Drug Safety 2010: Nissen Meets With FDA Leadership as the Avandia Advisory Committee Meeting Looms

The most important single event for FDA’s drug review in 2010 and possibly beyond is coming this summer: the advisory committee re-review of GlaxoSmithKline’s diabetes drug

Since passage of the landmark FDA Amendments Act of 2007, the drug approval climate at FDA has improved steadily. To view The RPM Report’s analysis on the drug approval climate, click here

It appears one potential conclusion that can be drawn is that FDA’s comfort level with the postmarket control and monitoring tools given to them through FDAAA is adding confidence to approval decisions.

But the Avandia re-review could change all that. Whether FDA chooses to pull Avandia from the market, keep the drug on the market, suspend use temporarily or further restrict its use, the agency must ensure that it does one thing: make a credible decision. Any outcome deemed to be unsatisfactory by FDA stakeholders in Congress, and the experts they listen to, puts the improving drug approval momentum in real jeopardy.

Just to recall briefly: In May 2007, a meta-analysis by Cleveland Clinic cardiologist Steve Nissen published in the New England Journal of Medicine found that Avandia (rosiglitazone) was associated with over a 40% increase in heart attack risk. The House Oversight & Government Reform Committee put together a hearing before FDA could respond to the study. In July 2007, FDA convened the Endocrinologic & Metabolic Drugs Advisory Committee and the Drug Safety & Risk Management Advisory Committee to assess Avandia’s future.

The joint committee voted 20-3 that the drug increases cardiac ischemic risk but subsequently voted 22-1 against withdrawal of the TZD. The panel meeting surfaced an “internal disagreement” between the Office of New Drugs and Office of Surveillance & Epidemiology over whether to withdraw rosiglitazone over heart attack risks.

On October 2, 2007, FDA’s Drug Safety Oversight Board voted (8-7) to keep Avandia on the market. The non-public vote was questioned by ranking Senate Finance Committee Republican Charles Grassley (Iowa) due to the lack of transparency. On November 14, 2007, FDA issued a black-box warning for Avandia warning of heart attacks. GSK agreed to conduct a long-term postmarket safety trial of Avandia compared to competitor Takeda’s Actos to confirm a higher CV risk for rosiglitazone; the trial was named TIDE. The TIDE trial is expected to be complete in 2015.

The Senate Finance Committee released a major report on February 22 bringing to light internal emails and memos related to Avandia and heightened CV risks. On February 26, House Agriculture Appropriations Subcommittee Chair Rosa DeLauro (FDA’s chief appropriator) gave a detailed critique of GSK’s RECORD study, which the company maintains supports Avandia’s safety profile.

Now FDA is scheduled to hold another re-review of Avandia, likely July 13-14.

"Congresswoman DeLauro is looking forward to the advisory committee meeting and its findings,” a spokesperson for DeLauro says. “She believes that the TIDE trial is unethical and should be halted immediately, and has urged the FDA before to remove Avandia from the market until a truly independent, science-based advisory panel can evaluate the safety and effectiveness of the drug.”

DeLauro and her staff met with FDA Principal Deputy Commissioner Joshua Sharfstein and Assistant Commissioner for Legislation, and former staffer to Rep. John Dingell, Jeanne Ireland on May 20. The topic? “Drug safety.”

DeLauro isn’t the only one meeting with FDA leadership. Nissen recently met with FDA Commissioner Margaret Hamburg and Sharfstein to make the case that the TIDE trial was unethical and that Avandia needed to be withdrawn.

The major threat to the approval environment and the current FDA review structure is that an outcome on Avandia that is viewed as lacking credibility will energize those who want to split the Center for Drug Evaluation & Research into two separate centers or offices. A split would still be a long-shot, but a possibility nonetheless.

“As far as the FDA’s organization, the Congresswoman believes that serious consideration should be given to creating two independent offices within FDA – one that would be responsible for reviewing drug applications, and another for post-market surveillance,” the DeLauro spokesperson says. “It is something she has been concerned with for awhile, and the Avandia case serves as a reminder of just how important it is to address this situation.”

Here are a few points to consider as the Avandia re-review approaches:

1) How many advisory committee members will be assembled? In July 2007, there were 23 panel members convened for the meeting. That is a large number of committee members, many of whom were given temporary voting status. The makeup of the committee will be equally important in terms of the balance between drug safety specialists and E&M committee panelists (to view the 2007 final roster, click here).

