A team of researchers and health officials, including European Medicines Agency (EMA) Executive Director Guido Rasi, are proposing a three-step validation process to enhance the use of surrogate endpoints in regulatory and reimbursement decision-making.
The issue, they say, is that poorly validated surrogate endpoints can lead to products being approved or reimbursed that have little or no benefit, and in some cases even harm patients.
In recent years, drugmakers have increasingly relied on surrogate endpoints, such as biomarkers or performance on behavioral tests, to support the approval of new drugs, especially for rare or life-threatening diseases. Typically, a clinical trial using a surrogate endpoint can be conducted more quickly and at a lower cost than a study measuring a clinical endpoint.
As such, a growing number of products have been approved by regulators based on surrogate endpoints. One recent study found that two-thirds of cancer drug approvals by the US Food and Drug Administration (FDA) between 2009 and 2014 were based on a surrogate endpoint.
However, regulators are not the only healthcare decision-makers that have to make judgments on products based on surrogate endpoints.
"Evidence from surrogate end points may not only expedite the regulatory approval of new health technologies, but also inform coverage and reimbursement decisions. Over the past decade, between 27% and 50% of submissions to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Pharmaceutical Benefits and Advisory Committee in Australia and the Common Drug Review in Canada were based on surrogate endpoints," the researchers write.
Additionally, the researchers say that reliance on surrogate endpoints poses "serious problems" when it comes to making regulatory and reimbursement decisions about a product.
According to the researchers, surrogate endpoints might not accurately represent the benefit or risks of a product for patients. Furthermore, they say, health technology assessment (HTA) bodies and payers are then left to "extrapolate beyond the observed findings in order to estimate the expected true benefits to patients and health systems."
In one example, the researchers point to a study that showed Bristol-Myers Squibb's Sprycel (dasatinib) to be clinically superior to Novartis' Gleevec (imatinib) based on a surrogate endpoint. However, when NICE conducted their own extrapolation of the data, they found that Sprycel only provided an "incremental gain in survival (22.7 years versus 21.3 years) … at a patient cost in excel of €200,000 per quality-adjusted life year."
In order to address these issues, the researchers are proposing a three-step framework to validate surrogate endpoints.
First, the researchers say that the level of evidence supporting the relationship between the surrogate endpoint and the desired outcome needs to be considered. Specifically, whether the surrogate has been studied in individual patients, patient cohorts or ideally in multiple randomized trials.
Second, the researchers say that statistical analyses should be conducted to measure the strength of the association between the surrogate endpoint and the final outcome.
And third, the researchers say the relationship between the surrogate and the final outcome should be quantified. "This is crucial for decisions on coverage and reimbursement," they write. While regulators assess drugs based on safety and efficacy, reimbursement bodies must take into account an intervention's benefit compared to other treatments, as well as its cost.
Use of Surrogate End Points in Heatlhcare Policy: A Proposal for Adoption of a Validation Framework