Bridging the Gap: Pathways for Regulatory and Health Technology Assessment of Histology Independent Cancer Treatments

Article by: Marina Rodes Sanchez, Nadine Henderson and Lotte Steuten

Histology independent therapies represent a new era in how oncology patients are diagnosed and treated, by targeting a genomic alteration within all solid tumours regardless of where the primary tumour is in the body. Despite generating a paradigm shift these therapies are faced with multiple challenges to fit the regulatory and health technology assessment frameworks used by healthcare decision-makers. Yet, with an increasing amount of histology independent therapies coming towards the market there is a need to find solutions today.

To discuss the key challenges and ways forward, OHE hosted* an Educational Session at ISPOR Europe 2020 on histology independent therapies. Renowned experts and the audience provided their insights and opinions on how to bridge the gap between regulatory and technology assessment of histology independent therapies. This blog summarises the discussion and the audience opinions.

First, Lotte Steuten from OHE introduced the nature of problem and specific challenges, based on results of a recently published multi-country analysis. These were then discussed in-depth by Bettina Ryll, founder of Melanoma Patient Network Europe, who brought forward the patient perspective; Rosa Giuliani, oncologist at the Clatterbridge Cancer Centre in Liverpool gave her clinical perspective; the health economics perspective was presented by Stephen Palmer from the University of York, and the payer perspective by Entela Xoxi, previously with the Italian Medicines Agency and currently with the Catholic University of Rome, Italy. Audience opinions on various statements were captured using online polling.

Changing the picture may require a new frame

Histology independent therapies address an unmet clinical need in various patient groups, often those with cancer. In case of a rare or ultra-rare disease, the therapy can gain accelerated access through adaptive pathways implemented by regulatory agencies. Health technology assessment (HTA) bodies however pose multiple challenges for evidence requirements to inform coverage and reimbursement decisions. With an increasing amount of these therapies coming towards the market, there is a need to find solutions for their specific challenges. Recommendations from Steuten include “better alignment of evidence sources and endpoint requirements, acceptability of post-authorisation data collection models, and innovative payment models.” Of the respondents to the audience polling (n=119), there was nearly universal agreement (90%) with the statement that histology independent therapies present a changing picture of cancer therapies that require reconsideration of HTA methods/processes. When asked how HTA/payers should evolve the evaluation framework to accommodate those therapies and address unmet patient needs, 73% of 116 respondents answered that dedicated histology independent pathways should be created to reflect their complexity, and 23% thought that the current HTA pathways for all treatments should be adapted in response.

Heterogeneity is the starting point, not the conclusion

Bettina Ryll started the talk by stressing how different the real world is from the controlled environment many of us are used to see when working in science. According to Ryll, patients are not identical to each other and so heterogeneity should be the starting point and not a finding. In her words “Biology is heterogenous from the beginning; medicine is heterogeneous from the beginning; patients are heterogenous from the beginning; and then you add the therapy on top of it and you’re surprised that we get heterogenous outcomes.”

Ryll considered that what is really blocking progress is the unwillingness to truly look beyond silos of research and decision making for a solution that works for everyone. Histology independent therapies challenge our current way of generating, capturing and evaluating evidence. Therefore, one of her key messages was that “methodology should follow science, not the other way around”. From a patient advocate perspective, she considers pragmatic access models that allow combining timely access with evidence generation, and addressing optimal sequencing of therapies, to be part of the solution.

The audience, when asked what an HTA process that takes the patient perspective at heart should consider, responded that pragmatic access models combined with evidence generation are key (Figure 1a) and that real world evidence and heterogeneity in outcome (Figure 1b) are most important to consider given the rarity of some mutations targeted by these treatments.

Medicine is the science of uncertainty and the art of probability

The above quote by William Osler reflects the perspective of medical oncologists like Giuliani that are making decisions under uncertainty every day. The shift to precision oncology, while uncertain in many ways, is critical for the ability to tailor treatment for each patient based on the molecular profile of cancer. “It’s time that we move on for good from the concept that we need to treat groups of patients,” Giuliani said.