2) Will the full Actos safety data be presented? Our understanding is that FDA asked both GSK and Takeda for every shred of data related to Actos and have had the data for “months.” Whether or not those data are formally presented at the meeting will go to the heart of the credibility question whatever the committee and FDA decide to do with Avandia. The current buzz in Washington is that not all of the Actos data will be presented, but it is still too early to determine whether that will actually be the case in the end.

3) Will Nissen present? At the July 2007 meeting, Nissen did not make a formal presentation of his meta-analysis—the whole reason for the existence of the panel meeting—to the advisory committee. Instead, he sat in a chair along with the rest of the audience. Something similar happened with Sanjay Kaul, a Cardio-Renal Advisory Committee member who was barred from the advisory committee review of Eli Lilly’s anti-clotting drug prasugrel (to read The RPM Report story, click here).

4) Hamburg and Sharfstein have gone to great lengths to brand the Obama Administration’s FDA as a public health agency. The Avandia re-review represents the first major prescription drug safety, public health issue. How will they react? Hamburg has already gone to IoM for ethical and scientific guidance on postmarket studies (to read our analysis in The RPM Report, click here). Probably the best outcome for the drug industry at large would be a risk evaluation and mitigation strategies (REMS) program that controlled the use of Avandia, monitored patients on the drug, and provided FDA with valuable data on its cardiovascular risk profile. That result would validate the use of FDA’s drug safety authorities under FDAAA, hold together FDA’s current regulatory structure and keep the approval momentum going. But is that enough of a public health message for Hamburg and Sharfstein?

5) There are a number of important FDA officials who will be directly affected by the final decision on Avandia--maybe none more than the ones who will make that decision. Hamburg and Sharfstein will bear the brunt of public scrutiny around the decision. Perhaps no one will be under the microscope more than CDER Director Janet Woodcock, who concluded that Avandia should remain on the market in 2007 with stronger warnings. This is a major issue for FDA. Woodcock is held in high regard as a strong leader, effective manager, and there are few individuals at FDA who understand its operations—and runs them as efficiently—as Woodcock. While the FDA drug safety players are the same—Gerald Dal Pan and David Graham—the drug review management is different compared to 2007. In 2007, CDER Office of Drug Evaluation II Director Robert Meyer gave a public refutation of the conclusions drawn by Graham and Dal Pan that Avandia had to be withdrawn. Meyer is no longer at FDA and Curtis Rosebraugh is the current ODE II Director. However, Mary Parks was and remains the Division Director for Metabolic and Endocrine Drug Products. Both Rosebraugh and Parks will be important officials on the Avandia re-review. Lastly, CDER Deputy Director for Clinical Science Bob Temple will play a role in the Avandia decision but it is unclear exactly what kind and how big a role. Temple has presented publicly about FDA’s tough decision-making when it comes to taking a drug off the market.

There is still a lot of time before the advisory committee: much could change and there are sure to be surprises just as there were in 2007. But it would be an understatement to say there is a lot riding on Avandia.

The Next HHS Secretary: All Signs Point to Kansas

So we thought we would be done with this game, but apparently not. Now that Tom Daschle has withdrawn his nomination, the question on everyone’s mind is: Who will replace him?

All signs point to Kansas Governor Kathleen Sebelius. The Governor made a name for herself in her home state as an insurance reformer. She stopped Blue Cross Blue Shield from merging with another out of state company and she refused to accept contributions from insurance companies during her campaign.

She was a key surrogate for President Obama during his campaign and remains close to him. Maybe most importantly, she was already thoroughly vetted for Vice President and was thought by many to be a close second to Joe Biden. As a serving public official, she would bring none of the lobbying concerns that weighed down Daschle’s nomination and eventually torpedoed it.

If Sebelius is the pick, we imagine that Jeanne Lambrew will be named head of the White House Office of Health Reform and Sebelius will take on the more classic role of the HHS Secretary.

But…

If President Obama attempts to remake the pick in the mold of Daschle—a legislative general with knowledge of the issues—here’s our list of potential candidates.

Rosa DeLauro (US Congress): The Connecticut Congresswoman was originally a candidate the first time around, so why not the second? DeLauro currently chairs the agriculture appropriations subcommittee in the House, which among other things oversees FDA's budget. She's no fan of DTC ads, sloppy overseas manufacturing, or anything that looks like overly cosy relationships between industry and regulatory.

DeLauro knows as well as anybody the ins and outs of Congress and where the levers of power are.

And remember that cozy little Super Bowl Party President Obama threw at the White House for a select few members of Congress? Well, DeLauro was invited and attended. We’re just saying…The President may need her as part of the stimulus plan passage/maintenance/implementation but ignore her at your peril.

