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…

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.

CRfocus: Table of Contents of April issue

CRfocus 20(04) – April 2009

This is the Table of Contents of Clinical Research focus 20(04) for April 2009. Members of The Institute of Clinical Research can click on the links to read the full text of each article.

Weathering the storm

Consolidation or Sea Change?

Andrew Smith

In the current economic climate, it’s easy to reach the conclusion that the recent high-profile mega-mergers (eg, Pfizer/Wyeth, Merck/Schering-Plough etc.) are simple industry consolidation. 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. Andrew explores…

What a Difference a Year Makes: Survey of Executive Confidence

Tim Ewbank

The past 12 months have seen economic turbulence on a scale no-one could have predicted. So how has this impacted on the pharma and biotech sectors? Harten Group’s seventh annual industry survey takes a look at the facts behind the headlines. Tim Ewbank presents some of the findings of this research.

Maintaining a Positive Outlook: Survey of Jobseekers

Jonathan Hart-Smith

Following a recent survey at the beginning of 2009, jobseekers within the UK pharmaceutical and biotechnology industries have a very positive outlook. Their positivity is a breath of fresh air in stark contract to the general mood for the economies of Western Europe and the USA. Jonathan Hart-Smith presents the findings of this survey.

Research integrity

Investigating Serious Non-Compliance: Planning & Conducting For-Cause Audits

Nigel Crossland FICR Csci

A for-cause audit is defined as an independent and objective examination of a clinical research study in order to confirm the circumstances of a reported incident of serious non-compliance. In this article, Nigel describes some of the principles and practicalities involved in ‘for-cause audits’ and shares some examples of their findings.

Research Integrity: A European Perspective: EFGCP conference report

Andrew Smith

This year’s EFGCP Annual Conference, held in Prague at the end of January, aimed to provide a European perspective on integrity in the conduct and publication of clinical research. Andrew was there, and presents commentary on selected presentations, as previously reported on the CRfocus blog.

Book review

“The Trouble with Medical Journals” by Richard Smith

Reviewed by Debbie Early MICR

Prof. development

Tools & Updates: CTA Workshop Report

Judi Eaton

Judi reports on the latest ICR CTA workshop, aiming to give CTAs everywhere ‘Tools & Updates’ as part of the ‘Maximise Your Potential’ series. Topics included the draft CTA Handbook, a regulatory and ethics update and the ongoing development of the Integrated Research Application System (IRAS).

Regular updates

Our Institute, Our Future: Message from the Chair

Janette Benaddi MICR Csci

In her first message as Chair of ICR, Janette pays tribute to her predecessor, Susan Ollier, and sets out her vision for the coming year. During difficult times, it is important that we continue to support you in your careers and ensure that we are meeting your expectations. Janette explains that we are going to embrace these challenging, changing times and continue to add value to the services we provide for members of ICR.

It’s Not All Work, Work, Work…

Andrew Smith

Our regular look at the lighter side of clinical research, including “Ten things we hope sales & marketing won’t say to clinical” and engaging with patients in a “hip hop stylee”…

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.

CRfocus: Table of Contents of March issue

Making up for the delay with February’s Table of Contents, here is the Table of Contents for the March issue of Clinical Research focus 20(03). Members of The Institute of Clinical Research can click on each link, and log in to read the full article. If you want to become a member of ICR, visit www.icr-global.org/membership for more information.

Patient recruitment & retention

Adjust the Focus on Recruitment & Retention: Enabling CRAs to Develop & Implement Site-Specific Plans

Sherry Armstrong-Wilkinson MICR

If you want recruitment and retention to succeed, then it’s time to adjust the focus on where investment is made. When selecting and training CRAs, how much time and investment do we put into developing skills and expertise that will allow them to support sites fully in the development of robust and strategic recruitment strategies? Sherry explains how a strong, dynamic relationship between investigators and CRAs is crucial for optimal site management and is vital for devising and implementing successful site-specific strategic recruitment and retention plans.

