ARTICLE IN BRIEF
New guidance documents for research by the Food and Drug Administration include a number of notable changes and additions regarding five different neurological disorders: Alzheimer's disease, amyotrophic lateral sclerosis, Duchenne muscular dystrophy pediatric seizures, and migraine.
As part of a pilot program to expedite the review process of new therapies, the U.S. Food and Drug Administration (FDA) issued new draft guidance documents for industry-sponsored trials in five neurological disorders: Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), pediatric seizures, and migraine.
The guidelines aim to provide more specific instructions for meeting the agency's scientific expectations for clinical trials, an effort aimed at saving trial sponsors time and resources. The new documents include a number of notable changes and additions, many of which researchers in each of the five diseases told Neurology Today they support.
The new guidance for Alzheimer disease (AD), for example, updates a 2013 guidance on trials in early AD and reflects the agency's current thinking regarding the selection of patients with early AD and selection of endpoints for clinical trials.
Although there is no consensus on AD biomarkers, the agency said potential drug candidates that can demonstrate efficacy on multiple AD biomarkers, as a primary endpoint, could “in principle” serve as the basis for accelerated approval, with a post-approval requirement to confirm clinical and functional benefits.
However, until a particular biomarker is accepted as likely to predict clinical benefit, the FDA will not consider approval based exclusively on a biomarker as a surrogate outcome measure.
Rather than recommending any specific diagnostic criteria for early AD trials, the agency said criteria should reflect current understanding of the pathophysiology and evolution of AD. The FDA recommended an increased focus on evaluating AD drug treatments in the earliest stages of the disease, and diagnostic criteria that reliably define early AD. The criteria should include the earliest stages characterized by pathophysiological changes, suitable for evaluating potential drugs to delay or prevent emergence of overt symptoms, the FDA wrote.
Another major change is the agency's proposal to end the need for co-primary endpoints of functional and cognitive improvement, noting that such usage is inappropriate, because it implies that an effect on cognition itself, regardless of the nature of the observed effect and the manner in which it is assessed, cannot be clinically meaningful on its own.
Eliminating this requirement recognizes that this is not feasible in early stage patients, said Gil Rabinovici, MD, professor of neurology at the Memory and Aging Center at the University of California, San Francisco.
He said the guidance “moves the field forward” by providing a framework for approval of drugs that target very early pre-clinical stages of AD. “Despite great progress in biomarker development, we have yet to establish whether a treatment's effect in slowing or reversing disease-associated biomarkers translates into a clinical benefit, and establishing this relationship is a prerequisite for using biomarkers as surrogate endpoints in future trials,” he said.
“This guideline opens the door for integrating biomarkers as endpoints in a regulatory pathway, an evolution that may be critical for establishing efficacy at a pre-clinical stage. The FDA is also challenging the field, appropriately in my opinion, to develop the tools necessary to judge the clinical meaningfulness of early therapeutic interventions.”
Todd E. Golde, MD, PhD, professor and director of the McKnight Brain Institute at the University of Florida, Gainesville, agreed, saying that despite the lack of accepted biomarkers, the FDA emphasis on trials for early stage AD patients is a positive development, and that some consensus on biomarkers, whether for tau or beta amyloid, is probably not that far off.
“If we wait for patients to develop symptoms, treatment may be too late,” he said. “It's like statins. They were approved based on a biomarker, but only during post-approval were we able to understand the risks and benefits of individual drugs. The devil's in the details.”
The guidance document for ALS does not make major changes, only requiring that trials demonstrate “clinically meaningful benefits in symptoms, function, or survival.”
To demonstrate safety, trials must include a sufficient number of subjects and may include patient subgroups of ALS variants, the FDA said. Also, due to the significant progression of ALS, establishing a clinical benefit, even modest, can result in an approval consideration.
If long-term delivery is being studied, sponsors should consider co-development of delivery devices.
