by Sylvie Lapostolle at the RCFr oncology meeting

PARIS, Nov 24 (APM) - Early access to innovation in oncology in France has some shortcomings, especially concerning new indications for already approved drugs, experts said at a meeting.

A round table on early access to innovation at the RCFr French oncology meeting in Paris on Wednesday once again highlighted the positive results of the country's early access mechanism (ATUs).

“We are the only country in the world to have this. This scheme allows drugs to be available ahead of their marketing authorisation,” said Nicolas Albin, a member of health technology assessment body HAS's Transparency Commission (CT) and a haemato-oncologist at Grenoble's private GHM hospital group.

Thirty-three cohort ATUs were issued in 2016 and 33,000 patients were treated (excluding the post-ATU period), said Lofti Boudali from drug regulator ANSM.

However, there are also some flaws in these arrangements, said journalist Alain Perez who led the debate. He said the system is not adapted to the current situation for multi-indication drugs - of which there are many -, a problem oncologists in particular have raised regularly in the past few months.

In October, lack of access to Merck & Co’s anti-PD-1 Keytruda (pembrolizumab) in France was criticised when new results were presented (APMMA 55211). Pricing negotiations for its reimbursement are ongoing, while it is already available in melanoma.

Managed off-label access scheme not ideal

“For drugs that already have marketing authorisation and for which an ATU is therefore no longer possible, but for which another indication emerges - something that is ever more frequent, especially for immunotherapies - the RTU [managed off-label use authorisation] mechanism should take over, but this does not work very well,” said Jean-Jacques Zambrowski, an economist at Paris Descartes University and co-moderator of the round table.

“Indeed, for indication extensions, ATUs cannot be used, and RTUs do not work that well,” Albin acknowledged. However, he cited the “classic example of success” for Pfizer’s Xalkori (crizotinib), for which France's national cancer institute INCa had proposed setting up a RTU following promising results in ROS1-rearranged lung cancer seen in the context of the institute’s AcSé (secure access to innovative drugs) programme. This drug, which was already approved in ALK-rearranged lung cancer, was made available to the ROS1 patients.

“The problem is that this is the one and only example,” Zambrowski responded.

Dr Nadine Dohollou, a medical oncologist at the Bordeaux Nord Aquitaine clinic, expressed her “frustration as a clinician and on behalf of patients when we have the drug available - it is there - with an extension of indication in Europe, but we cannot prescribe it in France because of a reimbursement problem”.

She highlighted the “paradox” whereby it is easier to use a drug off-label than under an extension of indication.
She also said it should be easier to prescribe a drug due to the presence of a mutation where the multidisciplinary molecular meeting (RCP) considers this is recommended.

“We are not in favour of reimbursement being a 'free-for-all'. Therapy guided by a molecular event does not work in all patients, as we have seen with BRAF mutations in colorectal cancers: the anti-BRAF drugs did not work, similarly to immunotherapy with an anti-PD-L1 that was effective in bladder cancer in Phase II but whose results were not confirmed in Phase III,” Albin said.

“Early access is not a winner every time, and confirmation studies are required,” he said.

Boudali explained that the RTU system had been set up to manage off-label prescribing, which is why it does not correspond to the needs of new indications. "RTUs must be redefined so they favour innovation,” Albin added.

There is a lag between administrative and clinical approvals and patients should not be penalised by the choice of the initial indication, according to INCa director of recommendations and medicines Muriel Dahan. She was not present at the debate, but sent statements to be read out. The institute has made proposals on this but no decisions have yet been taken, she said.

Avastin 'unavailable' in cervical cancer

Brigitte Massicault, director of the Imagyn association for patients with gynaecological cancers, said she regretted that this lack of access to therapeutic innovation results in “loss of opportunity for patients, and discontinuation of treatment”.

She talked about how Roche's Avastin (bevacizumab) had not been added to the “liste en sus” list of expensive hospital drugs in the treatment of cervical cancer (APMMA 51651)

She said that throughout 2017 so far her her charity has been active in opposing this decision, which limits access to the drug and leads to unequal treatment, with some hospitals agreeing to pay the extra cost over the reimbursed flat-rate fee for hospital stays (GHS), while others - more numerous - do not.

“Since January, patients have been refused treatment while the same treatment exists in other indications. This injustice according to disease is not normal and it results in deaths,” she said.

“We got ourselves as much media coverage as possible, with support from scientific societies and oncologists, but we couldn't do anything about it,” she said.

“It is true that lack of availability of bevacizumab in cervical cancer poses a problem in practical terms, and we feel very uncomfortable about this situation. The drug must have its place. There may be inequalities in France in the case of this specific indication,” Albin admitted.

He acknowledged that this was a shortcoming of the system, but said it was due to the criteria for inclusion on the list being tightened up following a complaint from a pharmaceutical company.

He recognised the “inhuman” aspect of the decree setting out these criteria. “Ultimately, we end up with 'difficult' decisions like the one in cervical cancer. I dare hope this regulation will be reviewed,” he said.

INCa has requested a transitory solution and the ministry is reviewing the decree, the cancer institute told APM in July.

Roche 'open to price-per-indication'

Albin expressed surprise that no-one had mentioned Roche, “which has not agreed to a price cut for its drug although it has been on the market for more than eight years”.

Roche’s Stéphane Loze, who was present in the room, gave a similar response to one he had made on an earlier occasion. “We didn't get to that stage. The [health technology] assessment automatically led to non-inclusion on the liste en sus,” he said.

Loze pointed out that Roche is open to a price-per-indication approach and has initiated a data collection programme called PRM (personalised reimbursement models) with the aim of changing the pricing system (APMMA 42081).

Roche is currently collecting real-life data on breast cancer in 120 centres in France, “with highly coherent results on the possibility of moving towards performance contracts,” he said.

sl/aki/clg