FDA Guidances Seek to Spur Trial Innovation
The FDA left the door open to a speedier approval process for targeted therapies in final guidance issued last week.
Sponsors may get some leeway if they can show that a proposed treatment worked in clinical trials for molecularly similar diseases, or can demonstrate efficacy through computer modeling, close analyses of the molecular structures of disease variants, evidence from other drugs in the same pharmacological class or some combination of these approaches, according to the guidance on rare genetic variants of diseases.
The agency last week also issued draft guidance on how sponsors should measure and use minimal residual disease as a biomarker in blood cancer trials.
Both documents are part of an effort to encourage innovation in clinical trials, FDA Commissioner Scott Gottlieb said in a statement announcing the measures.
“We think innovative approaches have the potential to increase the likelihood of finding viable treatment options for those with less common mutations,” he said. “This is especially true when paired with innovative clinical trial approaches, such as those using a master protocol, where the efficacy and safety of a number of drugs can be studied at the same time, each targeting a different genetic subset of a type of cancer.”
The targeted therapies guidance says sponsors may want to include patients with variants that are less likely to respond to treatment or for whom the response can’t be predicted. Researchers can then either split a trial into subgroups or use an adaptive trial design that frequently checks a drug’s efficacy.
If it’s essential that a trial have accurate testing for a genetic variant to determine a drug’s safety or effectiveness, any test should be FDA-approved and commercially available before a trial can begin.
Sometimes, though, sponsors will have to offer post-market data for a therapy that targets rare disease variants.
“Maybe the take-home message is that these guidelines make it clear that any sponsor who is initiating a clinical trial where they’re doing genetic trials and they’re stratifying patients who have different variants really need to work with a genetic expert,” says Karmen Trzupek, director of clinical trial services for InformedDNA.
Trzupek says that genetics have wrought a revolution in medicine in the past two decades.
“When I started doing this almost 20 years ago, a genetic test meant: what’s the prognosis for your disease and who else in your family is likely to get it? Now, it’s totally different. Sometimes it means that they actually qualify for a gene-based therapy,” she says.
The draft guidance aims to bring clarity to blood cancer trials by focusing on minimal residual disease, which many scientists believe is a predictor of a blood cancer’s relapse. The difficulty is that tests for residual disease vary depending on the lab or technology. A 2017 analysis by the FDA found what the agency calls “inconsistent quality” in residual disease data in clinical trials.
For instance, most doctors don’t test for residual disease until a patient is in complete remission. The FDA is concerned those results might be biased and that any application that relies on residual disease data from patients in relapse may not be adequate to support a regulatory submission, according to the guidance.
Further complicating matters is the way in which residual disease either strongly or weakly predicts a blood cancer’s reappearance. It is the strongest predictor in acute lymphoblastic leukemia and is the standard measure for chronic myeloid leukemia but it is only associated with progression-free or ongoing survival for patients with chronic lymphocytic leukemia.
The FDA says sponsors must specify which technology they plan to use to measure residual disease well in advance of clinical trials. Ideally, they will only use a single technology, but the agency notes they may be able to use a combination of technologies as long as they’re clear about methodology.
Read the targeted therapies final guidance here: www.fdanews.com/10-15-18-molecularsubsets.pdf.
Read the blood cancer draft guidance is here: www.fdanews.com/10-15-18-hematologic.pdf.