In its 2020 Value Assessment Framework, the Institute of Clinical and Economic Review (ICER) stated its intent to pilot the use of real-world evidence (RWE) for reassessments of drugs that received accelerated approval from the U.S. Food and Drug Administration (FDA). ICER’s goal in this pilot is to “supplement the comparatively limited evidence base that often accompanies accelerated approvals with RWE” to address uncertainties and provide a more comprehensive view of the drug’s comparative and cost-effectiveness.
RWE-powered reassessments are on the forefront of the shift from health technology assessment (HTA) to health technology management. ICER and other global HTA bodies (e.g., NICE in the UK, CADTH in Canada, and TLV in Sweden), and even payers (e.g., the Centers for Medicare and Medicaid Services), are using coverage with evidence development and managed entry agreements to prompt industry to generate additional evidence post launch that will further inform reimbursement decision-making.
Here we discuss the key learnings from ICER’s first reassessment pilot—a collaboration with Aetion to evaluate three Hereditary Angioedema (HAE) treatments—and what the industry can expect as agencies move to assessing drugs at multiple stages of the lifecycle.
Topic selection and process
ICER focused on the following criteria for selecting a topic for the reassessment pilot:
- Drug(s) were approved through FDA’s accelerated approval pathway,
- Topic area that ICER had reviewed at least 24 months prior, and
- Cases where RWE could be used to reduce uncertainty and potentially improve the cost-effectiveness model.
For the pilot, HAE fit these criteria. ICER reviewed Cinyrze®, Haegarda®, and Takhzyro™ as long-term prophylaxis treatments to prevent attacks for HAE in 2018.
The original report noted a number of uncertainties that could substantially impact the cost-effectiveness of the three treatments. For example, the 2018 cost-effectiveness model was highly sensitive to baseline attack rates of patients before starting prophylaxis. There was also uncertainty around the percentage of patients who would switch to less frequent dosing of Takzyro if they were attack-free for six months, which FDA recommended in the drug’s label. The RWE study set out to address these uncertainties.
ICER publicly posted the RWE protocol and updated Model Analysis Plan, and contacted the manufacturers of the three products for comments before the analysis began.
RWE results and impact
One of the main objectives of the RWE analysis was to determine the frequency of HAE attacks before patients started prophylaxis treatment. We looked at severe attacks (requiring ED visits/hospitalization) and mild attacks (outpatient, home nurse, or self-administered, on-demand treatment). The analysis found the average baseline attack rate was 1.88 attacks per patient per month, which was lower than the rates observed in randomized controlled trials (RCTs) and were used in the 2018 cost-effectiveness model. Sensitivity analysis showed this rate to be stable. Exploratory analysis supported the effectiveness of prophylaxis therapy, as 77 percent of person-months were free of severe attacks after initiation of prophylaxis. Analysis also showed that, consistent with the label, 48 percent of patients who initiated Takhyzyro reduced dosing from bi-weekly to every four weeks, which lowers the acquisition cost of the drug.
As baseline attack rates were a driver of cost-effectiveness, the model results showed that the incremental cost-effectiveness ratio of these three HAE therapies was higher than the original 2018 model. Larger discounts off the list price are needed (52 – 75 percent) in order for the drugs to be considered cost-effective at ICER’s thresholds.
Learnings and key takeaways for biopharma
The RWE results provided timely and relevant inputs based on real-world patient experience to inform the cost-effectiveness model. For example, the 2018 cost-effectiveness model included inputs for HAE patient age based on studies published three to 11 years ago compared to the more recent RWE results. The 2018 model used average weights for men and women from a large U.S. based population study, whereas the RWE study looked at weight specifically for HAE patients. Finally, RCT patient populations are often different from patients in the real world, so understanding real-world baseline HAE attack rates is important for understanding the cost-effectiveness of these products in clinical practice.
Given the uncertainty in comparative effectiveness at time of launch, especially for drugs that receive accelerated approvals, HTA bodies and payers are looking for additional evidence post-launch to address unanswered questions and shift toward a world in which they assess drugs at multiple points across time. This creates a large opportunity for RWE to play a role in decision-making. Biopharma manufacturers should anticipate knowledge gaps in their clinical development programs and leverage the opportunity to conduct RWE studies to inform assessments in the future. By planning RWE studies and communicating plans with decision-makers, biopharma manufacturers can potentially help shape future evidence generation requirements from HTA bodies and payers, and influence the way RWE is incorporated into decision-making.