Pink Sheet: global policy and regulatory coverage
By Ian Schofield 27 Jan 2022
The European Medicines Agency’s assessment of the oral antiviral combination was conducted under the OPEN Initiative, which involves information sharing...
The clinical potential of immuno-oncology drugs does not seem to be reflected in approaches by health technology assessment bodies, with different interpretations of data, broad labels and cost all contributing to disparate reimbursement decisions.
Immuno-oncology drugs do not seem to be winning the market access that their potential suggests they deserve. Research by Context Matters, a US-based data analytics and software firm, suggests that IO drugs are not faring much better than traditional cancer treatments. This is largely down to the way different health technology assessment bodies interpret the data, the products’ high prices and the broad nature of labels, according to Ashley Jaksa, vice president of data & analytics at Context Matters.
Pharmaceutical companies are investing heavily in developing these treatments. According to a report from US pharmaceutical industry trade association PhRMA, there are 248 immuno-oncology medicines and vaccines currently in development. The space is developing rapidly and companies are keen to capitalize on the commercial potential of such products, developing combination therapies and forging partnerships. (Also see "Takeda Picks Next Big Thing In Immunotherapy: Gamma Delta T Cells" - Scrip, 15 May, 2017.) (Also see "Combinations Continue To Drive Immuno-Oncology Deal-Making" - In Vivo, 8 May, 2017.) [Editor’s note: this paragraph was updated June 2 with corrected number of products in development.]
In one major recent IO development, the US FDA approved Merck's Keytruda (pembrolizumab) for patients with microsatellite instability-high or mismatch repair deficient solid tumors, marking a new route into difficult markets for PD-1/L1 inhibitors (Also see "Keytruda Approval Opens New Routes For Immuno-Oncology" - Scrip, 24 May, 2017.).
Jaksa wanted to see if the promising efficacy data for IO drugs from clinical trials translated into market access, so her company looked at reimbursement decisions for checkpoint inhibitors by health technology assessment authorities in Australia (PBAC), Canada (pCODR), England (NICE), Scotland (SMC), Germany (IGWiG and G-BA) and France (HAS).
What Jaksa found surprised her. “We should be able to see the clinical data translate into market access and we actually don’t,” she said in an interview with the Pink Sheet.
“Checkpoint inhibitors seem to get more positive decisions, but when we actually look at them statistically, there’s no statistical difference between checkpoint inhibitors and all the other oncology drugs when it comes to being reimbursed,” said Jaksa.
Data pulled in February this year from French, English, Scottish, Canadian and Australian HTAs showed a 71% positive decision rate for checkpoint inhibitors (Bristol-Myers Squibb Co.’s Yervoy(ipilimumab) and Opdivo (nivolumab) and Merck & Co. Inc.’s Keytruda, compared with 62% for other oncology treatments.
“If checkpoint inhibitors are as promising as the clinical data suggests, I would expect to see a significant difference in positive decision rates versus other cancer therapies,” Jaksa added. (The data do not include decisions from Germany because IQWiG and the G-BA do not issue formal recommendations, but instead evaluate the additional benefit that the drug offers patients compared with rivals on the market.)
“Checkpoint inhibitors seem to get more positive decisions, but when we actually look at them statistically, there’s no statistical difference between checkpoint inhibitors and all the other oncology drugs when it comes to being reimbursed.” – Ashley Jaksa, Context Matters
One big issue that companies face in securing market access is how HTA bodies interpret and value the data. “There are obviously nuances in how these HTA agencies are interpreting the results, which we think can shed some light on expectations for how these new cancer therapies should perform, and on the challenges to market access for any new entrants into the market,” Jaksa said.
For example, Yervoy as a second-line melanoma treatment offered an absolute gain of 3.7 months in overall survival. However, HTA agencies came to differing conclusions on how important this gain was. All agencies noted this endpoint, but the SMC, PBAC and HAS gave the overall survival gain a “lukewarm reception,” said Jaksa.
