April 30, 2018
Novartis has launched an ophthalmic digital research app that will allow researchers to monitor disease progression through self-reported patient data. The app, FocalView, collects real-time, voluntarily disclosed data from consenting patients, which will allow Sponsors to adapt clinical trial design to patients’ routines. The goal is to eliminate some of the most common obstacles to trial participation and increase practical understanding of ophthalmic diseases. The company is planning to test the app in a prospective, non-interventional study to determine its use for evaluating visual function such as acuity and contrast sensitivity. “Because patients with eye diseases are often not as mobile, FocalView has the potential to offer tremendous benefit for the ophthalmic community and for researchers looking to develop better treatments for these patients,” said Mark Bullimore, dean of the Southern California College of Optometry, Marshall B. Ketchum University, who served as medical advisor for the creation of the app.
Boston University Study: Oncology Trials Underrepresent Obese Patients
Obese patients are underrepresented in cancer-related clinical trials, according to new research published in the Annals of Oncology. While cancer types associated with being overweight or obese comprise 40 percent of all U.S. cancer diagnoses, the median proportion of obese participants in 22 clinical trials was only 18 percent. None of these trials specifically listed obesity as a disqualification for involvement in the trials, but 93 percent did not specify whether such patients were eligible to participate. An even greater proportion — 95 percent — of trials did not include information on the proportion of participants who were obese. When unpublished data was taken into account, 41 percent of trials made clear that obese participants were eligible but it was unclear for the remaining 59 percent. This level of underrepresentation, researchers wrote, could potentially make the data produced by the trials less generalizable. “The lack of information regarding enrollment of obese participants stands in sharp contrast with the expanding real-world concern of obesity in cancer and ongoing reflections about improving the assessment drugs’ safety and efficacy in patients who will ultimately receive them,” according to the researchers from Boston University’s School of Public Health. “Given the role of obesity in shaping cancer risks and outcomes, our results highlight the critical need to improve the reporting of obesity status information.”
UK Plans to Stick with EU Clinical Trial Regulations Post-Brexit
The UK government aims to stay up-to-date with EU changes for clinical trial procedures amid uncertainties over next March’s implementation of Brexit. The new EU clinical trials regulations were initially meant to be implemented in October 2018, but were delayed by the European Medicines Agency until 2019 at the earliest due to technical difficulties. The agency has called the modernization process its most ambitious IT system requirement in the last decade. The parliament’s proposed Brexit withdrawal agreement and implementation bill allows EU regulations to continue to apply in the UK for the bill’s limited time period. If that bill fails to pass “we will give priority to taking the steps necessary to bring into UK law, without delay, all relevant parts of the EU regulation that are within the UK’s control” to allow those planning clinical research to do so with certainty, said Baroness Annabel MacNicol Goldie, in remarks before the House of Lords. Two key elements are outside of the UK’s control — the use of a shared central IT portal and the UK’s participation in the single assessment model — as they require a negotiated agreement with the EU about the UK’s involvement post-Brexit, she said. Those negotiations have not started, as the government “[does] not wish to do anything that might disadvantage the negotiating position of the UK” by giving more guarantees. The UK government is committing to “being as aligned with the new EU clinical trials regulation as we possibly can be, subject to the negotiatory aspects,” she said.
FDA Issues Final Guidance on Imaging-Based Clinical Trial Endpoints
Sponsors conducting clinical trials using imaging-based primary endpoints should consider the choice of modality — such as echocardiography or single-photon emission computed tomography — as well as centralized image interpretation and how often image evaluations should be performed, according to final guidance from the FDA. The agency also recommends trial-specific procedures for imaging that extend beyond the imaging performed as part of standard medical care. Sponsors should consider logistical issues when considering imaging modalities for a phase III trial. “Imaging modality upgrades and malfunctions are sometimes unpredictable,” the guidance states. Clinical sites may also experience “unforeseen limitations on the use of the modality or modality-specific imaging drugs and processes, such as the interchange of certain contrast agents that may not affect typical diagnostic imaging but may alter trial-specific quantitative imaging measures.” Sponsors must also decide between locating image interpretation at the clinical site or at a central site. Which option is best depends on the role, the susceptibility to bias and the variability of imaging within the trial. A centralized location may be less important for trials where the quantitative measures are widely performed and reported in clinical medicine and the trial design controls for potential interpretive biases. This also affects how soon after acquisition the images should be interpreted; it is normally done immediately for on-site imaging, but for centralized interpretations, Sponsors should determine a turnaround time appropriate to the anticipated trial design. When deciding whether to blind image interpretation to clinical data, Sponsors should factor in the underlying clinical condition and the precedent for using imaging as the trial’s primary endpoint.
Gottlieb Flags Clinical Trial Limitations in Budget Hearing
In remarks to a Senate appropriations subcommittee on the FDA’s FY2019 budget request, FDA Commissioner Scott Gottlieb discussed the agency’s plans to make use of real-world evidence to supplement what it learns from clinical trials. “No matter the design or size of clinical trials, we can never answer — or anticipate — all the questions we may have before we approve a new product. Thus, we must rely on post-market data tools,” he said. Gottlieb stressed the importance of having a real-time, real-world experience system, as it can give the agency additional ways to expand its knowledge of new product effectiveness. “We can better utilize electronic healthcare data to broaden the indications for use of approved medical products, eventually perhaps conducting much of late stage development in the ‘real world’ making our pre-market development process more efficient,” he said. Gottlieb noted that the budget contains a $100 million proposal to advance the use of real-world experience. It aims to provide efficient, lower cost ways to develop clinical data in order to speed up medical product development and inform patient care. The proposal would give the agency the capability to conduct “near real-time evaluation down to the level of individual electronic health records” for at least 10 million individuals across a variety of healthcare settings, improving the agency’s tools for safety evaluations and possibly reducing the cost of developing medical products, he said. The proposal would allow the agency to link across data sources, such as electronic health records, to evaluate broader sets of endpoints that are currently difficult to access, bringing a “fundamental shift from passive to active device surveillance.” “These are transformative initiatives that can modernize the foundation of FDA oversight and improve patient safety,” he said.
