FDA’s Lethal Weakness Requires More than Committees

FDA’s Lethal Weakness Requires More than Committees

Sun, 7 Nov 2004

Bloomberg News reports that New York State Attorney General Eliot Spitzer requested information from Pfizer about the promotion of some of its drugs for unapproved uses – the recalled diabetes drug, Rezulin and the antidepressant, Zoloft were named.

In what is surely the understatement of the decade, FDA’s director of the Center for Drug Evaluation and Research (CDER) acknowledged:

“Our current drug approval system has demonstrated that we don’t always understand the full magnitude of drug risks prior to approval of drug products.”

The FDA is under intense criticism following disclosure that the agency time and again failed to detect evidence of lethal drug hazards or to issue appropriate Black Box warnings to protect the public when such hazards were identified by the agency’s own experts – has led senior FDA officials to scramble for cover. The Washington Post and New York Times report that FDA officials have made several announcements to demonstrate a willingness to concede imperfection.

See: Marc Kaufman and Brooke A. Masters. FDA pledges to listen to dissenting scientists, The Washington Post Saturday, November 06, 2004, http://www.washingtonpost.com/wp-dyn/articles/A29124-2004Nov5.html

However, none of the proposed measures would address the inherent overriding problems that plague the agency. An insightful, hard hitting editorial in The Lancet points to an essential problem that the agency fails to address: “The inherent precedence that licensing of new drugs takes over safety evaluation is a serious flaw in FDA’s complex regulatory structure.”

FDA’s failure to identify and to warn the public about the “full magnitude of drug risks” is rooted in the fact that the FDA has given priority to the business interests of pharmaceutical companies–rather than public safety issues. Indeed, the agency has left the Office of Drug Safety without a director for over a year. The FDA has failed to fulfill its mission by pretending not to know that drug companies were concealing lethal side effects because disclosing the “full magnitude of drug risks” is risky for business.

The FDA has yet to act or even to respond to AHRP’s complaint about the failure of Pfizer to comply with FDA’s suicide disclosure requirements in a two page advertisement for its antidepressant, Zoloft, in The New York Times Magazine (October 24, 2004).

Public announcements do not substitute for enforcement of safety requirements. When a public oversight agency fails to perform its mission–protecting the public from hazardous drugs–its leadership must be held accountable and a thorough overhaul is called for.

The foremost objective must be to rid the drug evaluation process of conflicts of interest. Conflict of interest is like graft–it can’t be contained–if tolerated, it corrupts the entire enterprise.

The FDA announced that it would contract the Institute of Medicine to convene a panel to assess FDA’s handling of dangerous side effects. Unless that panel is free of conflicts of interest, its assessment will not be credible.

Unless there is zero tolerance for conflicts of interest in the drug safety assessment process and unless the process becomes transparent–public health is in jeopardy. To ensure that the drug review and approval process is not tainted–all voting members on FDA’s advisory committees must be free of conflicts of interest. All FDA’s consultants’ financial ties to industry must be disclosed. No more waivers of financial disclosure.

Contact: Vera Hassner Sharav
212-595-8974

BLOOMBERG NEWS

Pfizer Says New York’s Spitzer Requests Information (Update2) 2004-11-05 19:21 (New York)
By Nicole Ostrow and Marni Leff Kottle

Nov. 5 (Bloomberg) — Pfizer Inc., the world’s largest drugmaker, said New York State Attorney General Eliot Spitzer requested information about the promotion of some of its drugs for unapproved uses. Pfizer, based in New York, said Connecticut Attorney General Richard Blumenthal also requested materials on so-called "off-label’" promotion of its Zoloft antidepressant. The company disclosed the probes in a regulatory filing. Doctors sometimes prescribe medications for applications that haven’t been approved by U.S. regulators. While such use is legal, promotion of drugs for off-label use isn’t. Pfizer’s Warner-Lambert unit in May agreed to pay more than $430 million to settle U.S. charges that it promoted its Neurontin epilepsy drug for unapproved uses.

