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« on: October 25, 2013, 09:57:41 PM »

Pharmaceutical firms paid to attend meetings of panel that advises FDA

   By Peter Whoriskey, Published: October 6 E-mail the writer

A scientific panel that shaped the federal government’s policy for testing the safety and effectiveness of painkillers was funded by major pharmaceutical companies that paid hundreds of thousands of dollars for the chance to affect the thinking of the Food and Drug Administration, according to hundreds of e-mails obtained by a public records request.

The e-mails show that the companies paid as much as $25,000 to attend any given meeting of the panel, which had been set up by two academics to provide advice to the FDA on how to weigh the evidence from clinical trials. A leading FDA official later called the group “an essential collaborative effort.”

Lawmakers were worried a year ago about Columbia-based QSSI and how it got its contract. Patient advocacy groups said the electronic communications suggest that the regulators had become too close to the companies trying to crack into the $9 billion painkiller market in the United States. FDA officials who regulate painkillers sat on the steering committee of the panel, which met in private, and co-wrote papers with employees of pharmaceutical companies.

The FDA has been criticized for failing to take precautions that might have averted the epidemic of addiction to prescription drugs including Oxycontin and other opioids.

“These e-mails help explain the disastrous decisions the FDA’s analgesic division has made over the last 10 years,” said Craig Mayton, the Columbus, Ohio, attorney who made the public records request to the University of Washington. “Instead of protecting the public health, the FDA has been allowing the drug companies to pay for a seat at a small table where all the rules were written.”

Even as the meetings were taking place, the idea of FDA officials meeting with firms that had paid big money for an invitation raised eyebrows for some. In an e-mail to organizers, an official from the National Institutes of Health worried whether the arrangements made it look as if the private meetings were a “pay to play process.”

FDA officials did not benefit financially from their participation in the meetings, the agency said. But two later went on to work as pharmaceutical consultants and more than this, the critics said, the e-mails portray an agency that, by allowing itself to get caught up in a panel that seemed to promise influence for money, had blurred the line between the regulators and the regulated.

In a statement, the FDA said “we take these concerns very seriously.” But, it said, “we are unaware of any improprieties” associated with the group.

Douglas Throckmorton, a deputy director of the agency, said in an interview that strict rules of transparency and funding apply to the public-private partnerships that the agency engages in and that these efforts are important for the government and the industry.

But the group in this case was not initiated by the FDA, he said, and so was a private partnership to which those rules did not apply.

“There are rules in place for us to have these discussions,” Throckmorton said. This group “was set up as a private group.”

The group was organized by two medical professors, Robert Dworkin of the University of Rochester and Dennis Turk of the University of Washington, and the e-mails for the most part describe their efforts at financing and organizing the group’s meetings.

The two professors received as much as $50,000 apiece for a meeting, money that went to their academic research accounts and paid for research assistants and expenses “or to cover a small percentage of faculty effort,” they said. At one point in the e-mails, they proposed that they receive honoraria of $5,000 apiece for a four-hour meeting at a hotel near the FDA offices.

The meetings, typically held around the Washington metropolitan area, focused on the best methods for measuring the effectiveness of painkillers.

Lawmakers were worried a year ago about Columbia-based QSSI and how it got its contract. “The intent was to help everybody develop better drug trials,” Dworkin said in a phone interview. He and Turk responded to questions via e-mail, as well. A spokeswoman for Pharmaceutical Research and Manufacturers of America, an industry group, declined to comment, saying the organization was unfamiliar with the e-mails.

Exactly how to judge when a painkiller is effective has been a long-running problem for drug companies that believe that some of their products are effective but that their benefits are missed in standard clinical drug trials.

One goal of the group was to design clinical trials that would illuminate the benefits of new drugs that might be missed in standard tests, avoiding what the academics called “false negatives.”

The meetings, which involved about 30 to 40 people, included academics, FDA and NIH officials, and often as many as 14 representatives from pharmaceutical companies. Only the companies paid fees to attend.

Dworkin said the scientific guidelines the group produced were of high quality and that “we are not aware of a single negative comment that has been published.” The goal of the group was to publish “consensus” statements on scientific matters related to testing the drugs.

Bob Rappaport, the chief of the FDA’s analgesic division and an attendee at many meetings of the group, did not respond to e-mails or phone calls.

But he has touted the influence of the group, known by the acronym IMMPACT. A 2007 ­PowerPoint presentation he put together was called “The Impact of IMMPACT” and recognizes the group’s influence on FDA thinking. The presentation describes the committee as “a wealth of opportunity for communication” that was advancing the science and “approving new analgesic drug products.”

While science was the subject of the meetings, the subject of money runs through the e-mails.