FDA Issues ‘Streamlined’ Nonclinical Trial Guidance for Hematologic Disorder Drugs
The FDA released draft guidance on a “streamlined nonclinical program” for Sponsors of nonclinical studies for development of pharmaceuticals for treatment of patients with debilitating or life-threatening hematologic disorders, saying such nonclinical studies should consider general toxicology, pharmacology and reproductive toxicology. Ahead of any clinical trials for such drugs, Sponsors should assess how the drug potentially affects vital organ functions, including the nervous and respiratory systems, but stand-alone safety pharmacology trials are not necessary, the agency said. The planned dosage and proposed safety monitoring plan for trials should be based on nonclinical data similar to that of anticancer drugs. This typically means study lengths of one month to support first-in-human trials and three months to support phase III trials and marketing applications. “The Sponsor should initiate the three-month repeat-dose studies when a phase II trial starts or as soon as feasible when a pharmaceutical is designated as a breakthrough therapy,” the guidance states. The Sponsor should choose the design of nonclinical studies to approximate the various dosing schedules that might be used in initial clinical trials. Sponsors should assess genotoxicity for small molecule drugs ahead of a first-in-human study, but a full battery is not always necessary. One assay for gene mutation is usually enough to support single-dose clinical studies, the agency said. The starting dose for first-in-human trials should be justified scientifically based on nonclinical data, and Sponsors should determine the starting dose to minimize exposure to subtherapeutic dosages. The agency’s recommendations for assessing reproductive toxicity are similar to those for anticancer drugs in ICH S9. Sponsors may need to conduct fertility and early embryonic development studies, but these can be conducted after approval. The guidance further provides recommendations for timing of submissions of nonclinical study results, noting that the Sponsor can submit study results earlier than the timings listed when a “cause of concern” exists, such as unexpected severe toxicities in phase I clinical data. Read the draft guidance here: www.fdanews.com/04-23-18-Guidance.pdf.
Most Top Public Funders of Clinical Research Lack Transparency Policies, Says AllTrials
An audit of the 18 philanthropic and public bodies that spend the most money on clinical research found that the majority do not require researchers to report results and that only half of the funders ask for clinical trials to be registered, according to AllTrials, a clinical research watchdog. The audit, conducted at the University of Oxford, and published in the Journal of the American Medical Association, assessed the funding organizations’ policies on clinical trial transparency under three domains: trial registration, summary results reporting and patient data sharing. Three of them seem to ask for no commitment to transparency from their funded researchers — they don’t mandate any registration, summary result sharing or data sharing. Only two organizations have a requirement that covers all three domains. These are the UK’s Medical Research Council and Germany’s research funding organization Deutsche Forschungsgemeinscaft. Sixteen of the audited organizations are public bodies and two are philanthropic organizations (The Wellcome Trust and Bill & Melinda Gates Foundation). Between them, the 18 organizations spend around $40 billion on health research every year (figures from 2013, reference below). In May 2017 the WHO asked non-commercial funders worldwide to sign up to its strong standard on transparency. Six of the 18 organizations included in today’s audit have committed to eventually meeting the WHO standard.
CBER Issues Guidance on Datasets for Vaccine Applications
The FDA’s Center for Biologics Evaluation and Research published guidance on information to include in biologics license application datasets, including data on clinical trial endpoints and adverse events.When clinical disease endpoint efficacy is an objective in the trial, the efficacy data should be primarily reported in the clinical event domain with specific information in the microbiology specimen, vital signs and physical exam domain as necessary, the agency said. Domains to include from clinical trials in dataset submissions include the trial summary, demographics, subject visits, concomitant medications, exposure, disposition, protocol deviations and medical history, as well as physical exam information and laboratory test results, if applicable. Safety data for vaccine clinical trials should include reactogenicity data — a set of adverse events collected within a previously specified time frame, otherwise known as solicited reactions — unsolicited AEs, medically attended AEs and death. Deaths should be reported in the AE domain with supplemental information provided in the death details domain. For laboratory test results, a laboratory safety assessment of clinical chemistry, hematology and urine should be included. If laboratory results are outside of the normal range for a particular assessment, it should be reported with the highest level included.Medically attended adverse events should be noted in the adverse event domain, with additional data reported if necessary in the death details, vital signs, healthcare encounters and/or findings about adverse events domains. New onsets of a chronic disease should be noted in the adverse events domain. Unsolicited adverse events should be represented in the AE domain whether or not they occurred during the pre-specified assessment interval or after. The AE’s clinical details should be represented in the findings about adverse event domain and possibly in the vital signs, concomitant medication, healthcare encounter, procedures and death detail domains. Read the guidance here: www.fdanews.com/04-23-18-Vaccines.pdf.