A very interesting and depressing group of articles in today's BMJ. Retinopathy of prematurity is a small market compared to wet macular degeneration in the elderly, in whom VEGF inhibitors are proven to be extremely effective. Ranibizumab (I will call it RBZ) is far more expensive than BVZ for the effective dose, and the company responsible refuses to apply for a licence for BVZ for this indication, despite the 6 comparative trials which show equal efficacy, and a Cochrane review showing equal toxicity. The companies' tactics are appalling:

The NHS spends £244m a year on ranibizumab, the second highest amount for any drug. However, research and development costs do not explain why ranibizumab is priced 10-20 times higher than bevacizumab, Philip Rosenfeld, professor of ophthalmology at the Bascom Palmer Eye Institute in Florida told The BMJ. He was involved in the early phase trials of ranibizumab and was one of those who pioneered the use of bevacizumab for wet AMD. He said bevacizumab is also more expensive to make than ranibizumab.

Ranibizumab is a monoclonal antibody fragment derived from the same parent monoclonal antibody as bevacizumab. Both drugs act by inhibiting vascular endothelial growth factor (VEGF), preventing blood vessel growth. Roche holds the intellectual property rights for both, although Novartis has the rights to market ranibizumab in Europe. Bevacizumab is licensed for use only in cancer conditions, and Roche has never applied for a marketing authorisation for ophthalmic conditions—despite repeated calls from politicians to do so. This means only the more expensive ranibizumab has such a licence, and prescriptions of bevacizumab— even in its repackaged form for ophthalmic use—are “off label,” .....

But eight years on, bevacizumab is scarcely used for AMD in the NHS, and the companies have not done the necessary trials. ...... Minutes from a NICE workshop show that Roche said decisions not to develop bevacizumab for ocular use have been “due to corporate considerations.”

The article goes on to say :

An accompanying article shows how the manufacturers didn’t want to do the trials themselves and when it was agreed that the public should fund both a comparative and a dosing trial, they did all they could to scupper them—even turning to the Royal National Institute of Blind People (RNIB) for help. Then once these trials were published, they embarked on a campaign to undermine and divert attention from the results, raising safety concerns themselves and via their key opinion leaders and charities.

That accompanying article describes the way Novartis has tried to wreck other trials.

The need to compare bevacizumab and ranibizumab for ophthalmic use was perceived to be a priority for the NHS. And so the “randomised controlled trial of alternative treatments to inhibit VEGF in age-related choroidal neovascularisation” (IVAN) trial was conceived, at a cost to the public of about £10m......

However, there was resistance to the trial from the outset. Barney Reeves, professorial research fellow in health services research at Bristol University and one of the IVAN trialists, told The BMJ that it was a difficult trial to do politically. “The drug manufacturers didn’t want it done,” he said, adding: “Novartis tried to prevent UK ophthalmologists joining the IVAN trial, with their sales representatives lobbying potential principal investigators against the trial and telling them that the IVAN protocol was seriously flawed.”

Emails obtained by The BMJ under a freedom of information request show that clinicians with ties to Novartis urged some primary care trusts to pull out of the trial. The emails show discussions between ophthalmologists close to Novartis about how “big centres” in the US pulled out of the CATT trial because they would lose industry funding for other trials. The emails said that this situation “could be applied to the UK”—that is, researchers would be put off IVAN for fear of losing industry studies.

Emails also show that Novartis approached ophthalmology centres to conduct trials into other eye conditions for them at the same time IVAN was progressing. Novartis helped the investigators in these industry funded trials to obtain supplies of ranibizumab, in stark contrast to its approach to the IVAN trialists.

A new trial, not included in those systematic reviews has just been published in the NEJM. It showed that in diabetic macular oedema, nine shots of BVZ ($50 per dose), RBZ ($1,200 per dose), and aflibercept ($1,950) produced an equivalent benefit.

It was accompanied by an editorial which ended thus:

“We believe that all financial incentives and logistic barriers to providing the least expensive drug, among drugs equivalent in safety and efficacy, should be eliminated so that patients may benefit fully from the results of this Diabetic Retinopathy Clinical Research Network trial as well as those from other comparative trials.”

Which sounds eminently sensible, but not likely to hold much sway with Novartis, whose main consideration appears to be their own benefit, and not the patients.

Extreme preterms are small fry of course, in many ways. A single treatment, in a small number of babies, is not going to make a huge amount of money for anyone, unless you can find a way to restrict the treatment choices to only the more expensive drug. So Novartis are sponsoring a trial of RBZ against laser (NCT02375971), when, if we need to study RBZ at all, what is needed is a trial of RBZ against BVZ. Unfortunately such a trial would be likely to show that they are equivalent, as they are in adults, so I don't hold out much hope that Novartis will fund such a trial.