Real-world evidence use is expanding. What’s behind the change?

In the rapidly evolving landscape of drug development, real-world evidence (RWE) is making significant strides, finding its way into the early stages of the process. No longer confined to just the peri- and post-approval phases, RWE is now being tapped for external control arms (ECAs), aiding in health technology assessment (HTA), and informing payer discussions.

To maintain their competitive edge, biopharma executives need to develop a comprehensive early data strategy, noted executives from Evidera, part of the PPD clinical research business of Thermo Fisher Scientific, in a recent Q&A. This strategy should focus on carefully selecting and effectively harnessing real-world data (RWD) to support regulatory and HTA approvals.

The use of RWE, however, is not without challenges. Policy changes, such as the U.S. Inflation Reduction Act (IRA) and the EU HTA Regulation, are reshaping the regulatory landscape and imposing new requirements on how companies utilize RWE. To navigate these changes successfully, companies must be proactive in adapting their RWD strategies to address the evolving regulatory environment.

In the following interview, Ariel Berger, executive director, integrated solutions, real-world evidence discusses the expanding role of RWE in drug development and the importance of early planning. Almudena Olid Gonzalez, director, value and access consulting opens up about the impact of policy changes on RWE requirements and the role of post-launch RWE in market access.

Real-world evidence (RWE) has traditionally been focused on support of peri- and post-approval activities, such as burden of illness, real-world comparative effectiveness, etc., but that perspective seems to be changing. How are you seeing RWE used in product development?

Ariel: RWE is still commonly used to support peri- and post-approval activities, however, we are seeing its use extend into early development activities, and increasingly ahead of approval to support health technology assessment (HTA) and payer discussions. Examples of early use include RWE for external control arms (ECAs) to aid in the assessment of efficacy and safety of investigational assets. In such instances, being able to leverage real-world data (RWD) that can “mirror” the relevant trial with respect to sample selection criteria, assigning exposures, calculating key covariates and assessing relevant outcomes can be very successful, although limited in its use cases. Where permissible, this strategic use of RWE can substantially decrease time and budget required to gain regulatory and/or HTA approval of new therapies.

We see increasing interest in RWE early in development to inform prioritization of development where an asset may have activity across multiple indications, identify relevant comparators or understand market dynamics, and assist in identification of potential clinical trial participants, just to name a few. RWE also is being used in studying the natural history of diseases, and subsequently used to inform and optimize trial designs by simulating trial outcomes with different variables and measuring their impact on outcomes. 

Almudena: RWE is being developed earlier and used more frequently in HTA and payer submissions. For example, RWE provides understanding of health-related quality of life associated with current therapies in a specific disease area, as well as defining healthcare resource utilization of specific complications that a novel therapy may address. Both of these uses support the development of health economic models prior to HTA submission or even the development of a product’s value story. Several HTA bodies, such as the National Institute of Health and Care Excellence (NICE) in England and the Haute Autorité de santé (HAS)—or French National Authority for Health — in France, have released frameworks and guidelines for use of RWE. Some have even begun offering scientific advice specifically on RWE, such as Canada’s Drug and Health Technology Agency (CADTH). From a payer perspective, an example of the use of RWE in decision-making is the 2019 launch of Valtermed, the Spanish National Health System’s information system, which was established to identify the real-world therapeutic value of products with high clinical and economic impact.

The U.S. Food and Drug Administration (FDA) has relatively recently become much more accepting of the use of RWD/E in informing regulatory submissions (most recently through the pathway known as “Confirmatory Evidence”), perhaps nowhere as strongly as in ECAs. How has the FDA’s acceptance of ECAs impacted how companies should approach RWD/E during development?

