User Fees: Why FDA Reviewers Live in Fear
02/11/2008
[Report by Jim Dickinson] “They’re very afraid over there, they’re afraid to be seen with me. The only way we communicate now is by telephone because they think their emails are being monitored” — such is the fear that Public Health Service Veterinarian of the Year* Victoria Hampshire sees in her former colleagues at FDA’s Center for Veterinary Medicine (CVM). The fear, which she says is pervasive throughout CVM’s review divisions, came after Wyeth/Fort Dodge Animal Health mounted a multi-pronged, unscrupulous and successful campaign through FDA’s top leadership to force her from her job as CVM’s adverse event coordinator and then to impugn both her work and her character.
As detailed in a heavily-documented Senate Finance Committee report, Hampshire’s “offense” was her collection and promulgation of data damning to the safety of the companies’ ill-fated canine heartworm drug, ProHeart 6 in 2004-05. The product had been approved 6/01 and was withdrawn 9/3/04. Their campaign to get the drug returned to the market included fabrication of a conflict-of-interest charge against her based on the presence of a competitor’s drug, Heartguard, on a moribund veterinary Web site she had opened before coming to FDA and had never closed. It also included multiple efforts by numerous hired agents to buy that drug without a prescription (all failed — the Web site, built in 2000 mainly for family and friends, was essentially inactive by 2004), loading the site with bogus nonprescription purchases that made it seem active, sales reps slandering her throughout the veterinary community, and false charges that she was operating an Internet pharmacy selling products competitive to ProHeart 6.
Today’s fear among CVM reviewers, Hampshire told us, stems less from Wyeth’s subversive efforts than from the failure of FDA and CVM management to resist them. Since the advent of user fees at CVM, a sense of sponsor entitlement has grown as it has in other Centers dependent on such fees, and with it a management-fostered “customer service” mentality in reviewers’ contacts with sponsors. Drug companies are mostly led by people with marketing backgrounds, and in their world when you buy something — in this case, an FDA review of your drug — you’re entitled to satisfaction. In her unaccustomed role as a CVM “customer service” representative, Hampshire also was shepherding ProHeart 6 adverse events into a rapidly expanding dossier, and she made no secret of her opinions among colleagues and superiors.
In what may be seen as a high-water mark in a relentless tide of FDA politicization that began back in Ronald Reagan’s second term (commissioner Frank E. Young), Wyeth actually threatened to exert “highest level” (above FDA) pressure on CVM then-director Stephen F. Sundlof if he didn’t yield to its demands. The inference was plain — Wyeth had the ear of the White House. “Message received,” Sundlof replied. He and then-commissioner Lester M. Crawford took the threat on face value and from then on readily yielded, quickly turning Wyeth’s warped conflict-of-interest charges against Hampshire over to FDA’s Office of Internal Affairs without first attempting to get her side of it. Then, with assistance from then-chief counsel Daniel Troy, they helped escalate allegations they already knew were probably false into an internal FDA criminal investigation.
The clandestine FDA-Wyeth efforts were eventually scorned by the Maryland U.S. Attorney’s Office and degenerated into an FDA Office of Ethics investigation into why Hampshire had not renewed her previous disclosures about her Web site, which she was now winding down. Hampshire wrongly believed that since it had produced no income and was inactive it did not need reporting; her naivete ultimately earned her a verbal reprimand. FDA’s decision to make an issue of this minor technical infraction stands in great contrast to two large and prosperous outside veterinary commercial operations owned by other CVM reviewers who, while reporting their moonlighting and ownership activities had not been asked to disclose specific pharmacy transactions in their hospitals.
“You can imagine the inequality I felt when recently these same reviewers, who are partners or owners advertising in-house pharmacies, were promoted in the same organization that inflicted this treatment on me,” Hampshire told us.
FDA’s investigation of outside allegations against its employees often lacks the “prior notice” obligation the agency has in enforcing its regulations against outside entities. In this case, Hampshire was not told of Wyeth’s charges until they had escalated to criminal level late in the company’s campaign. Even then, it was a friend, CVM information officer Linda Grassey, who informally warned her about the investigation over lunch (Grassey was herself subsequently reprimanded for this indiscretion). The shock of Grassey’s disclosure, Hampshire recalls, “paralyzed” her for a week both at work and at home.
