The US Food and Drug Administration (FDA) has issued draft guidance to the pharmaceutical industry on using minimal residual disease (MRD) and complete response (CR) in myeloma clinical trials as a primary endpoint, to support approval under accelerated assessment. 

This follows a previous decision of the US FDA’s Oncology Drugs Advisory Committee (ODAC) to accept MRD as an “intermediate endpoint” in accelerated approval. You can read MPE’s Q&A on the ODAC decision here.

A primary endpoint is the main outcome measured in a clinical trial to determine whether a treatment has worked. Up until now, most FDA assessments have been based on clinical trial data using primary endpoints such as overall survival (OS) (i.e. how long patients live after treatment) and progression free survival (PFS) (i.e. the length of time until the disease progresses after treatment). The ODAC decision and the draft FDA guidance mean that myeloma drugs may be approved earlier in the US based on clinical trial data measuring MRD and CR, which take less time to collect than survival measures.

What is CR and MRD?

Complete response (CR), including stringent complete response (SCR), is where myeloma cannot be detected in blood and urine tests or in the bone marrow after treatment. It is used to highlight the depth of response that patients have to treatment.

Minimal Residual Disease (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 negativity indicating a very deep response to treatment. If this deep response is maintained over time, with repeat MRD testing, the idea is that on average patients will have longer periods of remission (PFS) and overall survival (OS).

Both MRD and CR are used to understand how well a patient has responded to treatment. Evidence suggests that if patients achieve and sustain a CR or MRD-negativity, they will on average have longer periods of remission (PFS) and OS. Therefore, by measuring MRD and CR in clinical trials, decision-makers can approve treatments earlier instead of waiting for the PFS and OS data to become available.

What does the FDA guidance say?

The guidance highlights how MRD and CR can and should be used in myeloma clinical trials being designed for regulatory approval under the accelerated assessment process. This includes how industry should justify their choice of endpoint and how they analyse the results. You can view the full guidance here.

Whilst it sets out the use of these endpoints, it also clearly states the need for industry to continue measuring PFS and OS to “confirm” the results of data submitted for accelerated approval.

What is accelerated approval?

The FDA assess the safety, efficacy and clinical benefit of new drugs in the US. In serious diseases with an unmet medical need, such as myeloma, the FDA may use an accelerated approval process. Under this approach, the FDA can consider earlier indicators of treatment benefit, such as MRD, instead of waiting for long-term outcomes. This process is intended to allow for 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 and CR, pharmaceutical companies can now submit MRD data in support of accelerated approval applications and the FDA will consider this within their assessments. The draft guidance sets out the rules industry should follow when generating this data.

What happens next and does it impact in Europe?

The FDA has set out draft guidance for a period of consultation until 23 March 2026. MPE will follow the discussions around the consultation with interest.

Whilst the US FDA decision does not apply in Europe, 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 to judge whether treatments are safe, effective and beneficial to patients.

MPE is continually working with our regulatory, research and industry partners to understand the implications of these decisions in Europe.