Legislative Review or Window Dressing?

One of the biggest news stories this month has been the latest announcement of an independent review of the regulation and governance of UK clinical research. This was announced by Health Secretary Andy Burnham on March 25^th, and will be conducted by the Academy of Medical Sciences, which called for such a review in its January 2010 report “Reaping the rewards: a vision for UK medical science”. In announcing the review, Mr Burnham said “It is becoming increasingly clear that medical research is getting tied up in red tape. For research to flourish and provide the huge benefit it can give to the health and wealth of the country, it needs freedom from unnecessary bureaucracy and interference.”

This sounds rather familiar, having been the rallying cry behind reviews, reports and reorganisations going back at least as far as PICTf nearly a decade ago. This was followed by the UKCRC set of initiatives (now mostly under the banner of the NIHR) and more recently the Office for Life Sciences, which published its own report on “Delivering the Blueprint” only a few months ago. All of these have overlapped, in goals and activities, and all have provided incremental solutions to specific problems. It is hardly surprising that problems still remain to be solved, but people criticising the current systems should remember the ‘bad old days’ that preceded them.

So, is the AMS review going to provide that ‘Eureka!’ moment, delivering transformative recommendations that none of the previous review panels were able to come up with? Or is it the latest window dressing on the long-running series of evolutionary reforms that have fought against the gradual ‘decline’ of UK clinical research competitiveness, as medicine development has globalised, throwing the UK’s inbuilt demographic disadvantage into sharp relief? Of course, editorial hyperbole aside, the truth of the matter will be somewhere in between. However, well-meant as it is, there are some pretty fundamental problems with this particular review…

For a start, there is the long history of reviews in this area, including the ones described above, plus internal reviews conducted by the MHRA, Department of Health etc. over the past few years (and that continue to be ‘works in progress’). Is it really plausible that the ACM panel could spot a flaw or propose a solution that had been previously missed? Indeed, the overarching issue seems to be not so much with identifying specific problems as with translating them into generalisable solutions that can be applied usefully across commercial and non-commercial research, balancing provision for public confidence with available resources, and taken up in a homogenous way by a very heterogeneous set of organisations (and combinations of organisations).

Information about the review is still pretty sparse, but it has been described as “rapid”. However, the UK is a matter of weeks away from a General Election. Even if the AMS can produce its report before the election, it will surely be buried under the media froth on other campaign issues from the economy, crime and foreign policy to the environment, UK military operations overseas and MPs expenses! With the election widely expected to result in a change of government, there is no guarantee that the incoming politicians will choose to implement any of the AMS’ recommendations, and might even decide to commission yet another review on taking office…

Finally, a similar debate has been taking place on a pan-European level, with the European Commission already being more than 12 months into a discussion on the impacts of the Clinical Trials Directive, with broad consensus that something must and will be changed, and increasing acceptance that the text of the Directive itself might be part of that change. There is surely much wrangling to be done at this level over the next few years, but when this is complete, the UK legislation will have to change all over again as a result, regardless of any improvements brought about by the AMS.

So, although its aims are laudable, there is little practical value in commissioning this review now: it duplicates reviews that are already in progress, it’s unlikely to be able to solve the multi-level problems it’s designed to address, and the broader legislative environment is likely to change soon anyway! Sometime, somehow, further reform of UK clinical research regulation and governance is certain to take place, but the timing and context of this review appear certain to undermine any value that it could add.

ICREL conference (part 3)

The final plenary session of this one-day ICREL conference on the impact of the EU Directive on clinical research in the EU brought together each of the four break-out groups to summarise their discussions.

Speaking about the impact on commercial sponsors, it was noted that there is also a strong drive to conduct studies in part outside the EU: 40% of studies in the EU also have sites further afield. It is unclear what role the Directive played in this, or what other global factors might have had to do with it. More significantly, it raises the issue of how the EU regulatory landscape should deal with studies also taking place outside the EU. Another key point was that the increase in quality desired by all necessarily requires increased resource, again questioning the grey area between ‘expensive bureaucracy’ and ‘paying for quality’. Finally, while regulators and RECs generally hit target timelines, there are sometimes hidden delays, due to scheduling, holidays, or validation periods, that are not counted. Future legislation should be more robust in eliminating these.