The assumed right of FDA management to ambush employees over their suspected transgressions, and the presumptive duty of other employees to not impede such ambushing, is a long-established and bizarre feature of FDA investigations into charges against employees, compounding the climate of fear.
Government Accountability Project executive director Mark Cohen, who represented Hampshire and other FDA whistleblowers, told us he sees this as part of an FDA management pattern. “It’s standard practice,” he said, “to undermine their credibility, isolate them and start a process of shunning. It begins to look bad if you’re seen socializing with them. There’s widespread fear.”
Cohen said the extent of high FDA management’s collaboration with Wyeth in the ProHeart 6 case “was unprecedented,” although something of the kind also occurred between CDER management and Merck in their campaign, also in 2004, against drug safety whistleblower David Graham, whom GAP also represented. The Wyeth-FDA collaboration reached the “unheard-of” extreme of the company being granted an ex-parte slide presentation of its case against Hampshire to the commissioner (Crawford) with no input from Hampshire or CVM. Wyeth chairman, president and CEO Bob Essner attended with two other corporate heavyweights; Crawford was accompanied by chief counsel Troy and policy analyst Dana Delman.
User fees have given drug sponsors a sense of ownership of the FDA review process, Cohen said. “You can’t help but come to that conclusion after seeing the way industry and FDA secretly negotiate PDUFA fee levels and set performance goals. Industry has all the money and FDA has little or no leverage.” This imbalance continues into individual drug reviews, Cohen said, where companies are able to “game the system” by burying safety issues deep in filings that are too massive and too late to get the kind of in-depth review that would find them without jeopardizing the performance goal. “Even the most conscientious reviewer couldn’t find them in the time allowed.”
And in a climate of fear, how many reviewers can be expected to be of the “most conscientious” kind, willing to jeopardize a new drug’s PDUFA performance goal until they are completely satisfied? Too much attention to a drug’s potential safety problems could brand an employee as not being a team player, diminish their career advancement prospects and begin the shunning process.
Former Ketek reviewer and whistleblower David Ross, who found 11 false statements in sworn testimony given on Capitol Hill by commissioner Andrew von Eschenbach last year, told us 2/11 he too had been ostracized and intimidated for pointing out Ketek’s problems. “User fees have corrupted the managerial culture by forcing FDA supervisors to focus primarily on meeting timelines,” he said. “Under these conditions, reviewers who ask inconvenient questions that slow up a review are not welcome. In its most extreme form, this certainly can lead to unhealthy interactions between FDA managers and industry — witness how Dan Troy was able to have numerous meetings with industry executives without anyone else present and with no notes taken (at least by FDA). I don’t believe it was an accident that Wyeth sought an audience that included Mr. Troy.”
For industry, if it can get past the marketing culture’s short-term bottom-line thinking, there should be a deeply troubling question in the hidden consequences of user fees that have been described here. It is this: How valuable in the long run can a product be that emerges from a hurried review process that is steeped in fear and operated by people who are demoralized?
As Adam Tooze makes clear in The Wages of Destruction: The Making and Breaking of the Nazi Economy, a demoralized workforce produces inferior products. While the analogy may be offensive, the point remains valid, applicable equally to tangible Chinese imports and to the intangible scientific and intellectual testing that FDA is required by statute and morality to apply in its product reviews.
FOOTNOTE: There is a silver lining in Victoria Hampshire’s story. She now works in the CDRH Division of Cardiovascular Devices reviewing animal studies, and calls this “a vastly different workplace under even greater pressure than the one I left,” yet it manages to be a “nidus of excellence” she hopes other parts of FDA will emulate.
* 2006
Reader comment:
My fervent wish is that this article were on the front pages of the New York Time/Washington Post/LA Times.
I understand that PDUFA 1 was negotiated and legislated in the context of a recession and industry pressure to decrease approval times. And the practice of requiring payment to local, state, or federal entities to allow access to services administered by those entities is widespread, to wit: fishing/hunting licenses, building permits, etc., etc.
