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On 18 October Pfizer announced that it would withdraw the first inhaled insulin, Exubera, from the market, as sales were too low. In January 2006 Pfizer bought the worldwide rights to Exubera from Sanofi-Aventis for $1.3bn (£0.6bn; €0.9bn), and in August 2006 the product was introduced in Britain. In the first nine months of 2007, worldwide sales of Exubera amounted to $12m, rather short of its projected $2bn blockbuster status. Instead it will cost Pfizer an estimated $2.8bn to “write it off.”
So why were sales of Exubera so far below expectations? Was it that:
Exubera's withdrawal has implications for the companies that make the insulin and the inhalers, as well as Nektar Therapeutics, which developed the inhaler and retains a stake in the product. Nektar has yet to announce how it will proceed. Several other companies have inhaled insulin products in development, including Eli Lilly, Novo Nordisk, and the MannKind Corporation, and it is not yet clear how the withdrawal will affect these programmes, although the companies have said they intend to continue.
In principle the lungs offer several opportunities for the delivery of peptides. Their large surface area aids rapid absorption, administration is painless, and trial participants who use Exubera have reported a high level of satisfaction and acceptability.1 2 3 4 However, the inhaled route is haunted by several unknowns. Could a high concentration of insulin in the lungs bind it to insulin-like growth factor-1 (IGF-1) receptors, influence proliferation, increase the amount of connective tissue, reduce lung compliance, and reduce the rate of gaseous exchange? Is the required monitoring of forced expiratory volume in one second (FEV1) accurate enough and reproducible for safety purposes? At an additional cost of about £500 per patient per year, is the low bioavailability of inhaled insulin an extravagance? Despite these concerns, the US Food and Drug Administration and the European Medicines Agency were sufficiently satisfied about the product's safety to grant a licence, although with some important exclusions (such as cigarette smokers, people with major pulmonary disease, and children) and a requirement for pulmonary function testing before patients started Exubera and then at intervals afterwards.
We believe this to be the first time that a licensed product for managing a common chronic disease has been withdrawn from the market so quickly for what would seem to be purely economic reasons. Despite any criticisms that might be levelled at Pfizer's marketing strategy, and practical difficulties with the device itself, it seems that restrictive guidelines may have contributed to the poor sales. In its preliminary consultation document the UK National Institute for Health and Clinical Excellence (NICE) did not recommend the use of Exubera at all (despite accepting the evidence that patients were more satisfied with it than injected insulin), saying that cost effectiveness had not been shown. After comments from groups such as Diabetes UK, the Association of British Clinical Diabetologists, and various nurses' organisations, NICE softened its attitude and recommended use of Exubera, but only in patients with a true needle phobia or where there were major needle site problems.5
The conclusions of NICE and similar bodies recommending Exubera only in restricted cases should send a warning to drug companies that their development programmes should look beyond what is needed to gain a licence: their studies may have to demonstrate cost effectiveness of the product and use in “real life” clinical practice situations. This may not be easy in the case of drugs for chronic diseases, given that hard data on outcomes are unlikely to be available by the time of the launch, so that surrogate end points may still be needed to demonstrate cost utility.
NICE guidance and labelling restrictions made it almost impossible for clinicians to prescribe Exubera to many UK patients who might have benefited from this new technology, including people with poorly controlled type 2 diabetes who refused to start insulin treatment because they did not want to inject (rather than those with true needle phobia) and those with type 1 or type 2 diabetes who needed to intensify insulin treatment to improve control but would not do so because it would mean more injections.
What do we do about our patients who already take inhaled insulin? One of us (AHB) runs an inhaled insulin clinic for patients who fulfil the NICE criteria. The response among those who have been prescribed Exubera has been almost universally positive. What are we to tell them? The lifeline that they have been offered and have taken up has now been cruelly removed, and they will have to wait at least two years for alternative products to appear. We also have several patients who have been promised access to this new technology and who now have to be told that it is no longer available.
Perhaps more worrying, however—if the decision on Exubera is indeed solely economic (as seems to be the case)—is that drug companies may now be less inclined to speculate in the development of new products unless there is greater assurance over reimbursement. As a result the industry may reduce its commitment to research and development of novel compounds and concentrate in other areas, such as “me too” products. The appetite to invent and develop novel treatments may be suppressed. This is in nobody's interest, least of all our patients'.
A licensed product for managing a common chronic disease has been withdrawn from the market for what would seem to be purely economic reasons