Payers are used to assessing individual therapies – these make up the vast majority of new drugs to market. However, what happens when a new branded product shows benefit when added to a branded product that is already marketed? How do payers ensure value for money whilst ensuring manufacturers get a return on investment too? New combination therapies are increasing so payers and manufacturers need to work to find solutions to the pricing issues presented. This article will explore why combination pricing is an issue, particularly in the oncology space, and some of the impacts.
What issues arise from the pricing of combination products?
While the use of combination therapies has been commonplace within cancer treatment for decades, companies are now combining their new therapies/molecules with existing branded drugs (rather than relatively inexpensive generics) which are the accepted standard of care in the therapy area. With the massive rise in the trial of combination therapies, such as the increase from 20 PD-1/PD-L1 combination clinical trials in 2013 to 467 in 2017, payers are now facing the issue of how to price these products.
The core issue of combination pricing is that the use of two or more branded products usually pushes the cost of the combination therapy above the threshold payers are willing to pay to treat the disease (below), since only one element of a combination is priced at a time. As a result, the added benefit of adding a new therapy on top of an existing branded one, is often less than is needed to justify the price of the new branded product.
As the attendees of a 2018 Sydney workshop (attended by payers, patient organisations and industry representatives) on combination pricing recognised: “Challenges only arise when more than one on-patent treatments are combined, and when different manufacturers produce the constituent parts of a combination”. This raises the issue of who should be responsible for funding the ‘shortfall’ – the manufacturer of the existing product, the manufacturer of the new product, or should the payer have to increase their willingness to pay?
As well as the pricing challenges, the combination of branded products can also be difficult to assess from a payer perspective. The payer must consider how the efficacy and safety demonstrated for a combination therapy should be valued given the constituent costs of the individual therapies. At the moment, there is no common consensus on how to overcome the pricing issues for combination products, as each product is evaluated via the same methods used for monotherapies.
The impacts of a lack of consensus for combination pricing
The most obvious impact is that manufacturers can struggle to achieve patient access for their products, or poor HTA outcomes influence the price achieved for their product. This is most stark in markets that rely on cost-effectiveness, where combinations may not be cost-effective even if the price of a new ‘add-on therapy’ is zero. Keytruda (pembrolizumab) with Inlyta (axitinib) is a good example. The National Institute for Health and Care Excellence (NICE) deemed the combination as not cost-effective, despite significant overall survival and progression-free survival over the comparator, especially as the product did not meet NICE’s end-of-life criteria. In markets focused on additional clinical benefit, however, the combination received positive HTA outcomes (ASMR III in France, considerable additional benefit in Germany) and a successful price based on the same evidence.
One positive impact for manufacturers in ‘cost-effective’ markets is that payers can be flexible in providing funding while more evidence is collected, such as via the Cancer Drugs Fund (CDF) in England. Collecting additional data while in the CDF was demonstrated in a separate case study of Keytruda (pembrolizumab), with carboplatin and paclitaxel. This combination was routed by NICE into the CDF for non-squamous non-small cell lung cancer (NSCLC) on the basis that initial trial data indicated that adding Keytruda to the chemotherapy regimen increased survival. Further evidence collection of survival benefit was enough for NICE to give Keytruda a positive recommendation in February 2022.
The success of drugs through the CDF suggests that combination products do bring substantial benefits to products, but the issue is that manufacturers often do not have the long-term data to prove it.
Why do some manufacturers fail to achieve reimbursement for their combination therapies?
However, combination pricing can lead to access issues even in markets focused solely on additional clinical benefit (e.g. France, Germany). There are multiple examples of drugs that have either not achieved access, or received unfavourable HTA outcomes, based on poorly designed clinical trials. For example, Imbruvica (ibrutinib) with Gazyvaro (obinutuzumab) received negative HTA outcomes in France and Germany after launch in August 2019. While both countries recognised that the combination therapy offered no OS superiority, there were also concerns about the trial design. In Germany, the lack of usable quality of life data was criticised. In France, the choice of comparator was criticised, as there was an absence of comparative data vs. Imbruvica monotherapy. Other common criticisms of combination product trials include immature OS data and comparator arms not reflecting standard of care.
