Lessons from an investigator-led trialDr Andreas Goebel talks candidly about the barriers he encountered in preparing a multicentre trigeminal neuralgia trial in the UK, and offers some of the learnings that could help inform both investigators and policy makers
In 2007, I won a competitive industry grant to study the efficacy of low-dose intravenous immunoglobulin (IVIG) in the treatment of refractory trigeminal neuralgia, in a 2-centre randomised controlled trial (RCT). Our previous trial in a different chronic pain condition had been highly successful1. This trial, unfortunately, was different.
Our regional registered clinical trials unit was unable to take the trial on, as the topic, chronic pain, was outside its remit. Likewise, my NHS Trust (the tertiary care University Trust at site A) was unable to sponsor this trial as it does not have the resources to oversee trial conduct at an outside centre. The trial was therefore sponsored by the combined tertiary Trust/University R&D department at the second centre, site B. The principal investigator (PI) at that centre therefore became the chief investigator (CI).
The trial protocol had gone through an external peer review process during the funding round, so we now wrote the full protocol, obtained further external peer review from a worldwide leading expert at the US National Institutes of Health, and adapted the protocol accordingly. The trial also underwent an internal (university) review process. As is usual in IVIG trials the question of blinding received particular attention. We appointed a UK professor of neurology who agreed to act as external safety advisor. Then we submitted for ethics and MHRA towards the end of 2007 and received approval in February.
We registered the trial with ISRCTN and applied for adoption to the CLRN portfolio, which was granted. The sponsor granted permission for the trial to start at site A in summer 2008. Site B (‘the sponsor’s site’) had no recruiting site with facilities dedicated to trials, so the sponsor encouraged us to conduct the trial either at the local pain clinic or at a neighbouring day care unit. The local pain clinic was unable to accommodate the trial unless the trial nurse was recruited from within the pain management team. Unfortunately, none of the pain team’s nurses were interested. We therefore decided the trial would initially only enrol patients at site A, my Trust.
In April 2009, however, we were able to recruit a trials nurse at site B from within the pain clinic. We then worked with the sponsor for one year to prepare the trial at site B. This proved unsuccessful as the sponsor requested more and more paperwork (protocol changes or clarifications, logs, standard operating procedures, procedural changes, working instructions). As there was never any clarity on what outstanding issues there might be, we had no opportunity to apply forward thinking to our preparatory work.
There was also inadequate coordination within the sponsor’s team, which led to new requirements that team members could never anticipate. One example was the request by a pharmacy technician – who had taken on the role of the sponsor’s trial pharmacist – to run mock blinding trials using the real IVIG bottles (the blinding protocol had already passed several external and internal reviews). We were unable to discuss this with the sponsor, and the sponsor had no authoritative coordinator in place who could decide such issues.
Another example was a sudden change of the sponsor’s unblinding requirements, which led to a request that we purchase the service of another Trust’s emergency unblinding service. Because of a lack of transparency and discussion by the sponsor we could not anticipate this change, but had to pay heavily with preparation time – creating protocol changes, new SOPs, etc. By the end of 2009 we had not progressed to permission, but had produced a respectable body of paperwork (see above photo). Then the sponsor was informed of an impending MHRA inspection.
This news followed a first visit of the sponsor’s monitor to site A. The sponsor decided that because of shortcomings at both sites A and site B (we disagreed) our trial was to be put on hold immediately on site A, and should not be started at site B. We were also told it might be best not to (re)start at either site until the inspection was over.
On the sponsor’s request, the MHRA inspection of all its investigator-led studies was then deferred until late 2010. New forms were forwarded to us which we duly implemented. In June 2010, we suggested a transfer of sponsorship, to be taken on jointly by the University (where I had been appointed senior lecturer) and Trust at site A. This was partially because the CI felt unable to comply with a new contract she had been asked to sign by the sponsor which gave her new responsibilities. The sponsor gave us six weeks to complete this process, but my Trust requested more time since its resources were bound by the preparation for an MHRA inspection of its own.
I informed the sponsor that our trial had been selected for this site A inspection. Shortly afterwards, the sponsor notified us of the termination of the trial. A complaint to both national and local ethics is still pending (but with no response given since July 2010), because patients who had participated at site A had given their consent in good faith that the trial would be conducted.
So can anything be learned from this experience?
- The mechanisms put into place to support investigators to comply with European trials directive requirements failed in our case
- If a doctor was conducting procedures for which they were not trained there is every likelihood they would be struck off the register before too long. So shouldn’t sponsors be made accountable for how they progress investigator-led studies?
- There should be clear timelines. The main problem for us was not our completion of paperwork, but the lack of clarity around the sponsor’s requirements (often this related to the sponsor’s interpretation of the European Directive requirements). This prevented us from being able to plan our preparations and cost us a lot of time. It can also be distressing for investigators when a sponsor is unable to clearly identify the requirements that will lead to permission to recruit.
- The requirement of the European Trials Directive, that we should conduct investigator-led trials of drugs with long-established safety profiles similar to those trials conducted by industry for, say new cancer drugs, can make investigator-led multicentre studies extremely difficult, and in pain medicine there are a myriad of clinical questions that can only be answered by conducting RCTs with long-established drugs.
The European requirements for investigator-led studies using drugs with long-established safety profiles need to be reduced and simplified.
- It is worth noting, of course, that it is not always the regulations that are making it impossible to run academic trials, but rather, an over-zealous interpretation of these regulations, lack of understanding of the purpose and intention of the regulations, lack of experienced and qualified staff within the administrative and pharmacy departments responsible for sponsor oversight for the academic organisations, and a general lack of common sense on the part of the staff doing the work.
- How should a clinical investigator best arrange the conduct of an investigator-led multicentre trial? Investigators are encouraged to contact a registered clinical trials unit that has an interest in the condition to be studied, on the premise that once a registered unit is involved, sponsorship should be obtainable. In my experience this doesn’t always work. Many UK registered units, although formally open to a variety of trials, will inform you that your trial does not currently fit into their plans – indeed, many units may already be working to capacity, and successfully, with local investigators. A way forward might be a simplification of the European regulations for investigator-led trials so that smaller recruitment sites with facilities dedicated to trials can manage the work and NHS Trusts can take on sponsorship for multicentre trials.
In my experience, the EU directive imposes a massive burden on sponsors and investigators involved in investigator-led trials. Furthermore, the system designed to support these trials in the UK simply cannot cope. This is in no small part a result of inexperienced and poorly qualified staff within sponsors’ overseeing departments who burden academic trials through over-zealous interpretation of the European trial regulations.
Acknowledgement: The author wishes to thank JZ, TN, CM and CW. This article has been supported by the Pain Relief Foundation, Liverpool.
Conflict of interest: Dr Goebel reports having received research support and speaker honoraria from CSL-Behring, Bern, Ch, Talecris Chapelville, USA, and Baxter, USA.
1. Goebel A, Baranowski AP, Maurer K, Ghiai A, McCabe C, Ambler G. Intravenous immunoglobulin treatment of complex regional pain syndrome: a randomised trial. Ann Intern Med 2010;152(3):152-8.
Dr Andreas Goebel is a senior lecturer and honorary consultant in Pain Medicine Pain Research Institute, Institute of Translational Medicine, Liverpool University, The Walton Centre NHS Trust.