Triumph of the Market over Science?

One of the most significant news items of the past few weeks was the announcement that Geron will discontinue development of its stem cell products in favour of its portfolio of novel oncology compounds. This news comes less than 18 months after Geron received approval to conduct the first ever clinical trial involving embryonic stem cells, which made it the “poster child” for the sector and gave hope to patients with spinal cord injuries and (indirectly) many other degenerative diseases for which stem cell products are considered to be the most likely route to a cure. This is a significant setback, which will send ripples far wider than the company itself.

It doesn’t seem that the decision was made on the basis of the underlying science, or even the specific compound, being flawed. Indeed, less than a month ago the company gave a positive update on the phase 1 trial on its spinal cord injury treatment. Instead, the announcement spoke of “the current environment of capital scarcity and uncertain economic conditions” and that the decision was made “after a strategic review of the costs, value inflection timelines and clinical, manufacturing and regulatory complexities“, concluding that the move was necessary to ensure there was “sufficient financial resources to reach these important near-term value inflection points for shareholders without the necessity of raising additional capital.“  In short, they chose to focus on less controversial products that are further ahead in their development rather than a product stream with more question marks over its regulatory and political acceptability that might “kill the company” before making it to market.

This was, of course, a pragmatic and sensible decision for a publicly-listed company to make on behalf of its shareholders. However, it is a saddening decision for the science as a whole and sends a worrying message about the capability of the biomedical industry to pursue the step-change type of innovation that it needs in the long-term.

In the near future, companies need to replace their current portfolio of blockbuster drugs (which are effectively “one size fits all”, and were introduced with relatively few constraints on pricing) with a larger portfolio of products, with their price tightly linked to effectiveness in precisely defined patient groups. This presents a set of managerial and economic (and, to a lesser extent, scientific) challenges which, although complex,  are meat and drink for the analysts who drive the investment community. However, this line of development will only get us so far before we hit a barrier where the cost of demonstrating safety, efficacy and value at the individual level outweighs the revenue these products can realise. There is only so much more efficient our clinical development can be…

Then we will need entirely new technologies enabling us to address areas of therapeutic need that are otherwise effectively unmet, such as stem cell technologies. While Geron’s decision is probably the right move in difficult circumstances, it is imperative that it does not provoke the entire industry (or, more importantly, the entire investment community) to shift away from this area of research. Geron shows some degree of commitment to this with its intention to sell or license its stem cell assets to other players, but for this to succeed the investment community needs to have more courage in addressing the regulatory, political and commercial unknowns around stem cell products and to extend its horizon for a return on its investment in this important area.

In the current economic climate, this is a “big ask” but the long term consequences of not doing so would be worse all round.

How Global is our Globalisation?

I’ve been writing in CRfocus about the ongoing globalisation of clinical research for so long that I’m sure many of you reading this know my starting point very well:

• That increasing globalisation is inevitable as a strategic result of shifts in demographics of patient groups and capability of societies to pay for medicines;
• That this shift has been accelerated by tactical advantages around speed and cost of conducting clinical trials; and
• That, provided these clinical trials are conducted with cultural sensitivity and to globally accepted standards of procedural and data quality, this is a ‘good thing’.

But how close is the correlation between the buzz and the truth? There is undisputed interest in many “emerging” countries, but how long is it taking for reality to catch up? Indeed, when we say global, do we really mean global at all?

Recently, I chaired a stream on “managing study globalisation” at the first ICR Symposium. Speakers and delegates alike shared their experiences, interest and commitment to carrying out “global” clinical trials for good ethical, practical and commercial reasons. Many countries were mentioned, and many details were discussed around the intricacies of working in the BRIC countries (Brazil, Russia, India and China) etc. I gave a presentation to close the stream, sharing an analysis I had done of the locations of studies listed in www.clinicaltrials.gov. My conclusion was that, while the pool of countries being used in clinical trials is certainly expanding, and increased attention on these emerging locations is certainly justified, the rate of change is perhaps slower than many might think, and the pool of countries is only expanding by a relatively modest amount.

I compiled a list of the top 25 countries mentioned in all studies in the registry and compared it with studies registered since 2009. While the ranking was altered, there was only one change in the countries listed (Hungary replacing Norway) and the BRIC countries were in both lists (albeit in the bottom half). Re-analysing the data again, to adjust for the absolute number of studies carried out in each country since 2009, only brought relatively minor changes in the composition of the top 25 countries, with a slight shift from Western Europe to Eastern Europe and the BRIC countries remaining outside the top 10 (although with Korea jumping up to 4th). When I asked delegates to highlight any countries they had worked in that were not in this list, only a few suggestions were given, and these were mostly in the next 25 in the ranking model.

So, while 146 countries around the world have hosted at least one clinical trial, the “global” operations of many pharmaceutical companies may well be constrained to only 50 countries, or perhaps more like 35, where it is logistically practical, commercially viable and of regulatory relevance.

There is one fairly major caveat to this analysis: the data I used was at a study level, rather than considering the distribution of sites or even patients within a study. This would mask the impact of studies still conducted in the USA or Western Europe, but with a substantial shift in the proportion of patients recruited from Eastern Europe, Asia-Pacific and Latin America, which is widely considered to be the case.

So, globalisation is increasing, is here to stay, and is a good thing. But, for the moment at least, the pool of countries we are working in routinely is still relatively small. As we gain experience of working in a wider pool of countries, and investigational site teams in those countries gain more experience of working to global standards, these metrics will continue to shift… but possibly somewhat slower than we might expect.

“Rumours of the demise of European clinical research have been greatly exaggerated”

This is not the piece I anticipated writing when I sat down… For the past few weeks, I have been a false harbinger of doom! My apologies to everyone I have spoken to about a “sharp decline” in clinical research in Europe: I have led you astray and caused you undue concern… and all for the sake of insufficiently thorough research.

It all began in June when, on my routine check of the EudraCT website, I spotted that the latest batch of usage statistics had been published (https://eudract.ema.europa.eu/docs/statistics/EudraCT_Statistics_June.pdf). I looked specifically at the metric given for the number of new EudraCT numbers issued since the start of the year, as a reasonable surrogate for the level of clinical research activity around Europe over the coming 18 months. As a “half year” figure is mildly more reportable than other periods, I decided to compare this figure with those from previous years (https://eudract.ema.europa.eu/document.html#statistics). Imagine my surprise, not to say concern, when I worked out that the latest published figure was more than 70% down on the same period in 2010! Keen to check that the first half of 2010 hadn’t been a bumper year for EudraCT, I checked the same mid-point of the few years before that, and in each case found they were broadly similar.

So, in ICR’s weekly news bulletin and in conversation, I duly reported this “fact”, with the intention of writing a piece such as this to explore the reasons for this sharp decline. It was only when double-checking my figures before sitting down to write, that I spotted my error. I pulled together the published metrics for every month since January 2007, hoping to draw a neat trend against which the current figure would be a distressing contrast. I did find a trend: downward, by around 30% from 2007 to 2010.

But then I looked at the 2011 figures. For the first time, current metrics were broadly on-track with those from the previous year. In this context, the June figure that caused me such concern must surely be a transcription error (I have alerted EudraCT to my suspicion, and I expect that they will republish a corrected version of the report in due course), and it looks entirely possible that 2011 could be a turning point for clinical research in Europe. With the cost-gap narrowing between European sites and their competitors in other regions, and the European Commission and national governments alike entirely convinced of the need to streamline regulation and governance processes, it seems that the rate of sponsors leaving Europe to conduct their studies is slowing.

