The Quest to Measure Drug Effectiveness

The agencies that decide how much to pay for a medicine are being twisted every day into new contortions by the challenges of measuring drug benefit. Highly innovative technologies are offering the prospect of dramatically transformative treatment—but they are often expensive, and their offer, in many cases, is  based on slender evidence. Direct-acting antiviral therapies for hepatitis C, for example, or the cell and gene therapies emerging in areas of high unmet need are increasingly reaching the market through accelerated pathways of development and regulatory review, obliging payers to work out new approaches to weighing the full benefit-cost ratio.

They can find themselves in the same situation as gullible customers at medieval markets, tempted to purchase a promisingly energetic “pig” offered for sale at an attractive price but inside an opaque and sealed bag (a “poke,” or pocket). Only after the transaction is completed can the bag be opened—and the unwary customer may then find they have overpaid for some utterly inedible contents (giving rise to the companion metaphor of “letting the cat out of the bag”).

Search for meaning

Distinguishing a valuable pig from a worthless cat is the challenge every reimbursement authority increasingly faces from accelerating innovation in therapies—giving rise to demands for better demonstrations of potential value even when classic clinical trial data cannot be supplied. In response to the lack of clinical trial data, the fashionable approach is to talk of the potential of real-world evidence (RWE)—but the meaning and significance of the term varies so widely from person to person and country to country that any consistent real-world use seems to be perpetually just over the horizon.

The Belgian healthcare payer INAMI/RIZIV is putting some energy and effort into clarifying the situation. It has commissioned an exploration of how RWE could help health technology assessment (HTA) agencies and reimbursement authorities make more effective use of it in their decisions. And the list of contributors that Belgium has recruited reads like a “who’s who” of European pharmaceutical strategists—which gives some resonance to the work.

The discussions embraced HTA bodies, payers, academia, patient groups, healthcare professional organizations, government bodies, and industry. The group has just completed an initial plan, which it is putting out for wide consultation until the end of the year (https://bit.ly/31xV8WE). The group’s first observation is that despite the wealth of attempts so far to bring definition to the concept of RWE, “past initiatives remain fragmented and lack clarity about mechanisms for implementation.”

Regulators have done better in agreeing on approach, but “now HTA/payers need to develop their own approaches.”

The ambitious aim is to provide “practical actions for implementation by each stakeholder,” so that “concrete issues” can be discussed “and clear actions agreed,” resulting in “better tailor-made decisions on reimbursement.”

The document reflects on how much valuable RWE can be obtained from real-world data (RWD), and which HTA questions can be answered accordingly, and under which conditions. And it sets out in some detail what each of the stakeholders should be doing.

The main conclusion is that  collaboration across stakeholders and across geographies is needed to develop the use of RWE and resolve some of the uncertainties that exist in HTA/payer decisions about highly innovative technologies.

Collaborative strategies are needed to ensure RWD/RWE requirements are aligned, it says. Transparency is also given high priority—including via a proposal for a public portal that summarizes the design and results of major RWE studies, on the model of existing clinical trial registries.

Shared learnings

The specific recommendations—on which views are now being sought by all interested parties—are geared toward creating “a multi-stakeholder collaborative learning network” with wide membership, the group says.

According to the commission, policymakers and national and European authorities should legislate to ensure a robust governance framework and to enable effective cross-country collaboration for using RWD; the HTA bodies/payers should be identifying the questions that could be answered with RWD/RWE, providing guidance on critical assessment of RWE, and implementing conditional payment models such as outcomes-based agreements using RWD.

Regulators, at the European and national level, should ensure that RWD collection strategies (such as registries) are multi-stakeholder and fit for regulatory purposes, and, where possible, take account of the needs of HTA and payers. They should also promote use of scientific advice/early dialogue processes with all relevant stakeholders during the development of a highly innovative technology, and support discussions with industry about non-randomized-controlled trial (RCT) methodologies.

Collaboration with HTA bodies should also seek common ground on registry qualification, post-authorization safety studies, and post-authorization efficacy studies.

The pharmaceutical industry should engage with other stakeholders on RWD collection, analysis, and reporting over the lifecycle of a highly innovative technology to generate robust RWE that helps resolve HTA/payer decision uncertainties.

Registry holders should involve all stakeholders in establishing registries and ensuring good governance that addresses data quality, accessibility, and sustainability. They should be prepared to collaborate with regulatory authorities at national and European levels and with  HTA bodies and industry, to identify whether existing registries could be used to resolve uncertainties during the development phase or for post-launch data collection, and to discuss the potential for new registries. Along with industry, they should also be aiming to develop disease-based, rather than product-specific, registries.

Patient input

Clinicians and patients should contribute their real-world experience to support collection of RWD that is useful and informs treatment decisions, at the individual and population-level. Healthcare professionals should gain a clearer understanding of the role of RWD in outcomes-based managed-entry agreements so as to ensure both correct usage and adherence, and to collect the data needed.

Patient groups should engage in co-creation of RWE, communicating the possible uses of RWD and good governance processes to encourage patient involvement. They should also develop EU or international patient group collaborations to engage in RWD initiatives and ensure that outcomes that matter to patients are collected.

In addition, patient groups, the document says, should provide recommendations on novel and efficient collection methods for RWD (e.g., devices, wearables, mHealth) and help promote the scientific and policy value of data collection and provide access within strict governance frameworks.

‘Real’ action

The collaborative platform envisioned would encourage implementation of these recommendations by each stakeholder group, and would check on progress. Where emerging issues require, discussion among all stakeholders should take place. And a body of case studies of challenges should be built up about the use of RWE in HTA/payer decisions, so as to develop and improve approaches.

Ultimately, what the group proposes is the development of widely-agreed guidance on use of RWE to promote access to highly innovative technologies.  But of course, as the document acknowledges, “this requires appropriate resourcing, knowledge sharing, and governance.”

There is always a cost to identify just what sort of pig is in the poke.

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