Last year, we
recounted some of the Post Approval Summit’s outstanding speeches by multiple FDA people, an ex-FDA boss and a dozen thought leaders from Pfizer, Genentech and other companies. We thought it would be hard to top that meeting at the Harvard Medical School. We were wrong.
The conference’s sponsor, technology vendor Outcome, puts on a substantive program, emphasizing science and strategy and forgoing a sales pitch. The 2006 summit featured more A-list luminaries unafraid of the toughest topics facing the industry.
A case in point: Alan Breier, chief medical officer of Eli Lilly. In a bravura performance, he reviewed the industry’s predicament and his thinking about how to fix it.
“Public trust is shaken in medical data,” Breier said. “Our business model is built on medical data, on information. It’s less about the molecule, the pill, the chemical bonds. Any suspicion about the soundness or veracity of the medical data that will guide a medical decision strikes very, very deeply.”
And, he said, the current model for drug development is broken. “Our current model relies a bit too much on trial and error,” he said. “We work in bands, in median data. But what the individual cares about is, is it going to work for me?”
Reviewing the oft-discussed trend lines for research spending (way up) and numbers of new molecular entities (way down), Breier said the entire industry faces a reckoning. “If this does not change, we are all going to be in dire straits,” he says.
“Major changes are needed in the traditional drug development paradigm,” Breier added. “Critical safety information that could lead to a black box warning comes late. It comes after the drug has been on the market a long time.”
The post-approval portion of research should be the pivotal one, he proposed. With a nod to Rodney Dangerfield, he added: “Instead of no respect, it should get the most respect.”
The crux of the matter is that the sample sizes in Phase III are never going to be big enough to give clinicians satisfactory answers. Many people in the industry concede this. The FDA no doubt understands it. There are not enough patients in Phase III. There never will be.
“Patients, payers want real-world data,” Breier says. “How am I going to respond? What happens to me? That’s the important question. I don’t see how we can answer it if we don’t pull Phase IV into drug development. The traditional paradigm is reactive.”
In Breier’s vision of the future, a drug’s label will not be revised once in a blue moon. The label would be dynamically updated continuously as new data became available. “Labeling becomes more iterative across the drug’s life cycle,” he says. “Forget paper. We’re talking about an electronic document that is searchable and source-able in a much more interactive way than we’re talking about today.”
Intensive use of technology is presumed, Breier said. Real time data will be pivotal. “You have learned more in that first month after launch than you would in any other situation,” Breier says. “This got to be an e-data capture world. We can’t afford time delays if we’re sitting on a safety signal. The technology is there to do that. We’re all using e-data capture.”
Without any action from the FDA or Congress, Breier suggested, the industry is making its own transition to more reliance on post-approval data. “There are more post-marketing commitments,” he noted. “There will be a day when we do not launch a molecule without some element of controlled launch.”
Breier didn’t walk through all of the details, no doubt assuming they were familiar to the audience. But under such a paradigm, an approval might be issued with the proviso that not every patient in every last U.S. county could receive the drug. A limited rollout, with serious data collection in Phase IV, would make that stage of the process the precursor to broad commercial release. This would be a bonanza for firms like Outcome, Ninaza, etrials, and other firms providing services and technology in Phase IV.
Yet the industry could also wind up with both the traditional demands of Phase II and III, plus newly extensive studies in Phase IV. Breier sums it up as follows: “If our requirements in Phase II and III go up and, like wearing belts and suspenders, we have post-marketing commitments on top of that, we could have the whole process getting longer and more expensive.”
Guess what? The FDA has no problem with the sort of limited rollouts that Lilly is talking about. The FDA’s Steven Galson, head of the Center for Drug Evaluation and Research (CDER) was also at the podium at the Post-Approval Summit.
Galson said that no law would have to change to have a more gradual product rollout. “There are not any regulatory impediments to implementing many of these ideas,” Galson said. “It can already take place with restrictions to try to get more data before the drug is more widely used. I am extremely supportive of any of these ideas.”
It was fascinating to watch Galson draw the razor line the agency has to walk with a drug like Accutane (isotretinoin). Its latest risk-management program, called iPledge and linking pharmacies and physicians, was just launched in March of this year. Covance manages it.
So far, 22,000 prescribers and 71,700 patients have registered with iPledge, according to the FDA website. As many readers will recall, the acne medicine causes severe birth defects; pregnant women are barred from taking it. It turns out that many dermatologists bitterly resent such restrictions.
Galson was philosophical about the risk-management plan. “It’s uniquely expensive,” he said. “It’s uniquely onerous. I have received tens of thousands of horrible emails about this. I continue to get them every day. We have had a strong negative reaction, mostly from the dermatology community. This is the community that has prescribed the drug to many pregnant women. They are very unhappy.”
The issue, Galson says, is paperwork. Granted, it’s paperwork that prevents horrible birth defects. But to some, it is just another government form. “It’s very clear we can support one or two programs like this,” Galson said, “but if every drug with a risk had a program like this, the health care system would collapse.”
Galson admitted that there are few rigorous algorithms to use in balancing the risks and benefits of controversial products like Accutane: “We sit around and look at the data. We make, many times, a subjective decision about whether the benefit outweighs the risk. We don’t have a specific way of balancing, numerically, the benefit and the risk. I’d like to see us move to a more scientifically rigorous methodology.”
That was part of his pitch for the Critical Path, the FDA wish list of research projects. In his oblique, discrete way, Galson appealed to the audience to think about how to help Congress understand the importance of new assays, new tools, new math, new approaches. Said Galson: “The Critical Path initiative needs support from you and from others outside the agency. We need more funding in these areas.”
Whenever we run quotes like that, we wonder what cynical readers think. Perhaps they whisper that the folks at PhRMA will make an energetic effort to push Congress to fund the Critical Path at about the same time that Nigeria and Ethiopia sweep the Winter Olympics.
The cynics could say the industry is indifferent because a dollar spent on FDA research is a dollar not spent processing a drug application. This is a pathetic state of play. Robust Critical Path funding would send a signal about the industry truly grasping that the public interest and its own are in close alignment.
Indeed, funds for Critical Path would be negligible by Congress’s wasteful standards, equivalent to less than a day of carnage in Iraq. If the industry lobbied for Critical Path funding, it would demonstrate the industry understands that the shortcomings in its own toolbox and the FDA’s are similar. Those shortcomings belong to the research community as a whole.