FDA Commissioner Robert Califf has called for major reform of the clinical research enterprise, particularly in how clinical evidence is gathered, to reduce health disparities between scientific advancement and actual U.S. life expectancy, a huge undertaking that some clinical trial experts question.

Writing in Clinical Trials this month, the agency chief and veteran clinical researcher urged an overhaul of the U.S. system for generating clinical evidence, proposing a deep overhaul of the postmarket setting, which he claimed is currently “disaggregated” and struggles to provide sufficient evidence critical to delivering optimal clinical care and treatments to American patients.

Califf’s proposed overhaul lays out three priorities that he believes are critical to bring about significant change:

• Improving the integration of and access to high-quality data from traditional clinical trials, electronic health records, and personal devices and wearable sensors;
• Restructuring clinical research operations to support and incentivize the involvement of patients and frontline clinicians; and
• Enabling responsible data-sharing that will help make implementing changes easier.

In addition to these focal points, Califf writes that it’s important to address “the systemic tendency to optimize individual components of the clinical research enterprise” without thinking about the impact these changes will have on the healthcare system in its entirety.

The article also includes a table that lists the issues, needs and actions potentially facing stakeholders that operate within the clinical research sphere, including sites, sponsors, health systems/hospitals, regulators and clinicians, among others.

Califf claims that postmarket systems in their current state frequently fail to provide the data needed to confirm/refute accelerated approvals and understand the benefits and risks of therapies in the real world, their comparative benefits and risks, and the resources needed to estimate their value as therapies.

Conversely, the article characterizes premarket systems for generating and assessing evidence as working “reasonably well” — and it’s this point that has drawn some commentary.

Mark Opler, chief research officer for WCG Clinical Endpoint Solutions, believes Califf’s article is on target with its identification of flaws, risks and disparities in postmarketing systems. And while he agrees with Califf’s description of the premarket setting to an extent, he believes this area is in dire need of sweeping change in many respects as well.

Opler cites the strikingly low success rates of most therapeutic development programs — which Califf acknowledges as well — but contends that their high rates of failure are not solely caused by limited technologies or limited biological understanding, but also by “systematic inefficiencies and misaligned incentives.” This rings particularly true in the realm of neuroscience, which sees some of the lowest levels of success and transition between phases of any therapeutic area, he says.

“Though this can be attributed in part to the tremendous complexity of finding ‘druggable targets’ in the brain that work as expected, the unacceptably high rate of failure is also due to elevated placebo response, inaccurate outcome measures and an industrial ecology that continues to favor quantity over quality,” Opler told CenterWatch Weekly.

He also recommends the FDA and other regulators focus more heavily on paving a responsible path forward for the use of novel assessment tools, such as remote automated tools for monitoring treatment efficacy, and a regulatory environment that allows for their safe, thoughtful use in both premarket and postmarket settings. Califf’s calls for the use of decentralized trials (DCT) and technologies to reduce access disparities will be more likely to be successful if this is done, Opler believes.

Overall, he feels that there should be less commentary and more decisive action in bringing transformative change to evidence production. “Dr. Califf outlines a future many of us certainly would love to live in,” he said. “What concrete steps can decisionmakers and stakeholders, from top to bottom in every level of organization, take to help get there? That’s a conversation worth having next.”

Nathaniel Katz, WCG Analgesic Solutions’ chief science officer, believes Califf’s paper represents leadership and an admirable attempt to drive change, but he agrees that its assertion that premarket systems function “reasonably well” is not an accurate characterization. Like Opler, he believes the premarket space needs significant attention for effective reformation of the clinical research enterprise to occur.

Katz calls Califf’s recommendation to merge premarket evidence systems with postmarket systems with the aim of accruing higher quality, more informative data from real-world settings an “interesting and visionary concept.” But, as Califf himself admits in the paper, this effort will require a great deal of collaboration among a diverse array of entities and, in Katz’s opinion, collaboration isn’t those entities’ strong suit.

The FDA may be better off focusing elsewhere: addressing deficiencies in the premarket setting, where the agency has more power to drive change. “It would be more productive for him to acknowledge the ways in which the FDA-regulated premarket evidence generation system is broken and fix that,” he says.

And overall, Katz says that the paper’s overarching argument — that revamping evidence generation for the better will turn around the failing U.S. healthcare system — is incorrect.

“His overall thesis is that if only we had better evidence, we could have better and more equitable healthcare outcomes in our society, like those of other wealthy nations who are doing much better than us. It’s immediately obvious that this thesis refutes itself: These other nations have exactly the same evidence we do and access to the same treatments yet have better health outcomes,” Katz says. “It’s due to a broken [U.S.] healthcare system, which remains broken due to perverse financial incentives that continue to dampen political will to create meaningful change. Evidence will not change that.”

But Kevin Potgieter, Medable’s vice president of regulatory affairs, believes that there are significant opportunities for the FDA to beef up its postmarket oversight and vigilance. As it stands now, the U.S.’ postmarket system primarily involves a “passive approach” of waiting for adverse event reports and other safety signals to roll in, he says, though certain products will require confirmatory studies, such as those granted accelerated approval.

Other markets, such as the EU, for instance, have enacted stronger postmarket vigilance approaches, requiring routine postmarket clinical follow up activities of manufacturers, something the FDA could consider attempting to emulate.

To Mohammed Ali, Medable’s chief domain expert, one of the most pressing demands in healthcare overall is the need for a harmonized way to identify the data most relevant for care, treatment and prevention as it pertains to patients, providers and health networks. Achieving this will come down to making data interoperable and interconnected across the healthcare system’s array of stakeholders, he says.

“Healthcare is a team sport. Understanding and managing disease and its impact on patients is a combined effort from multiple stakeholders across the patient ecosystem and care circle,” Ali said. “Within this ecosystem, information is not often connected and can reside in disparate locations, so the ability to connect the dots between lab data, healthcare system data, wearable data, payor data and even clinical trial data is critical to ensure the best and most practical solutions possible.”

Read Califf’s article here: https://bit.ly/40hdzi2.