Battle-worn: Setting up a multi-centre, randomised, controlled trial in the UK
Professor Roy Homburg and Dr Albert Opoku
Progress Educational Trust17 September 2018
Why has clinical evidence on IVF 'add-ons' not been forthcoming? A recent BBC Panorama programme investigated the use of these unproven add-ons – throughout the documentary there were repeated pleas for an evidence base for these treatments (see BioNews 880). Our experiences may shed light on why such evidence has not emerged.
I [Roy Homburg] have spent the last eight years working part-time in the UK setting up randomised controlled trials to investigate the effect of acupuncture, intrauterine seminal plasma injections, time-lapse imaging, intra-lipids and DHEA on IVF outcomes.
Three of these trials have proven a nightmare to organise – having to battle through a bureaucratic jungle of which Kafka would have been proud, as well as abysmal funding opportunities. If we so badly need the evidence, then researchers need a modicum of encouragement to produce it.
In the hope that the powers-that-be will be moved to streamline the process, an example of what is involved to set up a multicentre, randomised, controlled trial in the UK is presented here from our recent experience.
Dihydroepiandrosterone (DHEA) is being widely dispensed to help produce eggs for IVF. There were few studies on the subject, which are mostly observational with small numbers. We therefore planned to undertake a UK multicentre randomised, double-blind, placebo-controlled study to answer the question – does DHEA improve the outcome of IVF in poor responders?
DHEA is not licensed for clinical use in the UK and so we needed to apply to the Medicines and Healthcare Regulatory Authority (MHRA) for approval for the study. The irony is that DHEA is freely available online and, in the USA, it is a food supplement sold over the counter. The designated pharmacy for this study ordered the DHEA and placebo to be manufactured in China.
The study protocol written using a standard template for clinical trials of an investigational medicinal product (CTIMP) was also registered with the European Clinical Trials Database (EudraCT) as well as for an International Standard Randomised Controlled Trials Number (ISRCTN); all at a cost.
A pharmaceutical unit was designated by the MHRA to organise the manufacture and supply of the DHEA and placebo as they had previously done for a different study. The tablets cost us around £42,000.
The MHRA clinical trials application had to be submitted through the Integrated Research Application System (IRAS) portal, a voluminous application which manages to ask the same question over and over again in thinly disguised forms.
Although priding ourselves on our knowledge of the English language, we were left flummoxed by the wording of some of the questions and re-flummoxed in understanding what was wanted of us. This form could have been trimmed to about one quarter of its size.
The form was filled online, downloaded onto a CD with all documents and, as required, submitted by post. The MHRA application costs £3400 with an investigational medicinal product (IMP)dossier), thankfully reduced to £250 without the dossier after another group that previously submitted an application using the same IMP allowed us to cross-reference their study. Our initial application submitted in June 2014 was eventually approved in December 2014.
We won a grant (FORWARD Grant, 2016) in an open competition run by Finox Biotech, to fund the study in April 2016. After all the delays the grant providers have been extraordinarily patient in not withdrawing, despite the time constraints they imposed.
We had to submit an amendment to our MHRA application in May 2016 due to a change in the Chinese manufacturer of the raw material for DHEA. This new application had to go through a new online Common European Submission Portal (CESP) with another fee. This was eventually approved in August after their numerous administrative errors (such as e-mails sent to wrong addresses).
Having conquered the MHRA and REC (ethics committee) approvals, we were informed in September 2016 that a change in the national healthcare research approval system required us to submit an application to the Health Research Authority (HRA). This required simultaneous applications through IRAS and e-mail application.
Since January 2015, we enlisted sites to ensure proficient recruitment. To do this, we needed to apply to include the study on the National Institute for Healthcare Research (NIHR) portfolio. This again required a separate e-mail application with study paperwork and the IRAS REC form and was approved in November 2016.
The separate centres then had to go through feasibility review either via their R&D departments or with their local clinical research network (CRN). One centre is in Glasgow and, despite the Scottish referendum results, unbeknown to us, Scotland had achieved its (medical) independence and a large pile of further paperwork - including a study wide governance report, that was needed to ensure their participation.
Today, still not completed, one of the remaining disputes is that Glasgow insists the patient's name must be on the specially designed study prescription whereas our local English governance says this is in contravention to the study design although all are blinded to the randomisation. Hopefully, within the next year or so a solution will emerge from under the sporran.
Four of six centres were given permission to start recruiting following many minor amendments.
Now demands for explanations as too why we requested to prolong the time limit of the study, why recruitment has been slow, and the source of money – are raining in from bureaucrats hiding behind the acronyms of organisations.
Because of the lengthy time to set up the study, the medications ordered at great expense, were about to expire, ending their measly life span of 18 months. Almost all the medications received have been destroyed unused. However, we were prepared: five months before the dreaded expiry date we asked for delivery of the second batch which we had already ordered previously.
Being battle-trained, we were no longer stirred but shaken to receive a devastating e-mail just one week before the last date available to recruit any further patients (for fear of poisoning them with expired placebo tablets).
The message from the trial pharmacist simply said that the supplier was unable to source the DHEA powder from the manufacturer previously used and that they were looking for yet another alternative source. For this the IMPD has to be updated, a substantial amendment from the ethics committee sought, a re-application made to the CESP, the new products quality tested etc. and more money paid.
As the months taken to achieve these goals to allow the manufacture and delivery of our order roll on, recruitment has had to be stopped, the study has come to a shuddering halt and the money will probably run out.
What is clear is that we will never again embark on a similar project needed to provide evidence for unproven procedures unless obtaining a grant massive enough to employ a clinical trials unit. The methods will remain unproven until the powers-that-be in the UK simplify the regulatory processes and aid, rather than (albeit inadvertently), obstruct research.
The way forward is no longer the randomised control trial but the 'big data' studies. The new data protection act makes performing these yet another enormous hurdle for the future of research in the UK. I'm thinking about the next generation of young researchers.
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Reproduced with permission from BioNews, an email and online sources of news, information and comment on assisted reproduction and genetics.