A key difference with user fees and examples above and any I can think of, is that the express quid pro quo negotiated with user fees, by its very nature, strongly influences the process. Payments to authorities for building permits or zoning variances, in excess of those mandated by statute or municipal law, constitute prosecutable offenses and prima facie evidence of guilt.
The mystery to me is that although only a modestly well-informed person would reach the conclusion that user fees are akin to a "fox in the chicken coop," there seems to have been almost no dialog on the topic. No doubt the risk was significantly less when the ratio of taxpayer to industry support was greater than one, but common sense would have allowed the prediction that this ratio would not remain for long. I can only conclude that the lobbying expenses of big Pharma have delivered breathtaking returns.
The net result of nearly two decades of this system is becoming apparent. Formerly the 'gold standard' of drug regulatory agencies in the world, FDA has become a curiosity in the international drug regulatory environment. Whereas formerly the FDA played a leading role in policy development, emulated by foreign agencies, FDA now defers to others for guidance, depending upon foreign regulators for policy development, e.g. EMEA and HPB, the European and Canadian regulators. The doctrine of directive/prescriptive, arms-length regulation has been replaced with "you tell us what's important" approach, the useful, prescriptive policies and recommendations supplanted with fluff concepts such as Quality by Design, a term that nobody within or outside of the Agency has been able to define. The Centers for Drugs/Biologics recently spent in excess of $1.5 million for an outside consulting firm to develop a Quality Management Plan (QMP) to support the CMC review process. The efforts were documented in a 57 page report most of which is comprised of descriptions of the framework of the CMC reviewing function in CDER/CBER, definition of terms, and pie-in-the sky recommendations, e.g. ""CMC reviews by FDA scientists will assure the safety, purity, potency, strength, and effectiveness of products." The initiative continues with additional large sums apparently budgeted for this year.
As an old FDA reviewer commented recently, "... it'll take bodies in the street and a public outcry to change things."
The top FDA management officials who have placed and continue to place their own private agenda ahead of the Agency's mission, should not only be ashamed, they should be criminally prosecuted.
May You Whistle While You Work at FDA?
03/30/2007
[Guest editorial by Mark Cohen and Tom Devine*] FDA commissioner Andrew von Eschenbach so believes his agency’s view that cloning is safe that he apparently has copied his own body. How else to explain the two versions of him circulating in Washington these days? One is the champion of vigorous, robust scientific debate and a diversity of views at FDA. He swore to Congress his zero tolerance for FDA managers who pressure reviewers to change their conclusions, and that violators may be fired. But then there’s his evil twin, the despot von Eschenbach, who before dozens of FDA staff threatened to “trade” reviewers who speak out against FDA’s tacit approval of fraudulent clinical trials or who raise their voices against management pressure on reviewers to change scientific conclusions to the liking of drug sponsors. The latter von Eschenbach told a pro-PhRMA conference in February that it is “destructive” for FDAers to blow the whistle on safety and scientific integrity concerns to the public. He was probably thinking of Dr. David Ross.
Ross is, by his own estimation, an unlikely whistleblower. Soft-spoken, cerebral and possessed of a dry wit, the 40-something, Yale-trained Ross railed to his wife against his colleague, David Graham, when Graham rocked the Senate in 2004 with his revelations about the lethality of Vioxx and FDA’s complicity in putting that drug on the market. But Ross’s beef is no longer with Graham; on the contrary, it’s with culture of drug approval at FDA that treats industry as its primary client rather than the public.
Ross served as both primary safety reviewer and safety team leader on Ketek (telithromycin), a Sanofi-Aventis antibiotic for respiratory tract infections. As early as 2000, he was troubled by evidence that the drug caused a variety of dangerous side effects, notably severe liver damage. Ross was further alarmed when the evidence mounted that a 24,000-person clinical trial on Ketek was mired in fraud. When he asked his supervisors about informing an advisory committee about this data integrity debacle, he was stunned to be told that doing so wouldn’t be productive. Then a supervisor leaned on him to “soften” his negative review of Ketek; he reluctantly complied but submitted his original review as well and noted that he had changed the conclusion at her behest.