Ron Wyden (US Senator): Wyden, weirdly, has been one of the forgotten figures of health reform. However, he’s got a bill floating out there and he’s taken a long-term interest in health care. The Health Americans Act, co-sponsored by Utah Senator Robert Bennett, aims to get universal coverage by creating a new private insurance market and uses state-based purchasing pools.

Plus Wyden has served in both the House and Senate, so he knows both worlds well. Not only that, my friends (John McCain reference), but one Emanuel seems to really like his approach. That would be NIH’s Ezekiel Emanuel who is on detail at the Office of Management & Budget. But if one Emanuel likes your thinking, don’t they all?

Donna Shalala (former HHS Secretary): President Clinton had one HHS Secretary for all eight years: Donna Shalala. Is there anyone who knows HHS better? Or the lessons of the failed Clinton health reform plans?

She could step in from Day 1 and hit the ground running while coordinating seamlessly with the White House health care group. In addition, Shalala has spent her post-government life as a university president at the University of Miami.

She appears to garner wide respect from both sides of the aisle. President George W. Bush awarded her the Presidential Medal of Freedom last year. Shalala has also remained very engaged in the health reform debate showing up at reform meetings involving all of the critical stakeholders.

Jay Rockefeller (US Senator): If you can’t get a Kennedy, why not a Rockefeller? (that one goes to one of our blog colleagues). Rockefeller has been intensely engaged and personally moved by the health reform because of family experience. His stake in the Clinton Reform effort is well documented.

Rockefeller would carry the interest, knowledge, experience in the Senate, and gravitas to the position of HHS Secretary. And as Senate Finance Health Subcommittee Chairman, he has the right title.

He has been particularly visible during hearings on Medicare Part D drug prices over the last few years. Before you dismiss this one out of hand, we have it on good sources he considered the Major League Baseball Commissioner job very seriously many years ago because he loves new challenges. We would categorize health care reform and universal coverage as a challenge.

Richard Gephardt (former US Congressman): We think Gephardt would be perfect for the Daschle-like role of legislative general. He served in the House of Representatives from 1977 to 2005 and was both the House Majority Leader and Minority Leader.

In fact, we would think his Daschle-like temperament and experience would make him perfect for the job. Except for one thing: he’s been a consultant to DLA Piper and Goldman Sachs since he left public life. That probably sticks a fork in any chance of Gephardt getting the job even if he wanted it, but you never know. 

Congress Has Lump of Coal for FDA in Funding Bill

Congress finished some important work before leaving town for the holidays, finally enacting new funding legislation for the federal government for fiscal 2008. The bill, signed by President Bush December 26, is critical for the Food & Drug Administration, because it allows the agency to start using the new, higher user fees it was authorized to collect by the drug safety law signed in September.

That means the agency can continue its full-steam ahead approach to implementing the user fee provisions of the FDA Amendments Act—the one piece of the legislation that both FDA and industry share unreserved enthusiasm for.

But the new funding comes with a big hitch: a provision stipulating that FDA cannot transfer any money to its other initial priority in implementing the law: the new Reagan-Udall Foundation, a public-private partnership that is supposed to help FDA develop new scientific tools to enhance its regulatory mission.

That may not sound like much to worry about. The new foundation is broadly supported by industry, which welcomes any opportunity to advance drug development science—but it seems like an afterthought in the context of the big changes in FDA’s regulatory authority over drug safety that are the centerpiece of the new law.

There are, however, very significant implications to the dispute, which could ultimately be critical to determining what role industry will have in the development of a new active surveillance system for pharmaceuticals.

Representative Rosa DeLauro, who chairs the House Agriculture Appropriations Subcommittee that oversees FDA, is concerned that the foundation may be an avenue for the pharmaceutical industry to exert more influence over the agency. She registered her concerns in a letter to FDA November 1.

FDA didn’t help the situation when it selected the board members for the foundation. The agency chose a very distinguished group to oversee the foundation, including former GlaxoSmithKline R&D President Tachi Yamada, who now heads the Gates Foundation’s global health program. On paper, Yamada is a perfect choice—his industry R&D background and current philanthropic position are hard to beat when considering the type of people who should oversee the foundation.

But the timing of the choice was disastrous. FDA announced the board selections on November 15—the same day that the Senate Finance Committee released a report on its investigation of claims that GSK intimidated an academic researcher who questioned the safety profile of Avandia. The report reviews a number of communications between GSK and the researcher, including emails from Yamada, and concludes that “the documents in the Committee’s possession raise serious concerns about the culture of leadership at GSK.”