Ariel: As already mentioned, ECAs are a relatively new development that enable use of single-arm trials, “coupled” with the ECA, to gain regulatory — and HTA — approval. The availability of the ECA—at least in selected circumstances—has implications on how companies should approach RWD and RWE during development. With respect to the former, companies should develop an early data strategy that will help them identify, assess and select RWD sources that are fit for purpose to support ECA development. This may include developing relationships and partnerships with data sources/sites to ensure rigorous and relevant information is available if and when the company decides to develop an ECA. For example, if a company is developing an anti-cancer medication that will be the first ever to target a specific mutation, it is highly likely that existing RWD will be “silent” on the presence of this mutation. In this instance, the company should develop relationships with relevant sites that will enable mutation testing, resulting in populations that more closely mirror the clinical trial with respect to their relevance to facilitate comparative effectiveness analyses. It has been our experience that all companies interested in pursuing ECAs should obtain early advice — ideally that integrates regulatory and HTA considerations — to enable a more efficient approach to the design and execution of the ECA.

Almudena: From my HTA-focused perspective, I have seen a similar trend. Companies are becoming more active in planning their RWD generation earlier. I have seen increased interest in RWE from the health technology developer (HTD) perspective in general, and specifically on the impact to market access outcomes in terms of wider and faster patient access. Some companies are actively integrating learnings into their evidence generation plans.

We are also seeing an increase in integrated scientific advice with HTA bodies to validate RWD generation plans, specifically in advanced therapies and rare disease treatments. So, clearly, companies are planning earlier, and they are doing so in collaboration with key stakeholders. An important point to note is that companies need to consider the differences in acceptability, use cases and guidances that are issued by different HTA bodies when developing their RWE plans.

There are reimbursement and access policy changes happening that that have created concerns for the industry, such as the U.S. Inflation Reduction Act (IRA) and the EU HTA Regulation (HTAR). Can RWE address some of these concerns?

Almudena: The IRA and HTAR represent major changes in the status quo in the U.S. and Europe.

The IRA’s aim is to reduce prescription drug costs, requiring the federal government to negotiate prices for select Medicare Part B and D drugs with the highest total spend, among other changes. Negotiations will evaluate a product’s comparative efficacy against available therapies, the impact of the drug on a variety of patient outcomes and evidence in specific populations of interest (such as Medicare-age population). RWE can identify real-world therapeutic alternatives, measure key patient outcomes and define the unmet need to highlight the value of a treatment and maximize its price potential.

The EU HTAR’s goal is to harmonize HTA in Europe. An EU-wide joint clinical assessment (JCA) will be carried out alongside the European Medicines Agency (EMA) regulatory process. The JCA will define the relevant populations, interventions, comparators and outcomes (PICO) for the particular therapy in the indication. We expect there will be multiple PICOs for which evidence will not be available from pivotal studies. RWD can generate evidence for relevant populations and comparators to meet the needs of the PICO. However, the EU methods do not provide enough clarity and guidance on acceptable use of RWE, so we are eagerly waiting to see how assessors and co-assessors interpret the language used in the methods.

What is true for both is that strategic planning of RWD can help address several of the challenges we see with the new landscape in US and Europe.

Ariel: Just want to add that RWE can be used to help inform analyses to estimate the potential impacts of these and other government policies. This includes helping to understand the impact of removing innovative products from the market to assess the impact of not developing certain therapies due to concerns around reimbursement as well as the ramifications of changing how care is reimbursed to allow for broader access to life-changing (albeit expensive) treatments.

How can RWE generation be used strategically for more efficient development of a pipeline asset and support patient access?

Ariel: RWE provides important and relevant information across the life cycle, varying at each stage. In earlier stages, RWD generation can identify relevant competitors, market size and where an asset fits into the landscape. RWE also can support protocol optimization, including building models powered by RWD to simulate a trial, and ECAs in specific situations. Long-term follow-up studies gather evidence on efficacy, safety and effectiveness in the real world to support regulatory, HTA and payer commitments and concerns. Post-launch, RWD/E can provide understanding of product uptake, patterns of use, and real-world and comparative effectiveness.

Tokenization is another relatively new methodology in RWE that allows for the linkage of various data sources (RWD or otherwise) by unique patient identifiers, so technology advancements also have a significant and positive impact on generation and use of RWE. 

You mentioned demonstrating effectiveness in the long-term, can you expand a little bit more on the use of post-launch RWE as a condition of initial HTA recommendation?

