Transparency in Action: FDA Comments on Pirfenidone

It's no secret: FDA review managers would like to make "complete response" letters public.

We've heard that directly from them, and now the idea is moving forward as one of a number of proposals from the agency's Transparency Task Force.

This idea, to put it mildly, provokes mixed feelings in industry. "Mixed" in the sense that sponsors love the idea of seeing their competitors' complete response letters, but hate the idea of having their own made public.

But a recent presentation by FDA officials during the American Thoracic Society's annual conference has us wondering what the fuss is all about.

As reported by The Pink Sheet (relying on a transcript by one of the Wall Street analyst firm, ThinkEquity, who attended the briefing), medical officer Banu Karimi-Shah discussed the recent complete response letter for Intermune's IPF therapy pirfenidone, and outlined the agency's position that the existing dataset does not meet the statutory definition of "substantial evidence," and therefore another clinical trial is required. Karimi-Shah also discussed issues around the adequacy of forced vital capacity as a surrogate endpoint, and the relevance (or lack thereof) of Japanese clinical data with a different formulation of pirfenidone.

FDA rejected the application May 4, over-ruling an FDA advisory committee that voted in favor of approval--though the committee had significant misgivings about the sufficiency of the data as a basis for approval.

This is not be the first time an FDA official has commented on a non-approval decision during a public forum, but the extensive discussion of FDA's issues with the application can hardly be described as routine. So we asked the agency whether the remarks were cleared by top FDA officials or posed any concerns regarding the appropriateness of discussing the elements of a Complete Response.

Here is what the agency told us, by email:

"The information presented by Dr. Karimi-Shah was presented and discussed at the Pulmonary-Allergy Drugs Advisory Committee meeting on March 9, 2010, so her presentation was already in the public domain. Intermune disclosed in a press statement on May 4, 2010, that the FDA issued a CR letter and the FDA requested an additional clinical trial to support the efficacy of pirfenidone, so this information was also in the public domain."

See? There is really no reason to argue about making CR letters public after all. Right?

Okay, our tongue is firmly in our cheek on that. We'll have much more on the reaction to the transparency proposals in an upcoming issue of The RPM Report.

Nature Notes: IVB Podcast Emerges From Hibernation

Please imagine the hushed and dulcet intonation of Sir David Attenborough as we describe to you the reawakening of The IN VIVO Blog Podcast ...

Done imagining? Great. Now kick back and listen to Mike McCaughan and Ramsey Baghdadi do that thing they do where they promise to only rattle on for three minutes but then lose track of time and you've missed lunch. This week's topics? Where there's smoke, there's fire: FDA and Tobacco, Health care reform, and rumor-of-the-week.

While you're at it check out this piece from The RPM Report (The Threat of Reconciliation: Remembering the Part D Vote) and this here blog post on FDA/Tobacco. Not an RPM subscriber? Click here for a 30-day trial sub.

Oh and come back tomorrow for another podcast (when it rains, it pours) from Roger Longman and Ellen Licking.

For now, just click the button below to get started. And don't forget, you can access the podcast via iTunes also.

Listen for the Threat of the Medicare Rebate

Here we are shamelessly tooting our horn for calling the politics and action around pharmaceuticals and Part D correctly in 2007 and blowing a clarion call warning for 2008.

Tooting The RPM Report horn: In January a year ago, price negotiating and eviscerating the Medicare Advantage section of Part D were watched widely as two of the early objectives for the health leadership in the new Democratic Congress.

In the thick of the media obsession with those stories, The RPM Report pointed out how unlikely Congress would be to deliver on those goals in 2007 and why. (See here, and here and here, for clear foresight in retrospect).

Call to alert for 2008: This year, some in the media (for example, an interesting wrap-up piece in the Wall Street Journal January 23) are expecting a high-profile dangerous year for pharma.

Elections are always tough years for pharma in the news, but this one does not look to us like a year for major legislative initiatives against the drug industry.

Even the prospect of Democratic sweep in November may not be as threatening to Big Pharma as the Journal story suggests. The Democratic front-runners certainly do support action on pharma pricing that industry opposes--but their overall message is more nuanced and makes health care reform sound much less threatening to industry than it did 15 years ago. (You can read more here.)

There is one new threat, however, in a proposal that is generally beneath the radar for most observers: rebates to the government on Medicare Part D drug purchasers (see here).

We understand that rebates to Medicare sound pretty boring, wonky and not nearly as worthy of a headline as government price negotiation, but rebates could add up to big dollars from pharma. And the technical fix is just the type of tweaking to Part D that draws a real shiver from pharma execs.