From a non-commercial perspective, the increased workload was highlighted, and a call made for a risk-based approach to administrative requirements, particularly when studying a marketed product within its indication. The ‘demise’of the investigator-sponsor was commented upon, with institutions unwilling to allow their staff to take on such responsibilities. Ideas were also shared on how the burden of being a sponsor might be reduced: allowing the role to be shared between organisations, or for multiple sponsor organisations to build shared infrastructure and administrative capacity. Looking ahead to the prospect of ICREL2, they called for an appropriate quality metric to be collected, along with more detailed analysis of the impact of different national implementations.

Speaking for the group discussing competent authorities, Fergus Sweeney of the EMEA noted that the Directive did not appear to have attracted clinical research to the EU, but conversely speculated as to whether even less research would have been done in the EU if no legislation had been enacted. He reiterated that global trends in timelines, costs etc might also be a source of change, not solely the Directive. He called for comparison with data from outside the EU to assess this. Discussing the potential for centralised authorisation or mutual recognition, he referred delegates to the ongoing project by the CTFG to pilot a voluntary harmonised procedure. He also commented on the need to refine definitions of substantial amendments, provide more training for non-commercial investigators and sponsors, and to expand EudraCT.

Alastair Kent presented the views from the session on RECs, calling for ongoing mandatory education of REC members, complemented by programmes of accreditation, audit and inspection across all member states. He stressed the importance of patient safety, but suggested that patients themselves might usefully advise on the risk/benefit profile of their own condition. He reported a call for increased harmonisation, but also for allowing space for regional/national differences in moral attitudes. From a logistical perspective, he said that RECs have no use for SUSAR reports, and that they should not be burdened by receiving them; this is precisely what has been done in the UK, to great success. Finally, he called for a public registry of REC opinions.

The remainder of the meeting was given over to general discussion of the day’s topics. Ingrid Klingmann reminded us that in addition to the matters in need of urgent attention, we need to plan ahead by 5-6 years for any substantial formal revision of the legislation, and that the discussion between stakeholders that this meeting represents is precisely the kind of initiative that did not take place during the Directive’s planning stages, a lack which led to silo-thinking without powerful consensus. Other delegates spoke passionately about the development of pan-EU accreditation for RECs and a common understanding of the much-used term ‘risk-based approach’.

In his closing remarks, Stefan Fuhring of the European Commission stated that no decision on whether to review the Clinical Trials Directive would be taken by the current Commission, which has a little under a year of its term remaining; what its successor might do after Autumn 2009 was, of course, for that Commission to decide. If the Directive is reviewed, the findings of the ICREL survey will form a very interesting part of any potential impact assessment, although it would be beneficial to also consider related public health issues. He closed by saying he was looking forward to reading the final report and recommendations from the ICREL project when it is submitted to DG Research of the European Commission at the end of 2008.

Ingrid Klingmann then formally closed the meeting, as delegates applauded the substantial achievement she and her team had made with this project.

I will update this blog post when the ICREL report is published, which is expected to be in February 2009. I will also be interviewing Ingrid Klingmann shortly, for publication in a future issue of CRfocus.

ICREL conference (part 2)

The second plenary session of this conference on the impact of the EU Clinical Trials Directive has really provided the “meat” of the proceedings: the results of the ICREL survey themselves. Admittedly, these are currently preliminary results, and were far too detailed to discuss in full on this blog, but there were some interesting similarities between the results from the different stakeholder groups… and also some significant differences!

The key comparisons in the quantitative results were between 2003, before the Directive was implemented, and 2007. Results were reported from surveys sent to competent authorities, commercial and non-commercial sponsors, and research ethics committees.