Ross tried to alert his FDA superiors that Ketek was a bust. But it was his superiors who were championing its approval. So Ross took what was, for him, the extraordinary step of sharing his story with members of the Senate and House, Republicans and Democrats. When the media took an interest — the Wall Street Journal, New York Times, ABC and more — FDA management circled the wagons and lashed out.
Last June, nine months into his tenure as acting FDA commissioner, von Eschenbach was the featured guest at an invitation-only meeting on Ketek at the White Oak campus. Curiously, Ross, who by then had transferred two years earlier to a different office at FDA, was nonetheless invited to this meeting. CDER director Steven Galson told the assembled group that the meeting was to respond to the negative publicity about Ketek, a drug he continued to praise. Von Eschenbach seconded Galson that FDA’s decision-making on Ketek was proper, and he likened FDA to a football team in which differing views may be vented in the “locker room.” But on the field, the team speaks with one voice and any FDAer who blows the whistle will be warned the first time, benched the second time, and traded the third time. With a straight face, von Eschenbach testified before Congress in March that he is sorry if anyone misunderstood his football analogy to mean other than he fully supports the legal rights of whistleblowers. Hmmm.
FDA management’s heavy-handed approach to dissent helped drive Ross out of the agency, as it did to his colleague, John Powers. Until recently Powers was FDA’s lead medical officer for Antimicrobial Development and Resistance Initiatives and is a recognized international expert on the proper design of clinical trials. But he too was censured by his superiors and denied the right to speak at meetings with drug companies. Powers’s offense? He persistently drew attention to FDA’s acquiescence in drug sponsors’ use of inappropriate “non-inferiority trials” to demonstrate efficacy for relatively minor, self-resolving indications. Ketek, he noted, like 67 other antibiotics approved by FDA, had never been shown more effective than a placebo.
Ross and Powers — like Graham before them — were proven correct. Last December an FDA advisory committee, weighing the risks and benefits of Ketek, voted overwhelmingly to recommend that FDA withdraw approval for two of three indications for Ketek. For the lone remaining indication, it recommended that a black box warning be required. (FDA has followed the withdrawal recommendation but balked at the black box warning for anything but the rare disease, myasthenia gravis.)
The Ketek case illustrates the upside-down world that is FDA. Dedicated professionals who risk their reputations and careers to blow the whistle on unsafe or unproven drugs are threatened, punished and pushed out. Those deceiving the public about life-threatening risks remain ensconced in the leadership of this critical public health agency.
This surreal environment persists because government scientists who “commit the truth” are treated like criminals with no realistic chance to defend themselves. They need the protections of the Whistleblower Protection Act but that law has degenerated into the Whistleblower Removal Act. While the paper rights in the WPA are outstanding, due to hostile court and agency decisions, they are as reliable as FDA safety kudos for Ketek or Vioxx. Since 1994 when Congress unanimously made this the strongest free speech law in history, whistleblowers have a 2-179 adverse track record for decisions whether their rights have been violated. The administrative board for their limited day in court has not found a single case of whistleblower retaliation during the Bush Administration.
Fortunately, we are on the verge of a reality breakthrough. By a 331-94 vote on 2/14, the House approved legislation to put enforcement teeth in the Whistleblower Protection Act for federal employees and contractors. The reform’s foundation is normal access to court when their rights are violated. The House also went an extra step. Based on Graham’s experience, it specifically authorizes challenges to — “(1) any action that compromises the validity or accuracy of federally funded research or analysis; (2) the dissemination of false or misleading scientific, medical, or technical information; [or] (3) any action that restricts or prevents an employee or any person performing federally funded research or analysis from publishing in peer-reviewed journals or other scientific publications or making oral presentations at professional society meetings or other meetings of their peers”
Hopefully the Senate will quickly follow suit. This reform could be a real life saver. For the professional lives of honest government scientists who fear that whistleblowing currently is the sound of professional suicide. For the lives of American families, endangered when they trust government deception about drug safety. And for the lives of politicians, since a recent Democracy Corps poll found 79% of likely voters want the new Congress to pass strong whistleblower protection — second in priority only to eliminating illegal spending. There is no time to delay. Until the whistleblower reform becomes law, those who defend the public cannot defend themselves.