Of course, things will never return to the levels of activity that we saw in the 1990s and early 2000s: the “globalisation genie” is out of the bottle, and a significant proportion of research will continue to be done in the BRIC countries and surrounding regions (for good reason: there are plenty of patients there, who will take part in a clinical trials and, later, form the target market for the drug). But, on a closer analysis of the EudraCT metrics, rumours of the demise of European clinical research have been greatly exaggerated!

Multinational Studies Need Multinational Professionals

The proportion of industry studies taking place in a single country, with the exception of small early-phase studies, has decreased significantly over the past decade or more. This has been an inevitable consequence of globalisation, and if the studies are conducted to the same high standards of ethics, professionalism and data quality, then this is surely a good thing. However, multinational studies have more complex management structures and operate in more diverse environments of national regulation and oversight. Many people working on such a study would have tasks and accountabilities in several of these different environments, and those responsible for the overall conduct of the study must have an appreciation of the differences of approach that are required beyond the level of similarity driven by SOPs. An outcome of this is the evolution of a new generation of professionals with skill sets that didn’t exist 10 years ago. This is the age of the “multinational professional”.

The globalisation of clinical research driven both by demand (ie, pharmaceutical companies wanting more information and experience of new markets in which they hope to sell new drugs) and supply (ie, investigators in more countries wanting the intellectual, therapeutic and financial rewards that taking part in clinical trials can bring for themselves and their patients). The decision to include a new country in a global development programme (as distinct from the decision to exclude an incumbent country) says more about strategic changes in the pharmaceutical market than about the performance of traditional countries: the bigger picture includes dimensions beyond short-term cost and speed of completion. This means that the large, emerging markets will continue to play an increasingly significant role in clinical development, regardless of the success of performance-enhancing initiatives in the UK and other traditional locations. (It’s not a zero-sum game, of course, and countries such as the UK are specialising in the types of study that are most relevant for the national population, and the complex studies that are harder to do in less experienced countries.)

However, there are skills gaps emerging as a result of globalisation. It is well understood that many emerging countries have large numbers of physicians but relatively few of them, and even fewer of their support personnel, have clinical research training or experience. (This is an area where ICR is making a difference, both in our joint venture with the Pan-Asian Clinical Research Association, PACRA, and via our new Global Trainers’ Network.)

The skills required to set-up and monitor investigational sites in emerging countries are also in relatively short supply. While this gap is also being bridged, with global CROs working with, supporting and sometimes acquiring local organisations, the medium-term will still see many experienced professionals either relocating to developing regions or country-hopping to monitor a study in multiple countries.

Thirdly, a whole new set of skills is being developed to manage all these activities. Managers (often based in “traditional” locations) need to develop robust project plans that are more clinically complex than their predecessors but also more complex in terms of diverse national regulations, healthcare organisational structures and cultures, as well as increased logistical complexity around supply of study drug and handling of samples. Management of global teams to deliver these studies also requires skills that were rare a decade ago, such as handling remote team meetings, cross-cultural performance management etc. Increased use of technology makes much of this possible, but this technology also requires new skills to use effectively.

This is not a change that is just beginning: it has been going on for several years and is now effectively the “new normal”. A poll is currently running on the front page of the ICR website (www.icr-global.org) which asks about the proportion of working time spent managing sites or studies outside the country where the respondent is based. The poll is still open and, although the number of responses is still relatively small (n=40 at the time of writing), the trend is clear:

• Fewer than 25% work entirely within their own national borders.
• Over 50% work “mostly” or “entirely” outside the country where they are based.

This topic, and the skills that we need to work effectively within this “new normal”, is one that ICR hopes to discuss in more detail at an event in the near future. This is the age of the “multinational professional”; we need more of them, and in all likelihood it is people like you who will be in the forefront of our profession’s next generation.

How Much Does a New Medicine Really Cost?

If you meet someone at a party and say you work in clinical research, the chances are you’ll be asked “why are medicines so expensive?” The commonly accepted answer to this is “because it costs so much to develop them” but this has become so much of a mantra that we often accept it without really analysing or questioning the underlying figures.

