A recently published study in the British Medical Journal by Wieseler et al. of the Institute for Quality and Efficiency in Health Care (IQWiG) found that the majority of new drugs entering the German market do not have an additional benefit over currently available products. The authors challenge the assumption that innovative products are more prevalent now than in previous periods and called for a number of policy changes to drug development and regulatory approval processes.
One noticeable gap in the paper was the omission of how real-world evidence (RWE), a pragmatic pathway to understanding a drug’s performance in the relevant population, can improve value decision-making. We shared this perspective in a letter to the editor, and elaborate on the opportunity below.
HTA agencies in Germany
IQWiG and G-BA, the health technology assessment (HTA) agencies in Germany, are tasked with evaluating all drugs seeking reimbursement in Germany. IQWiG conducts the benefit assessment, which it provides to G-BA, and G-BA makes the final determination of actual benefit. IQWiG and G-BA’s main role is to determine the level of additional benefit (considerable, major, minor, unquantifiable, or lower) the new product offers over the relevant comparator(s).
IQWiG and G-BA have strict evidentiary standards: they require drugmakers to compare the results of randomized controlled trials (RCTs) using locally relevant comparators (i.e., efficacy data). Non-interventional studies, including real-world data trials, are only accepted under limited circumstances, for example, for orphan drugs.
According to the Wieseler et al., only 25 percent of drugs were determined to offer considerable or major benefit among the G-BA/IQWiG assessments between 2011 and 2017 (n=216). A large number of drugs which received “no added benefit” did not have head-to-head data versus the German standard of care (n=64) or the head-to-head comparator was inappropriate (n=42), thus the benefit could not be determined.
RWE and the efficacy-effectiveness gap
HTA agencies are charged with evaluating how effective a drug will be in their country’s treatment pathway and patient population. In most instances, the HTAs require and rely on randomized control trial data in their evaluations. This, however, leaves what the industry has termed the efficacy-effectiveness gap. How will a drug that worked in a clinical trial work in clinical practice?
While RCTs have excellent internal validity (due to homogeneous patient populations and very controlled circumstances), their generalizability to clinical practice is questionable, which leaves HTAs in a difficult position. The good news is that RWE can bridge this gap by evaluating a drug in current clinical practice, with current standards of care, and in the relevant patient populations.
Bridging the gap in Germany
Half of the drugs evaluated in Germany between 2011 and 2017 (n=106) did not have comparative evidence against an appropriate comparator, and thus an improvement in benefit could not be determined. Appropriately designed and methodologically sound RWE could generate these comparisons. For example, using external control groups constructed with analytical methods like propensity score matching or weighting could be a method to supplement RCT data and provide an estimation of the effect of the drug versus the appropriate comparator in the German patient population. There is precedent for this type of comparison. For example, an external control group was used in the FDA’s accelerated approval of blinatumomab for the treatment of acute lymphoblastic leukemia, with standard of care as the control group derived from registry data.
Another strategy that IQWiG/G-BA could employ is conditional approval with an RWE generation requirement. RWE could provide post-approval evidence when the agencies aren’t sure of the drug’s benefit. To reduce this uncertainty, IQWiG/G-BA requested that manufacturers complete and submit six additional post-approval RCTs based on the initial assessment. The agencies, however, requested RCT data (not RWE), and none of these studies were completed or submitted on time.
From the manufacturer’s perspective, the lost time and added cost of post-approval studies is a significant challenge, one which RWE studies can alleviate. For example, the RCT DUPLICATE collaboration between the FDA, Brigham and Women’s Hospital, and Aetion showed that RWE can exponentially reduce the time-to-evidence generation compared to running a post marketing cardiovascular outcomes RCT without compromising quality and results. Furthermore, this model allows flexibility to explore additional variations of the study implementation that are not otherwise possible via traditional RCT designs to evaluate the robustness of the results under differing conditions.
Opportunity for RWE in Germany
RWE is rarely used in German assessments. In an evaluation of the use of RWE in melanoma HTAs, RWE was only used for estimations of prevalence and incidence in German assessments. RWE was not used in any cases to evaluate effectiveness. Similarly, in an evaluation of the use of non-randomized evidence within IQWiG HTAs, only one 2015 assessment of a hepatitis C drug found non-randomized evidence to be appropriate.
There is a large opportunity to leverage RWE to supplement RCT data in support of value assessment by German agencies. RWE will provide a more robust evidence base of a drug’s performance versus the appropriate comparator in the relevant patient population. A number of HTA agencies, including CADTH in Canada and NICE in the UK, are exploring how they can maximize the use of RWE in their decision-making. Given this global movement in evidentiary standards, the time seems right for Germany and other countries to consider following suit.