Doctors are trained to deliver bad news in a gentle, sensitive manner. Alan Breier, chief medical officer of Eli Lilly, may have missed that lecture.

A psychiatrist and former academic, Breier took the podium at the Clinical Trials Congress in Las Vegas and bluntly declared that many of the major organ systems of pharmaceutical research are failing. The only question, in his mind, seems to be the degree of urgency with which the rest of the industry receives his diagnosis. Breier reviewed the familiar two-line fever chart of rising research costs and falling numbers of new chemical entities. But the malaise goes deeper, Breier warned.

“Major changes are urgently needed in the traditional drug development paradigm,” he said, noting that perhaps half of all patients do not respond to the drugs they are prescribed. “That’s a weird business model. I don’t think there are a lot of business models like that. You drive a new car off the lot, and it works fifty percent of the time?”

Public Trust

Moreover, Breier noted ominously, key stakeholders are increasingly skeptical about the data the industry provides. “The public trust is shaken in medical data,” he says. “The public view of drug development is becoming increasingly negative.”

For Breier, companies in the life sciences only incidentally manufacture drugs, devices or proteins. “We are information companies,” he says. “A pill sitting on a table has no value. It’s the information we extract and wrap around the medicines. The most important resource we have is information. You can’t stay in business if your most important asset has cynicism around it.”

New Paradigm

Beyond that, he said, the industry’s traditional approach to finding patients for clinical trials is “sterile” and “artificial,” yielding minimal insights into the benefits and risks of drugs in the real world. Teasing the audience, Breier suggested it would not be eligible for trials now under way at Lilly. “None of you would get into any of our trials,” he said. “We get these pristine individuals who make it through our inclusion criteria.”

Instead, he said, ordinary consumers simply want to know if a drug will work for them, with all their idiosyncratic conditions and various medications. When a new drug doesn’t work, there is understandable disappointment.

So what to do? The first step, Breier contends, is to rethink the protracted, astronomically expensive, four-stage paradigm of clinical trials. He told the audience in Las Vegas that a new interactive, dynamic approach is needed, one dependent on technology and data from real patients in the real world. 

‘Learn and Confirm’

For lack of a better term, the current approach to drug development is linear, with a compound slowly passing through prescribed clinical check points along the way. Breier is imagining something more circular. Insights from later stages of the process would be funneled back into the early part of the process. At Lilly, they call this learn and confirm. It resembles the way automotive engineers tweak the engine of a race car, drive the car for a few laps, adjust the engine again, and drive it a few more laps.

It appears to astound Breier that Phase IV trials, which he termed the Rodney Dangerfield of clinical development, are not used to send real-world insights back into the scientific process. Instead, today, the drug safety “horse” is long out of the proverbial barn when drugs are approved. When safety issues arise, in the current regulatory landscape, it’s difficult to assess their significance. As the audience in Las Vegas was all too aware, drugs that might have benefits for small subpopulations may be pulled off the market completely.

Emphasizing Phase IV

Here’s how Breier put it: “Why aren’t we constantly learning about our molecules post-launch in an iterative, dynamic, learning model? What if we were learning things about it we couldn’t learn before launch?” He’d like to expand a drug into a circle of perhaps 100,000 patients, and have physicians rigorously record what happens. Only if a drug survived that period of study would it be released to every physician or pharmacy in the land.

ClinPage has heard Breier make a case for Phase IV before, at a conference sponsored by Outcome at Harvard, but he’s making the argument with more vigor and clarity now. “Phase IV is in,” Breier says. “It should be brought in to the heart of drug development. It should be pulled into the absolute center of drug development. It is equally as important as any other phase.”

Throughout his address, Breier circled back to drug safety more than once. He described well-known limitations of clinical trials with small numbers of patients and, post-approval, the limits of spontaneously reported incidents. The current system, he said, requires a certain measure of luck or even faith that serious adverse events will be discovered and analyzed correctly and quickly. “Get the rosary out,” Breier said. ”It’s a wait and see paradigm.”

Iterative Process

Breier would prefer a world in which there was no single launch, no one dramatic debut, for each provisionally approved drug. He’d prefer a staged, gradual expansion of a product’s availability. As a drug proved itself safe and effective (or not), its label might be changed, its circle of release widened. 

“The labeling becomes more iterative across a drug’s lifetime,” Breier explained. “In the current model, which is very retrospective, an adverse event emerges and it is very hard to qualify that event. The new paradigm would be proactive. We would unhinge ourselves from this launch mentality and expand that space into a data gathering and research model.”

Praising Technology

In his “learn and confirm” paradigm, Breier sees a pivotal role for technology. “Absolutely key to this is using electronic databases and electronic data capture,” he said. “Being able to access that data in real time becomes very important. It can’t be a slow, sluggish system.” To hear a clinical person like Breier talk about technology with such force was unusual and surprising.

He also endorsed data standards. It was equally surprising (and welcome) to hear that somewhat nerd-friendly topics such as HL-7 and CDISC had percolated so far up the organizational chart of Lilly.

Dual Roles

Breier believes such a shift may require more clinicians to wear dual researcher-clinician hats. If Phase IV takes on more significance, if Lilly’s learn and confirm model is encoded into law or regulation, it will eventually mean that more than a tiny fraction of physicians will be acquainted with pharmaceutical research. Says Breier: “The clinician becomes investigator. The data goes into a repository and is brought back in real time. That’s dynamic. That’s learning. It’s not static.” Lilly’s already done as much, he suggested, in its Progress trial, undertaken in 37 countries and studying 12,000 patients.

Where is the FDA on his plan? It’s not clear. The agency likes some aspects of adaptive trials, even though it has trivial amounts of money to research the technique. Breier sounds hopeful. “The FDA is hearing this conversation and they are stepping up.”

Political Capital

His vision is dramatic, even radical. But it’s not a solitary epiphany. Portions of Breier talk were echoed by other speakers at the Clinical Trials Congress. Other speakers were also searching for ways to simultaneously address the industry’s declining credibility and escalating costs. It’s clear that the media will need extensive pre-education on the topic. 

Whether politicians and the public could get their heads around a soft launch is another matter. Does the pharmaceutical industry currently possess the political capital to coax the U.S. Congress to get behind a more iterative, real-time vision of clinical trials? No.

But Lilly’s ideas are compelling all the same, offering appeal to shareholders and the public. Life science companies could see a faster return on research investments; the public could see a cheaper, faster, and ultimately safer path to find drugs that work—and those that do not.

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