Given DeLauro’s position that the foundation is an avenue to give industry undue influence over FDA, that made the selection of Yamada seem like a blunder.

Industry should hope that cooler heads prevail, and that DeLauro’s concerns can be assuaged. The Reagan-Udall Foundation should be a positive for drug development, and so pharma wants it to get off the ground.

But it is also the most viable short-cut to getting moving on a new active surveillance system for pharmaceuticals. The new law directs FDA to set up a public-private partnership to help build the database and develop the tools for analyzing signals to make regulatory decisions. The agency is leaning towards giving that mission to the new foundation—McClellan was one of the champions of including the provision in the FDA law in the first place.

Putting the new foundation in charge of developing the active surveillance system would address industry’s biggest concern with the project—whether product sponsors will have an appropriate role in shaping the new system.

That’s where things get really tough. DeLauro is already concerned about industry influence in the foundation. And Chuck Grassley, the ranking Republican on the Senate Finance Committee who oversaw the Avandia report, wants to play a role in shaping how the active surveillance project develops—at least to the extent it involves Medicare claims data. And Grassley’s view is that industry should have no role in analyzing that data.

So the fight over Reagan-Udall is probably just beginning. For industry the stakes may be higher than they seem.

The New Administration: More Names to Consider

We didn't wait for the election to start the speculation about who might play an important role in an Obama Administration. But now that the voters have spoken, we've heard a few more names bandied about for key posts in the new Administration.

So, without further ado, here are some additions to our prior post:

HHS Secretary:

Rosa DeLauro (US Congress): We thought Tom Daschle was sure to end up as HHS Secretary, but now we hear he may instead be leading the health care reform effort from within the White House. (You know, kind of like Hillary did in the Clinton Administration. Not exactly like that, we hope.) And we've heard that maybe Connecticut Congresswoman Rosa DeLauro (pictured) will get the job. DeLauro currently chairs the agriculture appropriations subcommittee in the House, which among other things oversees FDA's budget. She's no fan of DTC ads, sloppy overseas manufacturing, or anything that looks like overly cosy relationships between industry and regulatory. In other words, she would make a verrrrry interesting secretary for the pharmaceutical industry. The suspense on this position won't last long, so stay tuned...

FDA Commissioner:

Ezekiel Emanuel (NIH): The National Insitutes of Health's chief bioethicist has a cv that is longer than a typical issue of IN VIVO, packed with publications, books, awards and honors. The one thing not on it: his brother, Rahm, was just named chief of staff to President-elect Obama. Those family connections ensure Emanuel will be an influential figure in the new Administration; whether FDA is the right fit is a different question. Still, his involvement in addressing conflict-of-interest issues--both within NIH and in other professional societies--is likely to set the tone for how clinical research and medical education evolve in the years ahead. (FYI, the third Emanuel brother is an agent in Hollywood. That's right: Mr. and Mrs. Emanuel have one son who is a hard driving political operative, one who is a hard driving Hollywood agent, and one who is...a bioethicist.)

Jerry Avorn (Harvard): One of the pioneers in the field of pharmacoepidemiology, Avorn's post at Harvard gives him an in with the Obama health team and the Massachusetts Senate delegation. FDA is prey to internal disagreements between its clinicians and its epidemiologists, and historically the leadership has come from the clinical world. But the emphasis on drug safety and post-marketing surveillance could make someone like Avorn an attractive candidate.

Joshua Sharfstein (Baltimore Commissioner of Health): Kennedy is the traditional power broker for FDA, but it is an open question whether his health will allow him to continue to play that role in 2009. So someone like Sharfstein, who once served on Rep. Henry Waxman's staff, could be a more likely candidate since House members have a strong interest in FDA as well. And he has Steve Nissen-like drug safety credentials, having helped led the charge to withdraw pediatric indications for OTC cough/cold medicines. A pediatrician by training, Sharfstein graduated from Harvard Medical School in 1996.

David Kessler (UCSF): Yes, that David Kessler. Plenty of folks are suggesting that he wants back into government and that he could end up back at FDA. We've been telling people for more than a year the next FDA commissioner will be from the Kessler mold, so we certainly can't resist passing on the notion that it will just be Kessler himself. He recently lost his post as Dean of the UCSF Medical School--under unpleasant circumstances--so we're betting a move back East would not be unwelcome.

