Healthy Skepticism Library item: 1007

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Publication type: news

Davies N, Arlington S.
Powering up the pipeline
Source: Pharmafocus 2003 Jan 16

Full text:

By 2010, the pharma industry will provide much more than just drugs. Companies that provide ‘targeted treatment solutions’ will deliver bigger returns than ever before.

The shortage of good new drugs in the pipeline, the imminent expiry of the patents on numerous blockbusters, intense competition, a more demanding market that has begun to specify the sort of innovations it wants, and what it is willing to pay for them: all these challenges are making life hard for the pharma industry. Yet two great advances – a better understanding of the molecular sciences and a massive increase in computing power – could help pharma transform its pipeline. The latest report from IBM Business Consulting Services, ‘Pharma 2010: The Threshold of Innovation’, proposes a new model of drug discovery and development that could accelerate cycle times, and cut attrition rates and costs, dramatically.

Unravelling the molecular mysteries

The molecular sciences are gradually giving man a much better grasp of the factors involved in a particular disease state, including its severity, how it progresses and why certain people are susceptible in the first place. This knowledge will fragment the market, but it will also enable the industry to define diseases much more accurately and make highly profitable drugs for smaller patient populations.

Pharma will eventually be able to separate diseases that are currently lumped together as if they were the same disease, and treat them as different diseases within a particular disease family (or collection of related diseases). Take asthma and cancer – both general terms for a cluster of diseases with distinct molecular mechanisms, environmental triggers and genetic features. Scientists are now working on the development of different drugs for different forms of asthma and molecular biomarkers for distinguishing between conditions that superficially seem the same. They are also working on at least one system to segment breast, prostate, lung and other forms of cancer into subtypes.

Learning from the pioneers

Any pharma company that wants to capitalise on this new understanding of disease will need to alter its entire scientific model. The current discovery process cannot cope with the plethora of potential targets the Human Genome Project has produced, and conventional chemistry cannot generate a sufficiently diverse range of molecules to interact with those targets.

In fact, several companies (including Amgen, Human Genome Sciences and Cambridge Antibody Technology) are already using a disease-centric, biological approach to discover drugs for life-threatening conditions, and have succeeded in cutting target validation cycles to about two years. The techniques they are using show how the process will evolve. By 2010, a pharma company will choose the disease family it wants to focus on, and define the different disease pathologies and molecular mechanisms in that family. It will then use the molecular sciences to identify targets and test them against various biological molecules that have been designed to interact with the targets – and start developing diagnostics based on molecular markers.

Redefining diseases much more accurately at the molecular level makes it much easier to validate a target and find molecules that will interact with the target. Similarly, using biological molecules reduces the danger of producing a drug that produces intolerable side effects. Biologics generally have a much lower toxic load than chemical entities – one of the main reasons why research from CMR International shows they have a four-fold greater chance of making it to market from the point at which they first get tested in man.

Testing new treatments

The development process will also need to undergo a major overhaul. The current paradigm, with its reliance on double-blinded, randomised control tests, is very costly and inefficient. How will it will change?

First, the scope of the process will expand. At present, most companies make a disparate collection of ‘white powders’ but, by 2010, they will produce a range of healthcare packages for different disease subtypes – including drugs, diagnostics, monitoring devices and patient-support services. They will also use a much more iterative approach, and feed data gleaned from working on products for one disease subtype into the development of other products for related subtypes in the same disease family.

Second, the electronic links that underpin the process will become much stronger, with an integrated network of communication channels that ensures people from multiple locations and disciplines can share data. This will make it easier to recruit trial investigators and patients, and provide them with the support they require. It will also accelerate trials by providing almost immediate access to the information that is generated.

Third, the way in which trials are conducted will alter. Modelling, simulation and high-performance computing will enable the industry to model how drugs act in whole body systems, organs and at a sub-cellular level; design accurate trials; and conduct ‘adaptive’ trials – where information acquired during a trial is used to alter the course of the trial without compromising its validity. Several companies, including Lilly and Pfizer, have already used adaptive design principles in dose-ranging and phase I trials.

But if pharma is to ensure it makes products people really want, it will also need to get clinical and commercial feedback from doctors, patients and healthcare payers at a much earlier stage in development – and this will result in an even bigger change: the move from phase III trials to ‘in-life’ testing. Promising new drugs will first be tested in man in late-stage discovery. They will be tested still further in phase II trials and submitted to the regulators for approval. They will then be launched on the market and subjected to extensive in-life testing, using various remote monitoring devices that exploit advances in bandwidth, networking, mobile telecomms, radio frequency technologies and miniaturisation.

