And far from being caught unawares, said Russ Somma, president of SommaTech, some companies may even be angling for an approvable
letter—rather than withdrawing what they know is a flawed NDA. "It certainly looks better to stockholders," he said. And at
certain large-cap pharmas, he explained, there's an unwritten policy not to yield to any FDA demand, turning the approval
process into a game of Uncle.
The Carrot-and-Stick Approach
Let's not overlook the possibility that FDA is using approvable letters to push pharma to get with the program. Although Jenkins
did not mention it, FDA officials have complained that the quality of recent NDAs has fallen off. "There's probably some truth
to that," said APCO Worldwide's Wayne Pines. "Drugmakers feel enormous pressure to get applications to FDA as fast as possible.
Some are submitting packages that don't have sufficient pivotal data, even at the risk of having FDA reject it and ask for
There are plentiful signs that the frustration pharma feels about FDA is returned by the agency. According to Somma, it's
less the NDAs than the high number of postapproval filings that are clogging the system and causing the approvable letters.
"Companies are not always being up front about their business plan for a new drug," he said. "They come in a month after approval
with a shopping list of changes they want to make rather than building this into the NDA. And FDA has to manage all of this,
too, so the approvable letters are a way to deal with this increasing workload." In fact, the agency's chronically understaffed,
overcommitted condition is a cause for considerable alarm inside FDA and pharma alike.
The agency may be drawing a line in the sand about the quality not only of safety and other data but of its relationship with
pharma. "FDA has been sending a few important messages," said Somma. "It wants industry to sign onto its Quality by Design
and 21st-Century initiatives. But it also wants transparency and honesty. More and more, FDA looks at NDAs and says, 'Is that
all there is? You guys have spent 12 years and a billion dollars to make this drug and this is all the data you have?'"
The heart of the drug-review process is, after all, a power struggle over access to information. "Legally, FDA can demand
to look at every single piece of data," said Somma. "If they trust a company, they won't do that, but if you try to pull the
wool over their eyes with the magic of your technology, say, or simply by hiding data, they're going to give you a hard time"—in
the form of an unapprovable letter.
Ultimately, the message FDA is sending to industry is "work with us, not against us." An agency-funded study in 2005 by Booz
Allen found that the more meetings a firm has with FDA about an NDA, the better its chances of getting its application approved.
And Chris Milne points out that not a single fast-track or orphan drug, which are developed with maximum pharma–FDA teaming
up, has ever been withdrawn from market. Yet for pharma, such close collaboration too often adds time and cost to the process
without increasing the quality of the data. Certain safety signals will materialize only when a drug is on the market and
in wide use—no matter how many Phase III trials are run.
In addition to costs of one kind of another, it may also come down to a question of trust, or the lack thereof. Both Big Pharma
and FDA have, fairly or not, suffered a serious loss in public trust in recent years, and both remain under enormous stress.
Given the current political climate, it's not clear what option FDA has other than to push back against pharma on issues like
safety and transparency. It will be up to each drugmaker to decide how to respond. Yet the fact remains that the fortunes
of Big Pharma and FDA are tied to each other, and rise and fall together.