CMS Administrator

Judy Feder (Ex-Georgetown): Feder is also certain to play a prominent role in the Obama health team after her unsuccessful bid for Congress in Virginia. Feder's campaign was closely aligned with the top of the ticket, and though she fell far short of unseating incumbent Frank Wolf in Virginia's 10 District, she is likely to be rewarded for helping increase Democratic support for Obama in what proved to be a pivotal state for the campaign. A veteran of the Clinton Administration (she was HHS principal deputy assistant secretary), she surrendered her position as Dean of Georgetown's Public Policy Institute before launching her unsuccessful bid.

Elizabeth Fowler (Senate Finance Committee): Fowler, one of the key Democratic staffers who worked on the Medicare Part D benefit, certainly has the resume for the job: in addition to her time on the Democratic committee staff, she worked as VP-public policy at Wellpoint, as an attorney at Hogan & Hartson, and as a health services researcher with HealthSystem Minnesota. Ironically, one drawback could be the key role she played as one of the few Democratic staffers who helped draft the Medicare Modernization Act. Changes to MMA are atop the agenda of many in the Democratic Congress, and having a CMS administrator so closely tied to the 2003 law could be a problem.

Cybele Bjorklund (House Ways & Means Committee): Bjorklund, on the other hand, would be the staffer who represents the Democratic opponents to MMA still bitter about being shut out of the end of the debate that created Medicare Part D. In the House, Bjorklund has worked on legislation to undo the "non-interference" clause in Part D - including proposals to have Medicare launch its own prescription drug plan.

Kevin Concannon (Iowa Department of Human Services): Concannon is only one of many state Medicaid program directors who could be considered for positions in the federal agency. However, he bubbles to the top of the pack because: (1) He has led two state Medicaid programs, first in Maine and now in Iowa; (2) In Maine, Concannon implemented a state-wide drug discount program that withstood a court challenge from the brand name pharmaceutical industry; (3) His boss, Gov. Tom Vilsack, helped deliver Iowa for Obama (after Vilsack ended his own presidential campaign, and then supported Clinton in the rest of the primaries), and may join the administration in the Department of Agriculture; and (4) Iowa is the home state of Finance Committee ranking Republican Chuck Grassley, which would presumably help Concannon get through the Senate.

Laying a Foundation for Success: Mark McClellan’s Vision for Reagan-Udall

If you want to build a new house, you start with a solid foundation. But if you want to build a solid foundation, where do you start?

For Mark McClellan, chairman of the Congressionally-chartered Reagan-Udall Foundation, that question turns out to be more difficult than anyone expected when the FDA Amendments Act—which chartered the foundation—was signed into law in September.

Reagan-Udall was supposed to begin operations with some seed funding from FDA, but concerns in Congress—primarily those of House Agriculture Appropriations Subcommittee chair Rose DeLauro—blocked that. So for now, the foundation has had to rely on 14 board members working on a pro bono basis to get up and running.

And the board has to accomplish two goals at the same time: crafting by-laws and processes to allow fundraising to begin, while working methodically to win over DeLauro and other concerned stakeholders to the broader mission of enhancing the scientific base governing the mission of the Food & Drug Administration.

“It will be a step-wise approach with getting the right bylaws, getting the right staff in place, having further opportunities for public input and discussion, and moving on to doing some broad based projects to improve the science for the FDA,” McClellan says. (For a complete transcript of our interview with McClellan, click here; a free registration is required.)

The first step in the process, finalizing the bylaws, should be complete in a matter of weeks, McClellan says. “Once our bylaws are in place and published, that is when we can start with the fund raising. There are a number of organizations and non-profit groups and the like that are interested in providing some of the core initial funding for the foundation. So that will be the next step and that means we will be able to have a staff in place and ongoing support for the product areas and initiatives.”

So it will still be a while before the foundation can actually get to work on supporting FDA’s scientific mission. There are at least three critically important areas where Reagan-Udall could play a prominent role in shaping the future of the agency and the pharmaceutical industry it regulates.

First, there is the directive for the foundation to shepherd and support FDA’s “Critical Path” Initiative, a program that has at least the potential to accelerate drug development. Second, the law also contemplates that the foundation will run a scientific fellowship program for FDA—a program FDA has already announced and is eager to get going.

Last but not least, the foundation is a good candidate to play a central role in the implementation of a new active surveillance system under development by FDA. That system could be the most revolutionary outcome of FDAAA, but its impact depends critically on scientific and procedural details that have yet to be worked out.

The foundation seems well on track to begin operations and start taking on those roles no matter what its Congressional critics think. However, the impact of the foundation’s work depends on winning over the concerned voices on the Hill. If the foundation ends up being painted as a vehicle for undue industry influence on FDA, any contributions it makes to the agency’s scientific underpinnings will become political hot-buttons.

