German and UK Payer Perception of Combination Immune Checkpoint Inhibitors

Although there were a number of combination therapies already available on the market for malignant melanoma, in May 2016, the EC approved Opdivo/Yervoy, the first – and currently only – immune checkpoint inhibitor combination for the treatment of malignant melanoma. Industry watchers and payers expressed trepidation regarding the EU5 market access success of this therapy, given that other oncology combination therapies have struggled to optimize – or even achieve – market access in the EU5 countries. And those combinations did not comprise two relatively recently launched therapies, each considered to be expensive in their own right. Could the immune checkpoint inhibitor combination succeed where others have failed? The health technology assessments (HTA) conducted by the National Institute for Health and Care Excellent (NICE) in the UK and the Gemeinsamer Bundesausschuss (G-BA) in Germany paint a complicated picture.



NICE, uncharacteristically, was first out the gates, with a decision made merely a month after EC approval - and the day after rejecting Roche’s Cotellic/Zelboraf combination for malignant melanoma. In one of the fastest appraisals ever carried out by NICE, Opdivo/Yervoy got the green light, to the surprise of many. Patients in England and Wales would become the first in Europe to have access to the new life-extending therapy. What was the secret of Opdivo/Yervoy’s success? Payers interviewed by DRG indicate that, quite simply, in addition to demonstrating robust clinical efficacy and safety data, the therapy was able to meet NICE’s stringent cost-effectiveness threshold. The reason it was able to do that was because BMS was willing to negotiate a Patient Access Scheme (PAS). That is, as per a simple discount managed entry agreement (MEA), effectively bringing the combination therapy’s price below the cost-effectiveness threshold.


Opdivo/Yervoy’s NICE success story hits on two themes that we see across the EU5. First, managed entry agreements -- whether they be simple and finance-based or complex and outcomes-based -- can make or break a therapy in some countries. And second, when it comes to combination therapies, it is an advantage when all component are marketed by the same manufacturer. Payers indicate that there are a number of reasons why this is a lever for success, but overall it comes down to the pricing and reimbursement (P&R) negotiations. When there is only one manufacturer stakeholder for the combination, it is easier to exercise the necessary pricing flexibility required to optimize the uptake potential of the drug - and to take a pricing hit on one of the drugs where necessary to guarantee P&R success for the combination overall, as BMS did with the PAS on Yervoy.


Initially, the possibility of HTA success in Germany seemed promising as well. A few months after NICE’s speedy decision, the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) found that Opdivo/Yervoy demonstrated considerable added benefit in men, and a hint of non-quantifiable added benefit for women. As long as the G-BA agreed in its assessment, which it does the majority of the time, then Opdivo/Yervoy was on its way to a premium price in Germany. However, things did not go according to plan. In a decision heavily criticized by BMS, the G-BA changed the preferred comparator for the combination treatment during its assessment, despite an early consultation with the manufacturer on this subject. BMS had submitted trial results for Opdivo/Yervoy versus Yervoy monotherapy in the dossier, with no data comparing the combination with Opdivo or Keytruda, which the G-BA argued in its assessment would have been more appropriate. With that, the G-BA concluded that Opdivo/Yervoy demonstrated no added benefit, because the wrong comparator was used. In the decision dossier, the G-BA declared that it was justified in this specific case, given the rapidly evolving treatment landscape. German payers we spoke to reiterated this point, stressing that in an indication like malignant melanoma, the standard of care is constantly changing.


The snafu in Germany really drives home the importance of trial design when it comes to market access for oncology therapies in the EU5, especially if those therapies are as costly as an immune checkpoint inhibitor combination. The standard of care comparator, robust efficacy (i.e. unequivocal added benefit) and safety data and wisely chosen end-points (with a strong preference for OS and PFS) are critical for a therapy to succeed in the increasingly stringent EU5 HTA landscape.


How have Opdivo/Yervoy’s HTA success and stumble translated into uptake though. As perhaps would be expected given the nod from NICE, the combination therapy had robust patient shares among our surveyed UK medical oncologists for first line unresectable or metastatic malignant melanoma compared with other immune checkpoint inhibitors, exceeding the patient shares of Opdivo and Yervoy in monotherapy.More surprisingly though, in Germany, patient shares were also very respectable, despite the “no added benefit” rating from the G-BA. In both BRAF wild-type and BRAF mutation-positive patients, Opdivo/Yervoy in combination had shares similar to those of Opdivo and Yervoy in monotherapy, and either matched or exceeded Keytruda’s shares (an immune checkpoint inhibitor therapy that did demonstrate added benefit in some patient populations according to the G-BA).


So, an HTA stumble does not necessarily correlate with poor uptake. However,  interviewed payers in Germany were concerned about the price of combination therapies and stress that there has been considerable pressure from state-level payers and physician groups to adopt indication-specific pricing, specifically for combination therapies. That sentiment was not unique to payers in Germany, and in fact the, seemingly increasing,  influx of combinations and their current costs emerged as a significant concern when it comes to future HTA success and long-term uptake of current and emerging therapies across the EU5. As one payer told me, when it comes to combination therapies like this, one plus one simply cannot equal two. A combination therapy’s price cannot simply be the price of the two drugs combined, there has to be flexibility on the part of the manufacturer to make the therapy more affordable. We saw that in the UK with BMS taking the hit on Yervoy, and the G-BA forced that situation when Opdivo/Yervoy was found to have no added benefit and thus no hope of a premium price.

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