Given that multinational (often ‘massively multinational’) trials are now the default position for anything beyond the earliest phase of clinical research, it is somewhat surprising that they still polarise opinion. To some, they are the only way to complete large studies even remotely on deadline and within budget. To others they are damaging to local professionals and research infrastructure and of limited clinical relevance to a medicine’s target patient population. However, the truth is never so ‘black and white’. Like multi-centre trials before them, multinational trials are not going to go away, so we need to understand all their driving forces and work out how best to engage with them to make them as effective as possible. In this extended editorial, I take a look at the evolving bigger picture of globalising clinical research and suggest how we might find a new balance point to deliver global performance combined with local relevance.
Not in Kansas anymore…
Many of us working in clinical research look at the world from a relatively local viewpoint: “my unit”, “my organisation”, “my region”, “my country”. We engage with patient populations at this level, and when a treatment is being developed that we think will benefit this population, we want to be involved. Due to the strong tradition of conducting clinical research and the moral drive we feel to help patients near us, many of us in the developed world see it as a duty or even a right to be involved from as near the start of development as possible through to the last post-marketing study. And we are aggrieved when told that our site, our CRO or our national affiliate company has not been selected to participate in this part of the study programme.
This passion is laudable, but should be tempered by the understanding that this is not how the world works any longer. Working with anyone, anywhere, who wants to be part of the running of a study would be a logistical nightmare, a wasteful dilution of resources and far more expensive. Decisions about where a commercial development programme should be conducted are made without sentiment, with cost-effectiveness of the clinical trials being the major concern (particularly for studies or programmes that have been outsourced) but with broader considerations around trends in global market values also playing an increasing role.
In short, as more countries become capable of running clinical trials to acceptable levels of quality, studies will increasingly be done wherever in the world its sponsors decide will add most value to the medicine being developed. As different countries have differing advantages in terms of patient demographics, research resources/infrastructure etc. it is reasonable to expect that no two drugs in development (or, indeed, no two study phases in the same development programme) will have the same distribution of investigational sites around the world.
Waiting for the upswing
The pharmaceutical ‘developed world’ has been concerned at the impact of the wider economic recession, with development programmes being delayed or cancelled, and pharma companies and CROs alike being hit by restructuring, ‘defensive’ mergers and redundancies as a result. Those affected by these problems have consoled themselves with the idea that every recession is followed by a recovery, and when this comes volumes of ongoing clinical studies, staffing etc. will return to something like pre-recession levels.
However, as we’ve noted in previous issues of CRfocus, many of the problems facing the pharmaceutical industry (ie, patent expiry, tightening purse-strings for reimbursers, increasing requirements for safety/efficacy evidence, declining productivity in discovery as well as development etc.) were well known before the recession and had arguably already been incorporated into pharma companies’ market valuations. Similarly, many of the strategic realignments were already in progress before the recession (indeed, near-continual tweaking of business tactics and management structures are fairly commonplace in contemporary business) so it could be argued that the tightening economic conditions have had more impact on the speed of change than on its extent.
All of which is not to say that we should expect to remain entirely in recession when the rest of the western economy begins to improve. Some decisions to suspend or terminate development programmes were made to reduce costs, particularly by smaller pharma and biotech companies. Similarly, young companies depending on the financial markets for working capital have found this more difficult to come by. And the increasing use of outsourcing, technology etc. in preceding years has meant that all of these problems have had knock-on effects in the CRO and enabling technology sectors.
So, as general commercial conditions improve, we should expect to see a positive impact on the overall volume of clinical research being done. However, this upswing will be smaller and slower in the UK and similar countries than elsewhere, as the strategic realignment continues to take effect. This strategic realignment will be much more significant, and while value for money in the development process plays a part, there are also other factors in play, including pressures on top-line revenues, shifting global patient demographics and increasingly sophisticated local analyses on which safety and value decisions are based.
Cost, speed & value
In the selection of any commercial service, the decision is made on the basis of two fairly straightforward parameters (cost and speed) and one often very nebulous one (value).
Cost: Yesterday’s issue?
Of these parameters, direct cost is the simplest to compare in advance and to measure, and was initially the main determining factor. Many in clinical research have been obsessed with reducing cost, and conducting studies in developing countries with lower per-patient fees certainly appears to do this. This was the driver behind the initial migration of studies from the USA and western Europe to Central and Eastern Europe (CEE) and, more recently, to Brazil, Russia, India and China (the ‘BRIC’ countries) and others.
Direct cost, though, was always an over-simplification, with the low wages for study personnel being offset by indirect costs to meet the need for increased training, investment in support personnel, equipment and infrastructure. As time has passed, experienced personnel and usable infrastructure have been developed and this “resource hump” has been overcome. However, the success of this investment in experience (and greater awareness of global market rates) has in turn increased the direct costs, reducing the savings to be made simply by conducting studies in these countries. This squeeze has been exacerbated in the short term by fluctuating currency rates and declining wage levels in the developed world, as a result of the recession.
In short, the drivers to conduct studies outside the traditional countries on grounds of cost alone are fast being eroded. However, transparency of cost calculations and consistency of costing models are still significant when analysing the value for money of working with a specific site or country.
Speed: Quicker to completion, quicker to market
Cost alone is something of a ‘red herring’. For a successful medicine, the increase in potential revenue resulting from getting to market earlier, with a few additional months of patent protection in place, will far exceed any cost saving made during the development process. Indeed, sponsors will tolerate higher costs if they result in quicker and more consistent regulatory/governance processes, site set-up and subject recruitment.
