Research Article: Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: An example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO

Date Published: June 5, 2019

Publisher: Public Library of Science

Author(s): A. V. Ramanan, L. V. Hampson, H Lythgoe, A. P. Jones, B Hardwick, H Hind, B Jacobs, D Vasileiou, I Wadsworth, N Ambrose, J Davidson, P. J. Ferguson, T Herlin, A Kavirayani, O. G. Killeen, S Compeyrot-Lacassagne, R. M. Laxer, M Roderick, J. F. Swart, C. M. Hedrich, M. W. Beresford, Beth K. Potter.

http://doi.org/10.1371/journal.pone.0215739

Abstract

Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion.

Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting.

Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments.

The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.

Partial Text

Chronic nonbacterial osteomyelitis (CNO) is a rare bone disorder producing sterile inflammatory lesions. While some patients show timely limited monofocal disease, others will develop chronically active or recurrent courses with multifocal bone involvement, which is then referred to as chronic recurrent multi-focal osteomyelitis (CRMO) [1]. Primarily affecting children and adolescents, CNO/CRMO is characterized by the insidious onset of bone pain that may be severe and disabling, potentially leading to permanent damage [2].

Fifty-one clinicians from across Europe, Turkey and Russia who completed the electronic survey, registered their interest in attending the CNO/CRMO consensus meeting, 32 of whom met predefined “expert criteria”. Three experts were based in Turkey or Russia, and due to funding constraints were not considered further for participation in the meeting. Fifteen of the remaining eligible experts, representing eleven clinical centres, were based in the UK (fourteen experts) or Ireland (one expert). These experts were first listed in alphabetical order; in cases where more than one expert had the same affiliation, only the expert occurring highest in the alphabetical ordering was retained. From the reduced listing of eleven experts thus compiled, six were randomly selected (BJ, JD, AK, OGK, SCL, MR): three of these experts represented a centre that had more than one volunteer. In these cases, all of the experts from that centre were contacted and invited to nominate a single representative to attend the consensus meeting.

Table 3 lists answers of the thirteen experts to the ten principal elicitation questions (labelled QP1-5 and QA1-5). The group accepted as their consensus answers to these questions the arithmetic means of their individual answers. Consensus opinion was that a typical new patient treated with pamidronate would have an 84% (chance of registering some improvement in his/her pain score relative to baseline at 26 weeks and an 83% chance when treated with adalimumab. Experts thought there was a 50% chance that a new typical patient on pamidronate would record a pain score of 28 mm or better at 26 weeks and a pain score of 30 mm on adalimumab. These answers reflect the general opinion that a typical patient’s 26-week pain score would be broadly similar after treatment with pamidronate or adalimumab.

Three hypothetical datasets from a future CRMO trial randomising 40 patients between pamidronate and adalimumab were defined as follows:

There are no published RCTs comparing the relative effectiveness of adalimumab and pamidronate in treating children with CNO/CRMO [8, 16]. The rarity of CNO/CRMO leads to significant challenges in conducting RCTs with sufficient power to provide a definitive outcome. We proposed this using a Bayesian clinical trial design and have described the process and outcome of the elicitation exercise to establish expert prior opinion. The process was done in a structured format [27], led by a statistician experienced in Bayesian statistics (LVH), and informed by a systematic review [32] providing principles for best practice in prior opinion elicitation.

 

Source:

http://doi.org/10.1371/journal.pone.0215739

 

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