Even for a pharmaceutical company, the $20,000 price for an invitation to a Washington meeting seemed high.

When some drug companies balked at the fee, the organizers of the meeting, Dworkin and Turk, were firm.

“20k is small change, and they can justify it easily if they want to be at the table,” Dworkin wrote to Turk in July 2003, after an Eli Lilly representative bridled at the price. “Everybody has been very happy with [the meetings] and they are getting a huge amount for very little money (impact on FDA thinking, exposure to FDA thinking, exposure to academic opinion leaders and their expertise, journal article authorship, etc.) and they know it.”

“Do they really expect it to be any less than 20K per meeting for all this?” Dworkin wrote.

At another point, a company representative called to say that he could come up with $10,000 to attend and was “trying to find more,” as Dworkin told Turk in the e-mail.

“He didn’t realize we were inflexible on the 25k, and then asked, a bit testily, how many companies were already on board and when I said 10 he then asked whether it costs 250K to hold a meeting in DC,” Dworkin wrote. “I gave our standard response to this, which appeared to mollify him fine.”

And in another: “The native(s) is (are) restless regarding finances for IMMPACT,” Turk tells Dworkin in late 2002.

“I don’t know how we will bury the post doc funds if we are too specific,” Turk says in another.

In the interview, Dworkin said that the costs of running such a meeting could run as high as $150,000, and because they never knew how many sponsors they could attract, it was difficult to know where to set the price. To make its gatherings more transparent, the group posted to its Web site copies of meeting presentations.

Even so, at least a few of the government officials attending the meetings seemed to be nervous about appearances.

At one point, an NIH staffer indicated that given the fees paid by drug companies, as well as that the meetings were private, IMMPACT could be criticized because it was “paid for by a few large pharmaceutical firms who are assumed to be influencing the outcomes.”

The NIH staffer suggested holding the meetings on the NIH campus and opening the meeting to all interested parties to “avoid the stigma that this initiative is a ‘pay to play process.’ ”

Dworkin responded in an e-mail: “It is difficult to imagine how an open meeting would develop consensus recommendations.”
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« Reply #1 on: October 25, 2013, 10:00:18 PM »

What the FDA isn't telling.
By Jeanne Lenzer

Traci Johnson's body was discovered on Feb. 7, 2004, hanging by a scarf from a shower rod in an Indianapolis laboratory run by the drug company Eli Lilly. The 19-year-old college student had been serving as a test subject in a clinical trial of the experimental antidepressant duloxetine. Investigators from the Food and Drug Administration rushed to Indianapolis to determine whether the experimental drug was related to her death. The probe was inconclusive.

This left researchers in a quandary: Was the drug safe or not? Could duloxetine trigger suicide, as some experts suggested? Or was Johnson's death an "isolated tragedy," as Eli Lilly claimed? When drug manufacturers fail to publish negative study results, as studies show is often the case, the best source of information about these questions is the FDA. The agency—which was rocked last week by the sudden resignation of Commissioner Lester Crawford—requires companies seeking approval for a drug to provide data from randomized controlled trials, studies in which some patients are given the drug and others are given a placebo. But when researchers and the press started asking about duloxetine, the FDA didn't scour its database and go public. It kept quiet.

The FDA gave a legal rationale for its silence: Some clinical trial data are considered "trade secrets," or commercially protected information, and thus are exempted from release under the Freedom of Information Act. Since the FDA doesn't routinely perform comprehensive reviews of drugs once they are on the market, when uncommon but deadly side effects tend to be picked up, independent researchers are often the only hope of catching such flaws. But the trade-secrets rule can leave researchers in the dark about the most worrisome data—negative results that support a failed application to market a drug.

The argument for secrecy is that failed efforts at drug development need protection lest entrepreneurs suffer a competitive disadvantage when other companies aren't forced to expend the same time and money exploring dead ends. And at first blush, there would appear to be little need for clinical data on a drug that isn't in use. The problem is that many drugs have multiple uses. Duloxetine, for example, is marketed under the brand name Cymbalta to treat depression. Traci Johnson committed suicide while taking duloxetine during tests for selling the drug to treat stress urinary incontinence, under the brand name Yentreve. If a drug is on the market for one use and studies about another use suggest disquieting risks—as the death of Traci Johnson may—do the benefits of keeping the study data secret outweigh the costs?

The FDA approved Cymbalta to treat depression in August 2004. By the end of that year, Cymbalta sales topped $61.3 million. At some point—the date is undisclosed—Eli Lilly began testing Yentreve. In January 2005, as Cymbalta sales climbed to $106.8 million for the first quarter, Lilly announced that it was withdrawing its application for Yentreve. Then it cited the trade-secret rule in refusing to disclose why the drug did not win approval. Perhaps the rationale was harmless—the drug didn't work for incontinence. But duloxetine has been approved as a treatment for incontinence in Europe since August 2004.

