From The Editor | September 29, 2017

Clinical News Roundup: FDA Says Clinical Trials System Is Broken

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

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Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, told attendees at a workshop what many in the industry have already suspected: The clinical trials system is broken.

Woodcock’s comments came during a real-world evidence (RWE) workshop held at the National Academies of Sciences, Engineering, and Medicine. Woodcock noted there needs to be new ways to collect and utilize patient data. She also stated the use of master protocols, which look at multiple therapies in a single disease or a single treatment in multiple diseases, “need to be the future.” 

The FDA’s use of RWE in certain circumstances will be expanded by both the 21st Century Cures Act and the new user fee laws. However, Woodcock noted there has been little historical use of RWE in drug regulatory decisions. She states the use of RWE in determining effectiveness is most important for incentives, but also cautioned that it tends to work when there's a "big effect."

FDA Selects Apple, Fitbit For Pre-Certification Program

Health technology vendors Apple, Fitbit, Samsung, and Verily were among nine companies chosen by the FDA for a pilot program that will test a new digital health software pre-certification process known as FDA Pre-cert. According to a release from The FDA, the pilot program will create a tailored approach toward digital health technology by looking at technology or software developers rather than individual products. After reviewing the systems for software design, validation, and maintenance, FDA will determine whether the company meets established quality standards. If so, the company will be pre-certified.

With information gained from the program, the FDA hopes to determine key metrics and performance indicators that could be used in the future. The agency also hopes to identify ways that pre-certified companies could submit less information to the FDA than is currently required to market a new digital health tool as part of a formal program. The FDA is also considering whether to allow pre-certified companies to not have to submit a product for remarked review.  

In addition to the large companies participating in the pilot program, there are also some smaller startups. The complete list of companies participating includes Apple, Fitbit, Samsung, Johnson & Johnson, Pear Therapeutics, Phosphorus, Roche, Tidepool, and Verily. Pear Therapeutics has developed a mobile app to help treat substance use disorder, and the app was recently approved by the FDA. Tidepool developed an open source platform for diabetes data.

New Clinical Trials Definition Concerns Autism Researchers

Autism researchers in the U.S. are concerned about new government rules designed to boost the transparency of clinical trials involving humans, saying red tape may paralyze promising projects.

Beginning in January 2018, the National Institutes of Health (NIH) plans to enforce new rules based on a revised definition of “clinical trials.” The regulations would apply only to research funded by the agency. The term “clinical trial” has traditionally been reserved for studies testing drugs or behavioral therapies in people. But the new definition’s interpretation of “intervention” and “outcome” could apply even to studies of basic biological mechanisms.

That means a brain imaging study that tests a person’s memory under conditions that interfere with memory could be considered a clinical trial. Researchers believe this type of test is far from clinical. “By some readings of this case, virtually all basic research still counts as a clinical trial,” says Nancy Kanwisher, Walter A. Rosenblith Professor of Cognitive Neuroscience at the Massachusetts Institute of Technology (MIT). Others have called the new rules “insane.”

The changes have been in the works for more than three years. But they mostly escaped researchers’ notice until August when the agency released guidance on a rigorous new grant application. Since then, more than 3,500 researchers have signed open letters to NIH director Francis Collins, urging the agency to seek more input from researchers before implementing the regulations.

In response to this overwhelming feedback, NIH officials revised the list of hypothetical studies in early September. Researchers believe the guidelines remain “ambiguous.”

In Clinical Trials, Standard Care Is Not Always Standard

Randomized controlled trials have served as the state-of-the-art method for determining the efficacy and safety of new, innovative treatment regimens for patients with cancer and other diseases. These trials are carefully designed to ensure they are scientifically and ethically sound and that an experimental regimen is superior or comparative to the current standard of care. However, researchers from The University of Sydney have found that 29 percent of breast cancer clinical trials reviewed failed to establish a control arm meeting the current standard of care.

The findings of the study, led by Rachel F. Dear, PhD, were published in the September 2017 issue of the Journal of the National Comprehensive Cancer Network (NCCN). "Inconsistency of choice of control arm undermines the quality of evidence generated by clinical trials, which in turn impacts systemic reviews, the development of clinical practice guidelines, planning of future trials, and, ultimately, patient care and outcomes," said Dr. Dear.

The Declaration of Helsinki, a set of ethical rules regarding human experimentation such as clinical trials, states the "benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods." Therefore, modern clinical trial design should include control arms representing the most current, evidence-based treatment standards at the time of implementation.

The researchers analyzed Phase 3 randomized controlled clinical trials in breast cancer. Taking studies from 2004 to 2014 comparing drug treatments to "standard of care," the team compared the control arm drugs and dosing to the concurrent recommendations within the Clinical Practice Guidelines in Oncology (NCCN Guidelines) for U.S. studies and the German Gynecological Group (AGO) for European studies.

Sixty of the trials failed to provide control group treatment in line with the concurrent standard of care.  Among trials recruiting in the United States, the control arm was not considered standard in 13 percent of studies. A higher proportion of trials that recruited exclusively outside of the United States (39 percent) were not consistent with the NCCN Guidelines.

Blacks, Elderly Missing From Cancer Trials

Four out of five participants in cancer clinical trials are white, a discrepancy that researchers believe may call into question whether other races are receiving good cancer treatment. The new findings also show women and the elderly to be underrepresented in clinical trials.

Prior studies have shown that the effectiveness of cancer treatment can vary based on a person's race, gender, and age. Despite this, clinical trials have failed to successfully recruit a diverse patient population upon whom to test new drugs and therapies. That means the data being used to guide cancer treatments largely come from one type of patient.

Researcher Dr. Narjust Duma, a hematology/oncology fellow at the Mayo Clinic in Rochester, MN, undertook the study after a conversation with a black lung cancer patient about possible chemotherapy treatments. A cursory look at chemotherapy research revealed that only a handful of blacks had been included in clinical trials involving hundreds of people.

To explore the issue further, Duma and her colleagues analyzed enrollment data from all U.S. cancer therapy trials completed between 2003 and 2016, winding up with more than 55,000 participants. Of those patients, 83 percent were white, 6 percent were black, just over 5 percent were Asian, almost 3 percent were Hispanic, and around 2 percent were classified as "other."

Researchers also found that only 36 percent of patients were aged 65 and older, even though cancer risk increases dramatically with age. Women were also underrepresented in clinical trials for melanoma (35 percent), lung cancer (39 percent), and pancreatic cancer (40 percent).