In many ‘pharmerging’ countries, the sheer size of patient populations, sometimes coupled with less accessible or affordable alternative treatments, gives a significant advantage in the number, rate and reliability of patients recruited. However, working in such countries can initially introduce delays due to administrative and cultural difficulties in selecting sites, less familiar approval systems, more complex logistics (eg, import/export licenses etc.). This can offset the speed advantage in the recruitment phase, although increasing familiarity with these systems (which themselves are often evolving to more closely follow FDA/EMEA models) makes these delays less significant. For large and/or relatively simple studies, the speed of recruitment can outweigh delays elsewhere.
Value: The last marketplace?
Many developed countries are realising that, while the initial cost advantages that attracted pharma to conduct research in ‘pharmerging’ nations are gradually being smoothed out, the issue of speed is unlikely to go the same way. Larger numbers of treatment-naïve patients passing through fewer healthcare centres are always going to maximise the efficiency of patient recruitment compared with traditional locations. In the past, it was argued that the quality of data coming from sites in these countries was not as good as from the developed world. This was always a shaky argument and has now been widely discredited (by audit findings, data query rates etc.). A diligently selected and well resourced site can deliver high quality clinical data wherever it is in the world, while poor conduct can also happen worldwide.
As a result, it is likely that the largest simple confirmatory studies will be conducted increasingly in these areas. However, as noted above, conducting such large multinational studies in countries with diverse regulatory and complex logistical systems will call for a tier of expert global project managers and support professionals to run these studies, and it is likely that this management expertise will come from the developed world, at least in the medium term.
However, for studies that are smaller and/or more complex the balance point may be elsewhere. These are the types of study where value is added primarily in other ways than simple patient numbers, such as integration with sophisticated patient care (eg, for third-line or other specialist therapies), exploratory or unusual methodology, or specificity to a localised population subgroup, healthcare delivery system or socio-economic setting. These types of study will be conducted “close to home”, either that of the sponsor or the society where the resulting information will be used to inform prescribing decisions.
Follow the money
Ultimately, any discussion on the development of commercial pharmaceuticals comes down to money. On one level, this is the “cost, speed, value” paradigm discussed above, with drug-makers looking for the most effective blend of sites to deliver data to meet the current requirements for product registration. However, the evolution of healthcare delivery (and reimbursement) models over the past decade means that these goalposts themselves are moving. While the traditional goal of clinical development was to demonstrate a product’s safety and efficacy in a broad population, it will become increasingly important that this broad demonstration can be mapped onto specific local populations and healthcare settings. It has been questioned whether data predominantly collected in one regional population can adequately be applied to the population of another region, with differing care pathways, morbidity/mortality rates etc.
Added to this is the growing requirement to demonstrate cost-effectiveness on a local level, both in direct terms (eg, the ‘£30k per QALY’ caricature of the NICE model in the UK) and ultimately in broader societal cost/benefit terms. As governments strain to contain burgeoning healthcare costs, this evidence of cost-effectiveness will only become more important, as reimbursement and accessibility become the dominant hurdles. This is an area where the UK in particular can thrive because of its early development of a Health Technology Assessment body and its consequent leadership and influence on other countries’ HTA systems. As clinical research professionals in the UK have had more experience in designing and conducting studies in this area, they should be well placed to lead this type of work as it is conducted in other countries around the world.
One possible result of these drivers in the medium term is a new tier of studies to replace current Phase IV post-marketing studies. These could run in parallel with (or even be part of) large Phase III studies but collecting additional data specific to the local healthcare setting and socio-economic conditions. Studies like this could offer new hope to professionals in the developed world that they might retain a ‘slice’ of the late phase that might move almost entirely to ‘pharmerging’ nations on the basis of cost and speed alone.
However, the long-term future might be somewhat different again. At the moment, medicines are primarily developed for patients in the developed world, hence the potential importance of localisation studies if the bulk of the confirmatory research is conducted in ‘pharmerging’ nations. However, as the next tier of global economies develop over the coming decade or two, an emerging middle class in these countries could well become the main market for medicines, in terms of size and commercial value. We could see a scenario where medicines entering early development in a few years time might be primarily destined for patients in India, China etc. with their development programmes adjusted accordingly.
New world order
It is comforting to believe that all clinical research should be conducted “here” (ie, whichever country we’re in) and any decision to do otherwise is the result of a failing that must be corrected by our profession, our organisations or our government. Unfortunately, this belief is now just plain wrong, reflecting the difference between how clinical research was done 30 years ago and the modern world. Globalisation is here to stay and if it’s used to develop more appropriate, affordable medicines for the people of the world, then it’s surely a good thing.
That’s not to say that we in the developed world shouldn’t strive to improve on the aspects of our performance that are criticised, but we should do it in a way that magnifies the impact of areas where we are strong, such as experimental medicine, complex therapeutic areas and trial methodologies, and developing the tools to demonstrate applicability of global data to a local healthcare setting and socio-economic context.
So, extrapolating from current trends, I envisage a world where the bulk of exploratory clinical trials remain in traditional countries, but the largest (and least complex) confirmatory trials migrate to countries with larger populations, where studies of this type can be delivered more cost-effectively. In conjunction with this, the type of questions about socio-economic impact currently addressed in Phase IV studies will increase in importance, complexity and local specificity, and will be conducted earlier in development programmes (probably at least partially prior to registration).
In my opinion, this is the new balance point we are currently moving towards. It’s neither better nor worse than the one its replacing, but it is more in step with how the globalised marketplace now works. Looking further ahead, there may well be a further rebalancing in the decades to come, as the pharmaceutical industry shifts its priorities to align with shifts in the global distribution of markets for its products.
We all need be aware of our position in the global market for clinical research, and the position of clinical research in the wider picture of development of medicines and delivery of healthcare. These are the pressures that will shape what we do and how we do it in order to stay at the forefront of our profession.