Regulators were the group who most actively responded to the survey. They reported that applications from commercial sponsors had risen slightly over that period while those from non-commercial sponsors had declined, but that there had been a spike of non-commercial studies immediately before the Directive’s implementation. Workload had almost doubled, both for scientific involvement and for admin, and budgets had risen accordingly, although fees had increased dramatically. Changes suggested by regulators included mutual recognition of approvals from other regulators for certain types of studies, clarification on SUSAR reporting and standardising the format and content of trial applications across member states.

Ethics committees were the worst group of respondents, with fewer than 10% replying to the questionnaire. This obviously undermines some of the validity of their results, but the increases in numbers of opinions, substantial amendments and SAE/SUSAR reports were clear. There was no significant change in the times to deal with applications, but increases in the number of employees and, signifncantly, fees charged to commercial sponsors.

Over 50 commercial sponsors responded to the survey, and reported an increase of 30% in the volume of studies between 2003 and 2007. This increase was more pronounced in earlier phase work, and particularly in multi-national studies. Even though regulators and ECs reported meeting their timelines, sponsors reported an overall increase of 30% in the time from final protocol to first patient, which rose to over 90% when the data was normalised by the size of sponsor. Workload increased significantly in gaining approval, coordination and pharmacovigilance, but the most startling change was in the cost of liability insurance. While not directly related to the Directive, it was suggested that it had been used as an opportunity to increase charges by nearly 400%! When asked to propose changes to the current systems, popular suggestions included enabling a single application for multi-national studies (whether by mutual recognition or a central authorisation process), use of a Regulation to replace national interpretation when implementing future requirements, harmonisation of REC applications, timelines and criteria between member states and a general simplification and harmonisation of procedures.

Discussin the responses from non-commercial sponsors, it was noted that multidisciplinary and oncology organisations were the strongest responders. A small decrease in studies on medicinal products was reported, with increases in device and observational studies. Again, time to first patient had increased, as had the workload involved with admin, monitoring, pharmacovigilance and QA. Respondants commented that the current system was not adapted to international investigator-driven research and called for further simplification and harmonisation along with a risk-based approach to regulation and further financial support and investment in infrastructure.

Closing the session with a broader view of the data, it was noted that RECs saw a larger increase in studies than regulators, and that increases were stronger for commercial than non-commercial studies. The number of centres and countries involved in these studies had increased significantly, as had the proportion of biotech and orphan products. Timelines from protocol to first patient had increased more for commercial studies, but workload had increased more for non-commercial studies (exceept for admin activities, which increased substantially for both groups).

The afternoon of this meeting will comprise breakout discussions of these results grouped by stakeholder area, concluded by reporting back and discussion by the plenary group. I hope to report on these by the end of the day.

ICREL conference (part 1)

In the first plenary session of the ICREL conference on the impact and potential changes to the EU Clinical Trials Directive, Ingrid Klingmann described the process of conducting the study during 2008. Discussions at this one-day conference will be considered when compiling the project’s final report, which is to be submitted to the European Commission by the end of 2008.

Representatives of five stakeholder groups gave their perspectives on the need for change and suggested the sorts of change they would like to see discussed.

These presentations will be reported in more detail after the meeting, but there appeared to be strong agreement throughout the group that change is needed and similarities in the shape that change should take. In all these things, though, the devil is in the detail, and I suspect that there will be plenty of strong negotiation before any change plan is implemented. Perhaps most significant was the presentation from Dr Chantal Belorgey, Head of the Clinical Trials department at the French regulator AFSSAPS and Chair of the Clinical Trials Facilitation Group of the Heads of Medical Agencies, who discussed ongoing plans to agree a core set of information to supply to all competent authorities and develop a harmonised assessment process for clinical trial applications, to be piloted in 2009.

The next session will present the results of the survey itself, with discussions of their implications for different stakeholder groups taking place in the afternoon. I hope to report more of this information during the lunch break.