Combination treatments are fast becoming the cornerstone of cancer care.1,2  With over 300 active clinical trials in the UK exploring the possibilities of different cancer treatment combinations, it’s clear scientists believe in this multi-pronged approach for transforming how people live with the disease.3  However, several unresolved challenges around value, pricing, assessment, and funding remain. 

The Life Science’s Vision outlines the UK government’s ambition to be the world leader for the discovery, development and launch of new treatments. However, access challenges could jeopardise additional investment and scientific advancements which would be detrimental to patients in the UK.4,5  In oncology, it’s vital that we address these challenges to keep pace with future needs, solidify the UK’s position as a global leader in life sciences and support UK patient access to combination treatments.

What are combination treatments and why are they becoming more important?

Two or more medicines used together that attack cancer cells in different ways1

Combining different drugs can help to make cancer treatment more effective, and reduces the risk of tumours developing resistance1

A growing wave of evidence supports their ability to overcome complex therapeutic challenges posed by cancer

In certain cancers, combination treatments can help patients to live longer and improve their quality of life compared to using one medicine alone6,7,8


Why is innovation still important in cancer?


50% of cancer patients in England and Wales are estimated to not survive 10 years with the disease.9


~90% of cancer-related deaths are thought to be due to drug resistance and the resulting ineffectiveness of the drug treatment.10

While research and pharmaceutical innovation has advanced at pace in recent years, there are many types of cancer where significant challenges to treatment persist. Cancers have become proficient at evading or resisting treatment, leading to relapse and disease progression. Treatments combining multiple mechanisms of action can block cancer’s escape routes from treatment, and in turn, have the potential to boost outcomes in many patients.

A major hurdle in oncology

Despite their potential, there are long-standing challenges that restrict patient access to combination treatments in the UK.

Who governs access to medicines in England?

In short, the National Institute for Health and Care Excellence (NICE). Set up in 1999, this independent organisation is responsible for deciding which drugs are available on the NHS in England, based on an assessment of their benefits for patients, as well as their cost-effectiveness, or value for money.

Wales, Scotland, and Northern Ireland have different bodies for approvals, these being the All Wales Medicines Strategy Group, the Scottish Medicines Consortium, and The Regulation and Quality Improvement Authority, respectively.

The current formula for a combination treatment to require NICE approval might look simple…

But in reality, there are many complexities and challenges with getting these combination treatments into the hands of doctors and their patients.

Since 2001: 

  • Almost a third (32%) of all terminated NICE appraisals for cancer were combination treatments11 
  • Over a third (37%)* of cancer combination treatments submitted to NICE were either not recommended (meaning NICE did not approve them for NHS use) or had their appraisal terminated11

In a member survey conducted by the Association of the British Pharmaceutical Industry (ABPI) last year, challenges related to combination treatments were cited as the main reason for terminations or non-submissions by pharmaceutical companies over the past five years.12

*127 combination treatments for the treatment of cancer were assessed by NICE from 2001 until July 2022. Of these, 29 combination treatments were not recommended and 19 were terminated (total 48). There were 58 total terminations. Percentages calculated using these figures.

So, what are the barriers?

1. Competition law restricts the ability of pharmaceutical companies to work together to offer a cost effective price for combination treatments

In many cases, the medicines in a combination will be manufactured by different companies. Competition law prevents manufacturers from speaking to each other to offer a combined price that represents value for money for the NHS and fair remuneration.

The Association of the British Pharmaceutical Industry (ABPI) and the Competition and Markets Authority (CMA) are currently exploring how collaboration on combination treatment pricing might be achieved, however, there are no guarantees a solution would be found. Ultimately, the main barrier to access remains the way that these treatments are evaluated. Current cost-effectiveness frameworks mean there will be cases where even if company-company dialogue is allowed to make the combination treatment more cost effective, the price may still not be deemed cost-effective.

2. Once a price for a medicine is agreed with NICE, it must be applied to all uses of that medicine, regardless of whether it is used alone or in combination

Even if companies could work together to lower the cost of each drug within a combination, the reduced price would need to apply in cases when those drugs are used alone too.

The lack of flexible pricing means the NHS must pay the same price for a drug even if it benefits patients to varying extents in different indications. For example, the same medicine might be more or less effective depending on the type of cancer in which it is used, but the NHS has to pay the same price regardless of the difference in value.

3. NICE's cost-effectiveness threshold is the same for one medicine as it is for two or more treatments used together13

NICE has a set threshold that the NHS is willing to pay for treatments to be reimbursed.  

Figure 1: Graph visualising NICE’s cost-effectiveness threshold and determination for reimbursement of new medicines. Adapted from Claxton, K., et al., 2008. Value based pricing for NHS drugs: an opportunity not to be missed? BMJ, 336(7638), pp.251-254.14

There are multiple challenges associated with this methodology. For example, combination treatments can lead to increased survival in certain cancers, meaning patients are on both treatments for longer. The longer patients are on each drug, the greater the cost to the NHS, and despite the additional benefit of the “add on” in the combination, the cost-effectiveness threshold might be surpassed.

Existing cost effectiveness parameters mean that when an approved treatment is priced close to the level deemed still cost-effective, there exists very little headroom for any additional costs associated with an “add-on” treatment. In some instances, even if the company manufacturing the “add on” gave it away for free, it would not be considered cost-effective for NHS use.13 Updating cost effectiveness models for combination treatments could offer a solution to enable patients access to the most effective cancer treatments.

