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.

My full comment to Nature Medicine on UK competitiveness…

A few weeks ago, I was contacted by a journalist writing up a news item for Nature Medicine on the drift in the UK’s competitiveness in clinical research, and the measures being taken to address it. I wrote a response, which I knew was far too long.

This morning, I read the news item as it made it to print in the February issue of Nature Medicine (http://www.nature.com/nm/journal/v16/n2/full/nm0210-134b.html). I knew that my comment was far too long for its subtleties to make it through into the printed version, but it might be useful to publish here the full text of what I said…

It is undeniable that the UK now provides a smaller proportion of patients to clinical trials than was the case a decade ago. To ascribe this to internal changes, though, oversimplifies the issue. The efforts to streamline clinical trial authorisation, start-up etc. have been successful, in that without them the impact of external factors would have been even greater.

Over the past decade, many additional countries (particularly the BRIC countries, Brazil, Russia, India and China) have entered the marketplace as locations for clinical trials, offering access to patients at a numerical scale, rate of randomisation and cost-per-patient that mature markets could not hope to match. Cost advantages are decreasing as these countries develop, but demographic advantages remain.

At the same time, standards of conduct have been raised, with the aim of increasing protection of clinical trial participants. Key developments have included the ICH Good Clinical Practice guideline (1997), the EU Clinical Trials Directive (2001, implemented 2004) and the various versions of the Declaration of Helsinki (most recently in 2008). In the UK, public concern following scandals such as Alder Hay also raised the priority of research governance for the Department of Health and NHS Trusts. These developments have made it much harder to conduct poor quality research, a publicly desirable outcome, albeit with increased administrative costs and (more importantly for clinical trials of patented products) timelines.

These factors, one an inevitable consequence of globalisation and the other clearly desirable, have impaired competitiveness in the UK and indeed throughout the developed world.

There is also a demographic aspect: clinical trials collect evidence that is hoped to demonstrate that a product will be effective in a given patient population, but also in the specific healthcare delivery regimen and socio-economic setting of its intended market. Drugs entering clinical development now could hope to receive regulatory approval in the early 2020s, by which time the increasingly numerous and affluent middle classes in the BRIC countries and beyond could comprise a market of equal or greater value to traditional markets in the “developed world”. If their economic development continues, conducting clinical research in these countries there will become more important regardless of any improvement in productivity in the UK, other EU countries etc.

All of these issues are having an impact on inward investment to conduct clinical research in the UK. With investigational sites in all countries competing to recruit the total number of participants required for a study, slow sites in the UK can lose out to quicker sites elsewhere, with payment following patients. In addition, some pharmaceutical companies and contract research organisations (CROs) are compiling lists of “preferred” countries in which to concentrate their research activities, mainly based on prior performance, and the UK is not always on these lists.

However, much has been done to address this. Common systems to submit study protocols for regulatory and ethics approval, guidelines to improve transparency and consistency of study costs, standardised contract terms, coordinated networks to share expertise and resources, and enhanced infrastructure and structured development and training for clinical research professionals are all having an impact. Implicit in this is the acknowledgement that there are certain therapeutic areas and types of clinical trial where UK sites do still perform well and add value, and it is in these areas where future efforts and investment should be concentrated.

There are still improvements to be made, and the next wave of initiatives were set out last summer in the Office of Life Sciences’ Blueprint. In addition, a process to review the EU Clinical Trials Directive has just begun, with a view to increasing harmonisation of regulation across the EU and reducing the administrative burden of compliance, without sacrificing protection of study participants.

It would be unrealistic to expect the UK to have maintained pre-2000 levels of competitiveness in the face of such strong external factors. Efforts are continuing with the aim of improving absolute performance, but the societal value of improved participant protection should not be understated. The UK should continue to focus its efforts on therapeutic areas and types of study where it performs best and adds most value.

