Last Friday, the US FDA’s Oncology Drugs Advisory Committee (ODAC) (FDA being the US medicines regulator) voted 12 – 0 to approve minimal residual disease (MRD) as an accepted endpoint for accelerated approval of new myeloma drugs. The committee’s primary role is to review benefit-risk data of new cancer drugs. You can see the full meeting and evidence considered here.
The decision means that myeloma drugs may now be approved earlier in the US based on clinical trial data measuring MRD. MRD is approved as an intermediate endpoint.
Following the FDA decision, MPE spoke to Dr Bruno Paiva, Director of Flow Cytometry and Director of the Monoclonal Gammopathies Research Laboratory, University of Navarra, Spain. Given his involvement in ODAC meeting and the I2TEAMM project, he commented:
“I welcome the news from the US FDA, as it marks the culmination of years of international effort on behalf of the myeloma community. It remains to be seen what the impact of this FDA decision will be for Europe. Until now, EMA has been generally cautious about the use of MRD as a surrogate endpoint in the applications for myeloma drugs. But the unanimous decision of the FDA Committee to approve MRD as an intermediate endpoint for accelerated approval could signal a renewed interest in MRD as a useful tool in regulatory approvals.”
In this patient Q&A article, we explore why the FDA made the decision and what it means for myeloma patients living in Europe.
What are intermediate and surrogate endpoints?
All clinical trials use endpoints to measure whether a new drug is beneficial or not. Typically, in myeloma, clinical trials measure two main endpoints – progression free survival (PFS) and overall survival (OS). PFS tells you how long patients have stable disease with the new drug and OS tells you for how long patients survive.
As new drugs in myeloma have become more effective, collecting PFS and OS data in myeloma clinical trials can take many years. To help bring medicines faster to patients, myeloma researchers have been looking at an endpoint called MRD to determine if it can be used predict PFS and OS outcomes in clinical trials.
MRD is now approved by FDA as an intermediate endpoint which means that MRD negativity is expected to lead to longer PFS and OS at the individual patient level. For it be considered a genuine surrogate endpoint the link between MRD negativity and improved PFS and OS would need to be strong at the trial-level. That is, that a treatment effect in PFS and OS can be predicted by the treatment effect in MRD negative rates. The level of association shown at the ODAC hearing was moderate and not strong.
What is MRD and why did the FDA ODAC consider it?
MRD is a very sensitive test and marker of treatment response in myeloma. It is a lot more sensitive than conventional tests for treatment response and can pick up one myeloma cell in one million normal cells.
Patients may either be MRD positive or MRD negative following testing – with MRD negatively indicating a very deep response to treatment. If this deep response is maintained over time, with repeat MRD testing, the hypothesis (that was reviewed by the FDA in their decision-making) is that patients will on average have longer periods of remission (PFS) and overall survival (OS). The link between MRD, PFS and OS potentially means that treatments can be approved earlier by decision-makers, instead of waiting for the survival data to read out.
You can find out more about MRD here.
What data did the FDA look at in their decision-making?
The Committee was assessing an application asking for MRD data to be used as an accepted endpoint in accelerated approvals for new myeloma drugs. The application was based on large-scale meta-analyses (i.e. statistical combination of the results of a range of clinical trials) of patient-level datasets from the University of Miami (Sylvester Comprehensive Cancer Centre) and I2TEAMM project (led by the International Myeloma Foundation). During the ODAC meeting representatives from both applicants presented their data and perspectives, alongside other stakeholders (including patient advocates) who provided their opinion.
What decision did the FDA reach?
Based on the data in the meta-analyses, FDA voted unanimously (12 – 0) to approve MRD as an intermediate endpoint in accelerated approval. This does not mean it will replace PFS or OS, but that MRD can be measured and presented to form the basis of earlier approvals.
The FDA outlined that whilst uncertainties remain in the statistical correlation between MRD negativity and PFS and OS, the data still showed strong evidence to support the use of MRD for accelerated approval purposes. Final regulatory approvals still require PFS and OS.
What is accelerated approval?
The FDA assess the safety, efficacy and clinical benefit of new drugs. In severe disease areas, which have an “unmet medical need”, US FDA use a process called accelerated approval. This means that FDA is willing to assess them on the basis of an intermediate endpoint, like MRD. The main reason is to allow the earlier assessment of new drugs and therefore earlier access, as it can take a long time (10-15 years) to bring new drugs to market.
You can read more about accelerated approval here.
In the case of MRD, the decision means that pharmaceutical companies can now submit MRD data in support of accelerated approval applications and the FDA will consider this within their assessments.
What does this decision mean for Europe?
The US FDA decision does not apply in Europe, but there might be indirect implications as all new drug applications typically go through both the FDA and the European Medicines Agency (EMA) around the same time and are assessed using similar data.
For example, one possibility is that industry trials will increasingly focus on MRD as a key endpoint for decision-making. Another is that in Europe we might have to wait slightly longer than in the US for new medicines to be assessed for marketing authorisation on more traditional forms of data (e.g. PFS and OS). It is important to note that MRD will not replace PFS and OS for anyone – they remain the most important endpoints to gather in clinical trials and for regulatory decision-making. In addition, Europe has its own, slightly different mechanism of accelerated assessment which currently allows earlier access to drugs.
Will Europe follow suit?
In Europe, there has been a lot of discussion around the EMA assessing and considering MRD as a genuine surrogate endpoint. According to the EMA’s reflection paper published in September 2021, “currently, the quantitative relationship between MRD-negativity and clinical outcome, i.e. in terms of PFS/OS, is not robustly confirmed. There are several uncertainties that need further investigation.” It is likely that the FDA decision will add to the continued discussion and debate around MRD in Europe.
Regarding accelerated approval, EMA has processes (including PRIME) that can see a drug being fast-tracked through regulatory approval, often on the basis of early phase data, given an unmet medical need or therapeutic innovation. This is known as Accelerated Assessment. Unlike in the US, however, the European accelerated assessment processes do not expressly mention intermediate or surrogate endpoints.
Finally, a further “hurdle” we need to consider in Europe, is that the EMA is only the regulator of new medicines and for a medicine to be approved for patients it requires funding decisions from national health authorities (i.e. HTA and reimbursement bodies).
MPE will continue to engage with relevant stakeholders on developments in Europe to understand next steps with MRD. In the meantime, if you have any questions, please email