“Even though these agencies noted that there was significant unmet need in this population, they still had a hard time thinking that 3.7 months was a very big gain.” For example, Australia’s PBAC had doubts about how long the benefit would last and the manufacturer had to make three submissions before PBAC was comfortable with the results. HAS said the overall survival gain of 3.7 months gave a “modest benefit.”
Meanwhile, IQWig/G-BA, pCODR and NICE gave more favorable opinions. The German bodies concluded that 3.7 months overall survival represented “major additional benefit,” while pCODR described the gains as “clinically meaningful.” Furthermore, there were different responses to data on quality of life, which was measured as a secondary endpoint.
Yervoy as a second-line melanoma treatment offered an absolute gain of 3.7 months in overall survival but HTA agencies disagreed on how important this gain was.
All agencies recommended Yervoy as a second-line melanoma treatment. However, the differences in opinion on the overall survival data illustrate some of the difficulties new products might come up against when going through HTA assessments. “It is really interesting that these agencies are taking a very important metric, overall survival, and interpreting it differently,” Jaksa observed. “Manufacturers and others should be aware that hard endpoints can be interpreted differently and this could lead to different decisions.”
Context Matters also examined responses to Opdivo as a second-line melanoma treatment. Opdivois authorized for both first and second line melanoma, and according to Jaksa, the broad label meant that the HTA bodies picked different parts of the evidence to focus on.
The SMC and pCODR reviewed the drug for first- and second-line treatment separately. Both agencies noted uncertainties in the evidence base supporting the case for second-line treatment – which came from the Checkmate 037 trial – and wanted additional evidence. Both the SMC and pCODR rejected the drug for second-line melanoma. IQWiG, however, did not review the drug as a second-line treatment due to issues with the study and therefore concluded it offered no additional benefit.
NICE and PBAC reviewed Opdivo more broadly across its label without splitting their assessments in two. Instead they evaluated only the first-line data, which they used to make recommendations for both first- and second-line treatment. NICE recommended the drug in full while PBAC’s recommendations came with restrictions.
“This is just another example of how the HTA agencies again are focusing on different aspects of the data and how that can have consequences for market access,” said Jaksa. “You would assume that the interpretation of the data would be very similar across these HTA agencies but, in fact, we’re seeing that there can be differences in how they’re interpreting the data based on what aspects they choose to focus on.”
There is little that companies can do about this, according to Jaksa. However, they can provide extra information – for example, they can conduct supplemental post-hoc analysis to back up their arguments. They can also try to understand the HTA decisions that agencies have already made so that when they create their dossiers, they can better understand how their data will be received, she advised.
“We’re seeing that there can be differences in how they’re interpreting the data based on what aspects they choose to focus on.” – Ashely Jaksa, Context Matters
Cost was another big factor in reimbursement decisions. Agencies that evaluated cost-effectiveness always issued a positive opinion when the economic analysis was positive, said Jaksa. She noted that companies made their checkpoint inhibitors more cost effective by offering a patient access scheme wherever this was possible, for example when submitting to NICE, the SMC and PBAC. Overall, manufacturers of checkpoint inhibitors were more likely to offer a patient access scheme than companies selling other oncology drugs and non-oncology drugs.
In addition, HTA agencies were more willing to restrict access to checkpoint inhibitors compared with other oncology treatments. “This is another way for the HTA agencies to really zoom in on the patient populations where the drug is most efficacious. They’re restricting reimbursement to those populations, mostly likely to control costs,” Jaksa said.
Some 33% of reimbursement decisions relating to checkpoint inhibitors came with some sort of restrictions in relation to the terms of the EU marketing authorization. In comparison, 17% of recommendations for other oncology treatments came with restrictions.
Jaksa presented on this topic at the Pharmaceutical Pricing and Market Access Congress 2017 in London in earlier this year.
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