In the first round of feedback with the journalist, I picked up on the aspects that he found most useful, and wrote a couple of summaries on those areas:

• “Like the rest of the economy, clinical research has globalised in the past decade, with rapid access to high numbers of patients now possible in countries that saw virtually no clinical research 15 years ago,” says Andrew Smith, editor of Clinical Research focus, published by the Institute of Clinical Research. “UK initiatives have succeeded in partially offsetting this, but when more competitors enter a market the leaders’ performance tends to be diluted.”
• The conduct of trials was also tightened up by international initiatives such as the ICH Good Clinical Practice guidelines and EU Clinical Trials Directive. The implementation of these into law, in the UK and elsewhere, have increased the administrative burden of clinical trials but have “made it much harder to get away with conducting poor quality research, which is a publicly desirable outcome,” Smith says. Current initiatives are trying to make compliance less costly without compromising patient protection.

I wouldn’t want my publication of this to be seen as criticism of the reporter or his editor, but I would like to get the finer detail of my points “out there”, so readers don’t misunderstand the balance of my views on clinical research in the UK, its recent difficulties, and the efforts that are being made against strong economic forces.

Should ICH GCP be reviewed and revised?

ICH guideline E6 (ICH-GCP) is, along with the Declaration of Helsinki, arguably the most important document in clinical research. Although neither has any direct status in the legislation of most countries where clinical research is conducted, their principles (and in many cases more substantive details) set the tone for how pretty much everyone conducts clinical research. Since its adoption in 1996 (in Europe; 1997 in the USA and Japan), ICH GCP has been the ‘bible’ for CRAs, auditors and other clinical research professionals worldwide.

Since 1996…

The world of clinical research has moved on quite some way in the past 13 years, and even more so when you consider the period of several years that was taken for the drafting, consulting, reviewing and negotiating prior to the guideline’s finalisation. Other guidelines (most notably the Declaration of Helsinki) have been updated several times in the past decades, and have a timeline for regular review every few years.

So, following a remark made by a speaker at the ICR Annual Conference earlier this year, we wondered whether ICH E6 should be reviewed and potentially revised. We put a poll on the front page of the ICR website, and were rather surprised by the result: over 80% thought that it should be reviewed (although from an admittedly small sample). We are currently undertaking a qualitative survey, asking what elements of the guideline should be updated and/or what should be added that did not exist in 1996. We hope to publish this in September’s issue of CRfocus magazine. If you would like to share your thoughts on this, and contribute to our article, please send your comments to andrew.smith@crfocus.org no later than August 10th 2009.

Of course, this is to an extent a purely academic exercise: many of the assorted national legislations, EU Directive etc. are subtly different, and the feasibility of renegotiating such a complex document with so many stakeholders (not least the more recently research-active countries that are outside the formal ICH process) is highly questionable. Indeed, some contend that the national legal arrangements have become so much more formal and sophisticated than they were in the 1990s that any thought of change to a founding guideline like ICH GCP is futile.

Still, it is useful to consider what aspects of contemporary clinical research are poorly served by the current fragmented global network of regulation and guidelines, and how different ICH GCP would look if it were being created in 2009. I’m interested to hear what you think…

End of term reports?

You can tell it’s summer! In the latter part of July, large parts of the clinical research establishment evidently winds down for a summer recess. In the past few days, three substantial and (to a greater or lesser extent) significant reports have thudded onto my desk (metaphorically, of course – I read them as PDFs…)

• Life Sciences Blueprint – A Statement from the Office for Life Sciences (July 14th)
• The Case for Globalisation: Ethical and Business Considerations in Clinical Research (July 21st)
• Appraising the Value of Innovation and Other Benefits: A Short Study for NICE (July 22nd)

I would like to be able to give a detailed analysis of each of these documents, discussing which of their many recommendations seem to be the most feasible and/or helpful. However, arriving so close together (and as we’re getting the August issue of CRfocus to print) I have only had time to skim them so far, so the best I can do is suggest that you take a look at them yourself.

As one early aside, it might be worth considering the OLS Blueprint (an action plan to re-energise and optimise the UK’s innovative pharmaceutical industry) in the context of PICTf, which was a series of reports, workstreams and metrics that ran in the first half of this decade. Much of what has made UK clinical research what it is today had its source in the PICTf work programmes, so it remains to be seen how much of the Blueprint builds on those developments, and how much re-addresses topics that PICTf initiatives didn’t quite manage to resolve. Also, with a UK General Election less than a year away, and a change of government certainly not beyond the realms of possibility, it might be interesting to wonder how many of the report’s 12 key action points would withstand a shift from Labour to Conservative.

