Challenges - summary
Attendees at the Sydney Workshop agreed that the challenges associated with valuing and paying for combination therapies in oncology were truly international. Although challenges manifest in different ways between systems, affordability, value for money and value attribution were consistently challenging issues that can impact patient access.
Whilst attendees agreed that the challenges outlined above are common and important, they were keen to clarify that the challenges only arise when more than one on-patent treatments are combined, and when different manufacturers produce the constituent parts of a combination. It was, however, noted that a different challenge to patient access to new combination therapies can arise where old drugs are repurposed and found to be clinically effective in a new low-cost combination use. Often these regimens lack a manufacturer sponsor to take them through regulatory and HTA processes. This is tangential to the challenges associated with providing access to new high cost combination regimens, but is an important issue that needs addressing [16,17,18].
Options for addressing the challenges presented by combination regimens
Attendees categorised potential solutions into three ‘buckets’ (Fig. 1). The general challenge amounted to the cost of combination regimens often being too high, given their perceived and/or assessed value when price is determined. The three buckets of solutions involved:
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1.
Increasing the value of combinations, through improved clinical development and trial design to optimise clinical regimens.
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2.
Being willing to pay more for combinations (over and above single treatments offering comparable value).
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3.
Aligning the total cost of the combination to the demonstrated value, by using flexible payment and pricing mechanisms to adjust the prices of individual constituent medicines.
The remainder of this section describes each of these options as they were discussed at the Workshop.
Bucket 1: Increase the value of the combination – clinical development and trial design to optimise clinical regimens
Attendees considered it may be possible to increase the benefits associated with combination regimens whilst potentially reducing their costs through optimising treatment regimens. This idea was not identified in the literature – it was suggested by Workshop attendees.
Optimising treatment regimens may involve altered dosing schedules, treatment durations and supportive care requirements. Reduced toxicity, improved quality of life, and lower costs could result, increasing the likelihood that treatments would represent good value for money. Discussion focused primarily on the use of stopping rules. It was noted that sometimes submissions to HTA agencies attempt to model these, but evidence on their impact on effectiveness is usually lacking – making it difficult for HTA agencies and payers to incorporate stopping rules into their decision making. It was felt that, if treatment regimen alterations such as stopping rules are deemed clinically valid and potentially cost-saving, evidence on their effectiveness should be collected.
Targeting combination regimens specifically at patient groups who are most likely to benefit from them was also identified as an approach that could increase the value of new treatments. Whilst valuable, this is difficult, because it is likely to require development of diagnostic tests and/or improved monitoring of patients to identify responders (or those most likely to respond). In addition, attendees agreed that it was important to ensure that all relevant outcome measures were collected in trials, including patient relevant measures, to ensure the true value of therapies can be demonstrated.
Attendees supported increased use of adaptive trial designs and platform trials, which could allow altered dosing regimens, stopping rules or diagnostic tests to be incorporated within ongoing trials [19,20,21,22]. Attendees supported the use of combined scientific advice processes – whereby HTA agencies, payers and regulators provide joint advice to manufacturers on trial design and clinical development programmes. This could identify at an early stage of clinical development cases where investigation of alternative treatment regimens could be particularly worthwhile – allowing useful data to be collected. Also, there was agreement that pharmaceutical companies and HTA agencies/payers should work to make more use of post-launch randomised and observational studies to provide information on alternative treatment regimens.
Bucket 2: Pay more for combinations
Attendees recognised that HTA processes could be amended to increase willingness to pay for combination therapies for cancer. Most HTA agencies have flexible decision-making criteria, such that recommendations are not based solely on whether a new treatment provides value for money according to rigidly specified thresholds or criteria. For example, ‘therapeutic added value’ systems usually compare the benefits and costs of a new treatment and those of other treatments for the same condition, with no explicit reference to a willingness to pay threshold. In systems that do specify thresholds, these are often flexible – NICE specifies a threshold range, which differs for end of life treatments and technologies defined as “highly specialised” [10, 23]. And in Sweden, different thresholds are used for different disease areas [24]. In general, it is not unusual for orphan drugs to be given special consideration by HTA and payer bodies [25]. Given this flexibility, ‘combination therapies’ could be used as a modifier in the decision-making or value assessment framework, permitting higher prices. This approach has been suggested in the literature [2].
Attendees generally agreed that there are benefits to having flexible cost-effectiveness thresholds, broader value frameworks and flexible deliberative processes incorporated into HTA. Attendees agreed on the importance of HTA processes capturing the full value of all therapies assessed. However, they considered that special provisions could only be made for combination therapies for cancer with an evidence-based justification. Evidence that society values combination therapies more highly than other treatments, including monotherapies for cancer, would be needed. Workshop attendees were not aware of any such evidence, and thus could see no grounds for such special provisions for combination therapies. It was recognised that if willingness-to-pay was increased for combination therapies and this was not consistent with societal preferences, this could come at the expense of other treatments offering more health gain, resulting potentially in net societal losses.
Bucket 3: Aligning the total cost of the combination to the demonstrated value – flexible payment and pricing mechanisms
Workshop attendees generally agreed that when existing monotherapies are combined and produce value that is not proportional to their combined cost, it would be appropriate for constituent prices to be re-visited and negotiated. Similarly, when new add-on treatments are combined with an existing backbone therapy and provide clinical benefit, it is appropriate for the price of the backbone therapy to be re-visited in its new use. This has been suggested in the literature, [2, 4] but raises issues of implementation, value attribution, and legal challenge, when the constituent therapies are made by different manufacturers. These issues were discussed at length at the Sydney Workshop, as reflected below. Another suggestion in the literature [4] - that combination regimes could be re-developed as single products - was also discussed but felt to be impractical. Similarly, attendees expressed a concern that without progress on ways to revisit and adjust prices of constituent therapies, manufacturers of new add-on treatments might decide to develop their own “me-too” versions of backbone therapies (over which they would have control of price), representing an inefficient use of valuable drug development resources.
