Sitting there at the 2007 Regulatory Affairs Professional Society (RAPS) conference in Boston, we had a premonition. It turned out to be Bob Dylan, circa 1965: “Something is happening here but you don’t know what it is.”

We couldn’t tell if Sandra Kweder was trying to relieve some of the pharmaceutical industry’s fears about a newly harsh regulatory landscape. Or was she firing a warning shot across the industry’s bow? Could it be both? Kweder, for the record, is deputy director of the Office of New Drugs in FDA’s CDER branch. 

“Regulation has to keep pace with science,” Kweder said. “It’s usually science that is leading the way.” And science, she went on to say, is impermanent, in flux. She said that that inevitably leads to real pain inside the industry and inside FDA, as new evidence or techniques emerge about medicine, and even for consumers taking therapies that no longer work.

Learning From Vioxx

One interpretation of her remarks is that the recent drug safety controversies have been, in effect, no one’s fault but the result of new data, new instruments, new insights that always displace old scientific data, old instruments, old insights.

At the same time, Kweder was blunt. She mused about direct-to-consumer ads for drugs, seeming to regret the confusion that such ads may engender after many experts in the industry and the FDA work diligently on crafting calibrated label language that is correct.

Taking questions from the audience, Kweder rejected the notion that the agency is suddenly tougher in its review of new drug applications in the post-Vioxx era. She believes new federal user fee legislation, passed by Congress just a week ago, may prevent another Vioxx. But she also deftly put a bit of distance between her own troops at FDA and Vioxx’s manufacturer.

Kweder said: “The problem with Vioxx that is dealt with in the [user fee] legislation is not that we didn’t have the information. Once we had the information, it took a year to get it in the label and out to the public. Vioxx absolutely was probably the biggest example of a noncardiac drug having safety issues in cardiovascular outcomes. If we don’t learn from that, shame on us.”

Top to Bottom

Most of Kweder’s presentation was devoted to describing a re-engineering of the agency’s internal regulatory review process. This new review approach will be tested on one pilot application at each of the divisions within CDER during 2008.

Each division will be able to pick the application, and presumably will do so quickly, even in 2007, so that lessons learned can be harvested well before the end of 2008. The story of how the FDA developed that process is a man-bites-dog tale. As she described the process, CDER took a page from industry’s book, hiring a consultant and looking coldly at everything and everyone involved in its process.

The agency knew it needed help, Kweder says. “We had three divisions that were working on pain products—what sense does that make? It was just that we had grown,” she noted. “The work load we had with that was unbalanced. We had serious imbalances of work. We had some divisions that were drowning. We had others that were looking for things to do. That didn’t seem right. It’s bad for morale. And it’s bad business practice.”

To redesign the approval process, the consulting firm first had to figure out how the agency processes applications, which (as she graciously allowed) was news inside some quarters of the FDA. In other corners, of course, the best practices of an existing group   will be rolled out for everyone at the agency.

Outside Expertise

The consultancy (which was never identified) discovered a multiplicity of paths by which the FDA completed its statutory charter. Some of those paths were less circuitous than others.

One universal theme, however, was that intra-agency dialogue was not as fluid or productive as the agency would like. Unexpected lurches in the FDA’s internal conversation, Kweder said, can produce delays for the sponsor community. Her examples included a medical reviewer feeling the FDA process was nearly done, without knowing the field inspectors were awaiting instructions.

Balancing Discipline and Dissent

Or the agency’s lead pharmacologist might feel an application was complete until an FDA chemist raised a concern about an excipient. At such moments, the FDA review process stops. Cold. And the agency scrambles to look at the data more closely, or request new data, costing the sponsor time. Says Kweder: “These are real life situations. Many of you have had the situation in dealing with the agency. It seems like there is nothing coordinated.”

At the end of the consulting exercise, she reports, the FDA had a vast and hideously complex process chart. That chart was judged too frightening for the delicate eyes at RAPS; a simplified schematic was shown instead.

But the resulting process, a collection of best practices at CDER, has gotten good reviews within the agency. Some of the basic issues were tackled: who participates in a meeting? Who’s in charge of a meeting? “Application review will never be the same because of what this group did,” Kweder said.

Dictatorship vs. Democracy

It’s clear cross-disciplinary communication—even disagreement—will be encouraged. Some readers will be groaning at this point, fearing the prospect of additional FDA debate. (It’s like hearing of some new faction inside Iraq.) But Kweder clearly didn’t want to leave the impression that robust dialogue will mean chaos.

Indeed, she stressed the lead reviewer was still in charge. “Many of our reviewers thought that the goal of a review was to have consensus at the end of the day,” Kweder said ruefully. Not a chance. “At the end of the day, someone has to make a decision. Our regulatory structure demands that. Consensus is wonderful. We often have it. That doesn’t mean unanimity.” Too often, she says, a lead reviewer may allow a statistician or other domain expert to hold forth at length, commandeering the conversation.

”In the Data”

The law, the regs and the desired consistency from one review to the next require the leader of the effort to render a verdict. That philosophy has been enshrined in the agency’s new process. Critics of the industry could well wonder if some dissent will be squelched. Here’s how Kweder described her philosophy: “We need to hear from the reviewer who’s in the data. That’s where you get the independent thought and the robust scientific discussion. The statistical reviewer is not in the data.”

She has signed approvals herself, and said that her most gnawing fear as a regulator is that a colleague has failed to share a doubt, a concern. Facing someone like the fabled Robert Temple, Kweder said, new FDA staffers may be even more intimidated and unlikely to speak up.

But that is precisely what the agency is asking for. Kweder seems to believe that the fraternal scientific culture at the agency, within the freshly designed process, will encourage dissent but still allow a decision to be rendered. Speaking of reviewing team members, she says: “We’re making people responsible for having those conversations and raising their concerns. You need substantive involvement at every level of the organization.”

Editor’s note: A second part of this story can be found here.

d9A2t49mkex