Interview: Simon Day on subgroup analyses & bridging studies

Simon Day is a Statistical Expert at Roche Products, and is both Past President of the International Society for Clinical Biostatistics and Joint Editor of the Journal of the Royal Statistical Society. He was formerly Head of the Statistics Unit at the MHRA, and also sits on an ethics committee. Simon will be speaking at the ICR Annual Conference in London on May 14th 2012, where he will speak on the transferability of foreign data, asking whether the current standard methods of subgroup analyses and bridging studies provide sufficiently robust information when looking to apply clinical trial data generated in one region to prescribing decisions elsewhere in the world.

Hugo Cervantes of Deloitte on reversing the decline of IRR in pharma R&D

A new report from Deloitte looks at the decline in Internal Rate of Return (IRR) across pharma R&D, and suggests that improving late stage success rates has a far greater impact than reducing cost or development times. We spoke to Hugo Cervantes, one of the leading contributors to the report, about what these findings mean, and what pharma can do to improve the situation, from closer collaboration to a sharper focus on value throughout the development process.

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.

Interview: Steve Read on Inspirational Leadership

Steve Read is Managing Director of Adair International and the Helix Consultancy. Andrew Smith speaks with him about leadership in business and how professionals in the pharmaceutical industry can develop their leadership skills. Steve will be one of the presenters at the ICR Masterclass on Inspirational Leadership, to be held in central London on December 9th 2011. For more information, and to book your place, visit www.icr-masterclass.org.

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.

Clinical Research focus 22(2) – Table of contents for CRfocus March 2011

This is the Table of Contents of Clinical Research focus 22(2) for March 2011.

ICR members can download the entire issue [login required] using our eCRfocus service.

UK research networks

Lessons Learned from the North West Exemplar

Andrew Smith

In January, the report on the second phase of the North West Exemplar Programme was published, demonstrating that the personnel, tools and infrastructure available to facilitate commercial clinical research in the UK can result in set up and study delivery metrics that are comparable with the highest performance across Europe The report also makes over 60 recommendations on how this level of performance could be achieved consistently across the NIHR Clinical Research Network as “business as usual”. Andrew Smith looks at some of the recommendations in more detail, including comments from an interview with John Matthews, who is currently Director for Industry at the NIHR CRN Coordinating Centre. MICR and FICR members can also download an audio version of the whole of this interview.

More Effective Patient Recruitment: How Clinical Research Networks can Can help Help

Judy Ford RICR

In 2006, the Department of Health set up the National Institute for Health Research (NIHR), with the aim of creating a world class infrastructure for conducting high-quality clinical research, particularly randomised controlled trials. This article looks at how the CRN can help with achieving recruitment targets and how researchers can gain access to network assistance. Judy explains the three ways in which the NIHR research networks can help to achieve recruitment targets: selection of sites that are likely to deliver to time and target; infrastructure to enable sites to succeed; and performance management to identify and address problems at an early stage.

Professional development

Filling the Gaps: CRA Forum Report

Lynette James MICR

The 2010 CRA forum took place at London’s South Bank University. The forum was well attended by attended by a broad spectrum of delegates representing CROs, pharmaceutical industry and academia. Lynette James reports on a programme that included an industry perspective on study start-up, discussion of contracts, costings and R&D approval, monitoring electronic source data, archiving at the investigational site and health economic analysis of trial data.

Viewpoint

How Much Does a New Medicine Really Cost?

Andrew Smith

The estimate for the cost of bringing a single new medicine successfully to market is generally accepted to be around $1b, based on study data published in 2003 and subsequently adjusted for inflation. However, a paper 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 discussion about how such figures are calculated. Andrew Smith reports, and wonders whether the analysis should be updated from scratch.

ICR update

See You at the Annual Conference: Message from the Chair

Janette Benaddi MICR CSci

As this issue of CRfocus lands with you it will be very close to our ICR annual Conference which is on March 21st and 22nd. Janette welcomes all members to come along to the conference, and pays tribute to the team who have made it all happen: the Spring Meeting Working Party and the ICR staff who have spent months preparing for this flagship event.

Embracing the Future: Annual Conference Preview

Andrew Smith

It’s that time of year again: here at the ICR office, we are making the final preparations for our Annual Conference, which is just a few weeks away on March 21st and 22nd. The conference is ICR’s flagship event, and a high point of the year for clinical research professionals. Delegates, speakers and exhibitors come to learn about and discuss the issues facing professionals in their work designing, managing and conducting clinical trials. It has never been more important for clinical research professionals to embrace the future and to engage with their peers in a way that can only really be done through professional bodies like The Institute of Clinical Research, and through events like this conference. Andrew provides a preview of the conference, sharing some highlights of the programme, details of the exhibition hall and some of this year’s new events, such as the awarding of a Research Training Fellowship and the finals of the inaugural ICR Team Challenge.

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]

 

Clinical Research focus 22(1) – Table of content for CRfocus February 2011

Members of The Institute of Clinical Research can visit http://www.icr-global.org/crfocus/2011/22-1/ to read the full content of this issue

Cover story

A New Pathway: Inside the Academy of Medical Sciences Review

Andrew Smith

The Academy of Medical Sciences’ review of regulation and governance of clinical research, “A new pathway for the regulation and governance of health research”, was published early in 2011, making many radical proposals to streamline, simplify and improve the regulations, organisations and processes involved in conducting commercial and non-commercial clinical research in the UK. Andrew Smith looks at some of the recommendations in more detail, including comments from an interview with Prof. Sir Michael Rawlins, who chaired the review.

Online extra: Full audio interview with Prof. Sir Michael Rawlins (MICR & FICR members only)

Features

When to say ‘Yes’ in the NHS: Development of a Complexity Scoring System & Management Tool

Jacqueline Briggs et al

It is widely recognised that clinical research workload is hard to define and is often related to the complexity of the individual project. Also, there is a clear need to ascertain workload and complexity for a portfolio of clinical research within an NHS organisation across specialities. The aim is to be able to define an acceptable portfolio and workload for the resources available. Jacqueline Briggs and her co-authors describe a complexity tool that will enable teams to quantify and successfully predict workload with recognition of the differing complexity of individual studies.

Regulation of Companion Diagnostics for Stratified Medicines: Interviews with MHRA, NICE & BIVDA

Eddie Blair

Following the success of the Innovative Medicines Advisory Group (IMAG)-led session on stratified (personalised) medicines at the 2010 ICR Annual Conference, IMAG member Eddie Blair met with representatives of the MHRA, NICE and BIVDA to discuss where the UK is going with activities on the integration of diagnostic testing with pharmaceutical development and marketing. Extended versions of these interview transcripts are available from www.crfocus.org.

“The Undersigned Understands”: Walter Reed & Informed Consent

Allan Gaw & Michael H J Burns

The foundation stone of clinical research ethics is consent: consent that is given by legally and mentally competent individuals, and that is informed, comprehending and free. The history of clinical research ethics is, then, largely the history of informed consent. In the third of their articles recounting key moments in the history of clinical research and examining how they influenced (or failed to influence) modern practice, Allan Gaw and Michael Burns tell the story of Major Walter Reed, who, in the course of his work investigating the cause of yellow fever, developed a surprisingly robust informed consent process nearly 50 years before the term was even coined!

Regular update

Facilitating Networking & Paths to Growth: Message from the Chair

Janette Benaddi MICR CSci

The world of clinical research is huge and each day we come into contact with new members of our community mostly through work but sometimes through other avenues. In this month’s message, the ICR Chair reflects on the importance of networking to all of our careers, and how events like the ICR Annual Conference can play an important role in broadening our professional networks.