The agency also said that it plans to consider new outcome measures for clinically meaningful effects, noting that existing measures may not be appropriate. For now, efficacy can be demonstrated in day-to-day functional improvement and survival, but these should be controlled for bias due to patient reporting and motivation.
Because of the lack of treatment options for DMD patients, the FDA said that it may permit clinical trials on “less than usual” nonclinical testing “if justified,” and that clinical pharmacology testing “is likely not needed to support a new drug's approval.”
In addition, safety trials must include enough patients and enough drug exposure to adequately assess adverse effects. Although the guideline did not go so far as allowing approval based entirely on biomarkers for dystrophin, it acknowledged interest in dystrophin markers and said such data, together with biomarker data that “reliably reflects improvements in skeletal muscle at a biochemical, cellular, or tissue level,” may be used as surrogate endpoints to support accelerated approval, as can dystrophin-related outcomes on respiratory and cardiac muscle function.
Determining the number and duration of patient exposures needed to support approval will include assessment of the nature of DMD and other severe dystrophinopathies, but safety from at least one-year exposure will usually suffice, the FDA said. The guideline does not establish required or recommended clinical outcomes for trial designers. Instead, drug developers are encouraged to propose and develop valid and reliable outcome endpoints for patients with a wide spectrum of symptoms and disease stages.
“We appreciate the FDA for their forward thinking and scientific rigor in incorporating the learnings from the last four years into this guidance,” said Laura Hagerty, PhD, scientific program officer at the Muscular Dystrophy Association.
“The trial design recommendations provide clarity for the community and emphasize reducing patient burden during drug development. Of note is the inclusion of cardiac and respiratory endpoints, which may become important as patients are living longer and new phenotypes emerge.”
In a major change, the FDA said that because previous trials of seizure drugs in children have shown comparable dose-response results to those seen in adults, efficacy trials will no longer be required in pediatric patients. Studies in adults may be extrapolated to children over the age of four years, however formulations for pediatric patients must still take into consideration the special needs of children, and trials may be required to support approval of particular products.
The agency will still require safety trials to be conducted in children four years of age and older, but these can be open-label trials and include a minimum of 100 pediatric patients exposed to a drug for at least 6 months, although sponsors can change this on a case-by-case basis, depending on the expected and emerging safety profile of the drug.
Before an open-label trial is begun, however, sponsors must perform a simulation study to select doses, based on pharmacokinetic data, expected to achieve exposures similar to those in adults, and pediatric trials should quantify concentrations of the drug and its active major metabolites whenever there are severe or serious adverse events.
Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at the University of California, San Francisco, welcomed the new open-label provisions.
“This is extremely helpful. It is much easier to do an open-label trial of a drug that is already on the market for adult partial onset seizures when there is no placebo arm,” he said.
“If the open-label safety studies are able to be done in this way, it will allow us to get the necessary pharmacokinetics data, as well as safety and tolerability data, so the document gives us more guidance with regard to determining dosing [for pediatric trials]. Presumably this would also still allow sponsors to get the additional exclusivity extension so that there is still incentive for them to do these types of trials.”
Rather than requiring drugs to demonstrate efficacy on four co-primary endpoints — pain, nausea, photophobia, and phonophobia — the FDA has proposed that trials will only need to meet two primary endpoints: pain reduction and effect on a patient's “most bothersome symptom.” This can be determined at a study's outset or at the time of a migraine attack prior to administering a study drug.
The FDA also outlined secondary endpoints that manufacturers should address, including time to complete pain freedom, use of rescue medications, and pain relapse.
Stephen D. Silberstein, MD, FAAN, professor of neurology and director of the Jefferson Headache Center at Thomas Jefferson University, Philadelphia, said that the changes will help clinical trials by eliminating the need to address extraneous endpoints.
“Having to meet efficacy for pain, nausea, photophobia, and phonophobia has been a problem because many migraine patients do not have these symptoms. Allowing trials to target efficacy against a patient's ‘most bothersome symptom’ is a major improvement.”