Draft and Final FDA Guidances Detail Development of New Drugs for Neurological Disorders

The US Food and Drug Administration (FDA) on Thursday released seven draft, revised draft and final guidance documents on everything from how to develop new drugs to treat early Alzheimer’s, Duchenne Muscular Dystrophy and acute migraines to guidance on how to prepare a pre-request for designation for a combination product.

FDA Commissioner Scott Gottlieb noted the five guidances issued to address neurological disorders "benefited from the streamlined approach" of a pilot project testing "a new, streamlined process for writing science-based, practical guidance documents and getting them out more quickly."

Early Alzheimer's Disease - Developing Drugs for Treatment

This 10-page revised draft guidance is intended to assist sponsors in the clinical development of drugs for the treatment of the stages of sporadic Alzheimer’s disease (AD) that occur before the onset of overt dementia.

Following the agency’s consideration of public comments, FDA said in the Federal Register that this revision of a draft from 2013 addresses FDA’s current thinking regarding the selection of patients with early AD for enrollment into clinical trials and the selection of endpoints.

"This historical dichotomy of functional and cognitive assessments has led to common use of the terms cognition and function with respect to outcome assessment in AD clinical trials, with the implication that an effect on cognition is non meaningful unless accompanied by a benefit on an independent endpoint assessing function in a meaningful manner," the draft says. "FDA rejects this dichotomy and finds such usage 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. This is certainly not the case."

The guidance offers sections on diagnostic criteria, outcome measures, including clinical endpoints for early AD trials in Stage 3, 2 and 1 patients.

The guidance notes that in Stage 1 patients, an effect "on the characteristic pathophysiologic changes of AD, as demonstrated by an effect on various biomarkers, may be measured. Such an effect, analyzed as a primary efficacy measure, may, in principle, serve as the basis for an accelerated approval (i.e., the biomarker effects would be found to be reasonably likely to predict clinical benefit, with a post-approval requirement for a study to confirm the predicted clinical benefit)."

The revision also seems to omit a previous line from the initial draft that said: "Until there is widespread evidence-based agreement in the research community that an effect on a particular biomarker is reasonably likely to predict clinical benefit, we will not be in a position to consider an approval based on the use of a biomarker as a surrogate outcome measure in AD (at any stage of the illness)." 

Duchenne Muscular Dystrophy and Related Dystrophinopathies - Developing Drugs for Treatment

The 16-page guidance finalizes a draft from June 2015 to assist biopharma sponsors in the clinical development of treatments for X-linked Duchenne muscular dystrophy (DMD) and related dystrophinopathies.

In terms of changes from draft to final, FDA said it "reflects FDA’s consideration of public comments on the draft guidance and makes minor clarifying changes."

Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment

The 9-page draft guidance addresses FDA’s current thinking on the clinical development and clinical trial designs for drugs to support an indication for the treatment of ALS.

"This guidance addresses the clinical development of drugs intended to treat the main neuromuscular aspects of ALS (i.e., muscle weakness and its direct consequences, including shortened survival). This draft guidance is intended to serve as a focus for continued discussions among the Division of Neurology Products, pharmaceutical sponsors, the academic community, and the public," FDA said.

The draft features sections on early phase clinical development considerations, drug development populations, and efficacy and safety considerations, including information on endpoints and study design.

The ALS Association, known for its viral "ice bucket challenge," also put together a proposed draft guidance of their own, which FDA said provided the agency "with scientific advice and insight into the disease that helped us advance our own draft guidance that provides our clear thinking on drug development in this area."

Migraine - Developing Drugs for Acute Treatment

This 12-page guidance finalizes a draft from 2014 after a consideration of public comments and with minor clarifying changes, according to FDA.

The guidance features sections on the trial population, efficacy considerations, concomitant medications, statistical considerations, safety and labeling considerations and pediatric studies.

Drugs for Treatment of Partial Onset Seizures - Full Extrapolation of Efficacy From Adults to Pediatric Patients 4 Years of Age and Older

The six-page draft guidance provides sponsors with recommendations on the clinical development of drugs for the treatment of partial onset seizures (POS) in pediatric patients.

"This draft guidance explains how efficacy can be extrapolated from adults to children when it is reasonable to assume that children, compared with adults, have a similar progression of disease, similar response of the disease to treatment, and similar exposure-response relationship," FDA said.

How to Prepare a Pre-Request for Designation

The 15-page final guidance explains the Pre-RFD process at the Office of Combination Products (OCP) to help a sponsor understand the type of information to provide in a Pre-RFD.

A Pre-RFD is, according to the guidance, "a clear and concise written submission that a sponsor may make to OCP to request FDA’s preliminary, nonbinding assessment of (1) the regulatory identity or classification of a product as a drug, device, biological product, or combination product, and/or (2) whether CBER, CDER, or CDRH will regulate the product if it is a non-combination product, or which of those Agency Centers will have primary jurisdiction for the premarket review and regulation, if it is a combination product."

Submission of Content Necessary for Bioresearch Monitoring (BIMO) Inspection Planning for the Center of Drug Evaluation and Research

This draft guidance and BIMO Technical Conformance Guide describe and provide specifications for the electronic submission of certain data and information in standardized formats.

Both documents "address major (i.e., pivotal) studies used to support safety and efficacy claims in NDAs, BLAs, and NDA and BLA supplemental applications containing new clinical study reports that are regulated by CDER," according to FDA.