Pfizer spokesman Paul Fitzhenry said he couldn’t provide additional comment beyond the filing. Shares of Pfizer declined 27 cents to $28.79 as of 4:17 p.m. in New York Stock Exchange composite trading. They have fallen 19 percent this year. Pfizer also said it has given the Justice Department and the U.S. Securities and Exchange Commission information related to an internal investigation the company is conducting in Croatia. The inquiry involves "certain potentially improper payments made in connection with foreign sales activities in Croatia," Pfizer said in the filing.

Fitzhenry said he couldn’t provide further details. The U.S. Attorney’s office for the District of Maryland told Pfizer in an Oct. 13 letter that it has closed its investigation related to sales of the Rezulin diabetes drug, according to the filing. Pfizer acquired Rezulin when it bought Warner-Lambert in 2000. Rezulin has been the subject of personal-injury lawsuits, claiming the drug damaged some patients’ livers. The drug was taken off the market in 2000. Pfizer in last year’s fourth quarter had $955 million in costs as it set aside money to resolve claims over Rezulin.

–With reporting by Susan Decker in Washington. Editors: Simison, Todd.

http://www.nytimes.com/2004/11/06/politics/06fda.html

THE NEW YORK TIMES, November 6, 2004
F.D.A.’s Drug Safety System Will Get Outside Review,
By GARDINER HARRIS

WASHINGTON, Nov. 5 – Amid intense criticism that it is slow to raise the alarm about unsafe medicines, the Food and Drug Administration announced Friday that it would hire the nation’s top scientific review body to figure out whether the drug safety system is adequate.

In another step, after embarrassing disclosures that the views of its own drug safety officials had been suppressed, the F.D.A. said it would set up an internal appeals process. If someone inside the agency feels that superiors have made a mistake by approving a drug or, after approval, refusing to order its recall, that person will be able to make a case before a committee of experts, from inside and outside the agency, who were not involved in the decision.

“Our current drug approval system has demonstrated that we don’t always understand the full magnitude of drug risks prior to approval of drug products,” said Dr. Steve Galson, director of the agency’s Center for Drug Evaluation and Research.

The twin moves follow the agency’s handling of safety issues in two highly publicized cases.

First, after receiving studies indicating that antidepressants could cause children and teenagers to become suicidal, the agency took nearly a year to decide to require the strongest possible warning to that effect in those drugs’ packaging.

The delay, which agency officials said they had needed to be sure of the data, enraged patient advocates. Criticism mounted further when The San Francisco Chronicle reported that the agency’s own safety reviewer had concluded that there was a risk, but that his views had been suppressed by top F.D.A. officials.

Then, in a similar case, came the recall of Merck & Company’s big-selling painkiller Vioxx, whose long-term use was found to pose cardiac risks. After the recall, word leaked that one of the agency’s safety reviewers had decided well beforehand that this pill, too, was risky.

A stinging editorial Friday in The Lancet, a British medical journal, condemned the F.D.A.’s entire system of drug safety review and said the agency had acted out of “ruthless, shortsighted and irresponsible self-interest” in failing to demand the removal of Vioxx earlier.

In one of the moves announced Friday, the agency will hire the Institute of Medicine – a part of the Congressionally chartered National Academy of Sciences, the government’s top scientific reviewer – to study how well the F.D.A. assesses the dangers of unexpected side effects of marketed drugs.

Responding to the announcement of the new initiatives, Senator Charles E. Grassley, Republican of Iowa, issued a statement calling them “welcome, albeit late in coming.”

As chairman of the Senate Finance Committee, Mr. Grassley has spearheaded an investigation into the F.D.A. “It’s obvious,” he said Friday, “that the leadership of the agency must take on what look like deep-rooted problems when it comes to putting public health and safety first and public relations second.”

Mary Jane Fingland, a spokeswoman for the drug industry’s trade group, the Pharmaceutical Research and Manufacturers of America, said, “All medicines have risks, and it is important for patients, their physicians and pharmacists to decide whether the benefits outweigh the risks of taking the medicines.”