FDAer ‘Threatened and Intimidated’ Over Vioxx Safety
10/08/2004
CDER Office of Drug Safety associate director for science David Graham has told congressional investigators he was “ostracized” and “subjected to veiled threats” as he tried to get clearance for publication of a study raising red flags about Vioxx safety. Graham was interviewed 10/7 by Senate Finance Committee staff at the direction of committee chairman Sen. Chuck Grassley (R-IA).
Grassley issued a statement based on the interview saying it appears that Graham’s study and conclusions may have led Merck to withdraw Vioxx, even as FDA was delaying release of the information. “Dr. Graham said today that during the last month he’s been fighting an uphill battle within FDA to let his study see the light of day,” Grassley said. “He described an FDA ‘clearance process’ that he felt was trying to block the publication of his manuscript. Dr. Graham described an environment where he was ‘ostracized,’ ‘subjected to veiled threats,’ and ‘intimidation.’”
According to Grassley, the director of the Office of New Drugs suggested that Graham water down his conclusions and Graham wrote, “I’ve gone about as far as I can without compromising my deeply-held conclusions about this safety question.”
And, Grassley said, on 8/12, before Graham’s findings were presented, his supervisor wrote that Merck needed to know about the report before it became public so the company could be prepared for extensive media attention.
“So,” Grassley said, “it seems that while Merck was taking a fresh look at its clinical data in search of trouble, FDA was challenging its own researcher. Merck knew it had trouble on its hands and took action. At the same time, instead of acting as a public watchdog, FDA was busy challenging its own expert and calling his work ‘scientific rumor.’ What Dr. Graham went through is similar to what we now know another FDA scientist, Dr. (Andrew) Mosholder, went through when he wanted to let the public know about a link between antidepressants and suicide in young people. In both cases, what looks like foot dragging by FDA is downright alarming. Is FDA dropping the ball in protecting the safety of the American people?”
This isn’t the first time that Graham has figured in complaints alleging management intimidation and suppression of scientific staff dissent. In 2003, he co-authored a critical report on the safety of Aventis’ arthritis drug Arava (leflunomide) but management blocked him from presenting it to an advisory committee; he told the PBS “Frontline” show the incident was a “very hostile process.” He was later reportedly removed from the safety review of Hoffmann-La Roche’s Accutane.
FDA issued this statement 10/8: “As a scientific agency, FDA values open discussion and frank exchange about scientific and medical issues. Dr. Graham discussed with his supervisor the abstract of a poster about Vioxx he presented last August in France. Such a discussion is part of the standard FDA review process for this type of abstract. After that discussion, it was Dr. Graham’s decision to revise the abstract. He did so voluntarily and presented the abstract during a scientific meeting. He transmitted his completed report to his agency supervisors on September 30. The standard agency review process for this type of report is a more rigorous scientific peer review.”
PBS ‘Frontline’ Looks at Industry Influence on Drug Approvals
11/14/2003
FDA’s decision to keep Aventis’ Arava on the market despite staff sentiment to remove it and a negative FDA safety report on nine deaths and 38 serious liver injuries was one of three case studies aired 11/13 on a PBS’ “Frontline” investigation of industry influence on agency drug reviews since the enactment of the Prescription Drug User Fee Act (PDUFA). The other two drugs were Wyeth’s Pondimin-Redux (fen-phen) and GlaxoSmithKline’s Relenza. In all three, FDA staff involved in the reviews were overruled by supervisors after drug sponsors opposed or complained about their work, the program said.
Public Citizen Health Research Group director Sidney Wolfe told the program: “The culture of the FDA has become, ‘Please the industry … avoid conflict … look upon our role as getting out as many drugs as possible.’ This [PDUFA] system has created a very unhealthy relationship between industry and the FDA where the FDA says, ‘We have to be nice to these people because they are paying our bills.’”