Bucket 3: Implementation
Attendees recognised that if the prices of existing treatments are to be re-visited as part of a combination regimen price negotiation, a key consideration is whether the price is changed for all uses of the treatments (i.e. for their use as monotherapies, and/or their use in other disease areas), or only for their use as part of the combination therapy being appraised. To limit dis-incentives to price negotiation, attendees suggested multi-use pricing is likely to be required – allowing prices to differ for a treatment depending upon the disease area it is being used in, and/or depending on whether it is being used as monotherapy or as part of combination therapy [2, 14, 15]. Price discounts or budget caps could also be used to achieve price reductions for specified uses.
Pricing systems to allow multi-use pricing may be complex and costly to run and may need to be taken into account in assessments of value for money. Any multi-use pricing mechanism would ideally be based on good data on the use of cancer treatments, including clinical indication, therapy line, type of combination, dosing and treatment duration. In some countries, potentially appropriate data are already collected (e.g. the Systemic Anti-Cancer Therapy dataset in England [26]). Alternatively, reasonable assumptions about differential use of treatments would need to be agreed, based on epidemiological data and whatever health system data are available. Or, this information combined with a value assessment for each use of a product could be used to calculate an appropriate weighted average price across all uses of a product. Attendees noted that some countries lack sufficient flexibility to make this work.
Workshop attendees felt that the exact method used to implement price adjustments for constituent parts of a combination regimen was relatively unimportant – whether through multi-use pricing, discounts, budget caps, or combinations of these. However, having a system in place that could support such methods was crucially important – without this, price negotiation could not achieve a solution to the challenges raised by combination regimens. Attendees agreed that HTA agencies and payers should communicate clearly with manufacturers types of flexible pricing model acceptable to achieve price reductions for combination uses. In some countries, suitable pricing mechanisms and data collection systems may need to be developed.
Workshop attendees recognised a further barrier to re-visiting the prices of constituent parts of combination regimens concerns incentives. If a backbone therapy is in use and produced by one company, and a new add-on therapy is developed by another company, has the manufacturer of the backbone therapy sufficient incentive to enter into price negotiations with the producer of the add-on? [4]. In principle, patient access to the combination therapy could increase backbone therapy sales. If, however, negotiations are likely to reduce the price of the backbone therapy in the use under appraisal and in its other uses, the company may see limited gain, and could incur losses, from negotiating. The length of time remaining on the patent of a backbone therapy may also influence the willingness of a producer (and a payer) to negotiate, as might the producer’s own drug development pipeline. Multi-use pricing could alleviate some of the dis-incentives to negotiation, but attendees also suggested that appraisals of combination regimens that raise issues around the value for money of backbone therapies in the new use should trigger the re-assessment of (and possible disinvestment in) the use of backbone therapies in their existing uses. This could act as an incentive for manufacturers to negotiate.
Bucket 3: Value attribution
If the prices of the constituent parts of combination regimens are to be negotiated, consideration must be given to how prices (or values) of these parts should be determined, and who they should be determined by. This was of particular concern to a number of attendees.
Options for ‘how’ value could be attributed between constituent parts of a combination regimen have been discussed in the literature [2, 4, 13]. Simple options exist, for example, splitting the revenue equally. A formal quantitative value attribution framework could be used, where value is based upon the estimated benefit that each constituent part contributes to the combination – though this may not be straightforward to calculate. Attendees felt that research into value attribution frameworks for combination regimens would be useful, and should involve multiple stakeholders (including HTA agencies and academia) to increase credibility.
Attendees differed as to ‘who’ should be responsible for attributing value to constituent parts of combination therapy. Some attendees felt this was the responsibility of the pharmaceutical companies – several HTA representatives felt strongly that HTA agencies and payers are responsible for assessing the value of overall treatment packages, not individual constituent parts of combination regimens. Other attendees felt that value attribution was a natural role for HTA agencies and/or payers, because their remit was to value healthcare interventions. Even if an HTA agency did not feel it appropriate to attribute value to constituent parts of a therapy, there might be an important role for it as a broker of discussions between companies. Whoever attributes value, it was recognised that deliberative processes would be required. It is unlikely that prices could be set solely using quantitative methods. There was agreement that value attribution should be addressed early in the HTA process – ideally before reimbursement submission to HTA agencies or payers – to avoid delays in the appraisal process, which would delay patient access.
Bucket 3: Legal challenges
Many attendees were concerned about the legal challenges that price negotiations between companies present. Legal experts explained the issues, including competition law around collusion. Some attendees suggested that participation of a third party – an HTA agency or payer – may help, echoing the literature [2]. Attendees were also told about a platform designed to enable companies to trade, without meeting, under the supervision of HTA agencies. However, legal experts explained that the involvement of HTA agencies and payers in price negotiations may not solve the legal problems, and in some circumstances may raise additional issues.
Attendees recognised that the legal issues are critical, and may dictate whether price negotiations offer a practical solution to providing affordable access to effective combination therapies. Attendees strongly agreed there was an urgent need for pharmaceutical companies and HTA agencies/payers to explore the legalities of price negotiations between companies (with or without the involvement of HTA agencies and payers) recognising that what is permitted may vary by jurisdiction, and may require amended legislation.