McClellan, though, is optimistic that he can win over the skeptics. “We all share the same goal,” he says.

“There are a lot of good ideas from many members of Congress who all share the goal of improving the FDA’s ability to carry out its mission and improving the science available to promote the health of the public,” McClellan says. “Those perspectives are all going to get built into the further activities of the foundation.”

That’s why, in McClellan’s view, getting the process right on launching the Foundation is so critical.

“It is understandable that any kind of decisions involving FDA appropriations need to be made very carefully,” McClellan says. That is why there is “the need for transparency and clarity in the processes for the Foundation.” Concerned stakeholders must have “a good understanding of where funding would be coming from on the private side, and where it would be going,” McClellan says.

One example of how the foundation is working on its dual objectives: McCellan is relying on pro bono help from the DC law firm Zuckerman Spaeder to craft the bylaws. McClellan cited two former FDAers at the firm, Partner Bill Schultz and Counsel Peggy Dotzel, as providing the assistance.

In addition to the help they are providing on interpreting the Congressional directives for the charter of the foundation, Schultz and Dotzel’s involvement should offer some reassurance to skeptics in Congress. Both served in the Commissioner’s office under David Kessler during the Clinton Administration, and Schultz in particular established a reputation for independence from industry based on his prior experience with Public Citizen and with Representative Henry Waxman’s committee staff.

There is no doubt that the ramp-up of the foundation is going to take longer than its advocates wanted. But it seems clear that if there is any hope to build a strong Foundation to support FDA’s mission, the first step will be building a strong foundation of support from skeptics in Congress.

Heparin Investigation Takes an Ugly Turn for Baxter, Industry

There's nothing like a picture of pig intestines being sorted in China to dramatize the fears that outsourcing is jeopardizing the safety of the US drug supply.

The picture to the right is just one in a series posted on-line today by the Wall Street Journal, showing the first step in the production process for heparin, one of the mostly widely used hospital pharmaceutical products in the US. (You can see the rest of the pictures here if you have the stomach).

You can expect those photos of the heparin production process to show up again, any time someone wants to question the impact of manufacturing outsourcing in the pharmaceutical industry. Like maybe when House Agriculture Appropriations Subcommittee chair Rosa DeLauro holds a hearing on drug safety issues (and especially the Trasylol controversy) February 27.

The photos accompany a lengthy discussion of the investigation into an apparent increase in adverse reactions associated with Baxter's heparin product, which has been recalled in the US. The Chicago Tribune also weighs in with a story including some comments from Baxter CEO Robert Parkinson.

Now, bear in mind that no one knows for sure at this point that the Chinese facility has anything to do with the heparin adverse events. Not that that will make too big of a difference in how much damage the story will do to confidence in FDA, the industry and the drug supply.

First came the embarrassing admission by FDA that it never inspected the plant in China that serves as one raw material supplier for the product in question. That prompted a key overseer of FDA--Michigan Democrat Bart Stupak--to call for the resignation of Commissioner Andrew von Eschenbach.

But Baxter may face some tough questions of its own--at least based on comments made by top agency enforcement officials during a Food & Drug Law Institute conference February 19-20. According to the Tribune, Parkinson says Baxter wasn't even aware that the plant in question was part of its supply chain, since it was a subcontractor to the firm Baxter relied on for bulk API.

David Elder, director of the agency's Office of Enforcement, pointed out that FDA believes it is the responsibility of the finished dose product manufacturer to assure the quality of its products. He was responding specifically to a question about components of medical devices, not heparin. But he pointedly expanded to his answer to include finished dose pharmaceutical manufacturers being responsible for their suppliers.

Deputy Chief Counsel for Litigation Eric Blumberg also discussed the agency's ability to hold individual corporate executives criminally responsible for allowing adulterated products on the market. The authority--known as the Park doctrine after a Supreme Court ruling upholding the principle--allows FDA to file misdemeanor cases against executives even if there is no evidence of intent or even knowledge of GMP violoations.

The principle, Blumberg reminded FDLI, is that an executive has at least the opportunity to prevent a dangerous product from entering the market, while consumers cannot protect themselves from a contaminated drug once it is in distribution.

If Congress does look more broadly at supply-chain responsibility, things could get really interesting.

Both the Journal and the Tribune quote American Pharmaceutical Products Inc. CEO Patrick Soon-Shiong, asserting the advantages of his company's approach to supply chain management. APP is the big winner (if there is one) in the heparin recall, since its product is now the only one available.

