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FDA Releases Guidances on Clinical Trial Design for Neurological Treatments

February 19, 2018

The FDA has released five guidances on clinical trial designs and endpoints for developing treatments for a variety of neurological disorders, including Alzheimer’s disease, Duchenne muscular dystrophy (DMD) and ALS. The revised draft guidance on Alzheimer’s disease noted a greater focus on evaluating drug treatments during the disease’s earliest stages, partially due to the failures of clinical trials that aimed to alter later stage disease progression. Diagnostic criteria that reliably define an early Alzheimer’s population are suited for evaluating drugs that try to delay or prevent overt symptoms, the agency said. Enrollment eligibility for Alzheimer’s drug efficacy trials should be centered around current consensus diagnostic criteria, focusing on objective tests in addition to history and physical examination when appropriate, to determine the disease’s presence and rule out similar conditions. Alzheimer’s Stage 1 patients — who exhibit evidence of clinical impact — are important targets for clinical trials, although clinically meaningful benefits cannot be measured in them due to a lack of clinical impairment. However, effects on the characteristic pathophysiologic changes of AD — demonstrated by effects on biomarkers — may be measured in these patients, and the measurements may serve as the basis for an accelerated trial, as the biomarker effects would be “reasonably likely to predict clinical benefit,” with a post-approval study required for confirmation. The agency’s final guidance on DMD and related dystrophinopathies said endpoints measuring change of function in a wide range of deficits may offer advantages in the development of drugs that treat diseases like DMD and Becker muscular dystrophy, in addition to increasing the number of patients eligible for enrollment. Sponsors should consider using endpoints that are able to assess function across different stages of the disease — such as combining measures of upper body function and ambulation — and detect improvement and decline from baseline in order to capture the range of possible beneficial drug effects. Patient-reported outcomes (PRO) can be useful for assessing clinical meaningfulness of relatively small objective findings, and for contributing benefit and risk assessments. PRO instruments for dystrophinopathies should, in general, “include a limited number of items that assess the most important aspects of the outcome of interest.” The final guidance on drug development for acute treatment of migraines, which does not apply to over-the-counter products, elaborated on ideal trial design, trial population and entry criteria, dose selection, efficacy endpoints and concomitant medications, among other topics. Draft guidance issued on drugs for the treatment of partial onset seizures explained that “efficacy can be extrapolated from adults to pediatric patients when it is reasonable to assume that children, compared with adults, have a similar progression of disease, similar response of disease to treatment, and similar exposure-response relationship.” The draft guidance on developing drugs for ALS treatment addresses the clinical development of drugs intended to treat the main neuromuscular aspects of the disease and focuses on specific clinical drug development and trial design issues that are unique to the study of ALS. The guidances “signal how modernization of the new drug regulatory program includes an enhanced focus on incorporation of patient input into our thinking,” said FDA Commissioner Scott Gottlieb. Read the five guidances here: www.fdanews.com/02-15-18-Guidances.pdf.

FDA Finalizes Trial Design Guidance for BCG- Unresponsive Bladder Cancer
Sponsors of drugs for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer should use complete response rates in carcinoma in situ patients as their primary endpoint in clinical trials, the FDA said in a final guidance. Systemic therapies, which can carry greater toxicity, may need “substantially” greater efficacy to achieve an overall favorable risk-benefit assessment, according to the guidance. The agency also said sponsors should consider complete response rates in the context of the duration of the response. The guidance recommends against the use of partial response as an endpoint, as it has not yet been defined in this disease setting. The final guidance does not significantly differ from the agency’s 2016 draft. Trial participants can be considered BCG-unresponsive if previous treatments involved at least five of six doses of an initial induction course and either at least two of three maintenance therapy doses or at least two of six doses of a second induction course. For single-arm trials of BCG-unresponsive patients, the agency defines a complete response as involving either negative cystoscopy and negative urine cytology, or positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology. Sponsors should follow up with patients with BCG-unresponsive NMIBC every three months for two years, then every six months for two years and annually thereafter. The FDA suggests, but does not require, random bladder biopsies at fixed time points. Before initiating clinical trials, sponsors should use nonclinical studies to optimize intravesical drugs’ schedules and dosing. The guidance is available here: https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm529600.pdf.

CTTI Publishes Recommendations for Accelerating Pediatric Antibacterial Drug Development
Researchers at the Clinical Trials Transformation Initiative developed a roadmap for developing antibacterial drugs for pediatric populations and identified five barriers to overcome to implement timely and efficient clinical trials in children. Growing rates of antimicrobial resistance have made the development of new therapies a priority, CTTI said, adding that it may take 10 years to complete pediatric clinical trials after the approval of new drugs for adults. Published in the Journal of the Pediatric Infectious Disease Society, CTTI said protocol development and trial design processes need to be streamlined, with refined approaches to seeking and obtaining informed consent. Improved planning for pediatric drug development and proper engagement with healthcare providers will also speed the process, CTTI said. In addition, the industry needs to emphasize the rapid incorporation of new trial information into product labeling. The full article is available here: https://academic.oup.com/jpids/advance-article/doi/10.1093/jpids/piy001/4845932?guestAccessKey=17c9a805-1551-45ec-b7e5-49c5da5f6141.

FDA to Hold Public Workshop on Trial Designs for Rare Diseases
The FDA announced a public workshop to explore using innovative statistical methods and trial designs in rare disease settings, in cooperation with Duke University. The meeting is scheduled for March 19 in Silver Spring, Md.The workshop will aim to discuss the challenges associated with the development and regulatory decisionmaking for rare disease treatments, and to examine promising study designs and analytical methods. Topics will include master protocols, external controls in single-arm trials, analytical tools for multiple or novel endpoints and best practices for adaptive study designs. Small population sizes, limited scientific understanding of the disease and lacking market incentives often prevent the pursuit of more traditional clinical trial approaches, the agency said. Register for the event here: https://healthpolicy.duke.edu/events/innovative-tools-and-statistical-methods-treatment-development-rare-disease-settings.