4. Value Attribution Frameworks

Combination treatment value is determined for the combination overall and there aren’t any frameworks in place to assess the attribution of value between products within the combination.5 Without a recognised framework, value assessments don’t evaluate the relative contribution of each drug to overall survival (or progression-free survival) or quality of life gains.5 This can lead to a disproportionate value split between manufacturers of combinations, with the price of each component treatment detached to its contribution to the combination’s overall benefit.5

"We have strong evidence to support how two or more medicines can work together to attack tumours in different ways, leading to improved outcomes for people living with cancer. The need for multiple mechanisms of action has also never been clearer. However, despite the clear potential of these new combinations, if we don’t evolve existing reimbursement frameworks then patients in the UK will not have the same access as patients in other countries.”

Fleur Chandler, Head of Market Access for Sanofi UK and Ireland

Cross-sector collaboration is vital for advancing tangible solutions

While the reimbursement challenge facing combination treatments is not new, progress has been slow to overcome the multiple barriers to patient access to vital medicines. Key stakeholders, including pharmaceutical companies and wider health players such as payers and policymakers, should come together and show flexibility to find frameworks so that UK patients get access to innovative and potentially life extending treatments.

A number of collaborative measures can be introduced to support patient access to innovative combination treatments

  1. A future NICE modular update should consider increased flexible assessments of combination treatments. This could include raising the threshold for cost-effectiveness of combination treatments or removing backbone costs.
  2. Organisations from across the healthcare sector should work with the pharmaceutical industry and other partners to develop a framework for improving access to combination treatments which reflects the need to allow medicines to vary in price depending on their use.
  3. NHS England and NICE should continue to support efforts to enable fair and constructive discussion on pricing combination treatments between manufacturers, including prioritising implementation of the pending recommendations of the ABPI and Competition and Market Authority following their review into this area.

Access to combination treatments for many people living with cancer could mean better chances of survival and improved quality of life. Our goal is to make sure combination treatments benefit the lives of these cancer patients, while ensuring sustainable health system expenditure and encouraging pharmaceutical innovation.  

At Sanofi, we look forward to working with all relevant stakeholders to find a way to ensure we don’t stifle access to innovation for UK patients.

Survey

References

  1. Mokhtari et al. Combination therapy in combating cancer, Oncotarget. 2017 Jun 6; 8(23): 38022–38043.
  2. Haycock, L, et al. The Case for Combination Therapy - Clinical and Economic Value Differentiation Strategies in Saturated Oncology Therapy Areas. Abstract PCN279 
  3. ClinicalTrials.gov. Oncology combination therapy trials in the UK. Available at: https://clinicaltrials.gov/ct2/results/map/click?map.x=644&map.y=1014&term=combination&recrs=d&cond=cancer&map=EU&mapw=1899 Last accessed: October 2022
  4. HM Government. Life Sciences Vision. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1013597/life-sciences-vision-2021.pdf. Last accessed: October 2022.
  5.  Takeda Value Attribution Working Group. An Attribution of Value Framework for Combination Therapies. 2021. Available at https://www.takeda.com/49a844/siteassets/en-gb/home/what-we-do/combination-treatments/a-value-attribution-framework-for-combination-therapies-takeda-whitepaper.pdf. Last accessed: October 2022
  6.  Wright K, et al. Patient-Reported Outcomes Show Newer Drug Combinations Maintain Quality of Life Longer Than Current Standard-of-Care Treatments. 13 February 2020.

  7. Yardley DA, et al. Drug Resistance and the Role of Combination Chemotherapy in Improving Patient Outcomes, International Journal of Breast Cancer, vol. 2013, Article ID 137414, 15 pages, 2013. https://doi.org/10.1155/2013/137414 Last accessed: October 2022

  8. Khalil DN et al, The future of cancer treatment: immunomodulation, CARs and combination immunotherapy, MedicineMatters, available at: https://oncology.medicinematters.com/treatment/immunotherapy/the-future-of-cancertreatment-immunomodulation-cars-and-combina/12037350 Last accessed: October 2022

  9. Cancer Research UK. Cancer Survival Statistics. Available at: https://www.cancerresearchuk.org/health-professional/cancer-statistics/survival#heading-Zero Last accessed: October 2022

  10. Wang X, et al. Drug resistance and combatting drug resistance in cancer. Cancer Drug Resist. 2019;2:141-60

  11. NICE technology appraisal cancer recommendations, available at: NICE technology appraisal cancer recommendations, available at: https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technology-appraisal-guidance/data/cancer-appraisal-recommendations Last accessed: October 2022

  12. ABPI. Reasons for NICE ‘Optimised’ Recommendations and Terminated Appraisals, 2021, available at https://www.abpi.org.uk/publications/reasons-for-nice-optimised-recommendations-and-terminated-appraisals/ Last accessed: October 2022

  13. OECD, Addressing Challenges in Access to Oncology Medicines, 2020.

  14. Claxton, K., et al., 2008. Value based pricing for NHS drugs: an opportunity not to be missed?. BMJ, 336(7638), pp.251-254.

Job bag number: MAT-XU-2203348 (v1.0)
Date of Preparation: October 2022