The estimate that is generally accepted and used by industry was last published in 2003 by DiMasi et al,¹ which reported an average cost of $802m and has subsequently been adjusted (albeit only for inflation) to the $1b figure that we all quote. In fact, PhRMA the US trade association calculated a figure of $1.32b in 2006. However, a paper² was published last month that reworks some of this same data, and suggests that the true cost might be much lower: close to $55m! This paper has been picked up by some media outlets and provoked something of a furore… and opened an interesting discussion³ about how such figures are calculated.

There are a number of major differences between the assumptions and modelling methods used in the two analyses. These are discussed in much more detail online, but to summarise:

• Light and Warburton only consider the cost of the development process, excluding the costs associated with discovery/in-licensing and pre-clinical development.
• DiMasi et al assume clinical development and (FDA) regulatory submissions take a total of 7.5 years. Light and Warburton assume this takes 4 years.
• DiMasi’s analysis uses the mean of submitted cost data, while Light and Warburton use the median, which they argue reduces the impact of outlier costs.
• The groups’ treatment of tax on R&D expenditure is different.
• Light and Warburton model the cost of obtaining capital at significantly lower rates (3%, 5% and 7%) and DiMasi (11%). This is consistent with US and Canadian government guidelines, but some commentators think that this figure is unrealistically low for a sector where so few products entering development ultimately reach the market. Indeed, the cost of capital and the opportunity cost of not investing it elsewhere makes up a significant proportion of DiMasi’s estimate.
• Light and Warburton based their model on a “typical cohort” of 100 approved drugs, including a proportion of non-NME drugs which would have significantly lower development costs.

As with most things, some may have political reasons for wanting to portray development costs as very high or very low, and a more accurate estimate would almost certainly be somewhere between the two. Many of the assumptions and methods of Light and Warburton’s paper have been strongly criticised in comments. Based on anecdotal evidence from individual studies and ‘quick and dirty’ modelling based⁴ on benchmarking data published in 2006,⁵ contributors gave an estimate of $100m for the clinical studies required to bring a single drug to market. Again, this is low compared with the DiMasi figure because it excludes costs for discovery, pre-clinical, pharmacovigilance, cost of capital etc.

Another interesting question is how we might expect these costs to have changed since 2000, aside from simply adjusting for inflation. Studies are typically becoming more complex and thus more expensive; however, increased use of technology and automation should have reduced the cost of some activities. Increased outsourcing has enabled pharma companies to be more agile and save on total personnel overheads; however, paying for study teams CROs or staffing agencies would be expected to increase the per-study personnel cost. Similarly, changes in the wider economy may have influenced the attitude of investors towards the risks of drug development compared with other areas of technology; this might make DiMasi’s 11% too high for the current conditions or, indeed too low, given the prospects of reduced pharma revenues as we hit the ‘patent cliff’. The increasing globalisation of clinical development would also be expected to reduce the per-study costs, although the short-term net financial impact on pharma companies would be at least partially offset by restructuring costs.

So, comparing Light and Warburton’s $55m with DiMasi’s $1b is actually rather like comparing apples with oranges. Each may have some of their assumptions correct, and controversy remains over which has the more accurate methodology. On balance, many reading this will tend to side with DiMasi’s analysis, but as this is based on data nearly a decade old and pressures on price and value have never been stronger, perhaps now would be a good time for a really rigorous and industry-validated answer to the question of “how much does a new medicine really cost?”

