Drug Development: Time for real innovation in the process?

Over recent years the cost of bringing new drugs to market has escalated markedly (Table 1) with no sign of improvement in the cost structure, despite significant focus from financial analysts, writes Dr Ian Wilding, Executive Chairman of Pharmaceutical Profiles.

Historically over 75% of the full cost has been attributed to previous development failures, which is an alarming statistic for an industry that prides itself on innovative science. In practice, the situation could well worsen significantly over the next decade because new drug targets achieved by mapping of the human genome are predicted to further increase failure rate due to development complexity; the average cost of bringing a drug to market could soar to $1.6 billion in 2005 (Lehman Brothers 2001).

This change in cost base for the industry could not have come at a worse time. Regulatory conservatism has impacted on drug approval rates, just as Wall Street has increased its focus on Pharma earnings. To make matters worse, the ticking bomb of declining R&D productivity has exploded just as a large number of high value blockbuster patents expire; $100 billion of products face patent expiry by 2004 (Ernst & Young 2002). Consolidation in the market will be driven by the need for short-term growth to ensure earnings are broadly in line with estimates and this will only be achieved by the pharmaceutical industry engaging its marketing muscle to maximise revenue from existing drugs. But this will not solve the underlying problem of a lack of new drugs making it through the Development process. There is a risk that M&A will make the situation worse by creating a bureaucratic monster in which 'accelerate to market' is really more haste and less speed.

It is time to innovate drug development. There are many new steps that could be called innovative, for example, combinatorial chemistry, proteomics, and genomics, but it is based on a process that has not evolved at the same rate.

So why do so many drugs fail in Development? Failures are often for multiple reasons but can be broadly classified on the basis of safety concerns, lack of efficacy or poor bioavailability properties. The most high profile failures are often due to safety and efficacy but in reality bioavailability is the 'silent assassin'. The bioavailability properties of a drug critically determine the likely concentration of drug both in the blood but also at the receptor sites. If these properties are wrong then even if the compound has optimal chemistry to interact with the drug target then there is still a significant chance of unwanted side effects or marginal efficacy.

Over recent years the regulatory authorities have recognised the significance of drug bioavailability (sometimes referred to as pharmacokinetic) properties and there is now significant pressure on pharmaceutical companies to investigate the link between pharmacokinetics (Pk) and drug effect (commonly referred to as pharmacodynamics (Pd)). This is known as the Pk/Pd relationship and is now considered to be the cornerstone of any new regulatory submission. The Discovery focus has been heavily biased to the potential Pd effect with significant focus on the likely interaction between development compounds and drug target. The Pk characteristics have until recently had to play second fiddle to optimisation of the Pd properties. In fact, it is common to find many companies accepting a small incremental improvement in possible Pd effect paid for by a significant deterioration in the likely Pk characteristics.

Given this imbalance, it is perhaps not surprising that although the marketing emphasis is on tablets and capsules, many current drugs have Pk properties that make them less than perfect for oral administration. More specifically over 55% of new drugs have low aqueous solubility (drug can only be absorbed into the blood once it is in solution) and many drugs have poor intestinal permeability (the ability of the drug to pass from the gut lumen into the blood). In addition, the need to create more complex 'small molecules' to avoid existing patent libraries has produced a plethora of drugs, which are likely to be eliminated from the body via liver or intestinal metabolism. This leads to more variability in bioavailability and increases the potential for drug/drug interaction.

Thankfully in the last couple of years, a number of enlightened companies have recognised the need for 'developability' to be an integral aspect of drug Discovery. As a consequence, Pk or bioavailability issues now warrant a mention when selecting drugs as full Development candidates. However, the pace of change is too slow and one of the problems is the difficulty in screening for human Pk properties. A wide range of different techniques are currently available to conduct such screening studies, including a variety of in silico (computer), in vitro (laboratory) and traditional animal models. Although some of these technologies may be well suited to high throughput screening (HTS), output predictions are far from definitive and so need to be treated with caution. For example, the correlation between human and animal bioavailability is far from convincing with significant opportunity for both false positives and more worryingly for our paranoid industry, false negatives.

One of the pivotal reasons for the current prediction dilemma is that our understanding of what controls human drug absorption (uptake into the blood) is actually very limited. This is largely due to a lack of good techniques for assessing which factors influence drug absorption from different regions of the human intestine. For example, the respective importance of drug solubility and permeability varies depending on where in the intestine drug release occurs. This problem has now been solved with the introduction of specially designed, intelligent engineering-based capsules to provide targeted drug delivery to key sites of the human gut. The most advanced technology in this arena is the proprietary Enterion capsule from Phaeton Research that is emerging as the market leader. This device is extremely versatile and capable of delivering drug in a variety of different physical forms, including solution and powder, into a wide range of absorption sites in the intestine. As a consequence both pharmaceutical and drug delivery companies are now undertaking human drug absorption studies to provide a more reliable 'route-map' for development of drugs with complex Pk properties. Such studies are ideally positioned to radically innovate the current development process as they provide a mechanism for informed decision-making on the likely chance of bioavailability success for a candidate drug.

To significantly reduce development costs there is a need to better select candidate drugs in terms of their Pk and Pd properties and also a requirement to increase the attrition rate early in development to avoid late stage failures which skew the cost base of our industry. Recent statistics from Pharmaprojects (Table 2) suggest that our focus on increasing attrition rate has yet to pay dividends, presumably because of a lack of suitable tools for making the right decision earlier in development. Human absorption studies provide that mechanism when contemplating attrition based on Pk properties and need to form a routine part of our early clinical development research.

Researchers and regulators continue to search for faster ways to obtain early human bioavailability data both safely and ethically. Indeed, advances in analytical techniques have made it possible to conduct Pk studies with extremely low drug doses, well below therapeutic levels. This has led to the concept of 'human microdosing' or 'cassette dosing', where one or perhaps a cocktail of new drugs are administered to assist in lead optimization. This approach enables many more compounds to be screened in humans before candidate selection. The EMEA (European Agency for the Evaluation of Medicinal Products) has recently published (June 2002) a position paper for consultation, which will support low dose clinical screening studies in humans.

By combining microdosing or cassette dosing with a regional absorption study, it is possible to not only obtain human bioavailability data, but also gain a very early insight into the properties of the compound, which will determine its successful development. Such studies are likely to prove increasingly popular once the regulatory framework is established.

As Darwin said, "It is not the strongest of the species that survive, nor the most intelligent, but the one most responsive to change." Never has a quote been more appropriate to the Pharmaceutical Industry of today.

Table 1   Estimated full cost of bringing NMEs to market ($ million)

1991   231
1993   359
1997   429
1999   610
2001   802

[Source: Tufts University 1991, OTA 1993, Myers & Howe 1997, Lehman Brothers 1999, Center for the study of Drug Development 2001]

Table 2   Percentage of medicines dropped at each stage of Development 1997-2001

Year   Pre-clinical   Phase I   Phase II   Phase III   Pre-registration
1997   70   7.2   15   5.4   1.7
1998   66   9.4   15   6.2   2.4
1999   56   10.0   19   9.4   4.3
2000   61   9.1   17   8.3   3.1
2001   53   11.0   27   5.0   3.4
[Source: SCRIP Magazine, February 2002, page 72 (data from Pharmaprojects)]

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