Life Sciences and Energy

Into the eye of the storm

By Business & Finance
31 December 2012

EU medicines regulators and penny-pinching governments are locked in a battle that will shape Big Pharma’s future investment in R&D, writes Gary Finnegan.

There is a war raging between cost-conscious national health authorities in EU member states and the EU drug regulators who ensure that medicines are safe and effective. In one corner is the European Medicines Agency (EMA), a London-based EU agency which effectively decides – based on expensive clinical trials – what drugs make it to market and which ones are consigned to the scrap heap. In the other sit national agencies like the UK’s National Institute for Health & Clinical Excellence (NICE), which wants public hospitals to consider cost effectiveness when choosing which drug to give patients.

In Ireland, this debate has been kept well below the radar, but tensions over the use of a cancer drug to treat elderly patients with failing vision is threatening to bring the issue to a head.
Industry analysts warn that if hospitals are allowed to choose medicines based on cost rather than safety and effectiveness, the entire European medicines approval system will be undermined. Result: uncertain return on investment for pharma executives looking to sell into the European market.

Cost pressures

Some Irish consultant ophthalmologists are treating wet age-related macular degeneration (AMD) using Avastin, a drug that is licensed for chemotherapy in colorectal and breast cancers, as well as certain types of lung and renal cancers. It is not designed for use in ophthalmology, it has not been through rigorous clinical trials for AMD, and it is not licensed for injection into the eye.

In fact, the manufacturer of Avastin has written to ophthalmologists reminding them that this is a cancer drug, and highlighting a cluster of adverse events in Canadian AMD patients who were treated with Avastin. It was never shown that Avastin directly caused problems for these patients but it was seen as prudent to make it clear that the drug was designed for oncologists, not ophthalmologists.
So, then, how can it be that the Irish Medicines Board recorded ten suspected adverse events – ranging from infection to haemorrhage – in Irish AMD patients treated with Avastin?

Off-label use

To be clear, using medicines for purposes other than those for which they have been approved is in itself far from controversial. Indeed, it is fairly run-of-the-mill, particularly in treating children, older people and pregnant women – groups typically excluded from clinical trials for ethical reasons. And it is entirely legal for Irish doctors to prescribe ‘off-label’ or ‘exempt’ medicines in the best interest of the patient, especially when there is no alternative.

But here is the difference: with wet AMD there is a drug on the market that has been tested and licensed precisely for this purpose. The trouble is that the drug in question – Lucentis – is very expensive.

That is why the ophthalmic use of Avastin takes us into new territory – ethically, and perhaps even legally. It raises question marks over whether the decision to take the cheaper, off-label option can seriously be justified on clinical grounds.

Above all, if it becomes a trend, it undermines the potential profitability of drug makers.

The same but different

Despite the lack of an ophthalmic licence for Avastin, doctors all over the world began using it for wet AMD a few years ago. The precise safety profile was unknown and there was no guarantee that it would work.

However, through a series of educated guesses, some ophthalmologists figured they could use Avastin instead of Lucentis because the drugs are of the same class. Both are monoclonal antibodies, which target the same cell growth mechanisms. They are biochemical cousins; similar, but not the same.

All eyes were on Florida recently, where preliminary results of a head-to-head trial comparing Avastin and Lucentis were unveiled. It found similar visual outcomes after one year, but the Royal College of Ophthalmologists noted that the CATT study was not statistically powerful enough to comment on safety differences between the two medicines, particularly when it comes to systemic adverse events.

More research on safety is needed, said the college, adding: “It would be inappropriate for the college to compromise on safety and [we] urge caution in the interpretation of the CATT study.”

Patient concerns

The use of Avastin in ophthalmology is not a brand new phenomenon. The authorities know about it and politicians know about it.

Recently, the patient organisation Fighting Blindness sent a letter to Minister for Health Dr James Reilly, as well as taking their concerns to Irish MEPs. Avril Daly, the group’s chief executive, said Irish hospitals are using Avastin “as it is cheaper than the licensed therapy and therefore allows more patients to be effectively treated”.

She added that while off-label use of medicines is common where there is no alternative, this is not the case for wet AMD patients. “We are very concerned about the implications of these decisions by hospital managers on patient safety and in the reporting of adverse affects,” said Daly, who has made the same points in writing to former minister Mary Harney.

High-level clash

The issue has been on the radar in Brussels since last year but little has been done given the complex power-play between EU health agencies and national authorities.

Before Thomas Lonngren’s ten-year spell as executive director of EMA ended last December, he took the opportunity to open fire on NICE. Lonngren accused NICE of deliberately pushing the off-label use of Avastin over Lucentis in an effort to save money. The Finnish authorities stand accused of the same thing.

