC is willing to examine any new evidence relating to the influence of rheumatoid-factor status on health outcomes and the cost-effectiveness of these agents. If there is additional evidence supporting a review of the current listing, the PBAC would encourage the sponsors of these drugs to prepare appropriate submissions to enable us to evaluate these data. As Chair of the PBAC, I intend to continue to work towards the goal of greater transparency, whereby the outcome of any such new evaluation, and its basis, could be made available to Australian consumers and prescribers.