Thursday, March 26, 2009

Why Plan B Still Matters

Politics played a role in the review of Plan B? We’re shocked—shocked I say—to hear it.

That “gambling in Casablanca” moment is courtesy of New York federal court Judge Edward Korman who deemed FDA’s decision to set an age limit and behind-the-counter marketing conditions on Barr Labs (now Teva’s) emergency contraceptive to be “arbitrary and capricious” decision-making.

The March 23 ruling cites “repeated and unreasonable delays, pressure emanating from the White House, and the obvious connection between the confirmation process of two FDA Commissioners and the timing of the FDA’s decisions.” (You can read our coverage of the ruling here; the opinion itself is available here.)

Now, most biopharma companies may be tempted to dismiss the whole Plan B controversy as just a tempest in a teapot: further evidence that anything touching on abortion rights is political dynamite, perhaps, but not relevant to their day to day commercial lives.

We disagree.

In the second issue of The RPM Report, three-and-a-half years ago, we noted the irony of Plan B: despite the fact that Barr Labs’ application for an over-the-counter switch of the emergency contraceptive was making national headlines—and even played a role in the Presidential campaign in 2004—it was at best the third most important commercial issue for Barr at the time.

And even less important commercially for the rest of the biopharma industry.

But, we argued, biopharma companies could ill afford to ignore the controversy over Plan B. The political firestorm over Plan B would have long term consequences for the agency, we argued, as well as an immediate impact on the framework for over-the-counter switches across the board. (You can read that story, “Why Plan B Matters,” here.)

We feel the same way now—this is a case with limited commercial impact but big policy implications. Here are seven ways that the Plan B ruling could affect the entire biopharma sector:

(1) A Wild-Card for the Hamburg Confirmation

On paper, the ruling dovetails nicely with some themes of the incoming Obama Administration, offering another case study for the White House to use to argue that it is committed to science-based public health policy. (See, for example, stem cell research.)

Indeed, it is perfectly possible that the new FDA team—led by Commissioner-designate Margaret Hamburg—would have reopened the Plan B decision of its own volition to make that very point.

But we are betting that the Obama Administration would rather not have this come up in the context of the confirmation process. And biopharma companies—who stressed the urgency of filling the FDA vacancy during the transition—should be wary of any wrinkle that could delay the confirmation.

Plan B was a rallying cry for Democrats nationwide in 2004, but was more specifically associated with the Hillary Clinton campaign in 2008. And if the Obama Administration wanted to make it a rallying point this year, it could have embraced calls to name Susan Wood—the former FDA official who resigned over the handling of the application—as commissioner of the agency.

Regardless of what the new FDA team actually would have done with Plan B, it now has no choice but to revisit the application—and Hamburg is certain to be asked about it in the confirmation process. As the ruling itself notes, Plan B already helped delay the confirmation of the last two commissioners (Lester Crawford and Andy von Eschenbach). It is not out of the question that Plan B will cause another delay this time around.

(2) Reopening Old Wounds Inside FDA

To critics of the agency’s handling of Plan B, Sue Wood is the hero of the story. Now on the faculty at George Washington University, Wood has been an outside advisor to the HHS transition team. So when she was quoted by the Washington Post pointing out that two of the key figures in the review—Steven Galson and Janet Woodcock—still have jobs, that sounded ominous to us.

Galson is now acting Surgeon General, and, as we have written previously, he is considering various options once a new Surgeon General is appointed. Woodcock, of course, is the head of FDA’s drug review center and one of the agency officials considered most vital to a functional review process by most folks in industry.

Woodcock is a career civil servant, and no one we’ve talked to thinks it is likely that she would be pushed out because of Plan B or for any other reason. Still, after a long career at FDA, no one would be surprised if Woodcock decided this was her last transition.

(3) Raising the Bar for Top-Side Involvement in Approval Decisions

Much of the ruling focuses on the degree of top-level involvement in the decision on Plan B, in effect defining a direct, hands-on role by the commissioner (actually, three commissioners: Mark McClellan, Lester Crawford and Andrew Von Eschenbach) as indicating some form of undue political interference in its own right.

That by itself is a potential concern for industry. In this case, the commissioner’s involvement appeared to delay an approval—but what of David Kessler’s hands-on role in shepherding some of the earliest HIV therapies through the agency, in effect inventing accelerated approval in the context of a specific application?

More importantly, the ruling also highlights the unusual level of involvement of the center director (Galson) in many aspects of the review. The ruling stops far short of saying the CDER director can’t weigh in on approval decisions—but it sure seems to suggest that FDA may want to better define when or how the director can get involved.

That could have big implications if it takes some discretion away from the center director. Sponsors upset by a decision rendered at the top (cf. Momenta and generic Lovenox) may applaud; others hoping for a chance to head off a negative outcome may find it harder to engage FDA’s top management without going through a formal appeals process.

(4) The End of “Behind the Counter”?

Plan B’s currently approved OTC application dictates availability solely “behind the counter,” a development that took FDA a big step closer to the long debated idea of a formal “third-class” of drugs, somewhere between prescription only and traditional over-the-counter.