The wider fear is that if cost-effectiveness becomes the new standard for making clinical decisions, Europe’s entire drug approval system is undermined. If the choice is between two very similar medicines, both approved to treat a particular condition and with near identical safety profiles, then it is a no-brainer: prescribe the cheaper one. But the ophthalmological use of Avastin is, at best, a grey area.

While most legal experts and regulators refer to the use of Avastin by ophthalmologists as ‘off-label’, the IMB takes the view that it is an “exempt” or “unauthorised” product because it is “further processed” prior to ophthalmic use.

What they are referring to here is that while Lucentis comes in single-use sterile doses, Avastin comes in larger volumes which must be broken down into smaller quantities. This, incidentally, introduces a new infection risk even where wholesalers or hospital pharmacists exercise the greatest of care.
Fighting Blindness is not the only patient group to express unease. The National Council for the Blind in Ireland (NCBI) wrote to the IMB last summer questioning whether price was the main driver of off-label ophthalmic use of Avastin. In response, IMB chief executive Pat O’Mahony – who is also chairperson of the EMA – acknowledged that Avastin is not licensed for wet AMD, but he essentially knocked the ball back into the court of doctors and their employers. The IMB does not deal with pricing of medicines, O’Mahony said, and qualified doctors are permitted to use “unauthorised” medicines if they so choose. So what happens when something goes wrong?

Indemnity issues

In Portugal, in Germany, in Austria, in Canada, and in Australia, adverse events linked to injecting Avastin into the eye have been put into the public domain. Now, as revealed above, we know that Irish patients have also suffered infections and bleeding after treatment. Again, this does not prove causation, but it makes it worthwhile considering the legal consequences of a law suit against an ophthalmologist who spurns Lucentis for its cheaper cousin.

There are some data suggesting increased cardiovascular risks in comparing the two medicines used in an ophthalmic context – including a Portuguese paper published in Ophthalmologica in February. Could this be waved around by a patient’s lawyer in the years to come? And who would be standing behind the doctor on the receiving end of the suit?

The Clinical Indemnity Scheme (CIS) is run by the State Claims Agency (SCA) and covers doctors working in Irish hospitals. The SCA says it knows that Avastin is being used in AMD despite not being licensed for this indication. However, it gave the following statement: “The situation in relation to CIS cover is that if a hospital enterprise permits, for good clinical reasons, its clinical staff to use unlicensed medicines, such as Avastin, CIS indemnity cover will be provided in the event that the hospital enterprise (and/or its clinical staff) is sued in a personal injury action, alleging negligence caused by the use of such unlicensed medicine.”

On solid ground

The key phrase here is “for good clinical reasons”. Provided a doctor can clinically justify the use of Avastin there is no problem. But can they? A licensed alternative exists. The manufacturers advise against using Avastin for AMD.

The Royal College of Ophthalmologists’ guidelines say doctors can only use off-label medicines if they are satisfied that the “evidence base and/or experience of using the medicine” can demonstrate its safety. It said Lucentis remains the treatment of choice until Avastin’s long-term ophthalmic safety profile is established.

Add to that the fact that the Pharmaceutical Society of Ireland has issued guidelines stating that pharmacists should not source or supply “exempt medicinal products” where an authorised alternative is available in Ireland.

Things go wrong in medicine – with licensed drugs, with unlicensed drugs, with surgery. Everyone hopes errors and adverse events are rare, but if a patient were to sue a doctor under the above circumstances it looks less than clear that the State would be obliged to stand behind the medic. Support is implied but not guaranteed.

The SCA also notes that that the choice of Avastin over Lucentis is a policy issue as well as a patient safety issue for hospitals and the IMB to deal with. It is not for the CIS to issue clinical guidelines, it says.

The Department of Health, for its part, said the CIS applies to unlicensed medicines provided hospital management have given their consent.

The bigger picture

Meanwhile, in the UK, NICE openly uses Avastin as a price comparator drug in ophthalmology, meaning that if companies have a new product they would like used by the NHS, it better be cheaper and more effective than Avastin. The old approval system is out the window.

The recent CATT study has dragged ophthalmologists back into the spotlight. But looking at the bigger picture, the results of that trial are irrelevant. The New England Journal of Medicine says that the outcome of CATT is unlikely to change prescribing habits one way or the other.

What matters is that price pressures have backed doctors into a corner and placed them at the heart of a monumental struggle for control of how patients’ medicines are chosen. The Avastin story is a microcosm of what’s coming down the tracks in every specialty. We cannot afford to pay for every drug for every patient. The question is: who decides and how?

For pharmaceutical companies weighing the value of investing in innovation, the answer is of serious concern.

*This article was originally published in the Life Sciences Review in January 2012.