INDICATION EXPANSION – the use of a product in a patient population beyond that for which it was originally approved – is almost universally employed by pharmaceutical companies as a sales-boosting lifecycle management technique designed to keep generics manufacturers at bay. However, where will this strategy be left by moves to limit the lifecycleextending benefits of product label expansions, and by heightened safety concerns surrounding the use of drugs off-label?

Regulatory changes in the USA and Europe

A new report from independent market analyst Datamonitor has found that of the 50 top-selling drug brands in 2004, 84% have had additional indications approved since their initial launch in the US, and a further 6% are known to have subsequent indications in development. Further analysis reveals that not all indication expansions are planned to maximise return on investment (ROI). With indication expansion being such an established part of the brand manager’s armoury, it is vital that companies do not lose sight of the need to evaluate the suitability and likely profitability of a strategy before implementation.

Recent regulatory changes on both sides of the Atlantic are altering the environment for indication expansion. The new data exclusivity provisions of the recent review of European pharmaceutical legislation offer the potential to gain an additional one-year market exclusivity for new indications filed during the first eight years on market, says Datamonitor analyst Adele Schulz. “This exclusivity would apply to the product as a whole; seemingly an incentive for companies to seek approval for new indication. On the downside though, the new regulations also include a provision for generics companies to exclude patented indications or dosage forms from their product information.

“This prevents pharmaceutical companies from employing the historically used strategy of filing for multiple new indications across different European markets as a means to delay the entry of generics.”

Meanwhile in the US, the Medicare Modernisation Act (MMA) of 2003 has removed the ability of companies to benefit from multiple 30-month stays of generic approval each time a generics company challenges a patent listed in the FDA’s Orange Book. Whereas patents filed for multiple indications previously resulted in multiple 30-month delays of generic approval, MMA restricts each company to one 30-month stay, triggered when the originator company sues a generics player for challenging any listed patent.

Safety concerns regarding off-label usage

“While regulatory developments have reduced the potential for on-label indication expansion to act as a lifecycle extension strategy,” Schultz says, “recent high-profile drug safety concerns are also threatening to reduce the potential for companies to profit from off-label use of their products in an expanded patient population.”

Some of the most successful forays of products into new indications in recent years have been driven by off-label usage. Genentech/Roche’s Rituxan, for example, is a blockbuster drug that only holds US approval for a niche oncology indication; much of its success is due to off-label use in a broader range of leukemia patients. Likewise, Pfizer’s Neurontin was initially approved for adjunct therapy in epilepsy, an indication that made up only 5.3% of the blockbuster drug’s US prescriptions in Q2 2004 (MIDAS medical data, IMS Health, October 2004).

However, a number of high-profile drug safety issues (including the withdrawal of Vioxx in late 2004 and the investigation of links between SSRIs and suicide) are changing the environment for pharmaceuticals (and pharmaceutical marketing in particular), and may reduce the potential for companies to profit from off-label use of their products.

Schulz comments: “During 2005, the FDA has come under much criticism for its drug safety monitoring process and has reacted by putting in place plans for a number of drug safety reforms.

“One of these reforms, the establishment of the Drug Watch website, may have particular implications for levels of off-label prescribing by bringing attention to adverse events experienced during off-label use of products. As the FDA tightens up on drug safety regulation, it may also become more active in enforcing penalties for breaching of its guidelines to the industry.”

In Europe, 2005 saw the publication of the UK Government Health Select Committee’s inquiry into the influence of pharma companies on prescribing practice, patient groups and regulatory bodies. Companies’ influence on physicians through journal publications – a key way in which off-label drug use is encouraged – was singled out for particular attention. One of the key recommendations made in the report is for the publication of trials in an independent register to avoid publication bias. This fits in with moves being made toward this aim in the US, and may reduce companies’ ability to leverage promising trial results to drive off-label prescriptions.

In deciding the optimum indication management program, companies will now have to weigh the increased scrutiny associated with off-label indication management strategies against the possibly reduced rewards of on-label strategies. New indications that require a significant raising of awareness will increasingly be best pursued with an on-label strategy.

Off-label use will continue to have a place in niche indications with high unmet need, or as a feasible strategy for second- and third-to-indication members of product classes experiencing off-label uptake in an indication. “However,” Schulz says, “companies must be aware that off-label promotion in commercially attractive populations will be subjected to increased scrutiny in future.”

From indication expansion to indication ‘targeting’

Given the increasingly challenging environment for indication expansion, companies should focus on early planning and implementation of such strategies. This will solidify indication expansion’s role as a mid-lifecycle ROI boosting strategy, rather than as a late-lifecycle generic defence strategy.

Datamonitor expects to see an evolution of the lifecycle management strategy from indication expansion to indication ‘targeting’ or ‘selection’, which implies a more focused, product-specific approach. Schulz says: “Growing use of pharmacogenomics will contribute to this shift, as initiatives to streamline the drug development process using biomarkers to identify patient populations in which a treatment will have an enhanced risk-benefit profile grow in prominence.”

Although it segments the patient population, indication targeting will result in numerous lifecycle benefits including:

• Lower development time and cost, extending the product lifecycle.

• Potential for earlier line use of therapy or even preventative treatment, significantly expanding the patient population.

• Potential for rapid expansion into new subgroups once identified by biomarker.

• Increased prescribing of the drug through benefits such as increased compliance (when prescribed to those patients most likely to benefit) and increased cost-effectiveness.

Adele Schulz, Datamonitor pharmaceutical industry analyst, is available for comment. Her Datamonitor report ‘Lifecycle Management: Accessing New Patient Populations – Maximising Return on Investment of Indication Management’ is a case study-based analysis targeting the creation of best practice recommendations for entering new patient populations in the US and Europe.