Caution: you are entering phase III
pharmafile | December 8, 2008 | Feature | Research and Development |Â Â clinical trials, drug development, phase IIIÂ
Patient: "I've just gone into phase III! What are my chances of coming through alive?" Doctor: "Well the prognosis is not good – probably less than 50%."
These words are not from the script from an episode of the medical drama House. They are the reality of the industry's chances of successfully commercialising a product that is currently in phase III clinical trials. This mortality rate is frightening – at one top 10 pharma company the success rate over the past five years has been as low as 21%, although others have seen much higher success rates.
In this article, we review the causes of this deadly pandemic infecting the pipelines and prescribe a few simple remedies. First, the vital signs. Much interesting analysis has been conducted in this field. A 2006 study in IN VIVO, Why products fail in phase III by Gordian et al, found that 42% of phase III trials failed between 1990-2002. Fifty percent of these were because the molecule could not be shown to be better than placebo, 30% of the failures were due to safety issues and 20% due to an inability to show efficacy or safety benefits over existing products. These statistics are shocking, even more so when added to the fact that only one in four brands that reach the market go on to break even and repay their investment. While safety issues often need the larger patient numbers seen in phase III before they can be identified, an inability to confirm efficacy over placebo or existing products could have been signalled by a more effective phase II programme.
Before focusing on the specific issue of phase III attrition rates, it is worth looking at the 'patient history': The industry has created more blockbusters over the last ten years or so than ever before. It has done this by developing novel molecules offering step change improvements for diseases where they made a difference.
The problem is that these blockbusters are now the ones going generic. This poses two key problems.
Firstly, these brands have in themselves significantly reduced the unmet need 'headroom'. That means to have any chance of replacing them as the standard treatment, new molecules must offer significant improvements over yesterday's blockbusters, or target diseases with no current treatments. But, there is a reason why there are no current treatments for some diseases: nobody has managed to find one yet – it is difficult. Secondly, patent expiries create a massive revenue gap and an even greater profit gap.
The industry may have got better at creating blockbusters than ever before: more than fifty brands over $1 billion, and even ten over $3 billion, but Pfizer were always going to struggle to fill a $15 billion Lipitor gap. This means that the efficiency of new drug development must improve, as there are no longer the margins to bankroll the same percentage of late stage development failures.
Over the last fifteen years or so, the pharmaceutical development function has geared itself for speed in a race to achieve registration as soon as possible. This speed has been driven by two main factors: the goal to 'extend the marketing period before patent expiry' and the need to beat any class me-toos that are in development in other companies' pipelines. Heads of R&D when interviewed by industry journalists spoke of how they were re-engineering their departments to reduce development times by months or even years. Often phase II was where time could be cut, leading to many more companies lowering technical risk in phase II, but thereby increasing the likelihood of an uncompetitive drug making it to the expensive phase III.
Evidence shows that the generic-induced revenue haemorrhage cannot be significantly stemmed. The only answer is to pump in something to replace the losses. This desperate search for new life-blood is resulting in some deadly mistakes. The speed mantra of development described above is actually being accelerated further in the rush to replace lost revenues: 'more molecules in, faster development, more out the other end'. But the paradox is that the reverse is happening. A few years ago, for every eight molecules entering the pre-clinical phase one would successfully come to launch. It now takes 13 molecules into pre-clinical to achieve one launch. The need for speed is resulting in many of the development stages prior to phase III being reduced to the (technical) minimum. Consequently, several parameters have to be regarded as 'unknown' when entering phase III: dosing is often not optimised when starting phase III, the molecule may have a very acceptable tolerability profile but miss efficacy endpoints, or may hit an efficacy goal but with an unacceptable side effect profile.
This need for speed too often results in registration trials having relatively broad inclusion criteria for patient enrolment, whereas being more specific in terms of the patient types included (those with a higher need) would probably result in a greater clinical differentiation and endpoints being achieved.
This broad patient inclusion is often compounded by time-based milestone measures for the R&D function but also by commercial desperation to find something to fill the revenue gap. This is forcing new molecules to target large patient populations in the belief that a reasonable market share of the whole market is the only way to achieve sufficient sales. Often sales from a smaller patient segment but with greater differentiation and a higher unmet need will be more valuable.