Exploring Patient Recruitment: NIHR Primary Care Research Recruitment Methods Group

Elaine Ward, Julia Miller & Brendan Delaney

As government policy is encouraging a larger number of patients to be seen by clinicians in the community, more clinical research studies require some recruitment in primary care. The Research Recruitment Methods Group came together in 2007 in a bid to begin to tackle recruitment barriers in primary care. Between them, the members of this collaborative group have had considerable experience of research conducted in general practice settings. Their aims are to improve delivery of clinical trials by exploring the factors which affect recruitment and then to develop a programme to systematically test the impacts of those factors. The authors discuss this group’s past, ongoing and future activities.

Factors Driving the Evolution of Digital Outreach for Patient Recruitment

Gaynor Anders, Mary Schwarz & Jake Perez

Most are aware that the role of digital media, particularly the internet, in recruiting patients for clinical trials has been steadily expanding in both availability and acceptance worldwide. But, what has driven the emergence of digital outreach for patient recruitment and where is it headed? The authors take a brief look at how we arrived at the present use of digital media in patient recruitment and look ahead to its future applications. They also consider the driving forces for both the past and future evolution of digital outreach for patient recruitment and the implications for the clinical trial landscape.

Planning for Success in Patient Recruitment: An Interview

Missy Orr

Missy Orr is Executive Director, Sites and Patients Services at PPD. Missy joined PPD in 2003 and oversees the global operations of patient recruitment activities. In this interview, we break down the component parts of patient recruitment, discuss why an approach might be successful in some places but not in others, and consider that patient retention doesn’t get the attention it deserves. An audio version of the complete interview is available to download.

Features

Real World Data: An Important Addition to Your Late Phase Development Plans

Samantha Marshall

Traditionally, ‘real world’ observational research has been criticized for lacking the robust scientific methodology of RCTs. However, with the shift in NHS requirements, the focus of clinical development needs to change to ensure a well-rounded development plan that includes not only RCTs but also more pragmatic research in real clinical practice. Samantha explores…

Health Technology Assessment in the UK & EU: NICE & EUnetHTA Conferences

Alan Jones

Alan gives us our regular update on the latest developments in Health Technology Assessment, how it impacts on reimbursement for the medicines and devices we help develop, and how its importance will only increase for people designing and conducting clinical trials. This extended version of the article includes more detail on both the NICE and EUnetHTA conferences than was possible in the printed version.

Viewpoint

Research Integrity vs Getting the Joke

Andrew Smith

Were ‘cellist’s scrotum’, ‘guitarist’s nipple’ and the PIGPEN study on the treatment of headlice simply a bit of light relief for overworked physicians, or dangerous distortions of the scientific record… or even disease mongering? Andrew eschews his usual humorous streak to suggest that unacknowledged hoaxes in primary medical journals might not be a great idea…

Regular update

So Long, Farewell, Auf Wiedersehen, Goodbye…: Message from the Chair

Susan Ollier MICR Csci

Susan Ollier, Chair of ICR until she reaches the end of her term of office at the Annual General Meeting on March 17th, looks over some of our recent achievements, thanks those who have made it all possible, and says a fond farewell to the colleagues and friends she has met along the way.

Panel discussion on development of clinical trial protocols

Following on from the last presentation of the morning session, the speakers came back to discuss the morning’s topics.

Initial discussion concerned lists and flowcharts to summarise what needs to be done and what data needs to be collected at which visit. Sue Mackay agreed that this would be useful, but some sponsors prefer to avoid duplication wherever possible. This is precisely the kind of thing that the CDISC standard discussed earlier would resolve.

A delegate followed up by asking what sort of aid site staff use to schedule visits and activities. This varies according to the type of study (eg, patient types, working hours etc.) but Sue Mackay said she tries to create a schedule as far as possible. Adam Jacobs said that including this in the protocol would be beneficial. Another delegate said that this could cause confusion over which document is the source document for GCP purposes. In many cases, patient notes are used; eCRFs are being increasingly used, although these can be restrictive if patients report additional information.

Another delegate raised the issue of global trials, where practical issues differ between regions. Sandra Waechter mentioned that some units make local protocol amendments to accomodate local differences in care.