Almudena: We have seen an evolution of this in the last decade, especially since transformative yet expensive therapies have launched to the market. It is common for the evidence generated for transformative, advanced therapies, like cell and gene therapies (CGTs), to be associated with uncertainty. HTA bodies and payers do not like uncertainty, especially when it comes to a very expensive health technology. We have seen agreements in several countries between HTDs and payers/HTA agencies that market access is conditional based on a re-assessment after a specified period during which HTDs must present longer-term, real-world evidence on agreed outcomes to support initial claims. 

Ariel: I also believe that we are primed for the advent of pragmatic studies to provide more comprehensive insights and understandings (vs. clinical trials) as to which treatments/regiments should be provided to patients. Results of such studies would serve to demonstrate the impact of use of “treatment A” versus “treatment B” in the real world, thereby addressing concerns relating to generalizability and real-world clinical, and likely economic, impact; all of these items will be important to inform policy, including how providers are able to prescribe — and patients to access—therapeutics and products that prevent disease/enable healthier lifestyles.

How does RWD/E inform policy-driven work on coverage and payers’ approach to CGTs, which are incredibly expensive?

Ariel: Increasingly, clients in the CGT space are realizing the current coverage system makes it fairly challenging to bring these products to market. The traditional practice of paying upfront to obtain treatment is not usually problematic when thinking of a 30-day supply of medicine or a one-time surgical procedure. However, this quickly becomes less tenable when faced with therapies that may provide a lifetime of benefit following a single administration. It has become clear in many countries that “front-loading” the cost of CGTs, which often promise substantial durable benefit, quickly becomes unsustainable. This reality puts us at a crossroads, as innovation is only incentivized with the promise of success in the market. As thinking evolves about alternative policies to enable access to these life-changing therapies, RWD/E will be required to understand various factors that inform how reimbursement policies for these products should work. For example, in the U.S., estimates would be needed of annual disenrollment from various health plans by patients who would “qualify” for various CGTs, as well as the types of plans to which these individuals transition and the clinical and economic impacts of those who are and are not treated. These types of parameters can only come from RWD. 

RWD is ever expanding, with digital sources such as social media, wearables and devices with sensors the most recent examples of new types of real-world information. How has the availability of these sources changed the approach to RWE?

Ariel: One relatively recent development is the ability to use social media to harness patients’ (and their families and caregivers) voices as it relates to their disease and/or therapeutic journey. This is especially true for rare diseases, as social media has proven to be a means to bring this disparate population together in a very efficient manner through the internet. To the extent that their posts are public, they provide researchers with the unparalleled ability to examine their disease and treatment experiences, understand what matters to them, and determine how policies impact their lives (including the inability to access therapies). Before social media, the only way to conduct this research was to undertake costly and time-consuming activities to identify, consent, enroll and survey/interview these patients. Now, a social media listening study — assuming there are relevant posts identifiable — can provide information in a matter of months. 

Wearables and devices also represent another exciting frontier for RWE generation, as they collect volumes of data without those wearing them needing to do anything above and beyond living their ordinary lives to contribute relevant information for study. Technology is moving to the point where we can leverage these data through downloads to central databases, potentially including electronic health records, where they can be linked to other sources to help establish broader and deeper data to better answer questions of interest.

How can a company achieve the optimal development strategy for a pipeline asset?

Ariel: Starting early is key. It is important to define what the critical success factors are (e.g., meeting stakeholder expectations) early on and identify the gaps with existing plans. This helps understand and identify the needed evidence, specifically including RWE.

Mapping the key questions in the development pipeline that need answering is also critical to mapping the required evidence generation activities into each cycle of development. Refinement will be needed as new evidence is generated and the landscape evolves, but early planning will allow for faster execution overall. Additionally, a data strategy should be created to address evidence gaps. 

Almudena: Companies should familiarize themselves with the different RWE methodologies and potential challenges they might encounter in different geographies, helping to define areas that require RWD generation in countries of interest and identify value for key stakeholders. Validation of these areas and the approach to generating this evidence with relevant stakeholders through early integrated scientific advice is highly recommended. That feedback can then feed the creation of an evidence generation plan that clearly states what evidence is needed, the approach to RWD generation to address this need, and the level of impact for the different geographies where the new product will be launched.