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…

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.

Always Compete on Value; Never on Cost

The title was a maxim drummed into me at the start of my career. I’ve said before, as have many others, that a recession is not something to be simply ‘ridden out’, but as far as possible to be invested through. When the economic upturn comes, the individuals, organisations and indeed countries that will be best placed to succeed will be those that have continued developing through the lean times. Others, who might have survived by pulling in their horns, will need to adapt suddenly to an environment that has changed commercially, socially, demographically and scientifically. Simply minimising costs will not be enough.

We’ve seen wave after wave of initiatives to improve the efficiency of processes and as a result we’ve become very good trimming a few percentage points off the cost of delivering a study. If what’s important is completing Study X within budget, then this is ‘a good thing’, and many feel that this is the case. The problem is that it’s tempting for organisations to focus too exclusively on cost minimisation. When you’re very good at using a hammer, everything looks like a nail. However, this neglects the bigger picture and the importance of creating additional value for companies, shareholders and society as a whole.

In the short term, quality is better at creating value than cost minimisation. Data obtained cheaply but that is not robust is of no value, with rework outweighing any cost savings. (Improving quality to eliminate rework is one way that techniques such as Six Sigma reduce costs.)

In the medium term, speed is better at creating value than cost minimisation. For a treatment that makes it to market, a few extra months of on-patent sales will be worth far more than thousands of pounds saved during Study X. For a treatment that isn’t going to succeed, being able to make that decision earlier eliminates the cost of Studies Y and Z.

In the long term, strategy is better at creating value than cost minimisation. By far the best way to create value is to get better at planning the development programme. Compounds entering development now will face different challenges to demonstrate safety and efficacy, scientific developments enabling more precise targeting of responders and non-responders, traditional markets seeking more detailed analysis of socio-economic impact to justify pricing, new markets increasing dramatically in importance and patients being more vocal in specifying what they want from a treatment. Many of these factors will influence or even contradict each other, making it vital to have a detailed and integrated understanding of the entire picture. While some of these strategic insights will come from the clinical/regulatory sphere we are all familiar with, others will involve experts in economics and marketing.

Maximising value and minimising cost certainly aren’t exclusive. It could be argued, for example by CROs, that as long as someone is thinking about the bigger picture, then it’s okay to concentrate solely on containing costs. However, that’s could be short-sighted, because having efficient processes is of little long-term value if they can’t cope with the changing goals of future development programmes. In fact, with a broad view and portfolio of clients, being able to offer such strategic insights could be a deal-winner.

It might seem counter-intuitive, but when the overall level of business risk is high, the relative risk of trying to leap ahead through strategic innovation is actually lower than in ‘boom’ years. Some companies will fail, but some will fail anyway, and those that innovate and survive will secure their place at the forefront of the industry for a generation.

Consolidation or Sea Change?

Less than a month after Pfizer bought Wyeth for $68bn, today’s big merger news is that Merck will buy Schering-Plough in a deal worth $41.1bn. In the current economic climate, it’s easy to reach the conclusion that this is simple industry consolidation, with the cash-rich companies opportunistically buying up those less fortunate, integrating the businesses and continuing as before. But, as we’ve pointed out in CRfocus previously, the link between the global economic turmoil and the changes in the pharmaceutical industry is perhaps less direct than one might think…

Analysts have argued that the pharmaceutical industry is one of those least threatened by the global recession: big pharma companies are less highly leveraged (ie, funded by debt) than their comparators in other industries, many have substantial cash ‘cushions’, and share prices already reflected investors’ knowledge of the impending ‘patent cliff’ facing many companies in the next few years. Indeed, you could expect the sector to outperform overall stock markets as investors flee other ‘blue chip’ industries (eg, financial services, automotive industries etc.) that are suffering the brunt of the crisis.

So, if this isn’t a ‘fire sale’ to prevent Company X from going under (which, at these prices, it clearly isn’t), then why are these mega-mergers coming thick and fast at the moment? My view is that it’s a rush for a ‘critical mass’ of intellectual property, bargaining power and cash. The goal is to propel big pharma from the “invent it here, develop it here, sell it here” model that was the only game in town 20 years ago to the “license in candidates, contract out development, manufacturing and sales” model that’s been discussed in recent years as the only way to make big pharma sufficiently diverse and agile for the future. In the short term, this requires a pipeline broad enough to navigate the patent cliff safely, with key patents on many high-earning drugs expiring in the next couple of years. In the longer run, though, access to huge quantities of resources is vital, to manage such a deep strategic change while mitigating the operational shock and potential brand damage of changing how tens of thousands of people and their associated infrastructure are deployed.