Adam Jacobs discussed the pros and cons of detailed protocols vs broad protocols with more detailed appendices. One delegate questioned whether we could ever reach a ‘perfect’ protocol when it needed to meet the requirements of such a diverse set of stakeholders. Adam stressed the importance of having time to do the job properly: the situations in which his team have had problems have been when time pressure (eg, to meet an ethics deadline etc.) has been extreme. Although as little as 3 days is required to do the actual writing of the protocol, he agreed with the earlier speaker that 3 months would be an appropriate period to allow for the discussion, reviewing and negotiation processes.

Blogging from the ICR/EMWA joint symposium next week

I will be blogging live from (at least part of) the ICR/EMWA joint symposium next week. The meeting takes place at the Novotel London Paddington on February 24th, and is the second joint meeting arranged by the Institute of Clinical Research and the European Medical Writers Association.

The meeting is titled “Writing Protocols: Collaboration and Compromise or Conflict and Confusion?” and aims to bring together the different players involved in writing protocols for clinical trials, providing a forum for them to discuss and debate their different points of view. Presenters and panelists will include experts representing the different facets of clinical research, including medical writing, monitoring, project management, ethics committees and the investigative site.

The aim is to publish a full report of the conference in the July issues of CRfocus and The Write Stuff. As I did last year, I will be reporting on some of the sessions direct to this blog, with the other sessions being reported by Alex Dedman of Scinopsis.

I understand that there are still delegate places available for this meeting, at only £225 for a member of either ICR or EMWA (£325 otherwise), so visit the ICR website to find out more.

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?

ADVANTAGE study on Vioxx raises questions about “seeding studies” & scientific value

Earlier this week, a paper was published in the Annals of Internal Medicine that reviewed internal paperwork around MSD’s ADVANTAGE study on Vioxx, conducted shortly before the drug’s marketing approval by the FDA in May 1999. The paper is written by four physicians who took part in the litigation against MSD over Vioxx on behalf of patients, and draws on documents that were obtained to inform these legal proceedings. Some of these internal documents use the word “seeding”, and the authors contend that other aspects of the study also correspond with “seeding studies”, arguing that the FDA, ethics reviewers, investigators and patients were misled when they were not informed of market development and raising product awareness with potential prescribers as motivations behind the study.

This conclusion is the story that has been taken up by news agencies around the world, and also widely around the “blogosphere”… particularly by bloggers specialising in injury litigation. I haven’t yet seen much in the way of more rounded discussion of the issues raised by this paper.

Of course, true seeding studies, which investigate questions of spurious scientific value, using unnecessarily large numbers of investigators to give them information, access and experience with a drug at the optimum time to drive future sales, are “a bad thing”. Whether the ADVANTAGE study fits this description is a question on which I won’t offer an opinion: the authors of the original ADVANTAGE papers strongly dispute this, as demonstrated by a response to this week’s paper by Jonathan Edelman, Executive Director of Merck’s Global Center for Scientific Affairs.

The more important issue, though, is how we can stop seeding studies from being conducted. In an excellent commentary to the current paper, Harold Sox (Editor of AIM) and Drummond Rennie (Deputy Editor of JAMA) remind us that there are many levels on which we can “just say no” to them: regulators and ethics reviewers can withold approval, and each individual investigator can simply decide not to take part. This revolves around an assessment of the scientific value of the study, in the context of the current knowledge and understanding of the drug. This can be a fairly subjective judgement, but Sox and Rennie issue a “call to arms” to consider these issues more deeply every time an investigator considers a study.

My own take on this issue is that it’s all about the scientific value. If a proposed study is appropriately designed to answer a valid question, does it really matter if there are additional motivations behind the scenes? These could be the future sales of a newly-approved drug, but could equally be a portfolio of publications in the run-up to a review of academic funding. In the light of this, maybe they should be renamed “vanity studies”…

The current paper offers an understandable view of a specific study, of detailed interest only to one pharma company and the many lawyers and ex-patients involved in seeking recompense for a drug that didn’t work as well as anyone had hoped. However, the broader issues it raises are of great importance to clincial research professionals everywhere, and a strong reminder that we should always consider validity, appropriate design and scientific value with regard to every study we work on.