In the case of Arava, “Frontline” said FDA epidemiologist David Graham (who built the FDA safety case against Rezulin) co-authored a CDER Office of Pharmacoepidemiology and Statistical Science safety report on the drug but was ordered not to make a presentation at an 3/03 advisory committee meeting on the drug’s safety. Instead, “Frontline” reported, Lawrence Goldkind, leader of the review division that approved Arava, spent an hour defending the drug and minimizing Graham’s safety report, and Aventis got equal time to essentially do the same; the panel approved expanded use of the drug. Graham, who attended the meeting but remained silent, was interviewed by “Frontline” afterward in the hall outside and called it all “a very hostile process.” FDA Webview understands that Graham has since been removed from the safety review of Hoffmann-La Roche’s teratogenic Accutane, which is reportedly battling 3,500 pregnancies a year and apparently ineffectual efforts to curb off-label use. Graham declined to comment to us. Arava's labeling warnings were strengthened in June.
In the case of Relenza, “Frontline” interviewed former reviewer Michael Elashoff, who had opposed the influenza drug’s approval on grounds of its minimal efficacy (“pretty much no difference from placebo”) and risk of causing bronchospasm. The advisory committee voted 13-4 against approval and, “Frontline” reported, Elashoff’s supervisors blamed him in severe terms for this outcome. He was ordered not to recommend against Relenza’s approval again, and to change his critical report on Relenza. One change was shown on camera: Where Elashoff had written: “… patients will be exposed to the risks of the drug while deriving no benefit from it,” a supervisor had edited in red ink substitute language: “safety data should be considered in making risk-benefit decisions regarding the use of this drug …”
FDA approved Relenza, “Frontline” reported, after Glaxo filed a written complaint about Elashoff, saying he was judging Relenza “by stricter standards that what had been agreed upon before the review began.” Nine months later, the program reported, “FDA forced Glaxo to put a new warning on the label saying that deaths and injuries can occur from bronchospasm — the very thing that worried Elashoff.” By then, he had left the agency, but he told the program in an interview that his experience in being overruled was very common at FDA.
CDER acting director Steven Galson was also interviewed, confessing that “we’re not proud to hear that anyone has opinions like that.” Galson said: “We wouldn’t condone anyone being asked to change their review. I think the idea of forcing someone to change something that they’ve written or something that they’ve analyzed is highly unusual.” The program cut to Elashoff scoffing: “It happens all the time,” adding that the reason more cases don’t surface may be because reviewers start “censoring themselves.”
Galson observed that Elashoff’s incident happened three years ago and things are different now — “The people that work here are challenged, they’re gratified and by and large they enjoy what they’re doing.”
In the case of ill-fated fen-phen, “Frontline” interviewed retired drug reviewer Leo Lutwak, who said he was “punished” for urging its removal from the market in the face of growing heart-valve adverse events and deaths. The advisory committee voted the drugs unsafe, but on sponsor insistence, FDA scheduled a second meeting without critical consultants being invited to re-present their negative testimony, and this time fen-phen passed. Lutwak and other staffers, however, pressed for a blackbox warning. They were rebuffed by management, and the labeling appeared without it — “the company was jubilant,” Lutwak told “Frontline.”
“I started feeling enough heat to make me recognize that my opinions were not only not respected but they would be disregarded and pushed out of the picture,” he recalled. “I found myself trivialized within the FDA and I was reassigned to areas that I found very dull, unrewarding.” He is now consulting for plaintiffs’ lawyers. Wyeth was reported as having so far paid out $13 billion to litigants injured by fen-phen.
“Frontline” also analyzed the history of the now-withdrawn Bayer statin, Baycol, which FDA approved successive dosage strengths for despite rising rhabdomyolysis side effects.
The program interviewed recent FDA commissioner-candidate Raymond Woosley, now vice president of the University of Arizona Health Sciences Center, who called it “criminal” that FDA has only a staff of 50 to monitor postmarketing adverse event reports on drugs, which “Frontline” said arrived at the rate of 1,000 a day. The job “is just too overwhelming” for such a small staff, he said. “We don’t have a safety system in this country.”
“Frontline” gave the next-to-last word to Galson. FDA, he said, feels no pressure from industry money that comes through PDUFA — “We reject that we are actually influenced by that.”
The last word came from an industry spokesman, who pointed out that Congress has three times endorsed PDUFA, and expanded it.
