ICON partnered with a drug development sponsor to conduct a multicenter, randomised, double-blind, placebo-controlled, proof of concept study of the efficacy and safety of a treatment for patients with fibromyalgia. The studies faced a potential of bias at the site level and a risk of recruitment delays. ICON’s prompt evaluation and proactive solutions, in conjunction with the strong, collaborative partnership with the sponsor helped mitigate the risk of bias and recruitment delays.

In this study, the protocol endpoint was a patient reported outcome (PRO) and the screening period included a baseline PRO that determined eligibility. Subject interactions, training, and other contact could influence patient reporting, introducing a risk of bias and consequently have a negative impact on the trial endpoint. Additionally, the following factors required consideration to minimise the risks to meeting recruitment timelines:

• The protocol included stringent inclusion/exclusion criteria. Specifically, concomitant and rescue medication protocol limitations became the main rate limiting issues for recruitment.
• The screen fail rate was higher than anticipated. The higher rate was due to the inclusion and exclusion criteria as well as the use of concealed protocol.
• No advertisement budget was implemented at study start
• The COVID pandemic accelerated site closures affecting recruitment towards the end of the study

ICON implemented the following strategy to mitigate potential bias and avoid a negative impact on the trial endpoint:

• To manage the risk of bias at the site level, a concealed protocol was used to blind sites from some specific items within the protocol that impacted eligibility
• An ‘unconcealed’ ICON team was formed in order to limit the possibility that concealed information would be released to site staff and targeted ICON team members were selected for full visibility into the protocol
• IRB submissions were completed through a separate ‘concealed’ emailing protocol. All sites for this study were required to use central IRBs to facilitate the concealed protocol submission by ICON and limit the risk that site staff would inadvertently gain access to concealed criteria.
• All concealed documents were housed on a restricted drive and filed at the end of the study post sponsor approval
• A vendor was added to ensure unbiased subject training before PROs were initiated. The same vendor was used to identify data incongruencies throughout the subject’s involvement in the trial. When needed, subject retraining, using the non-biased vendor training module, was used.

Proactive recruitment solutions were incorporated to ensure all timelines were met.

Site selection 

To ensure strong sites were selected, the feasibility enrollment estimates provided by sites were verified during PSSVs using ICD10 code review and extensive discussion at the site

• Each subject was reviewed by an eligibility reviewer to ensure that the subject was suitable or the study (based on screening visit information). Eligibility review approval was added as an IC/EC criteria in an amendment and likely reduced early terminated subjects or potential ’poor’ PRO reporters.

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The stringent inclusion/exclusion criteria rapidly exhausted site databases

• ICON recommended that advertisement funds be included in site contracts and listed as ‘pending Sponsor approval’ to avoid site contract amendments and ensure Sponsor control of the implementation
• Sponsor chose to have sites document database exhaustion before providing approval of advertisement funds (delay in implementation of the mitigation plan should be avoided)
• It was further recommended that standard advertisement material be created
  for the study to ensure cohesion. This also limits Sponsor review of site-specific advertisement material and keeps IRB costing low.

Contracts 

Contracts were amended to a more favorable screen failure payment schema

• The concealed protocol paradigm limits subject and site bias, but also impacts randomisation. Therefore the typical 1:1 (SF:Rand) site payment ratio was a point of contention with the sites and was ultimately rectified.

Marijuana exclusion

Protocol was amended to allow for the use of marijuana

• This exclusion criteria was reported to be one of the most impactful during pre-screening exclusion and was raised as a risk early in the study as many sites are located in areas where marijuana usage is legalised
• The impact of this protocol change was not realised due termination prior to protocol amendment implementation

• Screened patients target for the study was increased due to the strict inclusion/exclusion criteria and the concealed protocol impacts
• Although timelines were met, the study was terminated due to a futility analysis
• The study reached 78% of rand. Target with a screen failure rate of 70%
• Overall, 45 of 50 sites screened patients and 35 sites enrolled patients