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The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”
The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”
The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”