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 The revised draft guidance on Alzheimer’s disease noted a greater focus on evaluating drug treatments during the disease’s earliest stages, partially due to the failures of clinical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:

EMA Draft ‘Strengthens’ Guidance on Safety Follow-Up for Advanced Therapies

February 12, 2018

The EMA published a draft revision to its guideline for clinical trials follow up of advanced therapy medicinal products, including gene therapies, cell therapies and tissue engineered products. The draft strengthens and clarifies the EMA’s 2008 guideline, and includes more details on designing post-authorization safety and efficacy follow-up studies. Sponsors need to provide safety and efficacy follow-up data in their marketing applications, including long-term data to analyze the benefits and risks of products. Objectives for safety follow-ups should be based the on specific product characteristics than on its classification, such as whether it is a cell- or gene-based therapy, or a combination. The evaluation of the long-term efficacy is a key issue for gene therapies as premarket clinical trials typically include a limited number of patients and with a limited duration. The EMA suggested sponsors provide long-term follow-up data in several situations, such as for cell therapies with a short shelf life, which may require monitoring of efficacy and the need for re-administration. Immunogenicity is also a critical consideration for the efficacy assessment of a cell-based product. The EMA’s draft guideline is available here:

Gottlieb Outlines the FDA’s Future Approach to Precision Medicine in Davos

February 5, 2018

The FDA plans to base future approvals of precision medicines largely on clinical trials that examine long-term durability and safety issues, Commissioner Scott Gottlieb said during a panel discussion at the World Economic Forum in Davos, Switzerland. Gottlieb said the key regulatory issues will be less about determining efficacy, especially with products demonstrating a strong proof-of-principle and early observations of effectiveness in small trials — and instead more focused on product issues related to potential off-target effects and their implications. The agency will also seek accelerated approvals for precision medicines designed to optimize benefits for particular groups of patients, especially through genomic or molecular profiling. “I think we’re really at an inflection point right now, where we’re … defining the modern rules for how these technologies are going to be regulated,” he said. “We’re going to be looking at accelerated approval endpoints for earlier approval on questions of efficacy, with more vigorous long-term follow up in some of these constructs where we have authority to do that under accelerated approval.”

Azar Confirmed as HHS Secretary

January 29, 2018

The Senate voted 55 to 43 Jan. 24 to confirm former pharmaceutical industry executive Alex Azar as HHS secretary. Support for Azar, who previously served as the department’s deputy secretary during the George W. Bush administration, was divided, with critics voicing concerns over his time as president of pharmaceutical giant Eli Lilly’s U.S. division. He also served as a member of BIO’s board of supervisors.

Senate Committee Clears Azar’s Nomination for Floor Vote

January 22, 2018

The Senate Finance Committee advanced the nomination of ex-Eli Lilly exec Alex Azar to serve as HHS secretary, by a mostly party-line vote of 15 to 12. He is expected to be confirmed by the Senate as a whole in the coming weeks. “Mr. Azar is well-credentialed to lead such a critical department at a time America’s healthcare system is facing difficult challenges,” said committee chair Sen. Orrin Hatch (R-Utah). Sen. Tom Carper (D-Del.) was the lone Democrat in favor. Much of Azar’s confirmation hearings focused on the rising price of drugs, especially during his tenure as president of Lilly USA, with Azar himself agreeing that prescription costs are too high. Many Republicans touted his industry experience as a positive, saying he would an insider’s perspective to the role.

Alex Azar Takes Senate Questions in Bid to Become HHS Secretary

January 15, 2018

Democrats on the Senate Finance Committee grilled President Trump’s nominee for HHS secretary, former Eli Lilly executive Alex Azar, and attempted to tie him to price hikes of several products during his tenure as head of its U.S. business unit. Republicans once again touted his industry experience as a positive. Azar himself agreed that drug costs are too high, and listed one of his major priorities as working to reverse the incentives that drive manufacturers to raise their prices — while still ensuring discovery and innovation through well-funded clinical trials and research. The committee’s ranking member, Sen. Ron Wyden (D-Ore.), described how Lilly more than doubled the list prices for Forteo, Effient and Stratera, as well as its top-selling diabetes blockbuster Humalog, during the five years that Azar was president of Lilly USA. Wyden also cited how, nearly one year ago, Trump described pharmaceutical companies as “getting away with murder” in terms of prescription drug costs.  “I don’t know that there is any drug price of a branded product that has ever gone down, from any company, on any drug in the U.S., because every incentive in this system is toward higher prices,” Azar told the committee Jan. 9. Azar also said the government should look at a more direct negotiation of lower prices under Medicare, but cautioned that a single, national formulary could end up restricting patient access. 

OMB Issues New Notice on Common Rule Delay

January 8, 2018

The OMB Office of Information and Regulatory Affairs (OIRA) posted a notice on its website Jan. 5  noting that OIRA is reviewing a final rule titled “Federal Policy for the Protection of Human Subjects: Delay of the Revisions to the Federal Policy for the Protection of Human Subjects.” This notice follows but does not replace an October posting noting the review of a proposed final rule titled “Federal Policy for the Protection of Human Subjects: Proposed 1-Year Delay of the General Implementation Date While Allowing the Use of Three Burden-Reducing Provisions During the Delay Year” suggesting a more general delay of unknown length.  The three provisions were not specified in the listing. It’s currently unclear whether either rule will be published as a final rule before the Jan. 19, 2018, implementation date. Read the posting here: