FDA: Questions of protocol, conflict

by Andrew Zajac

The Obama Administration has made increased transparency a priority, and few government agencies are in greater need of it than the Food and Drug Administration.

The FDA's recent handling of conflict of interest allegations against the agency's top drug official shows that openness has not yet triumphed over opacity.

Earlier this month, the FDA announced that it had found no merit to accusations that Dr. Janet Woodcock had a conflict because of her links to a firm vying for agency approval of an application to make a generic version of the commonly-used blood thinner heparin.

It wasn't so much the decision itself that's odd, though it's difficult enough to assess because the FDA hasn't offered much of an explanation for it.

What's unusual is the way that the FDA announced that Woodcock was in the clear.

Four FDA officials, including Principal Deputy Commissioner Joshua Sharfstein and Chief Counsel Ralph Tyler, placed a conference call to a Tribune Newspapers reporter on Feb. 4 to tell him about the decision. An attorney for Amphastar Pharmaceuticals Inc., of Rancho Cucamonga, Calif, which made the complaint, said the FDA confirmed its findings to him only after he read them in the paper the following morning.

From a journalism standpoint, it's great to be handed information before anyone else has it, but contacting a reporter before notifying interested parties is considered a breach of protocol in many business and government circles.

In a follow-up interview on Friday, Sharfstein conceded the matter could have been handled differently, "but we thought it was important to call the people who had been writing about it...I don't think there's a protocol for this."

In its Feb. 4 phone call, the agency made two main points:

--That neither the FDA nor the Department of Health and Human Services Inspector General found a conflict of interest in Woodcock's dealings with scientists connected to Momenta Pharmaceuticals Inc., which is competing with Amphastar to win FDA approval of enoxaparin, the generic version of low molecular heparin currently marketed as Lovenox.

--That Woodcock had voluntarily removed herself from any involvement in evaluation of the Momenta and Amphastar applications. The removal came either in October 2007 or August 2009 - the FDA first offered the earlier date, then the second, with no explanation for the switch.

In broad strokes, Amphastar's complaint is that a series of contacts in 2007 between Woodcock and Momenta-connected scientists, and her collaboration with them on an investigation of contamination of Chinese heparin the following year created the appearance of a conflict of interest that required her recusal from evaluation of the competing enoxaparin applications.

Why does any of this matter?

--The stakes are huge. Lovenox has worldwide sales in the $4 billion range. The value of a generic would be lower, but is still thought to have 10-figure potential.

--The Chinese heparin crisis remains an open book. The source of the contaminant has never been identified, and the tainted drug, marketed by Baxter International, of Deerfield, Ill., has spawned at least 650 lawsuits which have yet to be tried. The crisis remains a powerful illustration of the FDA's inability to monitor an increasingly globalized drug ingredient supply chain.

(The version of heparin that was contaminated is chemically similar to, but distinct from the kind Momenta and Amphastar are seeking to market.)

--Woodcock, the director of the Center for Drug Evaluation and Research, is a figure of some stature and controversy. In the late 1990s and early 2000s several drugs approved by CDER on her watch were pulled from the market because they were sickening and killing people.

At various times Woodcock's also been the FDA's chief medical officer and deputy commissioner for scientific and medical programs, and her name was floated in the early days of the Obama Administration as a possible commissioner.

In recent days, her office was criticized in a Senate report for its handling of the controversial diabetes drug Avandia, which has been linked to sometimes fatal heart attacks and heart failure. FDA declined to make her available for an interview.

Less than three weeks before the FDA's phone call, in the run up to a January 21 Tribune Newspapers story (link here) about Amphastar's complaint, spokeswoman Karen Riley told that paper that "Dr. Woodcock hasn't recused herself and that's still the case."

The FDA's top lawyer, Ralph Tyler, makes a very strong distinction between "recusal" -- something he said is done in response to a recognized conflict of interest -- and merely stepping aside, which he said Woodcock did in this instance "as an act of good grace."

But whatever term it's given, if Woodcock was effectively off the case, why didn't Riley say so when asked about her status by Tribune Newspapers?

Sharfstein defended Riley's parsed response. "There was nothing Karen said at the time that was wrong," he said in Friday's interview.

In the Feb. 4 call, Tyler initially said that "Dr. Woodcock has had no involvement in (the applications) since October 2007...and she formally withdrew in August 2009."

When it was pointed out that October 2007 happened to be the month before FDA publicly added new requirements to the drug applications that seemed to mirror Momenta-connected scientists' lobbying of Woodcock, Sharfstein broke in on the line to say that the agency wasn't sure about that that was the date of Woodcock's informal recusal and that the operative date of her departure from enoxaparin evaluations was sometime in August 2009.

"We're not saying Dr. Woodcock had no involvement in the history of this," Sharfstein said in the February 4 call.

Indeed, according to Amphastar general counsel Jason Shandell, Woodcock presided over a meeting with company officials about its application on November 19, 2007 at FDA offices in Rockville, Md.

According to Shandell, Amphastar didn't begin complaining about Woodcock's conflicts until January of 2009.

Sharfstein said Friday that the point of saying that Woodcock had no involvement in the applications in October 2007 was that "by late fall 2007 she was not making decisions...there were no decisions for her to make."

According to Tyler, Amphastar was notified about Woodcock's withdrawal last September.

That's an apparent reference to a Sept. 11 FDA letter to Amphastar clearing Woodcock of any conflicts because of an absence of a financial tie to Momenta. Amphastar, however, has never claimed that Woodcock had a financial conflict, but a conflict based on appearances.

The letter states that "Dr. Woodcock does not have either a financial interest or a covered relationship requiring her recusal from involvement in FDA's consideration of enoxaparin (drug applications)" but contains no mention of a voluntary decision to step aside.

Tyler subsequently backed off his assertion Amphastar had been notified, but suggested that the company should have figured out that Woodcock has stepped aside because of an absence of contact with her.

In recent months, Amphastar has had "multiple contacts with the agency and on no occasion have they been with Dr. Woodcock," Tyler said.

Shandell said his company would be foolish to make any assumptions about the lack of direct contact with Woodcock or any other senior FDA official because they could be making decisions behind the scenes.

If Woodcock has stepped aside in August, why wasn't that disclosed in the September letter?, Shandell asked.

Because, Sharfstein said on Friday, the FDA didn't have to. "The question of what she was doing voluntarily was not something we were obligated to tell the company," Sharfstein said.

Tyler said the FDA didn't notify Amphastar of the agency's decision because it regarded the conflict of interest allegations as an attempt by the company to game the drug evaluation process.

"I don't know that there wasn't a deliberate decision not to notify, but there's no desire to encourage these kinds of tactics," Tyler said.

What then, was the value of Woodcock's "act of good grace"?

The complaining party didn't know about it.

The public didn't know about it.

It's not even clear that FDA officials involved in the drug application review knew that their boss was stepping aside.

In Friday's call, Sharfstein said it didn't matter what anyone else knew or didn't know because in stepping aside, Woodcock was doing something she wasn't required to do.
Several days before the Feb. 4 call, Tribune Newspapers received a copy of an anonymous letter addressed to Sharfstein, in his capacity as chair of an internal FDA task force seeking to make the agency more transparent, alleging that the Momenta/Sandoz was being favored over Amphastar in the application process.

The letter, dated Jan. 22 and signed "Concerned CDER Scientists", claimed that Amphastar was being held to a stricter purity standard for its version of enoxaparin than Momenta/Sandoz.

Included with that letter was a copy of a letter from an FDA drug reviewer to Amphastar describing the purity standard required of the company, and a separate set of documents purporting to memorialize a series of November 2009 telephone conversations between FDA and Sandoz officials concerning the purity standard for the Momenta/Sandoz version of enoxaparin.

The Tribune Washington bureau forwarded a copy of the letter to Sharfstein and Riley for comment. Both declined to comment on any aspect of it. Sharfstein declined to confirm even to that he had seen the letter prior to receiving a copy from Tribune Newspapers.

A spokeswoman for Momenta also declined to comment.

(One curious aspect of the purported communication between FDA and the Momenta/Sandoz team is that it mentions only Sandoz, and lists only Sandoz employees as contacts. In press accounts, Sandoz, a division of Swiss pharma giant Novartis, has been portrayed as a silent partner, responsible for financing and the eventual marketing of enoxaparin. Nearly all of the comment on the drug development effort has come from Momenta, which has presented itself as the technology end of the tandem.)

An Amphastar official confirmed that the company received a copy of the Amphastar-FDA letter identical to the one sent to Tribune Newspapers.

Sharfstein said the decision to speak to the press about Woodcock's status had nothing to do with the appearance of the over-the-transom documents. That decision was dictated by the conclusion of the HHS IG's investigation of Amphastar's complaint. FDA learned the results of the inquiry a "week or two" before its announcement, Sharfstein said.

To contact the reporter on this story: azajac@tribune.com