Some conservative and industry analysts said they feared that the new steps could slow the agency’s approval of drugs.

“The public health consequences of slowing down drug development and approval far outweigh the risks from drugs whose side effects turn out to be unexpectedly bad,” said Sam Kazman, general counsel of the libertarian Competitive Enterprise Institute.

In a third step announced Friday, the F.D.A. said it would accelerate its search for a new director of its Office of Drug Safety. The post has been vacant since October 2003. One problem in finding someone qualified to fill it has apparently been competition from pharmaceutical companies, which can afford to pay far more than the $125,000 or so salary that comes with the government job.

In yet another initiative, the agency said that by the end of the year, it would publish guidelines to help drug companies manage the risks inherent in their products.

Still, Dr. Galson, the F.D.A. official, said he saw no need for a thorough overhaul of the agency’s culture or systems.

“We are very proud of our independence, and we think most of the charges being leveled are just not accurate,” he said. “We hope this won’t result in important products for the public health of the United States being delayed in their marketing.”

One physician who has long been an observer of the agency, Dr. Raymond Woosley, vice president of the University of Arizona, said he hoped that the experts from the Institute of Medicine considered an idea that he has pushed for some time: a permanent, independent review group that would play a role in pharmaceutical cases similar to the role the National Transportation Safety Board plays in plane crashes.

“Any time there is a significant event with a drug,” Dr. Woosley said, “there should be an independent panel that looks to see if the right decisions were made and what should happen in the future.”

Dr. Galson replied that such an independent agency would be expensive to create. “If we had several hundred million dollars lying around, we could do these independent reviews more regularly,” he said.

Further, he said, drugs’ risks cannot be assessed without a thorough understanding of their benefits.

Kathy Woodward, who became active as a critic of the agency after her 17-year-old daughter committed suicide while taking antidepressants, said she worried that the F.D.A.’s announcement Friday amounted to little more than a smokescreen for its failures.

“I just have a very uneasy feeling,” Ms. Woodward said, “about anything the F.D.A. is doing these days.”

http://image.thelancet.com/extras/04cmt396web.pdf
Comment
Vioxx, the implosion of Merck, and aftershocks at the FDA
THE LANCET Published online
November 5, 2004

Today we publish results from a cumulative meta-analysis which show that the unacceptable cardiovascular risks of Vioxx (rofecoxib) were evident as early as 2000 – a full 4 years before the drug was finally withdrawn from the market by its manufacturer, Merck. This discovery points to astonishing failures in Merck’s internal systems of postmarketing surveillance, as well as to lethal weaknesses in the US Food and Drug Administration’s regulatory oversight.

In a recent Editorial, we commended Merck for acting promptly in the face of new findings about the safety of Vioxx.1 Our praise was premature. The evidence showing that Vioxx caused significant adverse events was apparent well before data from the APPROVe trial triggered Merck’s overdue intervention. This week’s report by Peter Jüni and colleagues will add significant weight to ongoing litigation against Merck by patients who believe they were harmed by this drug.

These findings also come in the wake of new disclosures that suggest Merck was indeed fully aware of Vioxx’s potential risks by 2000. Investigations by the Wall Street Journal2 have revealed e-mails that confirm Merck executives’ knowledge of their drug’s adverse cardiovascular profile – the risk was "clearly there", according to one senior researcher. Merck’s marketing literature included a document intended for its sales representatives which discussed how to respond to questions about Vioxx – it was labeled "Dodge Ball Vioxx". Given this disturbing contradiction – Merck’s own understanding of Vioxx’s true risk profile and its attempt to gloss over these risks in their public statements at the time – it is hard to see how Merck’s chief executive officer, Raymond Gilmartin, can retain the confidence of the public, his company’s most important constituency.