The movement on Capitol Hill is just beginning for this way to recapture some of the alleged windfall that pharma reaped by moving Medicaid rebated drugs to Medicare. Listen for the distant horn.

The R&D Productivity Crisis: Is There a Bright Side?

Lots of interesting responses to our post on the historically bad year for new drug approvals this year.

One top R&D exec at a big pharma company focused on the last line: “Something needs to change.”

“It does and it is. If we can steer clear of major disruptions I am convinced that we can turn this round. A lot of change needs to happen, but directed at improving the process of choosing targets, getting them into man and to proof-of-concept quickly then streamlining a clumsy development engine.”

Another reader in a Big Pharma R&D organization writes somewhat less optimistically:

“I am sure everyone in the industry is thinking of ways to ‘innovate’ out of this situation and I believe the next year or two is going to be interesting for us all.”

And then there is this pragmatic response from the VC side:

“Depressing but very interesting. This shows why venture capitalists should leave it to the pharmas to try to get drugs approved!”

Speaking of depressing, we also received congratulations from a colleague at another publication for managing to work in a Philadelphia sports reference in a post about NME approval statistics. The depressing part is that it has been 25 years since a major Philly sports team won a championship. Yikes.

There is lot’s more to say about the state of R&D productivity. We have taken a deeper dive into the numbers on TheRPMReport.com, and coupled it with some of the observations of top industry executives at The RPM Report's FDA/CMS Summit.

There is one surprise: as bad as the past several years have been by all conventional measures of R&D output, there is a glimmer of hope. The optimistic view, that we are on the brink of an unprecedented flow of innovative new products—just might be right. (You do have to be a subscriber to The RPM Report to read our complete analysis, or sign up for a 30-day trial to get a taste of what you are missing.)

Please Note: our initial count of drug approvals in the IN VIVO Blog was off by one. It turns out there were 17 new molecular entity approvals, not 16—Fresenius Kabi’s hypovolemia agent Voluven (hydroxyethyl starch) was approved December 27.

Voluven was approved under the 505(b)(2) mechanism as equivalent to other blood volume enhancers, so it definitely does not add to our benchmark statistics (innovative commercial therapies, or ICTs). The extra NME also doesn’t change anything else in our analysis: 17 NMEs is still the lowest total since 1983, as is 19 novel molecules (NMEs plus novel biologics).

Voluven is nevertheless an interesting approval: it is the latest example of the emerging follow-on biologics pathway at FDA.

What’s that? You think there is no such pathway? Not so. Congress has yet to enact a legislative pathway for follow-on versions of biologics regulated under the Public Health Service Act. But for biologics that happen to be regulated under the FD&C Act (like human growth hormone, insulin, insulin-like growth factor, etc. etc.) follow-on approvals keep trickling out of the agency. Look for more on that topic as well, coming soon in The RPM Report.

Venturing to Washington II: Fleecing the Drug Industry

The primary concern of Day 1 of the FDA/CMS Summit was just how bad for the industry are the unofficial tollgates of a more safety-conscious FDA and the official post-approval burdens imposed by the FDA Amendments Act.

Day 2 focused on a perhaps more inchoate fear – the chance that payors of all stripes will take the savings they need out of the hide of the drug industry.

And they will need them. Amgen VP of Global Coverage and Reimbursement Josh Ofman noted the variety of ways drugs cut overall health costs – but ultimately acknowledged, as did a variety of other speakers, that cost-containment was going to hit drugs hard – either, says Ofman, through controlling market access, restricting coverage (e.g., through formulary controls), or by imposing conditional coverage.

Most speakers did not expect the industry nightmare of a single-payor to soon take flesh. And the popularity of unfettered drug choice makes dispensing restrictions political and economic non-starters. But without them, the easiest (and most politically popular) target for cutting costs, separately noted Eli Lilly’s top politico Alex Azar and Rob Seidman, the influential former pharmacy chief at Wellpoint, is the biopharma industry—through price reductions and rebates (which fatten PBM profits as much as they cut drug expenses). Drugs covered by Part D—where consumer choice is most obvious (“what do you mean I can’t have Lipitor?” the consumer bellows at the pharmacist)—will likely face the brunt of the pricing assault.

Unfair? Absolutely. As much BS as drug companies hand out about their R&D spend, the fact is they can’t invest in new medicines if they can’t charge enough for the ones they get to market. Investors, for one, won’t allow it. Rob Seidman somewhat cynically commented that if the drug companies can’t create new products for less than $1 billion, they “need to build a better mousetrap.”

