US FDA Reassures ALS Patients In Final Development Guidance
Executive Summary
ALS advocates succeed in getting the FDA to soften its stance on use of randomized, placebo-controlled trials for drug development; final guidance also encourages patient-reported outcomes.
New ALS drugs should still use randomized, placebo-controlled trials to show efficacy, the US Food and Drug Administration says, but the agency clarified that it is not necessarily married to the traditional study design for the products.
In final guidance on development of drugs for amyotrophic lateral sclerosis (ALS), the agency included much more patient-focused language in describing study designs, likely in part to avoid recruitment problems. Often, rare disease patients worry about joining a clinical trial because of the possibility of receiving a placebo.
The FDA wrote in the updated guidance, issued on 23 September, that "all patients in ALS trials should receive the best standard of care, and no patient should be denied effective therapies in order to be randomized to a placebo-only arm."
"Various strategies can be applied to expedite ALS trials and minimize unnecessary exposure to placebo," such as master protocols or adaptive designs and enrichment strategies. Add-on or time-to-event designs also were acceptable, the agency wrote.
In the draft guidance, issued in February 2018, the agency said plainly that it "strongly recommends that sponsors conduct randomized, placebo-controlled, double-blind studies" because they are the most efficient way of showing efficacy. The agency also said in the draft that add-on, dose-response, and time-to-event designs were appropriate and that transitions to an open-label treatment were possible.
Comments on the draft appear to have had a significant impact on the FDA. The agency announced the final guidance in a press release that quoted three top officials and noted that the new language addresses questions that were raised by stakeholders.
"While exposure to placebo may be the best way to determine the effectiveness of some products, the guidance also explains various strategies that can be applied to minimize unnecessary exposure to placebo and expedite trials," said Acting FDA Commissioner Norman Sharpless, Center for Drug Evaluation and Research Director Janet Woodcock, and Center for Biologics Evaluation and Research Director Peter Marks in the statement.
Indeed, the FDA has worked hard to include more patient views in drug development in the last few years. The agency's patient-focused drug development program included many disease-focused meetings where patients and caregivers commented on treatment needs.
The program also has led to some patient groups writing and submitting their own drug development guidances for FDA consideration. The ALS Association submitted an 89-page guidance on development in the disease in 2016. (Also see "Disease-Specific Guidances Reflect US FDA's 'Nimble, Collaborative, Patient-Focused' Approach" - Pink Sheet, 15 Feb, 2018.)
The FDA's 11-page final guidance, like the nine-page draft, is much shorter.
New Endpoints, Trial Infrastructure Suggested
Adding to the patient-focused theme, the FDA in the guidance also encouraged development of patient-reported outcomes (PROs) and other measurements of patient function as efficacy endpoints.
"PRO assessments, including those measuring activities of daily living, can be designed to assess the abilities and experiences of patients across a spectrum of disease stages and severities," the agency wrote. "PRO assessments can be useful to assess the clinical meaningfulness of an objective finding … even if of relatively small magnitude."
The agency wrote that loss of strength is a "hallmark of disease progression in ALS" and that a valid measurement of muscle strength may be an appropriate endpoint for treatments intended to preserve or increase muscle strength. That measure alone may not be indicative of a meaningful effect on daily living and must be supported by the magnitude of effect observed or demonstration of a drug effect on a measure of functions of daily living, the agency wrote.
An effect on respiratory function decline also may provide evidence of efficacy, the agency said in the final guidance. Nocturnal desaturation, aspiration pneumonia, and progression to mechanically assisted ventilation, as well as forced vital capacity, were listed as potential endpoints. But the FDA added that clinical meaningfulness must be supported by the magnitude of effect observed or a drug effect on activities of daily living.
The draft guidance did not offer as much detail on efficacy endpoints, other than that an effect on function of daily activities as measured by the ALS Functional Rating Scale-Revised and others may support efficacy.
Agency officials wrote in the draft that in general efficacy can be supported based on a survival benefit. That language was changed in the final guidance to say that generally efficacy should be established by showing a treatment effect.
The FDA also clarified in the final guidance that benefit can be established in trials that last six to 12 months even if the benefit it modest. The draft guidance said only that studies of a "practicable duration" were feasible to show benefit.
The FDA also suggested in the final guidance that the trial infrastructure be patient-friendly.
"FDA encourages the use of approaches and technologies to minimize the burden of trials on ALS patients and limit the need for travel to study sites," such as decentralized trials with key endpoint measures at baseline and at intervals during the trial conducted at central testing facilities, as well as remote monitoring for some visits. The agency also wrote in the guidance that it would consider using digital biomarkers as clinical endpoints.
Dozens Of Candidates In ALS Pipeline
The update should help many of the sponsors with potential new treatments in the pipeline. Informa's Biomedtracker lists 11 products in Phase I, two in Phase I/II, 10 in Phase II, five in Phase III, and many others in earlier stages. (See chart at end of story.)
Only three drugs for ALS have been approved by the FDA. Aquestive Therapeutics Inc. also has an NDA under assessment with a 30 November goal date. (Also see "Cytokinetics Sees Enough Evidence To Move Reldesemtiv Into Phase III For ALS " - Scrip, 7 May, 2019.) Biogen Inc. and partner Ionis Pharmaceuticals Inc. are among those with an ALS candidate in Phase III. (Also see "Biogen Growth Continues, But Analysts Worry About Near-Term R&D Prospects" - Scrip, 23 Jul, 2019.)