A culture in ferment: Why it's kill or cure for the world's pharmaceutical giants

At GlaxoSmithKline's annual general meeting last week, chief executive Jean Paul Garnier at times sounded as much like a field general as he did the head of the UK's biggest pharmaceutical company.

The tone was surely not lost on his industry colleagues. In response to animal rights extremists who recently threatened his company's shareholders, Mr Garnier called for resolve: "This is not the time to flee the battlefield." On why his contract was extended beyond the standard retirement age, he explained it was to smooth the way for the new research director to "go into the future with all guns blazing".

Military analogies are a bit over the top: the pharmaceutical industry is not fighting for its life. But it is definitely sick. "Gruesome" is how Mike Ward, an analyst at Nomura Code Securities, describes the state of the world's biggest drug makers in recent years.

The antidote, or at least a clue to it, may be glimpsed at the quarterly results this week of Cambridge Antibody Technology (CAT), the biotech company that GSK rival AstraZeneca recently announced it was snapping up for £702m.

CAT does not, and never has made money - some- thing big pharma is good at. But it does have a gift for coming up with new drug candidates - something big pharma finds harder.

Over the past five years, the world's top five drug makers have shed more than £60bn in market value, even as worldwide medicine sales have climbed. That's because much of that growth has been driven by aggressive generic rivals pushing cheap drugs at the expense of the more costly branded treatments.

The number of new drugs that major pharmaceutical companies are bringing to market, meanwhile, has stagnated, according to research firm IMS Health. Insiders acknowledge that after years of breakthroughs, the low-hanging fruit in terms of new products has been plucked.

Blockbuster drugs, those that reach more than $1bn in annual sales and are the lifeblood of the industry, are harder to come by. And at the same time a generation of big-sellers are about to lose, or already have lost, their patent protection and, by extension, the billions they generate in sales every year.

Meanwhile, the industry's image is still in the gutter. A recent report in the Public Library of Science journal alleged that the sector was populated by "disease mongers" that exaggerate ailments or conditions to inflate the markets for the drugs they invent. The botched clinical trial earlier this year that sent six volunteers to hospital aggravated safety concerns already dogging the sector.

All of which has led to a lot of soul searching. "The industry is at an interesting juncture," says Richard Barker, the chairman of the Association of the British Pharmaceutical Industry. "It is looking more closely at itself than it has for a long time."

Indeed, there is a creeping realisation that it is in need of fundamental reform. "For pipeline reasons, for public-image reasons, for cost-base reasons, for share-price reasons, we need to change," says one senior executive at Bristol-Myers Squibb [BMS]. "No one has the magic solution but clearly there is a will and desire to move our model forward, to look at the numbers and make it work differently."

The biggest question mark concerns whether the blockbuster model, on which the industry has relied for decades, is sustainable. Typically it takes up to 10 years and between $800m (around £425m) and $1bn to get a single medicine out of the development pipeline and into the pharmacy. To recoup that investment, once a drug gets final approval, the big pharma groups unleash their huge marketing and sales machines to push their newest pills.

But that model is under pressure. "The difficulty for these big guys is that the new products have to generate exceptional sales growth to have any impact on [revenue], so in many cases they are only compensating for losses in other areas," says Martyn Link of research group Wood Mackenzie. "When you get to $40bn in sales, growing by 10 per cent a year is a real challenge."

This is also why small biotechs, which make losses but are adept at developing new treatments, are being snapped up by the big boys. As well as AstraZeneca's swoop for CAT, American group Merck bought two biotechs earlier this month.

"The [drugs giants] recognise that a lot of the innovation coming out of biotech companies is not something they are necessarily good at," says a director at one biotechnology company. "That is changing the model."

Also changing are the sales forces of the largest groups, numbering in the tens of thousands of people. According to IMS Health, the number of new drugs had dropped steadily since 1997, until levelling off over the past three years. As the blockbusters peter out, those huge infrastructures built up to peddle them have become unwieldy.

"They are so fat, it's unbelievable," says the biotech director. "There are enormous costs that have to be stripped out of these companies."

Rather than "armies" pushing a whole basket of drugs, the industry will have to move towards "battalions" that sell treatments aimed at more targeted patients, he adds. "These companies are gearing down to look at opportunities in the $300m to $500m ballpark, rather than looking at billion-plus drugs."

"There was an arms race of ever bigger sales forces and promotions," says Mr Ward at Nomura. "That's changed. They have drawn back." Indeed, Pfizer's chief executive, Hank McKinnell, unveiled the "Adapting to Scale" plan last year, under which it hopes to trim $4bn from its costs by 2008. The company has already made over 12,000 workers redundant. Bristol-Myers Squibb and AstraZeneca have also cut their sales teams.

Nations, meanwhile, are spending less on medicines. In Germany, reference pricing - where the government finds the lowest- priced drug in a class and sets that as the maximum amount it will reimburse for any similar treatment - is gaining ground. Pfizer refused to include Lipitor, the world's best-selling drug, when the German government sought to do this for cholesterol treatments, leading to a standoff between the company and the state. Pfizer's peers commended it for making a stand, but the upshot was much less heartening. The government stood its ground and Lipitor sales in Germany are anaemic.

Rivals are worried other countries will follow Germany's lead. "The concept of reference pricing is something we are violently against," says the BMS executive. "It drives out innovation, which is not good for patients and not good for companies."

Even without this, prices are falling. In the UK, the Government and the industry agreed last year to an across-the-board 7 per cent price cut on medicines, and Japan has also been pushing for decreases.

Growth in America, so long the engine of the industry as the world's largest medicines market, has dropped dramatically in recent years amid rising public scrutiny of prices and perceptions of pharmaceutical company "profiteering".

But the drugs giants themselves have contributed to the stagnation, becoming more conservative in new development. The idea was to reduce the risk that new drugs would fall down during the trial phase by using different formulations of already-approved treatments or by focusing on areas where rivals have already blazed a trail.

This resulted in fewer truly novel drugs, just as governments cooled to "me-too" treatments that are only incrementally better than those already available.

Companies have woken up to the changed world and refocused on internal research and development, as well as buying candidates from smaller biotech companies. "They took their eyes off the ball a little bit," says Mr Ward. "We're just now seeing the first shoots of R&D recovery."

The problem, however, is that developing new drugs takes years - so the suffering, it seems, is still far from over for the big pharmaceutical companies.