Soon-Shiong has been in the news before. APP was the subject of a front page story in the New York Times in 2002 because of its relationship with the group purchasing organization Premier; that was during a time when Congress was looking into GPO practices following allegations by small device manufacturers that they were being shut out of the market.

Before that, Soon-Shiong played a part in the controversy surrounding generic launches of Bristol-Myers Squibb's paclitaxel (Taxol). APP asserted that a patent it held on a cremaphor free formulation of paclitaxel should block generics of the Bristol product. The issue briefly delayed generic launches and prompted a Federal Trade Commission inquiry. (Bristol ultimately settled a series of antitrust claims regarding its patent defense strategies for several brands; APP was never charged.)

One last thing: APP also has first-hand experience with the challenges of global supply chain management. The company acquired its injectable generic product line from Fujisawa USA in the 1990s. Shortly after the acquisition, APP had to recall injectable gentamicin due to endotoxin contamination. The culprit? A Chinese raw material supplier.

Soon-Shiong should make an interesting witness...

The Beginning of the End of the User Fee Era?

In the 15 years since the Prescription Drug User Fee program was created, the biopharma industry and its investors have gotten used to a once-unthinkable proposition--that FDA would give a clear yes or no answer about the approvability of a new drug by a tight deadline.

That record of reliability now may be in jeopardy.

Given the agency's ongoing resource problems, Office of New Drugs Director John Jenkins has given overworked and overwhelmed review divisions the green light to do what was once unthinkable: miss PDUFA deadlines.

According to a story in BioCentury this week, Jenkins’ unofficial and unpublicized directive could result in FDA missing more than 10% of user fee deadlines this year. That may not sound too bad, suggesting only a minor slippage from the agency's official commitment under the PDUFA agreement to meet its goals for at least 90% of its applications.

But in reality, FDA's track-record on meeting deadlines has been very close to 100%.

What Jenkins is describing is a limited number of missed deadlines—only in cases when a division feels overwhelmed by its workload. But once you start missing deadlines, it becomes very difficult to get caught up. And it's not like FDA is being overwhelmed by new drug applications these days. Imagine what might happen if new drug applications were streaming into FDA like they were 10 years ago.

For industry, the beautiful thing about the user fee process is its predictability: on new drug reviews, FDA promises to give a sponsor an answer by a certain date. And if company executives ask for a meeting with FDA officials to discuss an application, they know they will receive one within a set period of time.

Up until now, user fee activities have historically been considered sacred cows at FDA: industry fees have increased at a healthy clip at each reauthorization of PDUFA. It’s been all the “extraneous” activities funded through congressional appropriations—like professional development and, until recently, post-marketing safety—that have suffered due to a lack of funding.

And these days, it seems like FDA is stretched to the limit. Between the inspections debacle, the FDA Amendments Act implementation, and the new “Safety First” postmarketing safety initiative, FDA “has more work on our plate than we can possibly accomplish,” Jenkins told BioCentury. “We are having to prioritize. We are having to set aside some things, hopefully on a temporary basis, until we can get adequately staffed.”

But hiring and training new staffers is no easy process, thanks to a lengthy and arcane procedure under current HHS guidelines. Mary Pendergast, a former deputy associate commissioner at FDA, discussed this exact dilemma during Windhover's FDA/CMS Summit in December.

“The FDA has to hire many additional people. But as any FDAer would tell you, the new rules imposed by the Department of Health & Human Services—which took away from the FDA the ability to hire its own staff—has caused a very difficult time for the FDA in terms of making new hires,” she said. “The system is so long that most competent people will have found a new job by the time the FDA tells them they want them to be hired.”

So far, Congress has turned a deaf ear to FDA’s resources woes, wanting promises of an agency overhaul before appropriating any more money. Capitol Hill has sent a clear signal on where it believes FDA’s priorities should lie, and it’s not in faster review times.

Congress wants FDA to hold advisory committess for all new molecules, or justify a decision not to in writing. The logistics of scheduling committee reviews within six- or 10-month deadlines make that a tall order. And the decision to delay an advisory committee review for Theravance's televancin demonstrates the real-world consequences of placing safety concerns (in this case, the integrity of the trial data) over PDUFA deadlines.

Then there is the focus on the preapproval inspection process. When that program was created in 1990, the first impact was a delay in approval for a number of pending applications while the agency hustled to conduct inspections of the facilities. In the intervening years, FDA has developed a list of exceptions to the preapproval inspection policy--and Congress isn't happy about that. Another reason for delays.