I’ve previously commented that these changes of ownership will make relatively little difference to how clinical research itself is conducted: scientific requirements and professional standards are unchanged, and there is still more demand for clinical research than there are professionals to perform it (or patients, for that matter, but that’s another story…). Company cultures will differ, as will the precise nature of the SOPs to meet these professional standards and scientific requirements, but we will mostly be doing the same tasks, albeit increasingly in the CRO sector rather than within pharma.

This could make work more complicated, as the ground rules of successive studies change subtly as we work with a wider variety of sponsors, on studies that are getting increasingly complex anyway for unrelated, medico-economic reasons. However, it should also make life more interesting, as we work in a diversity of therapeutic areas.

So, is all of this a ‘good thing’? I’d have to say that it is, because the expiry of key patents is the ‘elephant in the room’ throughout the pharmaceutical industry. We may be well placed, as a sector, to ride out the current turbulent times but our own crisis was looming well before the financial services industry started crumbling. The political appetite for bail-out funds will almost certainly be gone before anyone in our sector needs one, so we need to take advantage of this opportunity to change the way our industry is organised.

Research Integrity vs Getting the Joke

In a recent letter to the British Medical Journal, Elaine and John Murphy confessed that their 1974 letter, in which they described a condition called “cellist’s scrotum”, had actually been a hoax, as humorous one-up-man-ship in response to a letter about “guitarist’s nipple”… which appears itself to have been another hoax! Responses to the letter were also witty, including a poetic reprimand, accounts of patients who had given up playing the cello following self-diagnosis (which may or may not have been truthful), and confession of another hoax study (on treatment of headlice) that is still indexed in Medline.

The lesson for readers is that publication in a prestigious journal is no reason for us to suspend our critical faculties. Anyone who actually watched a cellist perform should spot the physical impossibility of the condition. Similarly, anyone reading the paper on headlice should spot the spoof within the first sentence of the method… or even from the cultural reference to Charlie Brown in the name of the study (“PIGPEN”).

So, now the fun’s all cleared up, we can get on with the rest of our lives? Well, perhaps not… I don’t want to seem like a kill-joy; in fact, I’ve written several spoof articles for CRfocus over the years, plus the more overtly jokey “It’s Not All Work, Work, Work…” section at the back of issues since September 2008. The problem is that humour is subjective, and you need a certain level of awareness of the context of readers to be confident they’ll get the joke. Readers of the BMJ are smart, educated people, and within the immediate timeframe of publication they should get the joke… but some might not, and the further away you get from the cultural context of the joke (eg, non-musicians, people who didn’t grow up with the comic-strip culture of the 60s and 70s, non-medics who believe everything they read in medical journals etc.) the larger this latter group is going to get.

Medical literature is a permanent record, as much for the benefit of future physicians as for current ones. If an individual correspondent distorts this record with a hoax, it’s “all a bit of fun”… but if someone looks at a paper without the cultural background or the time to think critically about what they’re reading, patients could be treated differently as a result. If the letters had come from other sources, would “guitarist’s nipple” and “cellist’s scrotum” be considered disease mongering?

Is there a place for humour in medical journals? Can intelligent people with extensive shared knowledge and experience enjoy each other’s wit and feel more of a community as a result of shared jokes? I would like to think so, but perhaps with the addition of a “spoof” keyword to avoid anyone taking it too seriously… not to mention helping those of us who get the joke to find more things to laugh at…

Unthinkable!?

If you dig past the current economic doom and gloom spread throughout the media, you’ll come across the idea that a recession can actually be a great time to be innovative and entrepreneurial. If this can (and does) happen in the wider sphere of business, I would argue it can (and should) also happen in the development of new medicines.

Despite the instinct to stop training, stop advertising and stop investing in R&D, this is the very last thing we should be doing. Some will survive the next couple of years by simply cutting costs, but they will emerge into a world where the old models no longer apply. The rules will have been changed by maverick organisations who kept looking for the next big thing, and individuals who could ‘think the unthinkable’.

