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.

An Orphaned Article Gets Reprinted

Awards season feels like it’s winding down. The Oscars are still to come, but there’s already been Time’s Person of the Year, the Golden Globes – you even helped us choose a Deal of the Year. But recent events have made us look back on 2008 in a new light, and now it’s time to present the award for Least Read Article in “The Pink Sheet.” Last year’s, um – we’ll just call it an honor – goes to “Orphan Drugs Are Rare Area Of Agreement In Off-Label Debate.”

The article is sidebar to our coverage last year of FDA’s development of guidance on “good reprint practices” that would set goalposts for firms that wanted to distribute reprints of journal articles about their drugs that discuss uses not approved by the agency. The rest of our coverage about the draft is here, here, and here. FDA just finalized the guidance, and you can find coverage of that here and here. And don’t miss our related coverage of Lilly’s $1.4 billion settlement for off-label promotion violations (here and here).

So, yes, we write a lot about reprint issues, and maybe that’s the reason this particular article didn’t get the attention it deserved, or perhaps there was just a glitch in our page view accounting. Whatever the cause, we thought we’d give people another chance to read the piece. Because, as the Lilly settlement shows, issues that seem small at the time can become quite significant. Here’s hoping that our least read article of 2009 doesn’t become your billion-dollar problem in 2010.

Without further ado, here in its entirety is the Pink Sheet’s least read article of 2008. Both of you who’ve already read it can skip to the next post.

Orphan Drugs Are Rare Area Of Agreement In Off-Label Debate
While promotion of off-label drug use is a flashpoint issue, off-label drug use for rare or orphan diseases is not. Regardless of where people come down on FDA's draft guidance, they generally supported patients with limited access to approved drugs. For example, in an April 17 article in the New England Journal of Medicine which is generally critical of off-label promotion, Aaron Kesselheim and Jerry Avorn state that "In certain patient groups, such as children and patients with rare diseases, off-label use may reflect the standard of care."

Indeed, the National Organization of Rare Disorders -- which has often tangled with the pharmaceutical industry on issues related to patent extensions and consumer advertising -- in this case joins many drug firms in advocating for the draft guidance. The association did not submit comments to FDA, but, "I would ask Congress to keep in mind patients with rare diseases," Diane Dorman, NORD's VP-public policy, said at an April 16 media briefing sponsored by industry supporters of the guidance.

image from flickr user '... Tim' used under a creative commons license

BIO Has TiVo and It Knows How to Use It

Via our colleagues at The Pink Sheet, we learn a little about the Biotech Industry Organization's television viewing habits.

Wedged in between the Seinfeld re-runs and America's Next Top Model on BIO's TiVo is the CBS drama "Eleventh Hour" (which airs, oddly, at 10p on Thursdays). Why's BIO so interested? Well apparently the show involves a government scientist who tries to protect people from deadly experiments and the sketchier elements of science. The show's web site describes it thusly:

ELEVENTH HOUR from acclaimed producer Jerry Bruckheimer follows Dr. Jacob Hood, a brilliant biophysicist and special science advisor to the government, as he investigates scientific crises and oddities. His jurisdiction is absolute and Hood is dogged in his pursuit of those who would abuse and misuse scientific discoveries and breakthroughs for their own gain. His passion and crusade is to protect the substance of science from those with nefarious motives. He is called in at the eleventh hour and he represents the last line of defense.

Nefarious motives! Absolute jurisdiction! Dogged pursuit! Brilliant biophysicists! So far, so harmless sci-fi fun, right? Well, sure, but "At first we were concerned how the show might portray the industry," BIO VP of communications (and keeper of the TiVo remote) Jeff Joseph tells Pink Sheet's Brenda Sandburg. "We wanted to use it as an opportunity to educate people."

And thus BIO's own www.eleventhhourfacts.com was born. So far BIO has used the site--which is advertised via Google's AdWords program--to inform viewers about cloning technology and heart attacks. ("Eleventh Hour" premiered on October 9 with an episode about a father trying to clone his dead son and followed up last week with eleven year old heart-attack victims.)

We understand BIO's urge to educate television audiences and think the association is on the right track using what could be a popular program to inform interested viewers about its members and their science. But we would argue that BIO has bigger fish to fry than "Eleventh Hour." Come on people, have you not seen NBC's "Heroes"? There's more gene-altering pseudoscientific mumbojumbo in five minutes of that program than in entire months of programming on the SciFi Network. (Full disclosure: Heroes is, despite the unintentional hilarity, a personal favorite, though we have never seen Eleventh Hour.)

But tonight BIO is upping the ante and Live Blogging (!) the third episode of "Eleventh Hour"--which promises some delicious facts about food-related paralysis.

Enjoy your dinner!

image from flickr user LynGi used under a creative commons license

What to Expect for Drugs in Pregnancy

What To Expect When You’re Expecting has become bedside reading for many pregnant women. For curious regulatory professionals, there’s no book yet titled “What To Expect When You’re Expecting To Submit An Application For FDA Approval,” but FDA has just published a proposed rule that might fit well under that title. The proposed rule would specify how information about pregnancy and lactation should appear in product labeling.

The reg would scrap FDA’s current five-sizes-fit-all category system. Drugs wouldn’t be rated X anymore, but they couldn’t score an A either; FDA feels the categories oversimplified many risk issues, especially the question of whether the information was based on human or animal studies. In place of the categories, FDA would call for more narrative description to put a product’s potential side effects in the context of the background risks of birth defects and the dangers of not treating a condition.

The new labeling could lead to wider prescribing during pregnancy. The agency is aware of that and is simultaneously asking drug sponsors to provide better data collection about products. It’s another sign of how FDA wants to use a better post-marketing system to allow access to even drugs with outstanding safety issues.

That’s the positive side of the increased regulatory and safety burdens that has the drug industry tied up in fits. (Subscribers to “The Pink Sheet” can read about how the proposed reg offers a template for other risk communications and how FDA hopes it will encourage the use of registries. “The Pink Sheet” also has the scoop on what parts of the proposal FDA seems most amenable to changing.)

One part of the reg that caught our attention was the prominence given to asthma. In a portion of the document discussing the importance of treating chronic diseases during pregnancy, asthma has its own section. “Other chronic conditions” -- including diabetes, hypertension and epilepsy -- are all lumped together in the next section.

Also, the first example of a mock label showing what the new format would look like uses a made-up asthma drug, Alphathon. “Prescribers should consider alternative treatments,” the fictional example states. In all, asthma is mentioned 15 times in the proposed rule, compared to five times for diabetes.

Whether this leads to a heavier dose of relabeling for asthma drugs remains to be seen, but sponsors should be on notice: This regulatory action is now more than just a twinkle in the agency’s eye.

– M. Nielsen Hobbs