‘Conservative’ FDA, Frets Ruffolo
July 23, 2007
Sitting there in Arlington, Virginia, at the ExL Pharma meeting on clinical trial design, we had an unexpected humanitarian pang. Was it cruel to put Robert Ruffolo, Wyeth’s president of research and development, on the program?
Yes, Ruffolo has been making the rounds of the conference circuit for years. But could Wyeth’s 21st century story be unsettling for companies that are mentally stuck in the 1980s, doing clinical trials the old way? We can only guess.
For starters, Ruffolo’s delivery was darkly humorous. He acerbically expressed indignation at the industry’s predicament. “Every time I hear a Congressman or -woman smack around the FDA, I shudder,” says Ruffolo. “Drugs are no longer approved by the FDA. They have to be approved by Congress.” Don’t get him started on black boxes that, he says, by sheer ubiquity have lost their power to warn.
Reviewing The Record
In perhaps 30 minutes, Ruffolo described the reorganization of the company’s discovery, preclinical and clinical operations. It was impressive. The Wyeth reorganization isn’t new. But Ruffolo offered more details about sustained, ongoing gains in clinical productivity across the enterprise. All of the progress has been independently audited because individual employee compensation (and Wyeth’s company-wide financial performance) is linked to the upheaval.
Ruffolo described both what Wyeth wanted to do and the actual results. “All parts of the clinical development process have been ripped apart and put back together again.” Ruffolo said. “We have made changes to create a new paradigm for clinical development.”
The effort was split into 70-some so-called “breakthrough projects.” These are ambitious, difficult and gnarly transformations of antiquated processes and technologies. DHL handles all the shipping. Accenture took over data management. All trials, this year, use some form of electronic data capture (with no details provided). Missing a patient recruitment goal by a single patient might mean missing your bonus. The company is setting hard numerical targets and raising them over time.
For a few years now, Wyeth has hit its goal of delivering two investigational new drug (IND) applications to the FDA. To do that, Wyeth has raised so many other benchmarks, cruised through so many other milestones, that we’re not aware of another company in the industry that can match its record.
One early insight. The company is walking away from sites that find a patient or two, no matter how eminent the physician who found those patients. It’s supporting regional centers of excellence in trials instead. After studying where the patients can be enrolled in quantity, Wyeth is aggressively moving trials to Latin America and Asia. “In certain parts of Asia, I’ve got 10 times more patients than employees,” noted Ruffolo. “You can see where I am going to move resources. I have more employees in England than patients.”
Wyeth has raised discovery productivity by 500 percent, preclinical productivity by 600 percent, case report forms (CRFs) processed by 300 percent. The company is enrolling 100 percent, as in all of its planned patients, vs. just 60 percent a year earlier.
As a digression, a mere aside, Ruffolo said a few words about adaptive trials, the putative theme of the conference. He encouraged those in the audience to use the approach. It’s clear that Wyeth sees the adaptive trial as a vital strategic tool, something that will be facilitated by (and contribute to) its reorganization. We’ll have an additional article on what Wyeth and other companies presented on adaptive trials at the conference.
Beyond its own orbit, however, Ruffolo said the current political climate is worsening in ways that have ramifications for the industry. Specifically, he says, an “obsession” with drug safety is masking the benefits of many drugs and making long-term industry productivity trends even worse. He predicts the number of new medical entities approved by the FDA will hit a new low in 2007.
There’s no escaping the difficulty of the FDA’s position, Ruffolo suggests, squeezed between (to our manner of thinking, not his) posses of angry medical school professors and electrified department store mannequins that have somehow been programmed to read the news on TV.
But Ruffolo has another grievance with the FDA. A big one. “You’ll hear me complain a great deal about regulators,” Ruffolo says. “They are in a terrible situation right now. They are in a no-win situation. Guess who pays the price. We do. And patients do.”
Ruffolo says FDA is rejecting drugs by looking too zealously at safety, and not balancing the benefits of a compound with its risks. “They are more conservative now than in the past,” says Ruffolo. “Regulators deny they’re more conservative than in the past. But it’s getting worse after Avandia. I’m losing sleep on this.”
The Political Climate
At FDA advisory committees, he says, there is a shortage of real expertise and spine. He thinks the political and media climates have spooked the agency and its advisory committee members into considering only safety—and ignoring benefit. “The environment has basically prevented regulators from using their judgment,” says Ruffolo. “I think this is dangerous. The focus is on safety alone.”
As an example, Ruffolo described a recent experience at Wyeth with an unidentified drug. One statistical endpoint (out of four) was missed by a fraction of a hair. In their totality, all of the numbers trended in the right direction, with sufficient statistical power. But the FDA rejected the drug. Wyeth was forced to repeat a trial. In the pre-Vioxx/Ketek/Avandia era, Ruffolo suggested, that drug would have been approved.
A Trial, Repeated
Continued Ruffolo: “We repeated the study. We hit the four endpoints. I wasted somewhere between $10-100 million to repeat that study because a regulatory agency wouldn’t use common judgment. This is a very large amount of money that, in my opinion, was wasted by a regulator in this environment. That money could have been used on new drugs or additional drugs. That’s what happens in a conservative regulatory environment.”
Ruffolo went on to reflect on the challenges of managing scientists. Of the nine top pharmas in the industry, he said, six had dispatched high-level emissaries to discuss the current transformation at Wyeth. (We couldn’t help wondering which large competitors hadn’t bothered to see him.)
A Plan For The Future
And his rivals, Ruffolo says, often express disbelief at the change that Wyeth has imposed on its scientific staff. Said Ruffolo: “I am often shocked by what I hear from our counterparts: ‘Our scientists would never agree to that.’ It’s not a democracy. You want democracy? Go to Russia.” The more profound issue, it would seem, is whether rigid scientific mindsets will be a barrier to further productivity gains at drug companies less interested in top-to-bottom transformation than Wyeth.
Editor’s note: ClinPage wrote about Wyeth a while back, in a story discussing data management and other topics.d9A2t49mkex