This ‘unthinkable’ might be a genuinely new idea. But, like stories, there are only so many, and once we start constraining ourselves into a specific sector, genuinely new ideas are rare. A far more approachable category of unthinkables is those ideas that pop into our heads from time to time but are swiftly forced out again because we can’t see a way to make them feasible, beneficial or politically acceptable. If we can set aside the voices of criticism and negativity (whether internal or corporate) and try to view these unthinkable ideas in a different way, we might be able to do something with them.

This generally requires someone to look from a different perspective, to change how we interpret an idea or situation, perhaps as radical as taking a view diametrically opposite the ‘conventional wisdom’ to see whether the boundaries we imagine simply disappear. (As an exercise, try to think of ways to interpret the current recession in a positive way.) This, in turn, requires a dynamic kind of optimism or, to borrow the vocabulary of an American politician who is likely to define the next few years, “hope, for change”.

Of course, the problems facing us in clinical research are exacerbated, but not created, by the current economic turmoil. Patent expiries on blockbusters reduce the revenue we can plough back into R&D; regulators raise the bar for the size of patient safety databases; governments base reimbursement decisions on evidence for patient value; and drug discovery hands us candidates that we can’t find enough patients to test, let alone enough professionals to conduct the studies… It would be easy to get depressed by this ‘perfect storm’, even before the recession hit!

But, for a moment, try to look at this situation from a hopeful, positive perspective. If the current recession can be viewed as an opportunity for the next generation of innovators to change the way business will be done for the next decade, can’t the same be true for clinical research? If this is what it takes for us to change the way we evaluate new medicines, creating a model that is a step-change more effective and efficient than at present, then would it be unthinkable for me to say that we can view our situation in a positive way?

Who’s Buying, Who’s Selling? And Will It Make Any Difference?

One of the few news stories in the past few weeks not to be entirely ‘doom and gloom’ came from the widely-reported Datamonitor study that suggested some pharma companies might be quietly cheering the looming global recession. This is because big pharma companies are generally less ‘leveraged’ (ie, funded by borrowing) than many other industry sectors, particularly in comparison with their venture capital-funded colleagues in small biotech companies. The current problems facing many businesses could be used as an opportunity for pharma to open their ‘war chests’ and snap up some acquisitions to bolster pipelines (and share prices) for far less than might otherwise have been the case.

The flagship acquisition for this model was the spectacular emergence of Lilly as the ‘mystery suitor’ that snatched biotech company ImClone out of an increasingly bitter bidding war (and war of words) with prospective buyer Bristol Myers Squibb that had been going on since earlier this year. The purchase, worth $6.5 billion, gives Lilly a best-selling oncology compound Erbitux, along with a healthy pipeline and platform of other products in development.

Although any move of this value is risky (Lilly CEO John Lechleiter stated that “We place risky bets on our pipeline. This is what our shareholders expect us to do.”) the strategic thinking behind it is solid. It is the timing, though, that is significant; at a time when many companies are ‘battening down the hatches’ for a bumpy next few quarters, Lilly was willing (and able) to make a big investment to help transform its future portfolio. The authors of the Datamonitor report argue that this won’t be the last substantial acquisition in the coming months, as routes to other sources of funding dry up and venture capitalists look for liquidity to offset losses in other industries.

All of which is interesting enough… but how much will actually change for us down ‘at the coalface’, working on the clinical development of these pipelines? With many pharma studies now staffed by contract personnel or outsourced entirely to CROs, does the ultimate owner of the compound impact on the development process itself? Even when re-organisations lead to redundancies, the increasing volume of clinical research means that these are more a strategic shift in how studies are resourced, and experienced staff are quickly snapped up by other companies, possibly even to work on the same study although ‘wearing a different hat’! With overall revenues per compound declining, and increasing automation in manufacturing etc., our colleagues in other business units might not be so fortunate…

The current economic pressures were the trigger, but not the cause, of the current round of merger and acquisition activity, and any consolidation should enable us to meet the increasing demands of the next few years more effectively. At a personal level, any change of employer is somewhat traumatic, and different companies having differing cultures and ways of working, but the overall goal of clinical research, and the activities required to reach it, are the same for every organisation.

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!