The drive for statistical, rather than clinical, significance is also notable. However, while statistical significance will often lead to a registration, it does store up problems for reimbursement and marketing, as marketers try to convince the world to use a product with very little clinical differentiation.
US vs Rest of World
Repeating the processes which were the reason for success in the past is creating other problems too. At long last, payors and authorities seem to have put in place systems that restrict access to new medicines that provide negligible improvements or limited health economic value. But while this may be true for most of the world, the US still doesn't have such a 'fourth hurdle' and still achieves annual price increases. Global pharma companies are reluctant to do risky head-to-head comparisons, increasingly necessary in non-US territories, when an efficacy study vs placebo is sufficient for the world's biggest pharmaceutical market.
Regulators at the FDA have currently heightened their safety requirements, meaning that drugs with only a marginal efficacy improvement must prove themselves to carry no additional safety risk. But this begs the question: how would the FDA look at the same molecule if it had clearly demonstrated significant superior efficacy through head-to-head studies? It may in fact hasten approval. The truth is that, globally, the balance is starting to tip from weight of promotion to weight of evidence.
If you can see the bandwagon, it's too late
The objective of addressing 'unmet medical need' is a typical feature of pharma company mission statements. But meeting this need is increasingly difficult – they remain unmet for a reason. The breakthroughs from genomic science have been slower than promised but scientific understanding is moving forward. The problem is that most of that mechanistic science is available to all and once a new mechanistic target is identified the combinatorial chemistry and high throughput screening results in a multitude of patented candidates.
Consider lung cancer: 200,000 diagnosed cases per year in the US alone, 160,000 deaths, five-year survival less than 20% – a very high unmet need. Avastin was one of the first novel targeted therapies and improves median survival by 2.3 months. Sales in 2007 were just over $2 billion, more than 90% of that from the US, primarily due to reimbursement issues in Europe. Over 150 different targets now form the basis for nearly 300 therapeutics currently in development for lung cancer. So the drive for speed is seen clearly, and understood.
However, in many cases, decisive hesitation would be better than hesitant decision – choosing the wrong dose, or patient population, based on small and fast phase IIs, will lead to expensive and avoidable phase III failures. It will also lead to products gaining a license but without any data that can be used to demonstrate a place in therapy.
Conclusions
The issue of expensive failures at phase III is already the subject of progressive thinking. Writing in the Applied Clinical Trials journal in 2005, chief statistician at Pfizer Global R&D Mohan Beltangady noted that phase III failures - particularly when they concern how well a drug works – have been comparatively ignored.
"While safety outcomes explain many failures during the early development phase and have likewise played a prominent role in some highly publicised product withdrawals, efficacy failures in phase III have received little attention," he said.
"What we now know," he added, "is that a significant number of phase III failures are attributable neither to issues of safety nor product differentiation, but to an inability to confirm efficacy against placebo."
The problem of drugs that just don't work well enough is also familiar to Peter Kim. One of the first announcements he was called on to make, soon after becoming president of Merck Research Laboratories in 2003, was the cancellation of several key programmes, including depression candidate aprepitant because of efficacy problems.
Speaking in 2006 at the US BioIndustry Association's CEO and Investor Conference, Kim noted: "The pressures are real, and they are here to stay." He went on to outline a process whereby Merck is investigating in a more robust manner all of its early-stage molecules, including those not considered suitable for further development in order to gain the best understanding of molecules that are selected as lead candidates.
The need for change can be seen in the shrinking value analysts attach to pipeline assessments. Traditionally, analysts have heavily favoured well-stocked pipelines, but in recent years companies and share prices have tended to be valued wholly on their marketed products.
The rash of late-stage failures is often the result of conflicting rewards and behaviours in development – the desire to move a product along a clinical conveyor belt from phase II to III to registration without interruption, versus the desire to make a commercially attractive and competitive drug. Introducing proper dose assessment, comparators and segmentation at phase II may be inconvenient for all sorts of reasons, but it is a vaccine well worth taking.
Graham Hewitt is principal consultant at IDEA Pharma. For more information visit: www.ideapharma.com.
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