The Ever-Changing Face of NICE Guidance on Drug Innovation

Peter O'Donnell, Brussels Correspondent

The UK is firmly and definitively on its way out of the EU within weeks, but in one respect at least its influence will persist, with the internal reflections of its influential NICE (National Institute for Health and Care Excellence) continuing to shape thinking across the continent, and beyond, on reimbursement of new medicines – and consequently on drug development programs everywhere. So nobody in Brussels or member state capitals is going to ignore the latest methods review from England's health technology assessment body.

The aim of the recently-published proposals are to bolster the ability of NICE and its evaluation committees to support introducing valuable innovative technologies, and the consultation paper on the case for change ranges widely across issues a crucial as acceptance of risk, the modifiers relevant to judgments of value, and the use of real-world evidence.

NICE is considering removing its currently-used modifier for life-extending treatments at the end of life, and replacing it with a modifier better suited to valuing the benefits of health technologies, based on the severity of the disease. The change would be more broadly and fairly applicable than the previous end of life criteria, and "more accurately reflect society’s values," it says. It argues that there is limited evidence that society places additional value for life-extending treatments at the end of life, and greater evidence that society highly values health benefits in very severe conditions.

The new modifier would focus on the severity of the condition with current treatment, implicitly encompassing concepts such as the burden of illness and the degree of unmet need. And because of the overlap between severity of disease and end of life conditions, severity can work as a quantitative modifier that operates similarly to the current end of life modifier, NICE believes – although it acknowledges that "further work is needed to confirm how such a modifier should be defined and implemented."

There are no plans to introduce a specific modifier for rarity, despite wide public support for attention to rare diseases, but so that "people with rare diseases are not disadvantaged and that technologies for these conditions are supported," NICE is also proposing to adopt a more accepting attitude to uncertainty in this context. "Uncertainty should remain an important consideration in decision making," it says, and should be even more acceptable in some defined circumstances – notably where evidence generation is complex and difficult, and particularly in rare diseases. The concept should also apply to innovative technologies, technologies that provide large benefits, and when the uncertainty and risks can be monitored and controlled, such as in a managed access arrangement, it goes on. Amendments to the description and characterization of uncertainty, along with clarifications on how it should be taken into account as a modifier, are intended to permit a more robust and nuanced approach to risk for new technologies. Technologies recommended should always provide valuable health benefits, but greater flexibility could be exercised in identified priority areas – which includes, it says, "developments in commercial and managed access arrangements." Evaluations should include an overall assessment of uncertainty, including the effects of different types of uncertainty, whether uncertainties have been captured in analyses, and whether uncertainties can be addressed by additional evidence.

The review also considers the challenges that NICE faces in "fairly, efficiently and robustly" evaluating innovations in emerging technologies such as advanced therapy medicinal products or histology-independent cancer treatments. The objective is to secure rapid access to valuable innovations, and the changes envisaged to evaluation methods should "create a more receptive environment for emerging health technologies," says NICE. However, in all cases, the ultimate aim is improving the health gain from spending on new innovative medicines: "We should be aware of the effect of any methods changes on healthcare spending and on how healthcare resources are prioritized," it underlines.

NICE is leaning towards greater acceptance of the "valuable resource" of real-world evidence as "it is particularly important in the current health and technology landscape." It sees its merits in providing information on the generalizability of trial evidence in clinical practice, in supplementing and adding to clinical trial evidence when trial evidence is limited, in describing populations, patient groups, and clinical practice, and in describing the experiences of people with particular conditions and having particular treatments.

Evidence requirements for surrogate outcomes should also be updated to include information on different levels of evidence, expectations for evidence of validation, and how to account for uncertainty, and should include flexibility for surrogate outcomes in different evidence scenarios. Outcome measures should be selected in consultation with people with the condition or disease, since "patient-reported outcomes can capture important aspects of conditions and interventions, and should be appropriately validated and the methods used clearly reported."

Other changes envisaged are guidance on comparators and on agnostic tumor treatments. When clinical trials do not include a comparator group, several methods to derive comparative evidence should be explored, says NICE. And it urges that histology-independent indications should be treated as a single indication and not as a collection of tumor-specific subgroups. Challenges of heterogeneity, generalizability and unrepresented groups are common to many evaluations, although to a different degree, it says, and heterogeneity across tumor types is "an important theme," it says. This raises also the issue of generalizability from clinical trials to clinical practice. However, in practice, it concedes, "it will be difficult to justify not considering different tumor types to a significant extent in the evaluation," so "any assumptions about homogeneity, heterogeneity and generalizability to clinical practice must be clearly presented, tested and fully explored."

NICE says it will "consider responses from stakeholders" and then develop a structured decision-making framework which will include the changes in an updated program manual. Further phases of methods review are already envisaged for genomics, digital technologies and antimicrobial resistance technologies. The consultation also notes that the case could be made to changes how to value costs and health effects for health technologies in the future through the NICE discounting methodology. However, the policy and affordability implications go beyond the reach of the present review and will need to be considered separately before any change could be implemented, it says.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium