Clinical News Roundup: CRS Files Lawsuit Against FDA

By Ed Miseta, Chief Editor, Clinical Leader

The watchdog group Center for Responsible Science (CRS), along with clinical trial participants and the father of a deceased trial participant, has filed a lawsuit against the FDA for denial of CRS’ citizen petition, which was originally submitted in June 2014 and has since had several amendments.

Reports indicate there have been at least 153 treatment-related deaths in clinical trials in the last four years. CRS believes it is critical for the FDA to revise its informed consent regulations to increase the protection of participating patients. The petition requests that FDA ensure every prospective trial participant receives the information necessary to evaluate the risks posed by drug trials so they can make a true informed decision.

“To achieve true informed consent, trial participants need to understand that the drugs they are being given have been tested largely in animal models, which are acknowledged by FDA to sometimes be unreliable predictors of human response, especially for the new biologics coming to market,” reads a press release issued by CRS. “Indeed, preclinical evaluation of human risk in animal experiments for biologics can be difficult, and sometimes impossible due to species-specific reactions, which can expose human subjects to unexpected, potentially catastrophic effects.”

When the CRS citizen petition was submitted in 2014, the FDA responded that it involved “complex issues requiring extensive review and analysis by agency officials.” FDA recently provided a brief response denying the petition. CRS believes the response demonstrates the agency has undertaken little, if any, review or analysis of the petition and believes the agency has failed to address the serious concerns presented in the petition.

FDA Boosts Patient Access to Medical Devices

FDA Commissioner Scott Gottlieb announced the agency plans to improve patient access to medical devices by streamlining its regulatory actions. In a public statement, Gottlieb reiterated the agency’s commitment to improving patient access to devices and treatments while ensuring patient safety.

According to Gottlieb, the FDA is currently facing issues with small, iterative improvements to medical devices. These improvements are often essential for supporting patient safety. “Therefore it’s important for the FDA to enable innovators to have the flexibility to efficiently make these kinds of small modifications,” said Gottlieb. “At the same time, the FDA needs to establish modern tools and benchmarks for measuring the safety and performance of devices to make sure they’re delivering the expected benefits to patients.”

FDA created a medical device development tool (MDDT) in response. The first MDDT is targeted at developers creating tools for patients with cardiovascular disease. Standardizing the device development process will make it easier for developers and streamline the approval process. Ideally, this will help more patients access devices quicker.

Bracket acquires mProve Health To Advance Patient Engagement

Bracket, a clinical trial technology provider, announced it has acquired mProve Health Inc., a provider of mobile technologies for life sciences companies. The acquisition centers on both companies' support of tech-enabled clinical trials that improve patient engagement through the use of "Bring Your Own Device” (BYOD) mobile tools in clinical trials.

Bracket offers Electronic Clinical Outcomes Assessments (eCOA) and Randomization and Trial Supply Management (RTSM) mobile applications. mProve's suite of regulatory-compliant mHealth solutions includes mPulse, an Electronic Patient-Reported Outcomes (ePRO) platform for enabling data collection via standalone native mobile apps or SMS text. Other apps will enable communication with doctors and provide reminders and education.

In a recent report by KNect365, 94 percent of surveyed clinical trials professionals are looking to increase the utilization of mHealth, surpassing big data (86 percent) and cloud technology for EMRs (84 percent). These findings, among others, indicate mHealth may be one of the most powerful opportunities in clinical trials.

"We are excited to announce the acquisition of mProve as we take a major step forward in our support of tech-enabled clinical trials," said Jeff Kinell, CEO of Bracket. "As an early adopter of mHealth and BYOD, we recognize how these movements empower patients to become partners in their trials, and subsequently, deliver more accurate patient-reported outcomes and increase the likelihood of a successful trial."

"This acquisition is an opportunity to bring the shared visions of mProve and Bracket into focus," said Jeff Lee, CEO of mProve. "Both organizations center on improving patient engagement and driving adoption of mHealth. Together, we are well situated for a future of tech-enabled clinical trials."

