When German pharmaceutical company Bayer first synthesised the painkiller aspirin in 1897, little was known about how the drug worked. Despite becoming a blockbuster drug, it would take 74 years for aspirin’s anti-inflammatory mechanism of action to be published in 1971.
But aspirin had other secrets to reveal. The discovery of its antiplatelet effects made it the talk of the cardiology community, and the evidence that it can help certain people avoid heart attacks has been refined over the past 40 years. Yet still aspirin had tricks up its proverbial sleeve — namely its potential preventive effects against some forms of cancer.
If it weren’t for such widespread use of aspirin, many of its benefits may not have come to light through observational study. The feature in this issue (p653) describes how many recognised medicines may have potential use in the treatment of cancer, although for a variety of reasons these anticancer effects remain uninvestigated or, often, undiscovered.
Around 90% of drug indications first tested in phase I studies never make it all the way to market. Many thousands of compounds do not even reach clinical trials. It means that many failed but potentially useful medicines are hidden away.
What’s more, trial data on failed drugs often go unpublished. Having no access to the existing knowledge on these medicines is a barrier to them being investigated by researchers for other patient groups. Making public all preclinical and clinical findings from unsuccessful drugs could help avoid delays and expensive duplication.
Drugs available generically may be the low-hanging fruit. These medicines are relatively cheap, with well established safety profiles, giving them a bit of a head start when it comes to researching their effects in new disease areas. But here is the catch: it is their very low unit price that can make them less attractive to the industry.
So who is going to support the investment of millions in a promising treatment that may offer little, if any, financial return? If pharmaceutical companies aren’t interested, certainly governments could be in a position to make the case, also charities and foundations. There could also be hope in crowd funding, the online phenomenon whereby substantial sums can be raised from donors or investors with interest in the cause. Yet there remains the dilemma of whom would assume the costs and risk of seeking regulatory approval for a new indication.
Companies that hold a current patent for a medicine will be better placed to invest in the discovery of additional indications that could extend their market exclusivity. It is often the case that these additional therapeutic effects will be known to the company at an early stage in the drug’s development, or inferred from its pharmacology.
It might be argued that these do not represent major innovations, like the discovery of an unexpected molecular target would. Nevertheless, these new indications require substantial investment to go from proof of concept to registered therapeutic use.
Not smooth sailing
For companies that do go down the route of patent extension it can be far from smooth sailing, as Pfizer would attest.
The US giant developed the drug pregabalin and first launched it in Europe in 2004 as Lyrica for the treatment of epilepsy and generalised anxiety. Pfizer went on to license the product for nerve pain and was able to extend the period of market exclusivity in the UK to July 2017. But the original indications are now off-patent, and Pfizer has been battling in the courts to prevent generic companies from marketing their own versions of pregabalin while it still holds a patented indication.
With generic pregabalin products now on the market in the UK, NHS England has advised doctors and pharmacists not to supply generic pregabalin for the patented indication of pain, for which patients must be prescribed Lyrica. The commissioning board was instructed by the High Court to do this.
The current system does not make it simple to deal with differing indications for multiple products containing the same active ingredient.
Shifting this burden to healthcare professionals has created confusion and extra work, and Pfizer has even apologised to pharmacists and GPs for this. For pharmacists it means confirming the indication with patients or the prescriber and, if necessary, requesting a new prescription. This leads to delays for patients and further work for the GP surgery.
The pregabalin situation is unusual. New indications for existing medicines are not uncommon, but it can be easier for companies to avoid confusion for prescribers if the new indication has a different dosage and a new brand name to accompany it. For example, Merck Sharp & Dohme relaunched its finasteride product in 1mg tablets for male pattern baldness under a new brand name Propecia in 1999. The original product was a 5mg tablet, called Proscar, for benign prostatic hyperplasia. In this case, a doctor could still prescribe finasteride generically and the dose would indicate the brand and therapeutic use.
With a medicine like aspirin, it is easy to see why a company may not relish the idea of researching a new therapeutic indication if no effective mechanism exists for them to ensure prescribers choose the branded product if one were ever to be launched. And many would question the ethics of doing so, since a major win for patients would be access to an affordable existing treatment, not an expensive repositioned one.
New incentives are needed to facilitate research into additional uses for the medicines we have, while ensuring that the resulting treatments are affordable to society.