The bottom line is that folks like Reps. Rosa Delauro and Bart Stupak or Sen. Chuck Grassley are less concerned about missing a few deadlines than when FDA inspects the wrong heparin facility in China. Indeed, they are clearly uncomfortable with the entire user fee model--a fact that should give the biopharma industry pause.

If You Want a Job Done Right....

Well, this is a bit of a surprise.

After a lengthy search for a permanent head of FDA’s Center for Drugs Evaluation & Research, the agency is turning the reins over to an old hand—Janet Woodcock.

We admit it: like most of Washington, we didn’t see this one coming. While we wrote about the probability of a candidate emerging from inside FDA in last month’s issue of The RPM Report, we didn’t predict that Woodcock would be the final choice to head CDER.

But we take some comfort in the fact that no one else did either. For most folks in the policy world—including those on Capitol Hill—Woodcock’s return to CDER (she was director from 1994 to 2005) was a big surprise, and frankly, a bit of a head-scratcher.

After all, moving from the number-two spot at FDA to head the center for drugs could be seen as a demotion of sorts—especially since Woodcock was given a position in the commissioner’s office at a time when it was perceived that she might leave the agency altogether.

Rather than risk her leaving FDA altogether, Crawford gave Woodcock the title of deputy commissioner for operations and chief operating officer, and named Steven Galson to succeed her as CDER director. Under Andrew von Eschenbach, Woodcock became FDA's chief medical officer. But when Galson was tapped to be the acting Surgeon General, she stepped back in as acting head of CDER.

So if nothing else, relinquishing her commissioner office-level roles to become the permanent head of CDER frees up Woodcock's schedule a bit. According to FDA, the agency will be looking for someone to succeed her as deputy commissioner and chief medical officer. That may not be an easy task, given that the position of CMO was created precisely with her in mind after it was recommended by the Institute of Medicine in a review of the agency's drug safety programs.

So it comes as a bit of a shock that Woodcock is back in the director’s chair. But given that she was leading the CDER director search committee—and therefore ultimately picked herself as Galson’s successor—we assume she found enough good reasons to return.

Many point to a potential political advantage: as director of CDER, Woodcock will be well-positioned with the incoming Administration. Being outside the Office of the Commissioner will allow Woodcock to be viewed more as the career FDA official she is, rather than a political functionary of the outgoing Bush Administration.

But someone like Janet Woodcock doesn’t need to worry about playing politics to stay employable: there are plenty in industry and elsewhere who would welcome her with open arms—and a hefty pay raise. And people that know her well argue that she’s not the kind of person that would try to preserve her job at all costs.

Perhaps what Woodcock’s appointment really reflects is a commitment on her part to steer CDER through this time of transition. After all, there will be plenty of action in the drug center around the implementation of the FDA Amendments Act, a task Woodcock herself has acknowledged will be a unique and historical challenge.

Plus, she’ll be returning to CDER at a time when the future of the prescription drug user fee program is in question, so she’ll have an opportunity to fix the program that she first helped implement back in 1992. Indeed, the news that Office of New Drugs Director John Jenkins had given his medical reviewers the green light to slip a little on user fee deadlines may have helped push the CDER announcement along.

Plus—and let’s be frank here—given the resource and morale issues at CDER right now, who else would want that job? As one policy person we spoke to pointed out, there are only so many “buckets” of people that would even qualify.

FDA can’t bring in anyone that might appear to be conflicted, or risk the ire of Capitol Hill, so candidates with industry ties are out. That leaves either:

(1) academia. With CDER in such disarray, there are few academics with the management skills to steer the center through choppy waters; or

(2) current FDA officials. While CBER chief Jesse Goodman looked to be a solid pick to head the drugs center, Woodcock’s experience—and a thick skin that was on display at Rep. Rosa DeLauro’s appropriations hearing last month—ultimately helped make her the only viable choice.

For industry, this couldn’t be better news. Woodcock is well known by pharmaceutical and biotech manufacturers, and is certainly a familiar face to head CDER. While some critics question whether she is too cozy with industry, on the whole, she is seen outside the agency as a smart, honest and pragmatic leader.

The Pharmaceutical Research & Manufacturers of America issued a statement of strong support, noting her “willingness to work with diverse partners.” And one VP of global regulatory affairs, Amgen’s Paul Eisenberg, gave her a thumbs-up. When we asked him what type of person Woodcock should pick for CDER, he suggested that she should pick someone like herself. “She is really a leading driver for improvement of how FDA focuses on science and approvals," Eisenberg said.

Well, if the right prescription for FDA was to find someone just like Janet Woodcock to run CDER, then she certainly made the right choice.