In-life testing is currently too expensive and too risky to perform on a widespread basis, but the new technologies now emerging will make it much easier to collect and transmit biological data outside a clinical setting. This will enable the industry to test new products far more safely; it will obviate the need to expose patients to placebos or dosing levels that are pharmacologically ineffective, and increase the chances of picking up rare side effects and drug reactions quite rapidly.

A robust electronic infrastructure, modelling, adaptive trials and in-life testing will also reduce the duration of the drug development process substantially. It currently takes about seven years to conduct all three phases of testing but, by 2010, the most fleet-footed companies will be able to complete pre-launch trials within two years.

In summary, then, what should pharmaceutical companies do to pave the way for targeted treatment solutions?

create a disease-centric approach to discovery and ensure that they own the intellectual assets pertaining to the diseases on which they choose to focus, rather than relying on academia to generate that knowledge
transform their development processes with the introduction of adaptive and in-life trials
capitalise on the power of technology
construct an outcomes-based sales and marketing model
build a flexible, integrated supply chain that covers multiple kinds of products
forge closer relationships with the industry regulators, healthcare insurers and physicians
promote the use of in-home diagnostic, monitoring and communications technologies that can deliver real-time access to patient data.
This is an enormous task. But IBM Business Consulting Services’ research shows that a company that develops the infrastructure and skills to make targeted treatment solutions, as well as using traditional tactics to maximise revenues from the products in its existing portfolio, could enhance its shareholder value very substantially. If the transition from blockbusters to high density drugs and targeted treatment solutions is relatively slow, it can expect to double its value by 2010. If the transition is very rapid and successful, it can expect to see that value increase by a factor of four to six.

But what should pharmaceutical companies do to survive in the short-term?

review their entire R&D portfolio to assess the threshold of innovation each new product must overcome by the projected launch date
maximise the value of their overall portfolio by:

optimising prices
improving compliance and persistence
maximising their market reach
streamlining their supply chain and support processes
acquiring new products
extending the life of those products
making their R&D as efficient as possible.
Regulation

Clearly, all these changes also have a bearing on pharma’s relations with the regulators. Companies will have to initiate contact with the regulators regarding the development of a particular treatment while it is still in the early stages of discovery, rather than waiting until they are ready to file an investigational new drug application. They will have to submit clinical data on an ongoing, automated basis via rolling dossiers. And they will have to work much more closely with the regulators throughout the entire process.

The basis on which the regulators give permission to sell a drug will alter as well. The traditional one-off endorsement will be replaced by continuous evaluation. The right to market a drug will be granted and re-confirmed subject to regular reviews of its safety and efficacy – reviews that are even more stringent than the checks involved in adverse-event reporting.

Collectively, these changes will blur the boundaries between discovery, development and the marketplace. They will also massively reduce the time and cost of making new medicines. In all, IBM Business Consulting Services estimates that they could cut the time from target identification to launch from 10 to 12 years to between three and five years; increase success rates from first human dose to market by a factor of four; and slash pre-launch development costs per drug to about $200 million – a quarter of the current average.

Pipelines under pressure

Falling productivity in R&D
In 2001, the FDA approved just 24 new molecular entities – fewer than in any of the previous six years – even though the industry’s R&D spend has doubled since 1997. This trend looks set to continue; the FDA had approved only 10 NMEs by September 2002.

Product failures in late-stage development and the marketplace
In the three years to 2001, at least 28 products with potential peak sales of more than $20 billion were terminated in late-stage development. Between 1997 and 2001, 12 drugs with peak sales potential of more than $11 billion were also withdrawn from the market on safety grounds.

Multiple patent expiries
Within the next five years alone, the US patents on 35 drugs with global sales of more than $73 billion will expire.

Intense therapeutic competition
There are four COX-II inhibitors on the market and nine similar drugs in the industry’s late-stage pipeline or awaiting approval – just one example of the way in which therapeutic competition is increasing.

Shortage of blockbusters in the pipeline
Industry experts predict that there are only 14 potential billion-dollar blockbusters in the pipeline between 2003 and the end of 2008, and none of these new drugs is expected to make as much money as the current top sellers.