Perhaps more likely to maintain its relevance should the Conservatives win power next year is the report by Professor Sir Iain Kennedy’s report on how NICE might better handle the valuing of innovation in its analysis of the economic impact of new health technologies. Although it sticks with the basic ICER/QALY framework, it makes some strong recommendations on what further research is needed and on a pilot scheme for  innovation might be rewarded. This chimes with the “Innovation Pass” idea in the OLS Blueprint, which was initially portrayed in the media as something of a snub to NICE, but is perhaps more an anomoly of publication timings.

If these two reports are quite UK-specific, the middle one is definitely global in scope. Commissioned by the ACRO (the US trade body for CROs, representing the head offices of many of the world’s major contract research organisations) the report aims to demonstrate that clinical research in the “pharmerging” countries is of a comparable standard of safety and ethics of the traditional countries (ie, USA, western Europe etc.) and speed, scale and reduced cost present a compelling case for embracing the shift of larger clinical trials to these new regions rather than railing against it. From my initial reading of the report, this seems something of a tautology: because the studies are commissioned by western sponsors, often conducted by local affiliates of western CROs and designed to collect data to support western registration with the FDA, EMEA etc. is it really surprising that the standards achieved are broadly similar. Still, it’s important for the rest of society to recognise this if they hadn’t already (much of our industry realised this some years ago).

For all three reports, there is then the question of momentum. By the time the world starts getting back to speed in September, we might have had time to ponder some of their more complex recommendations, but others might have forgotten about them entirely! So, let’s make the effort and read them now…

EFGCP workshop on a single clinical trial application for pan-national studies

I’ve just worked out how long it’s been since I posted something here that hadn’t already been published elsewhere (ie, reportage or fresh comment rather than the Table of Contents of the current issue of Clinical Research focus). Things have been a bit manic here in the CRfocus office, with CRfocus and other ICR tasks (mostly related to our website and our 2010 conference) taking priority over blog-only posts. Hopefully, as the summer holiday season gets into full swing, I’ll be able to blog a bit more…

Ironically, today’s the day when I really would have preferred to reporting from Brussels on the EFGCP’s latest workshop, building on the ICREL workshop in December 2008 to discuss possible routes towards a single clinical trial application for multinational clinical studies. This could be of huge benefit to the efficiency of setting up large-scale clinical trials in Europe, and some of the contenders (eg, the “Voluntary Harmonisation Procedure” currently being piloted by the Clinical Trials Facilitation Group (CTFG) of the Heads of Medical Agencies) are very exciting indeed.

Unfortunately, my schedule is such that I couldn’t make it there without some incredibly long-winded travel plans that would have doubtless resulted in substandard reporting anyway…

I’m very supportive of this event, and this project overall. While I’m not able to report on it first-hand, I’m hoping to publish a brief report from someone else who is there today, and possibly arrange an interview or two with key participants over the coming weeks. This is too important a project not to do everything we can to engage everyone in the process.

Take part in our CRfocus reader survey

We’re always looking to make CRfocus better and more relevant to your work in clinical research. To help us with this, we’d be very grateful if you could take a short survey to tell us what you think. The survey is here and at the end of October we’ll draw a lucky winner from all those who complete the survey to receive a prize!

Comment on CRfocus editorial themes for 2009

This is the time of year when we draw up the main editorial themes that CRfocus plans to look at in the coming year. This year, we’re looking to open up this process for comments and suggestions, so please let me know what you think of these topics. Of course, if you’d like to submit an article for any of these issues, please take a look at the “Write for CRfocus” page on the CRfocus website.

So, without further ado, our proposed editorial themes for 2009 are:

• January – Career development supplement
• February – Enabling technologies (EDC, CTMS etc)
• March – Patient recruitment/retention
• April – Getting the most out of labs
• May – Quality matters
• June – Annual Conference reports
• July – Outsourcing/Insourcing
• August – Career development supplement
• September – Therapeutic updates
• October – Multinational studies
• November – Improve your performance metrics
• December – Future of Clinical Research

If you’d like to comment, please add a comment here, or email me directly on comment@crfocus.org.