Over four months beginning in January, I filed several Freedom of Information Act requests on behalf of the Independent on Sunday, a British newspaper, for all safety data related to Cymbalta and Yentreve. I received a database that included 41 deaths and 13 suicides among patients taking Cymbalta. Missing from the database was any record of Johnson, or at least four other volunteers known to have committed suicide while taking Cymbalta for depression.

When I asked the about the missing results, FDA officials cited a federal regulation that they said prohibited the agency from releasing study data—or acknowledging the existence of an application—for a drug that fails to win FDA approval. Since the FDA never approved Yentreve, all the data about it were off limits. The agency may have used a similar rationale in failing to release safety data about the pain reliever Bextra, which Pfizer, its manufacturer, withdrew from the market in April for fear of links to an increased rate of heart attack.

In its Web-site database, Eli Lilly initially listed no suicides and two deaths among patients enrolled in seven clinical trials of Cymbalta for depression. (Lilly's database won the company praise in a May New York Times article for being "the company that has gone furthest in disclosing results.") Today the Web site lists 10 clinical trials of Cymbalta and five of Yentreve, with one suicide and five deaths combined. Based on the dates of the trials and the circumstances of the deaths, it's clear that the Web-site numbers do not include any of the five suicides missing from the FDA database. Lilly admits that it has never made public at least two of those deaths. Lilly spokesman David Shaffer said that data was unavailable because some of the studies were still in progress. He also said that two of the suicides "took place in depression studies run by another company," and that "the decision about how and when to disclose such information rests with that company." Shaffer was referring to the Japanese firm Shionogi & Co., which has a licensing agreement with Lilly * to market duloxetine in Japan.

Meanwhile, my sources (sorry, they're gun-shy and anonymous) were telling me that duloxetine caused suicidal tendencies in patients who took the drug for incontinence—and who were not depressed. That news was potentially explosive. In the face of questions about a link between antidepressants and suicide, industry experts have long insisted that it's depression, not the drugs used to treat it, that causes patients to kill themselves. Johnson's death appeared to call that claim into question. She entered the clinical trial as a healthy, nondepressed volunteer in order to help pay her college tuition. And she was only approved for the study after undergoing thorough medical testing to screen out depression or suicidal tendencies.

Because one patient's reaction can't prove anything one way or the other, it was critical for researchers to analyze the results of all the patients in Lilly's duloxetine studies. Instead, the FDA's interpretation of the trade-secrets rule left only the positive data from the Cymbalta trials available for review.

In June, after the Independent article, the FDA (without issuing a press release) noted on its Web site that one suicide "was reported in a Cymbalta clinical pharmacology study in a healthy female volunteer." The agency added that new data from stress urinary incontinence trials showed that middle-aged women taking duloxetine had a suicide attempt rate of 400 per 100,000 person-years, more than double the rate of about 160 per 100,000 person-years among other women of a similar age. These findings had been withheld from the public, and the researchers asking for them, for five months after the FDA had reviewed data showing the increased risk.

The FDA claims it has no choice but to resist releasing information about drugs it doesn't approve. "My hands are tied," said Dr. Robert Temple, FDA's director of medical policy. "This is something only Congress can change." That may be as much a matter of the FDA's interpretation as it is of the law, however. Experts disagree about whether congressional action or a federal court ruling is needed to make data like Johnson's death available, or whether the FDA could choose to disclose more itself.

The voluntary guidelines promoted by the drug industry, however, are not a solution. These guidelines encourage companies to list every clinical trial they initiate. Registration would be helpful. But it would not compel companies to release the data from, or even the outcomes of, their trials, as long as they companies can argue that this information is "commercially protected."

The use of trade-secret laws to conceal deaths and serious side effects linked to drugs has the obvious flaw of putting profits before public health. It also subverts the covenant between researchers and study volunteers. Subjects like Traci Johnson are told that even if they do not personally benefit from a new drug, the scientific knowledge gained from the study in which they've participated will benefit others. The volunteers should be told instead that scientists will learn about their experience only if it's good news for the drug they're helping to test.

Correction, Nov. 2, 2005: The sentence originally stated that Shionogi & Co. partners with Lilly to market duloxetine. The companies have a licensing agreement rather than a partnership. ( Return to corrected sentence.)

Jeanne Lenzer is a freelancer whose work appears regularly in the medical journal BMJ. Her e-mail address is,d.eW0&cad=rja

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« Reply #2 on: October 25, 2013, 11:07:51 PM »

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