References

1. DiMasi J, Hansen R, Grabowski H (2003): “The price of innovation: new estimates of drug development costs” J Health Econ 22 (2): 151–85. doi:10.1016/S0167-6296(02)00126-1 [Accessed March 8^th 2011]
2. Light & Warburton (2011): “Demythologizing the high costs of pharmaceutical research”, BioSocieties 6: 34-50; advance online publication, February 7, 2011; doi:10.1057/biosoc.2010.40 available via www.palgrave-journals.com/biosoc/journal/v6/n1/pdf/biosoc201040a.pdf [Accessed March 8th 2011]
3. Noah T (2011): “The Make-Believe Billion”, Slate http://www.slate.com/id/2287227/ and subsequent comments [Accessed March 8^th 2011]
4. Ibid, comment by “Guosong Liu”
5. Cutting Edge Information (2006): “Clinical Operations: Accelerating Trials, Allocating Resources and Measuring Performance” Press release published on LifeSciencesWorld www.lifesciencesworld.com/news/view/11080 [Accessed March 8th 2011]

 

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.

OLS Blueprint: PICTf 3.0?

The UK pharmaceutical industry is one of the most significant industries to make money for ‘UK plc’ and re-invest it back into UK-based R&D, within their own organisations, in universities and throughout the NHS. As many have said, the UK ‘punches above its weight’ in our sector. Despite this, we often feel unloved, in terms of both media and public opinion and increasing constraints on revenue (eg, prescribing decisions being led by NICE guidance while reimbursement rates have been cut under the successor to the PPRS). However, the counter-balance to this top-line constraint has come in the form of various initiatives to make more of a contribution in terms of investment in education and training, infrastructure and organisational processes. As a globalised industry has far less binding ties to doing its R&D in the UK than it did 30 years ago, this policy makes a great deal of sense. Over the past decade or so, these initiatives have come under the banners of PICTf, UKCRC and, now, the Office of Life Sciences (OLS) Blueprint, which was published over the summer.

The Blueprint set out 12 key action points, which have been agreed across government, industry, the higher education sector and the NHS. This expands to 10 pages of specific policy measures, complete with timelines and budgets. The Blueprint has been widely welcomed by industry and commentators alike, and certainly, every policy measure should have a positive effect.

The measure that has received the most coverage is the Innovation Pass, ring-fenced funding for time-limited use across the NHS without appraisal by NICE (although NICE will define the criteria for medicines that can take this short-cut). This will be piloted in 2010/11 with a budget of £25m. While initially portrayed by the media as bypassing NICE, this could be a valuable experiment in ‘live appraisal’ mirroring the ‘live licensing’ model proposed by PricewaterhouseCoopers in their Pharma 2020 reports.

The policy that will be of most interest to us in the clinical research sector is the “package of measures to improve the UK environment for clinical trials”. This includes ensuring the UK “fully exploits its potential to be a world leader in heath informatics” (ie, making electronic patient records finally happen!), underlining the duty for SHAs to promote R&D, adding metrics on patient in clinical trials to Trusts’ Quality Accounts, and creating a national framework for local management of research (ie, transforming NHS R&D departments). Significantly, the last three points are essentially reworking areas covered by PICTf nearly a decade ago…

The questions that need to be asked about all these measures, though, are “Will they be implemented as planned?”, “Will they result in improvements in the productivity of UK R&D and uptake of resulting products?” and “Are they sufficiently different from previous initiatives to justify the top-line reduction in reimbursement for medicines?” The many intelligent and powerful people close to this project evidently think so. Far be it from me to disagree, but the fact that this is the third major initiative in less than a decade suggests that its predecessors did not maintain momentum in their improvements (or, more cynically, that pharma are getting increasingly itchy feet in the light of increasing competitiveness overseas).

To sound another small note of scepticism, the UK is less than 12 months from a general election, with a change of government far more possible than at any time since 1997. Although many measures in the Blueprint can be implemented almost immediately, many will take time to demonstrate success, and none will be immune from reversal under a new government.

So, I would like to raise two cheers for the OLS Blueprint: it talks a good game and will certainly have some success, but will it be enough to steady ship of UK competitiveness or just the latest in a series of defences against an insuperable drift to merely “punching our weight”? We will see…

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…