Politically expedient or not, that made it a precedent setting approval.

That precedent, though, may be overturned. The court ruling specifically addresses a petition seeking to have Plan B made available over-the-counter without restriction. The ruling does not change Plan B’s behind the counter status, but directs FDA to re-review the question based on the science (with a strong indication that the judge views the science as supporting unrestricted access).

Coincidentally, the Government Accountability Office released a report on BTC status the same day as the ruling, and let’s just say that GAO is skeptical about the entire idea. (Read our coverage here.)

(5) Discouraging “Creative” Risk Management Ideas

While the court is leaving it to FDA’s discretion to reconsider the question of behind-the-counter status, the order does change one condition of the approval right away: Plan B is to be relabeled for use by those age 17 and up, rather than the current 18 and up restriction.

That overturns a last-minute change to the proposed label for the OTC version of the drug that the court attributes to former Commissioner von Eschenbach.

He “decided that 18, rather than age 17, is the ‘more appropriate cutoff point’ for OTC use of Plan B because of ‘well-established state and private-sector infrastructures [which] restrict certain products to consumers 18 and older,’” the judge wrote.

That, in the judge’s view, was entirely unsupported by FDA’s administrative record.

It does, however, seem logical: 18 is a well-defined milestone defining the boundary between teenager and adult. That rationale reminds us, at least, of some of the types of suppositions the agency is starting to make more routinely in negotiating risk management plans with sponsors. (Now formalized as Risk Evaluation & Mitigation Strategies authorized by statute.)

At its heart, the risk management process involves additional controls in the commercial setting intended to align better with real world practices. The logic of the Plan B ruling suggests that FDA may need more than common sense to justify a restriction on access that isn’t supported in the clinical database.

(6) Less Predictability in the Advisory Committee Process

We’ve written lots and lots about the ever evolving role of advisory committees in the review process—and the loss of any measure of predictability for sponsors facing a make-or-break event for their products. (Latest update: Sid Wolfe calling on FDA reviewers in the audience to offer an opinion.)

The Plan B ruling highlights the advisory committee process for two reasons. First, the court puts great weight on the fact that the advisory committee reviewing the switch voted overwhelmingly in favor of approval—but FDA ended up sending a “not approvable” letter. The court notes that FDA is not bound by advisory committee rulings, but cites a Government Accountability Office review of Plan B showing that the agency never previously overruled an OTC switch recommendation.

Any sponsor to get a positive committee review and then a rejection from FDA may think that’s good news, but we don’t see it that way. First, as we’ll argue below, no one we’ve talked to thinks a sponsor would win a case against FDA solely on those grounds. More importantly, if FDA is (or perceives itself to be) bound by advisory committee rulings, the agency will be much more conservative in its approach to those meetings, and is probably unlikely to even ask approvability questions if it is concerned about a “wrong” answer.

The ruling also touches on a more current issue about staffing committees, concluding that FDA’s leadership tried to stack the committee with people who would vote against the application. The court found that “the Office of the Commissioner appointed members to the advisory committee not for their expertise, but to achieve what the Office of the Commissioner called a ‘balance of opinion’ on the panel.” The ruling then notes that CDER officials say that is contrary to standard practice: “CDER is ‘not . . . looking for people who have an opinion coming in. That’s exactly what we don’t want. We want people who can look at what’s before them and render an assessment and recommendation on the basis of that.”

That sentiment now goes by the name “intellectual conflict of interest,” and if the recent advisory committee review of prasugrel is any indication, FDA still has some work to do on that policy. (Look for more coverage of that point soon in The RPM Report.)

(7) A Chilling Effect on Pre-NDA Commitments

Last but not least, the ruling could affect FDA’s communication about approvability issues in the pre-NDA setting.

The judge cites FDA’s pre-NDA discussions with Barr about its “actual use” study plans for Plan B as evidence that its subsequent concern about use in adolescent girls was a fig-leaf for political issues. As with the advisory committee vote, the ruling stops well short of declaring that the agency’s pre-NDA discussions should be treated as binding.

Still, some sponsors may read the case as a reason to rethink the conventional wisdom that suing FDA is a waste of time and money at best—and counterproductive at worst.

Food and drug lawyers we spoke with are unanimous in saying that there is no reason to change the conventional wisdom. In their view, Plan B is an outlier, a rare circumstance where suing the agency can (and did) work. And, they note, Barr didn’t file the suit—women’s health advocates did.

However, even if FDA doesn’t face a wave of lawsuits from sponsors asserting that, for example, the new diabetes endpoints are arbitrary and capricious, the ruling could cause the agency to consider new policies about pre-NDA communications.

That raises at least the potential that advice to sponsors may be less valuable because the agency will be more careful about avoiding any implication that any given data set will justify approval without further review.

For all those reasons, biopharma companies will need to keep their eye on the fallout of Plan B. The Obama Administration may be only too happy to play down the ruling and let the controversy over this application die.

But the Plan B controversy illustrates one other thing: you can’t keep politics out of the FDA. Even with a court order.

1 comment:

Anonymous said...

What about "Plan C" where FDA appeals the whacky judge's decision and wins and then makes all this nonsense moot?