Well, you asked for more R&D articles, so this week Mike Rea turns his thoughts to phase III trials and what might be going wrong.
Patient: "I've just gone into phase III! What are my chances of coming through alive?" Doctor: "Well the prognosis is not good - about 20%"Well, you asked for more R&D articles, so this week Mike Rea turns his thoughts to phase III trials and what might be going wrong.
Patient: "I've just gone into phase III! What are my chances of coming through alive?" Doctor: "Well the prognosis is not good - about 20%" Mike Rea
Patient: "I've just gone into phase III! What are my chances of coming through alive?"
Doctor: "Well the prognosis is not good – about 20%”
These words are not from 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 20%, although others have seen higher success rates (although with paradoxical problems). That is an awful lot of product ideas dying on the vine.
A 2006 study 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/ should 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.
The industry is still better at creating blockbusters than ever before: more than fifty brands over $1 billion, and even ten over $3 billion, but Pfizer, for example, 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.
"A 2006 study found that 42% of phase III trials failed between 1990-2002."
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, 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.
The speed mantra of development 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.
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.
Repeating the processes which were the reason for success in the past is creating other problems too. Increasingly, payors and authorities are putting 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 today’s biggest pharmaceutical market.
"If the idea of your product is what you study in phase III, in many cases decisive hesitation would be better than hesitant decision…"
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 the idea of your product is what you study in phase III, 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.
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 (that is, something that physicians and patients want). 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.