Evidence for Good Quality: The Hidden Cost of Inspection
Professor Richard Gray & Joan Perou HonFICR
Session chaired by: Helen Springford MICR
Reporter: Suheila Abdul-Karrim MICR CSci
Keywords
ICH GCP, Inspections, Source Data Verification (SDV)
While good quality data is the absolute core of clinical research, this session stimulated thinking around the whether the methods currently used to obtain this data are the best.
Evidence-based proportionality
Professor Gray, as part of his introduction, said that he was representing the trialist. He stated that clinical trials involved a lot of hard work and most people start doing clinical trials out of altruism: to find a better way to treat a particular disease. His focus was to look at how to improve clinical research, not by criticising but by looking at it constructively.
He said that there was a need for an evidence-based overhaul of GCP monitoring. What is currently being done is ritualistic and data is being collected in a systematic way. While the basic principles of GCP are unquestionable, it is their interpretation that poses a problem for Professor Gray. He said that ICH GCP was developed for commercial trials and not for large pragmatic non-commercial or academic trials.
He felt that the interpretation of ICH GCP was conservative, in that some of the procedures and checks were over-burdensome and it was not evidence-based. He also expressed concern that while other documents (such as the Declaration of Helsinki) are periodically revised, ICH GCP has stayed the same since 1997 and felt that it was outdated. He felt that the cost-effectiveness of traditional on-site monitoring is highly debateable and that central monitoring is the way to go. He preferred that site visits not be done, because in a trial with large numbers and a 5-year follow-up, trying to scrutinise folders would kill the trial. He said that it is all about getting the right balance between safety and data quality.
Prof. Gray presented examples of clinical trials in which GCP was implemented, that still had bad research practices and where serious breaches in research had occurred. To improve the quality of data, he said, larger trials were needed. Larger numbers would provide more reliable results and central monitoring should be done. The focus would be on important safety and data issues, where only important data would be collected.
He also expressed concern about regulatory systems not encouraging better-designed trials and that the role of sponsor was still based primarily on commercial trials. He felt that a working party should look at inspections of non-commercial trials and obtain consensus on what checks are important to provide high quality data and ensure safety. He stated that the hidden costs of inspections at Academic Research Units (ARUs) had not been addressed and that they were expected to step up to the same level as pharmaceutical companies despite not having comparable resources. By expecting the same standards from ARUs as from industry, the system does not allow for the separation of different types of research. He emphasised that a “one size fits all” model is not appropriate.
He concluded by stressing that the criteria for a good quality trial are two-fold: asking an important question and answering it reliably. Important questions in common diseases must be addressed and reliability is obtained through rigorous, large-scale randomized trials with minimal burden on the participants.
Remaining inspection-ready
This presentation was followed by a look at the hidden costs of inspections by Joan Perou. She highlighted the fact that standards had risen and hence there may be hidden costs for those who are not prepared for an inspection.
She said that ICH GCP was a good initiative but agreed with Prof Gray in that it was only mandatory for pharmaceutical registration studies, not for non-commercial and academic studies. However, GCP was transposed in to UK law in 2004 and became a legal requirement. This was followed by the second EU Directive (2005/20/EC, implemented in 2006) and MHRA inspections became mandatory. This laid down one standard for all.
Joan explained that inspections involved looking at how investigators conducted trials. This meant that the sponsor has to ensure that measures have been put in place because inspectors would look at SOPs. These SOPs should be updated, as regulations and best practise are continually changing and implementation of this has to be filtered through to everyone involved in trials.
In discussing the negative aspects of MHRA inspections, Joan shared with the audience how sites start rushing around to make sure that everything is in place, which raises costs. Therefore, preparation should start early, with a goal of always being “inspection-ready”, and not when notification of an inspection is received. Joan informed us that it costs £2500 per inspector per day in the UK and if all was not in order and the inspectors had to come back, there would be a charge of the same fee again.
More positively, an MHRA inspection can bring about teamwork and improved communication between all involved in the trial. Joan said that the results of this kind of teamwork can include a vast improvement in general performance at the site.
She informed the audience how to prepare for an inspection. An inspection co-ordinator and deputy co-ordinator should be appointed and a compliance group involving a representative from the different departments should be set up. This way the communication could be filtered back to each department and they could start “plugging the gaps”. Joan stressed that in order to have a good inspection, one had to plan with military precision. From her experience, Joan had seen investigator files that did not have the right documents and only contained information on travel to meetings, informed consents that were missing and had no version control and protocols with no version control.
In contrast to Professor Gray, Joan stated that the lack of monitoring is a big issue. In the current regulations, the sponsor has the lions’ share of the responsibilities and face-to-face monitoring is essential to avoid serious breaches. She said that a serious breach in sponsor responsibilities, no investigators brochure at the site, and a breach in maintaining the trial master file are all new criminal offences. In order to avoid theses criminal charges one needs to have face-to-face monitoring meetings where the files are reviewed and maintained. Another great concern for her is that site staff and monitors do not keep up with local regulations and sometimes are not even aware that changes have been implemented.
In parting, the audience received advice on inspections. Joan emphasized that safety was always under the spotlight and one had to ensure that all events had been reported and recorded. While investigators can delegate responsibility, they cannot delegate authority and are ultimately accountable for their site. She said that everything must be documented and a paper trail maintained.
Discussion
This session certainly ‘rattled’ the concept of ICH GCP. Many of us had cut our teeth on this guideline when starting out in clinical research. It was (and still is) handed to CRAs in booklet form when starting at a new company and a great importance is placed on knowing the booklet very well. In fact, it becomes a companion when monitoring at a site. This discussion provided a different view about ICH GCP and for the first time we heard ICH GCP being questioned.
Yet, around us a lot is changing. The level of monitoring has dropped in the last 5 years with source data verification (SDV) being decreased, again something that is not stated in ICH GCP. Moreover, it was evident that while knowing ICH GCP very well, an inspection could still go wrong if monitors and staff were not also trained on local regulations and updates made to these regulations. Could it be that there is too much focus on ICH GCP when it is actually the national regulations that crosses the T’s and dots the I’s? Now that another view has come to the fore, it will be interesting to see if ICH GCP still has such a strong hold in 10 years’ time and if hidden costs for inspections will increase, or perhaps there would be vast improvements in good quality data which may reduce the hidden cost. Definitely something to keep an eye out for!
Professor Richard Gray is Director of the Clinical Research Unit at the University of Birmingham.
Joan Perou HonFICR is an independent GCP consultant and Trainer.
Suheila Abdul-Karrim MICR CSci is an independent consultant providing CRA services and training within the pharmaceutical industry in South Africa.
