Operation Trialblazer and Why Clinical Trials are Leaving the US: Q&A with Richard Graham

FDA’s latest initiative to improve the drug approval process is Project Trialblazer. The pilot program is designed to accelerate early-stage clinical trial.

This effort comes as the global clinical trial space is becoming more competitive, and many companies are moving their trials to other countries, such as China and Australia. The current administration hopes to solve this issue by simplifying the entire trial process.

According to the initial announcement, FDA hopes that this initiative will reduce clinical trials by six-to-12 months, which would hopefully bring more trials back to the United States.

Pharmaceutical Executive spoke with Dr. Richard Graham, chairman and co-founder of TruTechnologies about FDA’s new program and how he expects it to impact clinical trials. He also discusses why trials are actually leaving the United States and where he sees the true bottlenecks in FDA’s approval process.

Click here for the full interview!

Pharmaceutical Executive: How realistic are the goals set by Project Trialblazer?
Dr. Richard Graham: Operation TrialBlazer incorporates multiple elements, largely regulatory, operating through HHS. The first component you're mentioning could cut several months from development timelines; six to twelve months is the figure that's been cited, and that was largely framed around reducing the time required for IND review.

There is a relatively lengthy process from the time a company begins working on an IND to the time that IND is approved in the US and patients can be dosed. As we've discussed, that's quite different from Australia, which has invested significantly in building the infrastructure to support its CTN process, which is effectively the equivalent of no IND at all.

So TrialBlazer is directionally correct in the sense that we should be removing regulatory friction and moving faster. But you're competing with a system that requires no IND. It's hard for me to reconcile how this is going to produce a meaningful improvement when many of the companies I work with today are already defaulting to Australia for their Phase 1 studies. Once the toothpaste is out of the tube, it's hard to put back in.

Directionally, I think this is the right move, but I'm struggling to understand how it will actually shift company behavior back toward filing INDs in the United States, when the path they're already on is filing in Australia. And that's before you factor in the significant R&D tax credits that come with conducting studies there.

PE: What countries is the US competing with for clinical trial control
Graham: The way I think about it, based on what I've been seeing in the work I've been doing, is that for Phase 1 studies, companies are primarily going to Australia for the reasons we just discussed. For later-stage trials, starting as early as Phase 1b in patients but certainly through Phase 2 and sometimes Phase 3, there's a significant push to do that work in China. So it's actually both countries, both regions, but I think about it by phase or stage.

Now, if we shift gears and think about those later-stage trials, which TrialBlazer doesn't directly contemplate the way it does the expedited IND review process, China has done a remarkable job of getting trials up and running fast, far faster than they used to, and completing them faster than we do in the United States. There are multiple reasons for that. One is the large pool of treatment-naive patients available for enrollment. The other is that China ran a top-down, state-coordinated program that essentially said: sites, sponsors, and CROs, work together to make this happen. I'm not suggesting we replicate that model in the United States. I am fairly certain that we are missing the mark with TrialBlazer and the other initiatives we've discussed, because we have so many stakeholders involved in running a clinical trial in the US, and they are not all working toward the same goal.

Think about it as a diagram with the trial at the center and spokes radiating outward: patients, sponsors, sites, CROs, investors, payers, regulators. How can we fix one small piece that one stakeholder cares about and expect everything to suddenly move fast enough to outpace China? I'm not offering a solution here, but I am highlighting a problem that is solvable. In my view, we are not thinking holistically about what the underlying issues actually are.

PE: What would be the most beneficial situation for the United States when it comes to clinical trials?
Graham: Clinical trials should always be conducted around the world, especially in later-stage development, because you're developing a drug that will be used across different patient populations. We have meaningful genetic, cultural, and ethnic differences that affect how a drug performs, whether that's pharmacokinetics, efficacy, or safety. Global trials are necessary.

But who holds the IND? I would love to see the United States do better. By better, I mean generating higher-quality data, faster, the way we're seeing in Australia and China, but doing it in a thoughtful and systematic way.

What we have instead is a series of one-off initiatives. Today it's TrialBlazer. Three months ago, when we spoke, it was the real-time clinical trial initiative. I keep seeing bits and pieces without anyone stopping to ask the bigger question: with nine or ten major stakeholders who all need to be rowing in the same direction, why aren't we on the same boat? That alignment simply isn't happening.

PE: Where do the true bottlenecks exist at FDA when it comes to clinical trials?
Graham: I don't want to sound negative, because I think directionally, people and organizations are trying to do the right thing. But here's what bothers me, and let's use TrialBlazer as the example.

We just talked about expediting the IND review process. That falls into what I think of as the startup phase, or everything that happens before a study is actually executed. If you break a clinical trial into three phases: startup, execution, and then analyzing and reporting data. The execution phase is where I see the vast majority of bottlenecks, and it's where almost no meaningful work is being done to address them.

Why is that? Probably because the execution phase is the one that the people who control clinical trials at the top have the least visibility into and the least direct control over. The entities with the most control in that phase are clinical trial sites and CROs — and that's exactly where the inefficiencies compound. Enrollment takes far too long because of systemic inefficiencies at the site level.

Here's a concrete example. The TrialBlazer document that HHS released includes a section I genuinely appreciate, which argues that in order for the United States to reclaim clinical trials that are now being run overseas, we must be innovative and on the leading edge of technology. I agree completely. But at TruTechnologies, every time we initiate a new study for a client, we receive a blanket letter from one of the major cancer centers in the United States, a center everyone in the industry would recognize, that says, in effect: we are not willing to embrace clinical trial technologies in our lab, and we expect you to send us paper case report forms. That is not innovation. But that is the reality at the site level.