Yet, a rational shift to precision oncology means tailoring treatment for each patient based on the molecular profile of cancer. She stipulated that this requires a need to re-define the concept of ‘[target] population’. For Giuliani, precision oncology demands precision medicine strategies at medical and non-medical level. Learning how to manage and mitigate uncertainties depending on the type of generated evidence is key. Reshaping the model of evidence generation in the era of molecularly driven histology independent therapeutics is ongoing.

The majority (69%) of audience respondents added that, given decision uncertainty is inherent to every day medical decision making, HTA bodies should monitor the real-world performance of new treatments and allow this to inform payment decisions.

Giuliani concluded that this can only succeed if all stakeholders are truly willing to engage in and foster joint regulatory and HTA initiatives. Disjointed activity may break assessment pathways further apart which serves nobody, patients least of all.

Need to move beyond the ICER

Steve Palmer discussed innovative study designs and analysis methods, critical challenges regarding heterogeneity and uncertainty from the perspective of health economics and HTA. He noted the emergence of new and innovative study designs to expedite drug where we use a single master protocol. Basket trials, which are the ones most looked at in the context of histology dependent therapies, are typically phase II, single arm studies, looking at single or combination treatment regimen. Primary endpoints are typically based on a standardised response measure. Although these designs offer real advantages in terms of drug development, they are also creating challenges for HTA and reimbursement in terms of data maturity, the absence of a control group, the fact that some tumour sites are not represented in the data, and concerns of heterogeneity and uncertainty.

The audience opinion on limiting reimbursement recommendations for histology independent treatment to just a few tumour types, even when the regulatory label is agnostic, is shown in Figure 2. This shows a majority (58%) to be in favour of Pay for performance as the most inclusive approach while allowing financial risk-sharing between payer and manufacturer and 13% thought this to be unjustifiable as it excludes some patients to benefit from a biomarker driven therapy with an agnostic approved label.

While new regulatory pathways provide opportunities for these types of treatments, Palmer emphasises the importance of considering heterogeneity in the way basket trials are designed and analysed and extending these approaches to other endpoints. He urged the need to recognise the various sources of heterogeneity and the way HTAs consider the cost of diagnostic testing. In conclusion, Palmer recommended that HTA should “move beyond the ICER” by considering impacts on population health and alternative ways of managing uncertainty and risk. In response, twenty-five percent of the audience considered stratification to be justified when this would improve population health and reduce payer uncertainty.

Discounts won’t cut it

The payer perspective was presented by Entela Xoxi, who started by saying that while our understanding of cancer biology is rapidly increasing, the thinking of payers related to histology independent therapies is still focused on uncertainty. Collecting data on the clinical effectiveness of histology independent drugs, through post-marketing studies or data collection in clinical practice, might help reduce clinical uncertainty and will enable more informed recommendations to be made. European payers and HTA bodies remain hesitant however to use innovative payment arrangements on a wide scale. Many payers prefer to manage decision uncertainty by negotiating price discounts rather than performance-based risk-sharing agreements. Interestingly, only 3% of the audience respondents considered simple price discounts to be a good approach to manage uncertainty regarding histology independent therapies.   

Finally, the audience and experts discussed whether histology independent therapies can be considered orphan drugs, the problem of histology independent therapies typically being the last line of treatment at which point the ‘headroom’ to generate substantial health gains is rather limited, and finally the application of stratification to study designs.

This interactive session provided insights in the regulatory and HTA challenges that histology independent therapies in various countries struggle with, and clear opinions on how to facilitate more timely and inclusive patient access, while generating the much-needed real world evidence and managing uncertainty around these game-changing therapies.

*OHE received financial support from F.Hoffmann-la Roche Ltd. for running this session. 

Related Research

Rodes Sanchez M., Henderson N., Steuten L., 2020. Bridging the Gap: Pathways for Regulatory and Health Technology Assessment of Histology Independent Medicines. OHE Consulting Report, London: Office of Health Economics. Available at:

Posted in Health Technology Assessment, Innovation, Pricing and Reimbursement | Tagged Presentations