Strategies for generic asthma inhalers: Copy or create?

David Harris

BCC research claims that the global pulmonary drug delivery market will be worth a staggering $44 billion by 2016.1 With key drugs and delivery devices soon to come off-patent, the race is on to take a share of this highly profitable market – but should pharmaceutical companies copy successful products or create something new?

Unfortunately for the world’s population, inhaler use continues to grow. Rapid industrialisation (especially in BRIC countries) together with better access to healthcare has led to a continuous rise in asthma diagnoses and resulted in a global market currently worth over $26 billion a year.

Pharma companies around the world, especially those in India, are looking for ways to address this market, and one route is to capitalise on long established therapies which are now off-patent.

This is certainly the case for the DPI (dry powder inhaler), a sector currently dominated by GSK’s Advair Diskus – often used by patients who find it difficult to use a pMDI device (pressurised metered dose inhaler). Although more expensive – and therefore less frequently prescribed than the pMDI – Advair has become the therapy of choice for millions of patients around the world, generating a staggering $7 billion of revenue in 2009 for GSK.

Key patents relating to Advair have started to expire, opening the market to a host of new competitors. Not surprisingly, many of these have been waiting for this moment for many years, with device replication a common response strategy. Given the investment GSK made in developing Advair, and the proven success of the product, replication seems the most obvious way to quickly enter a highly profitable market, but one which is also driven almost exclusively by price. If the copy is the same in every aspect except cost, then market share is virtually guaranteed.

But some competitors have chosen not to replicate but to innovate instead. By comparison, innovation – higher risk and higher cost – seems almost inappropriate, given that most users are happy with what they already have. But some companies are innovating, and innovating successfully, challenging the almost automatic assumption that replication is the best route forward.

Replication for fast market share

Replicating off-patent therapies to create cheaper, ‘own’ or ‘no brand’ alternatives has a long and well-established history. In the Indian domestic market alone there are at least 12 variants of the original Miat capsule DPI, for example. Although studies showi that a recognised brand can improve therapeutic effect, there is still a large market share to be had when patient choice is driven primarily by price, especially in sectors such as tablet-based analgesics.

The relative ease with which many generic drugs have entered specific markets has perhaps developed a false assumption that all generic equivalents are ‘simple’ to create, especially when formulations are well documented, and off-the-shelf packaging systems ready to buy. But recreating a device as complex as a DPI requires much greater and wider ranging expertise, and it is becoming clear that R&D teams can underestimate the challenge involved.

In particular, many companies fail to appreciate the importance of the delivery device, seeing it as just another form of ‘packaging’. The replication of a DPI, however, requires an understanding of the complex interactions between device and formulation, and of areas such as fluid dynamics and aerosol science, often beyond the scope of many inhouse R&D teams. DPI design tolerances are critical, given the nature of its operation and its small size; poorly designed copies can exhibit undetected faults such as air leaks or poor powder aerosolisation characteristics, significantly affecting efficacy and success in the clinic. Price may be a driving factor, but the device still has to work just as well as the branded equivalent. In addition, the regulators now require evidence that devices are safe to use: this means that it cannot be assured that a device based on outmoded functionality will meet current regulatory requirements.

The important interaction between the DPI powder formulation and the delivery device is also frequently misunderstood. DPI formulations typically comprise active pharmaceutical ingredients (APIs) and lactose carrier particles in a mixture which has to remain homogenous when stored or transported, as any vibration can cause preferential segregation, compromising dose content uniformity throughout the life of the inhaler. For Advair, GSK developed a highly sophisticated packaging system which loads and seals single doses of the compound in a specially designed foil sealed blister pack. The packaging process is so precise that even though no headspace exists within each compartment, the compound is not compacted – simply held securely. This prevents movement, and therefore minimises segregation, but also means that when the Diskus device removes the foil seal, the compound is moved only by the inhaled breath and at the minimum flow rate to ensure an efficient dose. If packed too tightly, the compound may form a solid lump, too loosely and the active compound may separate from the lactose carrier. In both cases, the dose would be delivered incorrectly and given that each dose is already only 25 – 30 per cent efficient, getting this right is crucial. This attention to detail by GSK is one of the many reasons why Advair has been so successful – and why generic alternatives may fail to replicate the performance.

A final hurdle for a replicated product is to show that it is ‘substitutable’ – that the instructions given for the original device can be used with the new. In the case of Advair – with elements of the Diskus still protected by design rights – achieving this level of reproduction is, again, a serious challenge. Not impossible, but rarely achievable without some expert input across the R&D process.

Innovating for future growth

When successful, copying is undoubtedly a much quicker route to market. Clinical trials are shorter, saving significant time and money, and market success is guaranteed if the product operates correctly and is priced aggressively. However, any product chosen purely on price is always vulnerable to competition from alternatives developed in just the same way. Replication can certainly generate short-term profits, but is perhaps a less appealing longer-term strategy.

An alternative was demonstrated in 2010, when one of the leading Indian pharma companies, Sun Pharma, announced the imminent launch of a brand new DPI design, developed to work with a generic version of the Advair formulation. Sun worked with external design houses to create a device which may not be cheaper than a Diskus copy, but which offers much better value for money. Sun’s strategy was to offer an improvement over the market-leading Diskus inhaler, both in terms of clinical performance and features. Overall, the device is sleeker, simpler and more intuitive to use – and it even glows in the dark.

Undoubtedly, Sun’s decision was not without risk. The process to develop a new DPI is expensive and must take place in a highly competitive space; around 400 patents have been filed in the last year related to DPI technologies, indicating the level of activity in this area. In addition, we would approximate, based on data that we have seen and anecdotal evidence, that currently, the accepted success rate for new inhaler devices reaching the market is only around 10 per cent, further underlining the challenges inherent in this sector.

But a crucial feature of the Sun device – and a compelling argument in favour of innovation – is that it is specifically designed to adapt to both current and future formulations which could be developed by Sun. This means that users familiar with the Sun device can stay with the same technology as drugs improve. This future-proofing also addresses a number of regulatory issues associated with DPI design. For example, many current devices would not meet regulatory approval if they were designed today. By starting from scratch, Sun has created a device which meets and exceeds current standards and guidelines, is better for patients, and which should also generate a bigger, and more sustainable return on the original investment required to innovate. However, it must also be said that the Sun device still leaves room for further, more radical innovation.

Deciding on a future strategy

The response to off-patent DPI therapies is teaching the industry many useful – and possibly uncomfortable – lessons, and one of the most important is never to underestimate the complexity of an established design. Effective replication requires an understanding of all the many reasons why the therapy has proved so successful, and access to the full range of skills and technologies needed to create a viable product is essential.

Replication, however, is certainly one of the best strategies for short-term income generation. For many companies it will still make better economic sense to invest in getting a copy right, thereby securing their share of such a huge market, than to create a brand new device which carries with it a much higher level of risk.

But Sun Pharma’s experience shows that innovation is not as unrealistic as may first seem, and in fact offers many opportunities for better product design, enhanced performance, greater clinician and patient support, and – crucially – future potential.

References:

1. Branthwaite A, Analgesic effects of branding in treatments of headaches, British Medical Journal, 16 May, 1981