Have you had a regulatory inspection? Share your thoughts…

I haven’t posted to this blog for a couple of weeks, but I thought it might be useful to add a note about an article I’m working on for a future issue of CRfocus on experiences of routine regulatory inspections. I’m interested in the different styles of inspection used either by different regulators (MHRA, FDA, BfArM etc.), or by regulators inspecting different kinds of company (eg, big pharma, small pharma, biotech, CRO, freelance consultant etc.) What do you think is proportionate and constructive to maintaining appropriate quality while optimising productivity?

I’m also interested in learning about the indirect costs of being inspected, particularly in terms of diverting staff and resources from their regular activity to prepare, take part in, and follow up on the inspection. How do you think this cost (plus the direct cost in terms of inspection fees) matches up to the value that being able to say you’ve passed a regulatory inspection add to your business.

If you have been inspected by your national regulator, or are an inspector who’d like to share their thoughts on this matter, I’d very much like to hear from you, and possibly set up an interview.

Are you going to ICPM next week?

I’m still juggling my diary and travel plans, but I’m hoping to make it along to at least part of the 15th International Conference on Pharmaceutical Medicine (ICPM), held in Amsterdam in the first part of next week.

In a packed 3 day programme, the International Federation of Associations of Pharmaceutical Physicians (IFAPP) and it’s Dutch association the Nederlandse Vereniging voor Farmaceutische Geneeskunde (NVFG) will be mapping out the current state of the art in areas including:

• Translational medicine
• Trial design
• Post-marketing research
• Off-label pharmacotherapy
• Outsourcing
• The evolving system for getting new drugs to market

The meeting will also see the formal launch of the Dutch Medicines for Children Research Network.

For more information, and to book a last-minute delegate place, visit www.icpm2008.org. If you are there next week, please do look out for me…

NICE approves Lucentis but remains in the eye of the storm

Earlier today, the National Institute for Health and Clinical Excellence (NICE) announced its final guidance, approving reimbursement for the use of ranibizumab (Lucentis) and pegaptanib (Macugen) for the treatment of age-related macular degeneration (AMD). This will please many (ie, patients, prescribers, pharma companies and, it seems, the press and the public).

But the decision will also irritate others (ie, the payers), because a course of treatment will cost NHS Trusts up to £10,000 per eye. This is particularly hard to swallow because it will indirectly end the possibility to treat AMD patients with a related drug, Avastin, that is significantly cheaper. Avastin is approved for colorectal cancer, but has been used off-label to treat AMD. The company that developed both Avastin and Lucentis has announced that it has no intention to register AMD as an indication for Avastin, on the basis that Lucentis has been modified in a number of ways that make it more a appropriate treatment. Clearly, delivering more value justifies an increased price, but many observers consider the price increase in this case to be unduly high.

Surely feeding into this decision was the innovative compromise negotiated with Novartis, who markets Lucentis in the UK, for the supplier to meet the cost of any injections required by a patient beyond the 14 specified in the guidance. This is an example of risk-sharing and value-based pricing that I, for one, applaud, and hope to see more frequently.

But despite NICE pleasing many with this announcement, they remain in the centre of a media storm following its recent decisions not to approve a number of drugs for patients with advanced kidney cancer. A few days ago, a number of eminent cancer specialists wrote of their dismay in a letter to The Times. They argued that the UK spends less than two-thirds of the European average on cancer drugs and that the models used by NICE need to be radically changed.

These are two separate points, and agreeing with one doesn’t necessarily extend to the other. The UK is widely regarded as a world leader in the field of health economics, so while I’m sure even NICE would agree that there is room to improve on their modelling, one should not assume that more sophisticated models would bring the UK into line with the rest of the EU; in fact, the models used elsewhere in the EU are likely to become more similar to those of the UK.

The one thing that does differ, though, is public attitude to value, and this is where the question becomes more one of politics than of science or economics. If a society decides to place more value on treating cancer, recognising that this would mean spending less on other conditions, perhaps without such an active patient advocacy group, then the parameters of the health economic model would change and reimbursement decisions might be different.

If a sophisticated analysis is carried out in a timely, efficient way but arrives at an answer we don’t like, the first place to look is the public values used to underpin the analysis. If these are accurate, maybe it isn’t NICE that should be criticised, but society in general.