The FDA’s position is no less comfortable. The public expects national drug regulators to complete research, such as that published by Jüni and colleagues, in their ongoing efforts to protect patients from undue harm. But, too often, the FDA saw and continues to see the pharmaceutical industry as its customer – a vital source of funding for its activities – and not as a sector of society in need of strong rregulation. Worse still, the FDA’s Office of Drug Safety co-exists in the same centre – the Centre for Drug Evaluation and Research (CDER) – as the Office of New Drugs, the part of the agency that works most closely with industry to license new medicines.

Once a licensing approval has been made it is naturally in CDER’s own interests to stand by its original decision. CDER’s reputation would be damaged if its licensing judgments were constantly challenged by its own staff. This understandable but dangerous tendency to discourage dissent makes the Office of Drug Safety, which sits lower in the hierarchy of CDER than the Office of New Drugs, weak and ineffective. The inherent precedence that licensing of new drugs takes over safety evaluation is a serious flaw in FDA’s complex regulatory structure. In the case of Vioxx, FDA was urged to mandate further clinical safety testing after a 2001 analysis suggested a "clear-cut excess number of myocardial infarctions".3 It did not do so. This refusal to engage with an issue of grave clinical concern illustrates the agency’s in-built paralysis, a predicament that has to be addressed through fundamental organisational reform.

On Nov 2, 2004, the FDA tried to shore up its tarnished reputation by posting on its website an early version of a recently completed observational study into the safety of Vioxx. The report comes with a warning that it has "not been fully evaluated by the FDA and may not reflect the official views of the agency". The FDA investigators estimate that over 27 000 excess cases of acute myocardial infarction and sudden cardiac death occurred in the USA between 1999 and 2003. "These cases", they write, "would have been avoided had celecoxib been used instead of rofecoxib". This study is presently under review at The Lancet. It is unclear why the FDA could not have waited for the fully evaluated report to have been scrutinised, revised, and published according to the norms of scientific peer review. Bypassing independent peer review smacks of panic in the FDA, which is under intense reputational pressure.

And yet its decision to try to undermine the integrity of this work again shows that the agency’s senior management is more concerned with external appearance than rigorous science.

The licensing of Vioxx and its continued use in the face of unambiguous evidence of harm have been public-health catastrophes. This controversy will not end with the drug’s withdrawal. Merck’s likely litigation bill is put at between US$10 and $15 billion. The company has seen its revenues and market capitalisation slashed. It has been financially disabled and its reputation lies in ruins. It is not at all clear that Merck will survive this growing scandal. But the most important legacy of this episode is the continued erosion of trust that public-health institutions will suffer. Failure to act decisively on signals of risk might minimize short-term political criticism for regulators, or shareholder unrest for company chief executives. But the long-term consequence of prevarication is a tide of public scepticism about just whose interests drug makers and regulators truly represent.

It is no good saying, as some academic physicians have said to me, that one must expect pharmaceutical companies to do all they can to protect their products, even in the face of clear evidence of risk. And it is of little help to suggest that regulators have a nearly impossible job of balancing harms and benefits. Defenders of our systems of drug regulation argue that the blame for the Vioxx debacle instead rests on allegedly credulous specialists who should have asked tougher questions about the drug they were prescribing. Why clinical investigators studying Vioxx did not do more to raise concerns is a fair question that needs to be answered. But in doing so, we must not diminish the importance of the covenant of trust that society has established with powerful commercial and governmental institutions.

For with Vioxx, Merck and the FDA acted out of ruthless, short-sighted, and irresponsible self-interest.

Richard Horton

The Lancet, London NW1 7BY, UK

1 Editorial. Vioxx: an unequal partnership between safety and efficacy. Lancet 2004; 364: 1287­88.

2 Matthew AW, Martinez B. E-mails suggest Merck knew Vioxx’s dangers at early stage. Wall Street Journal Nov 1, 2004: A1.

3 Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med 2004; 351: 1707­09.

2 www.thelancet.com Published online November 5, 2004 http://image.thelancet.com/extras/04cmt396web.pdf

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