The use of targeted combination therapy is increasingly becoming the standard of care in oncology as cancers are attacked through multiple inhibition mechanisms. In 2018, 2,250 clinical trials were evaluating PD-1/L1 immunotherapy agents, with over 75% of these trials studying these agents in combination with other cancer therapies1. Moreover, there are several other disease areas where combination therapy may prove beneficial.
These high-cost combinations are posing a budget challenge to health systems and an economic return challenge for companies developing them. The question is, considering the scale and potential impact of combination therapies coming to market in the next 2–3 years, will that force a change in pricing and reimbursement policies for combination treatments?
Pricing and Access challenges associated with high-cost combinations
Combination therapies are unlikely to be considered a good value for money
A combination therapy combines two or more individual component therapies to treat a single disease. It can be comprised of a ‘backbone’ therapy and one or more ‘add-on’ therapies.
A backbone is a drug already approved for use and whose use is well-established. Being the initial entrant to the market, the backbone is priced at a limit where it is considered ‘good value for money’ and currently, once recommended is unlikely to be reassessed from a pricing/access perspective for that indication.
An ‘add-on’ therapy is a drug that is added to an existing backbone therapy. This drug may have previously been introduced into the market as a monotherapy, or it is specifically developed to work in combination with the backbone therapy. It is often challenging for an add-on therapy to demonstrate incremental clinical value to justify its price point and be considered good value for money2. Let’s consider two drugs that already exist as monotherapies which both bring a value of ‘1’ and are correspondingly priced at ‘1’. Combining the two drugs provides a value of 1.5, but at a price of 2. Whilst the price of therapy has doubled, the value has not, and therefore the combination would not be considered good value for money3.
Combinations may not be cost-effective, even if price of new add-on therapy is zero
Such situation occurred when UK’s National Institute for Health and Care Excellence appraised pertuzumab in combination with trastuzumab and docetaxel for breast cancer4,5. Although pertuzumab increased survival, it was not considered cost-effective even at zero price because all ‘allowable incremental costs’ were taken up by an increased duration of the backbone5. The issue is that the backbone is priced at the limit of what a payer is prepared to pay given the outcomes delivered, and payer’s willingness to pay for a new add-on drug to backbone therapy is limited to the additional benefit. If the combination involves extended duration of treatment using the backbone (as with pertuzumab) as well as other extra costs, then no price may be low enough to demonstrate cost-effectiveness6.
Add-on manufacturers have little control over their treatment combination price
When components of the combination are manufactured by different companies, the anti-trust law does not allow companies to discuss and re-align on the individual component prices. Moreover, in most cases there is no incentive for the backbone manufacturer to reduce the price of their product. Therefore, manufacturers of the add-on drugs only have control over the price of their own product and not the overall cost of the treatment combination2.
Potential solutions for challenges associated with valuing and paying for combination therapies in oncology can be placed into three broad areas which focus on clinical development, HTA processes and flexible payment and pricing mechanisms3,6:
- Be willing to pay more for combinations – this could be achieved with higher cost-effectiveness thresholds / willingness-to-pay thresholds or QALY weighting for combination treatments compared to monotherapy drugs. However, altering HTA decision rules specifically for combinations seems challenging because there is no clear reason for paying more per unit of benefit for combinations compared to other types of therapy
- Increase the value of the combination by optimizing treatment regimens – improved outcomes could be achieved by improving clinical development to identify optimum treatment paradigms such as treatment durations and stopping rules that optimise health benefits and minimise adverse effects and costs. This is important but challenging and significant progress seems unlikely in the short term
- Reduce the price of the combination through flexible payment and pricing mechanisms (such as discounts, multi-indication pricing or budget caps) – this could be the most realistic solution however, re-visiting the price of the backbone raises several issues around implementation approaches (backbone may be already available as a monotherapy so indication based pricing may be needed), value attribution (aligning individual drug prices with the value attributable to them in that combination), and legal challenges regarding pricing of two products from different manufacturers (anti-trust law)
Currently the methodology for assessing combination products is the same as for single products, therefore it is not surprising that it is difficult to find a price at which an add-on therapy is cost-effective or represents value for money. Failure to provide combination therapies at an acceptable price results in societal losses such as delayed or restricted patient access to combination treatment, disincentives for research and development, and fewer life years gained. Potential option to address this are limited, are not straightforward and are likely to require further development. Collaboration and input is needed from pharmaceutical companies, HTA agencies, payers, clinicians, patients, ethicists and legal bodies in order to address the best way forward in order to make the funding of these potentially life-saving therapies possible.
- Tang J. et al. The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. 2018 https://www.nature.com/articles/nrd.2018.210
- Briggs A. et al. An Attribution of Value between Combination Therapies: Illustration, Discussion & Case-Studies.2021.https://www.takeda.com/49a844/siteassets/en-gb/home/what-we-do/combination-treatments/a-value-attribution-framework-for-combination-therapies-takeda-whitepaper.pdf
- Danko D. et al. Challenges in the value assessment, pricing and funding of targeted combination therapies in oncology. 2019. https://pubmed.ncbi.nlm.nih.gov/31337514/
- Latimer N. et al. Not cost-effective at zero price: valuing and paying for combination therapies in cancer. 2021. https://pubmed.ncbi.nlm.nih.gov/33472440/
- Henshall C. et al. Time to Tackle the Challenges around Combination Therapies for Cancer. 2021. https://www.ohe.org/news/time-tackle-challenges-around-combination-therapies-cancer
- Latimer N, Pollard D. Pre-read document 1: Challenges in valuing and paying for combination regimens in oncology. 2019. https://www.sheffield.ac.uk/scharr/sections/heds/discussion-papers/20_02-1.882458