So—some mousetrap suggestions. First, there are ways of cutting that cost. Lilly’s Chorus division has shown it can get products to proof-of-concept much quicker than traditional development programs, giving their late-stage clinical colleagues a much broader choice of likely programs to push forward (and their business development colleagues a slew of out-licensing candidates that would otherwise have been dust-collectors on lab shelves).

Second, former Pfizer exec Stephen Williams, now with a new firm he founded called Decisionability, offered an interesting solution to the rising reimbursement risks – securitizing them in much the same way private equity firms and royalty buyers have learned to securitize drug-development programs. Instead of packaging development-stage products into tradeable securities (e.g., Morgan Stanley’s Pharmaceutical Royalty Monetization Assets—click here for more on just how clever the financial community can be), theoretically one could bundle approved products into packages that could cut a sponsor’s risk of reimbursement problems and permit investors to share in the upside of a positive outcome.

But drug companies also need to figure out ways of cutting reimbursement risk without turning to Wall Street. And one very practical solution is to start exploring how to create at least two formulations, one Part D and one Part B, for a molecule entering development (it’s a point we’ve mentioned before—here for example). That means exploring how a small-molecule headed for Part D might be useful in an IV infusion…and doing so at the earliest stages of planning for proof-of-concept. Take those biotechs, for example, developing small-molecule therapies for cancer or as replacements for niche drugs in orphan diseases, like lysosomal storage disorders: oral is convenient, sure. But IV can have both therapeutic and reimbursement advantages, too.

It’s reimbursement-oriented portfolio management – and it’s why R&D executives need to be au courant on the challenges their commercial colleagues face with payors (and why the marketing guys should focus on more than just market size when they kibbitz on drug development issues).

Final suggestion: there were roughly 200 attendees at the FDA/CMS Summit. More than half were the drug companies’ policy mavens. It’s clear, at least to this blogger, that what was once inside-the-beltway wonk material is now central to financial and drug-development strategy. If senior marketing, finance and R&D execs are leaving this stuff to their Washington groups, they’re leaving themselves wide open to the competitors who aren’t.

The Cost of FDA's Credibility Gap

In previous posts, I have talked about the rising challenges facing the pharmaceutical and biotech industries stemming from FDA's credibility gap. In fact, I think FDA's credibility gap is one of the most pressing business problems for biopharma companies right now and for the foreseeable future.

I want to point you to a story I just wrote, hot off the Internet's virtual presses. The story, "Avandia and the Commercial Impact of FDA's Credibility Gap" can be found on our new website http://rpmreport.com/. Just register for the free trial, and you can read that, and many other stories we've written for our September issue.

Some of the takeaways from the story are:

1) FDA's credibility is one of the top commercial challenges facing biopharma decision makers.

2) Business leaders are re-thinking their drug development programs as a result of the current environment.

3) The FDA advisory committee on Avandia did more to hurt than help FDA's credibility crisis.

4) FDA is grappling with how to manage incoming information faster and more effectively.

Registration is easy, so go take a look. I'd love to hear thoughts from the investment community about this issue. Also, tell us what you think of the http://rpmreport.com website.

Drug Safety...or Food Safety...or Tobacco Safety...or Pet Food Safety...or Dietary Supplement Safety?

So which is most important to you? Well, if you're in charge of FDA, they all are. That came through loud and clear during a health care reporters breakfast with commissioner Andrew von Eschenbach organized by the folks at Health Affairs.

But fortunately for us here at the IN VIVO Blog, we only have to worry about drugs and biologics. With Congress taking off for their August recess, it looks like the Prescription Drug User Fee Act reauthorization as part of the much grander FDARA drug bill will have to wait until September to get passed.

So wait, doesn't that mean droves of FDA employees will be out of a job come September 1st because there will be no money to pay them (FDA gets half of its drug review budget from user fees)? Not so much. Von Eschenbach said the agency has already dipped into "carry-over" funds to ensure the agency will run smoothly while they wait for lawmakers to act. He expects/hopes the bill will pass in the first few days when the House and Senate come back from recess. Von Eschenbach emphasized he was working very closely with specific players in Congress to make sure that happens. The "carry-over" money, which seems to have magically appeared, is enough to last a couple of months before FDA would have to send out lay-off notices.

The RPM Report will be hosting a webinar on August 14 in partnership with the law firm Ropes & Gray to explain the commercial impact of the new drug safety rules for pharma and biotech companies. This will be the first in a series of audioconferences on the pending drug safety reforms.

The RPM Report has fancy new e-digs

Our colleagues from The RPM Report (and fellow bloggers here at The IN VIVO Blog) have a beautiful new web site over at http://therpmreport.com/, which we wholeheartedly encourage you to visit for the best analysis of biopharma regulation/policy/market access on these here internets.