Combination therapies are the cornerstone of cancer care, they bring significant benefits to patients through enhanced efficacy compared to monotherapy approaches due to the synergistic effects of the constituents and potentially lower the risk of drug resistance and toxicity in patients. Although the mono-therapy approach is still a very common treatment modality for many different forms of cancer, this conventional method is generally deemed less effective than the combination therapy approach[1].

Despite the significant value combination therapies bring to cancer care, there are several challenges to their access in Europe, especially in the case of combination therapies whose constituents have multiple indications and are manufactured by two or more companies and combinations made up of at least two novel therapies.[2] Ultimately, these challenges impact patient survival and outcomes due to delayed or denied access to effective medicines. While these challenges, and their impact on patient access and potential solutions have already been well documented,[3] the feasibility of the proposed solutions remains a subject of debate and the different views persists on the practical approach to address the issue. For example, the possibility for manufacturers to jointly participate in price negotiations, or the opportunity to assess the value of each constituent individually.

What are the access challenges for oncology combination therapies?

There are a number of access challenges for oncology combination therapies stemming from value assessment, pricing and reimbursement processes that have traditionally been designed to deal with medicines used as monotherapies, or combinations where there is only one novel constituent, used with existing generic medicines.[4]^,[5] There are often limitations in the access process and sensitivities around competition which may prevent manufacturers from jointly participating in price negotiations with the payer. The possibility for manufacturers to discuss price solutions with each other is often limited by concerns that these may infringe competition law. While in some countries there might be the theoretical possibility to discuss a joint negotiation approach on a case-by-case basis, the lack of a systematic legislative provision, or safe harbour, for such negotiations creates considerable uncertainty around access opportunities. Value assessment methodologies exacerbate the issue: for instance, countries adopting strict cost-effectiveness analysis can result in a combination therapy being deemed as not cost-effective even if one of the constituents is priced at zero.[6]^,[7] From a payer perspective, oncology combination therapies may also be considered as posing additional burden to their budgets and their value may not seem to be justified as it is not a simple sum of the value its parts. Other fundamental challenges lie into infrastructural barriers, such as the impossibility to negotiate the price of each indication individually (e.g., establishing a price for the value a medicine delivers as monotherapy and a price for the value delivered in combination, therefore indication-based pricing is a sine qua non to realize the full potential of combination therapies) and/or the lack of a mechanism to track the usage of a medicine in specific indications.

How can we resolve these access challenges?

The first step towards a solution is to recognise that a collaborative approach is needed to address the problem. At EFPIA, industry partners are coming together to explore and advocate better solutions on how to address this challenge.

We are mapping the key barriers and status quo in European countries and are supporting national trade associations to engage with leading stakeholders to discuss the extent of the challenge and to showcase potential alternatives. Combination regimens which are shown to improve efficacy are often found not to represent good value for money by health technology assessment (HTA) agencies and pricing and reimbursement bodies due to application of rigid thresholds. For these reasons, patient access to effective novel combination therapies for cancer is restricted or denied in many health systems.

The second step is to recognise that there is not a single solution - although the issues are similar across European countries, the differences between healthcare systems, regulations and legislative processes, value assessment and pricing and reimbursement mechanisms require the adoption of solutions tailored to the specific national situations.

However, there are some general considerations, however, that apply to all countries, such as 1) the inability to attribute a value to each of the constituents of an oncology combinations, 2) concerns about the implications of competition law on pricing discussions involving multiple companies and 3) infrastructural barriers to pricing mechanisms. In particular, a value-based differential payment mechanism is considered by various stakeholders as one of the critical enablers for mitigating the access barriers to oncology combinations.[8] To do this, accurate tracking of prescription information such as dosing, indication, duration of treatment is essential for calculating the costs. There also needs to be clarity as to how manufacturers of different constituents will be enabled to conduct bilateral conversations through a streamlined pricing negotiation process, whether this is through clarification of the competition laws, safe harbour clauses or third parties as intermediaries.

It is becoming critical that we address the access barriers to oncology combination therapies. The current approach of a case-by-case review of the new therapies is unsustainable and is delaying or denying patient access to important new treatments, preventing treatment optimisation and longer term, eroding the incentives for innovation in oncology.

A summary of the key asks of industry

1. A collaborative, multi-stakeholder approach across policymakers, payers, competition authorities, physicians, patient organizations and the industry is needed for developing solutions to address the access challenges for combination therapies
2. Recognition that there is no single solution which is applicable to all countries given complexities in the health systems
3. Solutions need to consider the three key issues in access challenges, 1) value attribution of the constituents 2) uncertainty around the competition law for bilateral discussions and 3) infrastructure barriers

Veronica Calzada – Sanofi Global Haematology & Policy Head on behalf of the EFPIA Oncology Platform

[1] Mokhtari R. Bayat, Homayouni T. S., Baluch N., Morgatskaya E., Kumar S., Das B., Yeger H. Combination therapy in combating cancer. Oncotarget. 2017; 8: 38022-38043. Retrieved from https://www.oncotarget.com/article/16723/text/

[2] Latimer, N. R., Pollard, D., Towse, A., Henshall, C., Sansom, L., Ward, R. L., ... & Deakin, C. (2021). Challenges in valuing and paying for combination regimens in oncology: reporting the perspectives of a multistakeholder, international workshop. BMC Health Services Research, 21(1), 1-9.

[3] Wilsdon, T. and Morlotti, L. (2022). Principles to support access to multi-indication oncology combinations. Value & Outcomes Spotlight, Vol. 8, No. 2.

[4] Danko, D., Blay, J. Y., & Garrison, L. P. (2019). Challenges in the value assessment, pricing and funding of targeted combination therapies in oncology. Health Policy, 123(12), 1230-1236.

[5] Chapman, S., Paris, V., & Lopert, R. (2020). Challenges in access to oncology medicines: Policies and practices across the OECD and the EU.

[6] Latimer, N., Pollard, D. et al. (2020). Challenges in valuing and paying for combination regimens in oncology. Available at https://bellberry.com.au/wp-content/uploads/Meeting-report-final-draft-May-2020.pdf

[7] Towse, A., Lothgren, M., Steuten, L., & Bruce, A. (2021). Why we need a new Outcomes-based Value Attribution Framework for Combination Regimens in Oncology (No. 002320). Office of Health Economics.

[8] EFPIA (2020). Addressing healthcare challenges: Novel Pricing and Payment Models: New solutions to improve patient access. Available at: https://www.efpia.eu/media/554543/novel-pricing-and-payment-models-new-solutions-to-improve-patient-access-300630.pdf