Francis Collins, director of the U.S. NIH, said in a public forum that the agency is "really bullish" about precision medicine. However, while precision medicine requires mounds of data, which soon may be available, Collins said the NIH All of Us research program has drawn the interest of more than 300,000 willing participants to date, adding that the target enrollment of 1 million should be accomplished before the end of 2022.

Collins gave the keynote speech at the 2019 edition of the annual FDA science forum, stating that he has been witness to "an extraordinary partnership between NIH and FDA." While the NIH is enthusiastic about precision medicine, researchers "need a lot of data about a lot of people" to make precision medicine a clinical reality, Collins said. The NIH is still targeting an enrollment of participants for the All of Us initiative with a special focus on rural communities and the economically disadvantaged, a focus Collins said will help ease disparities.

Enrollees get their data

There is a need to guard enrollee data and privacy, but unlike the participants in most clinical trials, "they will be getting their data back" from All of Us, Collins said. He noted that recruiting for All of Us, a precision medicine undertaking, should reach the target of 1 million participants in about two and a half years.

Much of Collins' speech at the FDA gathering was directed toward the collaboration between the two agencies, and he noted that he has been part of the FDA-NIH joint leadership council since being appointed to the NIH directorship in 2009. In a reference to the churn at the FDA commissioner's post, Collins quipped that "somehow FDA keeps changing and I'm still here." The remark was especially poignant given the rumors that the Trump administration is considering at least one candidate to take over as the permanent FDA commissioner. Acting FDA Commissioner Ned Sharpless who could not make the meeting, took the job at the FDA despite his work as the director of the National Cancer Institute (NCI), which at present is overseen by acting NCI director Douglas Lowey.

Collins reviewed some of the challenges facing the two agencies, such as gene editing and CRISPR, as well as neurotechnology and the BRAIN Initiative. Of the latter, Collins said, "This is going to have some very significant impact in the field of diagnostics." Also among the programs Collins reviewed was the Partnership for Accelerating Cancer Therapies, a five-year, $220 million precompetitive effort that enjoys the support of the NIH, the FDA, the Foundation for the National Institutes of Health and 12 companies. Collins said that program has accelerated immunotherapies for a number of cancer types and patients, although he noted that solid epithelial tumors have proved resistant to immunotherapies to date. He described immunotherapy as an attempt to "take the immune system to graduate school and teach it what to look for."

Also of interest for Collins was gene therapy, about which he said, "the exciting thing is, it's really starting to work, and some dramatic examples of that" are in clinical use. He said the NIH's focus is on resolving the barriers to basic research, particularly for ultra-rare diseases, adding that he and Peter Marks, director of the FDA Center for Biologics Evaluation and Research, are of the view that manufacturing science must be improved as well, given the high cost of producing some therapies. While the ex vivo approach to gene therapy has taken center stage for the most part, Collins said the NIH is also focused on developing the science behind in vivo approaches, although he noted that this is more challenging in some respects.

The NIH Heal (Helping to End Addiction Long-term) Initiative, Collins said, is looking for scientific solutions to both opioid addiction and development of alternative analgesics. He said the agency had expected it would be able to access $500 million in fiscal 2018, but that the budget dilemma in Washington impeded the agency's ability to review proposals before the end of that fiscal year. Consequently, the NIH will spend $994 million in FY 2019, some of which is carryover from the previous fiscal year.

In silico study more economical

Among those who presented on the first day of the 2019 FDA science forum was Aldo Badano, of the Office of Science and Engineering Labs at the FDA's device center, who described the VICTRE (Virtual Imaging Clinical Trials for regulatory Evaluation) Project, the first all-silico imaging clinical trial. "We've reached a point where some of these computational modeling tools are very, very advanced," Badano said, although he advised that while that approach to clinical trials is less costly in terms of time and money, the regulatory decision made with the help of in silico tools "has to be at least as good as the ones we're making today." He said there is an interest in regulatory efficiency as well, adding that simulation will eventually become an essential component in regulatory review.

VICTRE was intended to demonstrate that computational modeling can play an increasingly predominant role in regulatory review of imaging systems. The agency examined a number of completed clinical trials and settled on the pivotal trial for the PMA application for the Mammomat digital breast tomosynthesis system by Siemens Medical Solutions Inc., of Malvern, Pa. Badano said the VICTRE effort required the use of in silico phantoms, a simulated imaging system and a machine reader. The FDA approved the Mammomat in 2015, roughly the time at which the FDA began internal discussions of how it would approach the project.

The Siemens study enrolled more than 400 subjects and relied on more than 30 radiologists at six sites who read the images. The study took six or seven years, Badano said, stating that the VICTRE study made use of a model that produces random images of the dummy breast as well as random lesions. The algorithm employed finite element analysis to produce a virtual breast as compressed by a conventional mammography machine. The FDA staff designed the trial for about 3,000 virtual subjects, but excluded 14 virtual subjects. Half of those dropouts were due to failed insertions of lesions into the dummy breasts, while the another seven were taken out of the study "for other reasons."

"Overall, the results are very consistent" between the two studies, Badano said, adding that the FDA study took only two years vs. the nearly seven years Siemens needed for its study.

Badano said the VICTRE results suffer from "much less uncertainty" than the Siemens study due to the ability to repeatedly run the algorithm against the virtual images, although depiction of microclusters favored digital breast tomosynthesis. One obvious source of bias was that the FDA researchers knew in advance where the "lesions" were in the study articles in VICTRE, but the economics of the virtual study were quickly obvious.

Badano said also that Siemens had disclosed the amount of money the firm had expended toward the pivotal study for the Mammomat, adding, "'we think at most we were able to do this with one-third of their expenditures." The cost of this kind of effort should fall over time, he stated, noting that all the source code and datasets the FDA used in the trial are available. The actual trial duration was three weeks, Badano noted. That kind of virtual trial "has great potential to reduce, refine and possibly replace clinical trials for regulatory evaluation."

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