Study Reveals Why Alzheimer's Drugs Fail In Clinical Trials

A tremendous amount of Amyloid-β peptide (Aβ) accumulates in the brain of Alzheimer's disease patients. γ-Secretase inhibitors were designed to inhibit the enzymatic activity that produces Aβ. By reducing Aβ production, γ-secretase inhibitors were considered able to treat Alzheimer's disease. In fact, nearly 50 clinical trials have been conducted using potential γ-secretase inhibitors for Alzheimer's disease or several types of cancer. However, all of these trials have failed, except for two studies which are currently ongoing.

Osaka University scientists found that some potential γ-secretase inhibitors such as semagacestat, which have been used in large clinical trials that ended in failure, do not function as true inhibitors as originally expected, but rather cause accumulation of toxic intraneuronal Aβ. They proved this by introducing an original method to measure direct intracellular products of γ-secretase. They commented that the application of their evaluation method may help develop truly effective drugs for Alzheimer's disease. The study can be seen in Cell Reports and provides an explanation for why the clinical trials for Alzheimer's disease drugs have failed and gives new light on the discord between preclinical and clinical findings. "Aβ accumulates in the brain at the very early stages of Alzheimer's disease," explains Osaka University Associate Professor Masayasu Okochi, an expert on the disease who managed the project. "Aβ generation is based on the activity of presenilin/γ-secretase which mediates the cellular production of Aβ."

Of the promising sets of drugs for Alzheimer's disease were γ-secretase inhibitors like semagacestat. However, a clinical trial that began almost 10 years ago was terminated early because not only was semagacestat found to fail, patient groups that received the drug showed exasperated symptoms compared to the placebo group. This finding has put great doubt into the Aβ hypothesis.

Many Published Clinical Trials Inadequately Registered

Clinical trial registration may be a requirement for publication in the top anesthesiology journals around the world, but as a team of Canadian researchers found, the majority of studies appearing in the pages of these journals are still inadequately registered. This, they said, opens the door to questioning their findings, and may even have negative effects on patient care.

“Clinical trial registration is meant to be a transparent process where authors of randomized clinical trials commit—before the trial—the specifics of what they’re going to do and how they’re going do it,” said Jeffrey T.Y. Chow, BS, a graduate student and researcher at the University of Western Ontario. “Ideally, this reduces both publication bias and selective outcome reporting bias.”

With that in mind, the researchers sought to examine whether randomized clinical trials published in six general anesthesiology journals were adequately registered, and whether their reported primary and secondary outcomes corresponded with their originally registered outcomes.

Chow and his colleagues systematically screened and extracted data from randomized clinical trials published in the top six general anesthesiology journals by impact factor—Anaesthesia, Anesthesia & Analgesia, Anesthesiology, British Journal of Anaesthesia, Canadian Journal of Anesthesia, and European Journal of Anaesthesiology—during the years 2007, 2010, 2013, and 2015. They manually searched each journal’s table of contents, in duplicate, to identify eligible randomized clinical trials.

The investigators defined an adequately registered trial as having been registered in a publicly available trials registry, prior to the first patient being enrolled, with a clear primary outcome in the registry entry. For those trials deemed to be adequately registered, the researchers then compared the outcomes in the trial registry with those reported in the manuscript; any discrepancies were then documented and analyzed.

As Chow reported at the 2017 annual meeting of the Canadian Anesthesiologists’ Society, a total of 860 randomized clinical trials were identified in the four years analyzed. Of these, just 102 (12 percent) were determined to be adequately registered. The authors noted the proportion of adequately registered trials did increase over time: 0.6 percent in 2007, 4.0 percent in 2010, 19 percent in 2013, and 38 percent in 2015. In 2015, the most common reason for finding registration to be inadequate was registering the trial after the first patient had already been enrolled. “This defeats the whole purpose of registering in the first place,” said Chow.