Should combination products be considered differently?
The question remains as to whether combination products should be assessed differently by payers.
There has been some discussion, including by the Sydney workshop, that payers should aim to ‘align the cost of constituent therapies with their value within a regimen’ (i.e. manufacturers of the two products should agree a suitable price for both so that the total cost of treatment is acceptable to payers). While payers have the ability to renegotiate backbone prices in France and Italy, it is unlikely that this approach can be adopted globally, given the legal challenges that would arise.
Alternatively, manufacturers are keen that combination priced products should be assessed differently. Takeda, for example, have published a White Paper for their own proposed value framework for combination therapies. The NICE methods update, implemented in Feb 2022, is likely a missed opportunity to reassess the approach.
In conclusion, the difficulties in the pricing of combination therapies creates significant challenges for both payers (and HTA bodies) and manufacturers. If manufacturers want to get a branded price point for their product, they must have a well-designed clinical trial that allows for the collection of mature OS data against the appropriate comparator. Payers could also approach the combination pricing approach differently (e.g. different criteria, or more flexible pricing mechanisms). There is still an industry-demand for more flexible pricing mechanisms to be considered, especially as triplet therapies become more commonplace.
The problem is here to stay, and the challenges are likely to grow, with manufacturers now exploring triplet therapy regimens (i.e. three branded drugs used concurrently) in oncology, such as Darzalex Faspro (daratumumab and hyaluronidase-fihj) in combination with Kyprolis (carfilzomib) plus dexamethasone.
1Charles Schmidt. The benefits of immunotherapy combinations. December 20, 2017. Accessed March 7, 2022 https://www.nature.com/articles/d41586-017-08702-7
2Latimer, N.R., Pollard, D., Towse, A. et al. Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multi‐stakeholder, international workshop. BMC Health Serv Res 21, 412 (2021). https://doi.org/10.1186/s12913-021-06425-0
3NICE appraisal of Pembrolizumab with axitinib for untreated advanced renal cell carcinoma [TA650]. September 30, 2020. https://www.nice.org.uk/guidance/ta650
4HAS-TC. TRANSPARENCY COMMITTEE SUMMARY 13 MAY 2020. https://www.has-sante.fr/upload/docs/application/pdf/2021-01/keytruda_rcc_13052020_summary_ct18154.pdf
5G-BA. Benefit assessment procedure for the active ingredient pembrolizumab (new indication: renal cell carcinoma, first line, combination with axitinib). May 14, 2020 https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/511/
6NICE appraisal of Pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer [TA770] https://www.nice.org.uk/guidance/ta770
7G-BA. Benefit Assessment of Medicinal Products with New Active Ingredients According to Section 35a SGB V Ibrutinib (New Therapeutic Indication: Chronic Lymphatic Leukaemia, First-Line, in Combination with Obinutuzumab). February 20, 2020. https://www.g-ba.de/downloads/40-1465-6362/2020-02-20_AM-RL-XII_Ibrutinib_D-488_TrG_EN.pdf
8HAS-TC. TRANSPARENCY COMMITTEE OPINION 20 MARCH 2020. https://www.has-sante.fr/upload/docs/application/pdf/2020-07/imbruvica_summary_ct18212.pdf
9Takeda. An Attribution of Value Framework for Combination Therapies: Report by the Value Attribution Working Group. January 2021.
10ASCO Post. FDA Approves Triplet Therapy for Previously Treated Patients With Relapsed or Refractory Multiple Myeloma. December 25, 2021. Accessed March 4th 2022. https://ascopost.com/issues/december-25-2021/fda-approves-triplet-therapy-for-previously-treated-patients-with-relapsed-or-refractory-multiple-myeloma/