Our Views

FDA’s letter to GSK warns Big Pharma to get its act together and start reporting all adverse event information or suffer the consequences of fines and criminal proceedings.

In his In Vivo blog, Micheal McCaughan suggests that the warning letter sent to GlaxoSmithKline (GSK) about its diabetes drug Avandia is more than just bad news for the company, but a warning for other biopharmaceutical companies as well.

After inspecting the firm’s post-market adverse event reporting procedures and discovering that GSK has not filed all the necessary reports on Avandia, the FDA issued a strongly worded letter, addressed to the firm’s CEO Jean-Pierre Garnier. Since the Food, Drug and Cosmetics act is a “strict liability” statute, top executives — starting with the CEO — can be held criminally accountable for violations they knew nothing about.

McCaughan says this is the key section in the letter:

FDA’s inspection revealed that your firm lacked appropriate knowledge of the studies associated with Avandia, resulting in the reporting deficiencies noted. Absent a clear explanation of the extent and cause of these deficiencies and an adequate plan to correct them, we are concerned that similar deficiencies in the postmarket reporting for your firm’s other FDA-approved drugs may exist . We expect that your corrective actions will include a comprehensive evaluation of your firm’s reporting of postmarketing studies for all drug products for which your firm holds an approved application.

McCaughan goes on to say: “The warning letter should be a must read for all biopharma companies with products on the market (and all companies who hope to be so lucky as to have products some day). The letter does indeed add to GSK’s headaches, but for the rest of the industry it should serve as notice that the agency is likely to do a lot more enforcement of postmarketing study reporting requirements in the months and years ahead.

“Congress, remember, has just handed FDA new enforcement authority over postmarketing trials, in the form of the ability to mandate Phase IV studies — and fine sponsors who fail to live up to their commitments.

“In the new world of post-marketing oversight and regulation,” he adds, “expect the agency to make sure that every company gets that message loud and clear.”

Post-marketing adverse events are what we, the public, are all too familiar with. That’s when we usually hear about drug problems — headlines citing injuries, deaths and massive lawsuits, or worse, learning that someone we know or love is a victim.

The FDA’s record on ensuring that prerelease drug testing is thoroughly done before drugs reach the market has been less than stellar in recent years. Many clinical trials showing that a drug had problems were kept from the FDA and the public. Most new drugs are released on the public after being tested with less than 1000 to 3000 carefully chosen patients. This is why the FDA admits that the real tests of a new drug only occur after their release to the public and is why post-marketing disclosures are so important.

That is why it is so critical that post-marketing adverse effects are reported promptly. But post-marketing muscle has been flabby as well, with drugs causing hundreds or even thousands of adverse events before the FDA acts.

Post-marketing inspection and reporting is at least as important as prerelease clinical trials and testing, because no program can possibly cover every possible scenario that could and will exist in the real world. Post-marketing vigilance is critical, and we’re glad to see the FDA stepping up to the plate to get the attention of Big Pharma, and exercising the new muscle given to it by Congress last year in changes to the FD&C Act.
We just hope that the FDA is not just making a show but are serious about this and will take affirmative action if GSK doesn’t immediately correct the problem.

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Whistle-blower lawsuit alleges Schering-Plough failed to reveal problems with a drug that killed five people, including two children, and seriously injured 53 others.

Schering-Plough recently spent $14.3 billion to buy the drug company Organon, and now must face allegations that serious “adverse events” associated with Organon’s neuromuscular blocking agent Raplon were not disclosed before or after FDA approval back in 1999. After five people died, including two children, and at least 53 others suffered severe bronchospasm, Organon withdrew Raplon from the market in March 2001.

Raplon was designed to paralyze a patient’s throat to facilitate intubation — inserting a breathing tube into the trachea — and claimed to induce paralysis faster than older generic drugs that cost less than $1 per unit compared with $20 for a unit of Raplon. Problems arose when patients receiving Raplon suffered serious bronchospasms that stopped their breathing.

According to Ed Silverman’s Pharmalot blog on the subject, the Raplon problems occurred when Schering-Plough’s senior vp for global fertility, Hans Vemer, was still the top man over at Organon. The whistle-blower, Jeff Feldstein, a former Organon employee, first filed his charges in 2002, about the same time he filed a wrongful termination lawsuit against Organon. The US Attorney in Boston declined to join the whistleblower charges at that time, so Feldstein now is pursuing the case independently.

Feldstein’s lawsuit in federal court in New Jersey alleges that Organon executives knew of the serious problems with Raplon and instead withheld the evidence from the FDA in order to get approval. As well as failure to disclose, Feldstein also claims that Organon’s behavior caused false claims to be submitted to Medicaid and Medicare.

Schering-Plough, of course, vehemently denies the charges, saying it will “vigorously defend Organon”. However, the evidence offered by the suit, including copies of internal memos, strongly suggests that Organon ignored the warning bells expressed by clinical investigators prior to the drug’s launch.

If it is determined that Organon did fail to disclose to the FDA its concerns about bronchospasm, it will be yet another blow to Schering-Plough, already suffering from its partnership with Merck over the Vytorin and Zetia debacle. Then there’s the $435 million settlement in 2006 for federal civil and criminal charges that it illegally promoted several drugs for off-label use, and defrauded Medicaid — the third such settlement for Schering in just two years. Schering Sales pled guilty to one count of conspiracy for making false statements to the government and paid a $180 million criminal fine as well.

So, yes, the FDA has some changes to make to prevent these kinds of situations, and they need to do it fast. New policies are needed to jolt Big Pharma enough to wake up and smell the fire and brimstone. It’s time for new business models, both at the FDA and for Big Pharma.

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Big Pharma’s ethics also need a major overhaul or the industry will go the way of the dinosaur.

The Journal of the American Medical Association (JAMA) reported this week that Merck and Co. faked reports on Vioxx. In other words, Merck employees wrote the reports, then attributed the articles to academic investigators hired and paid by the company to use their names.

Now that the JAMA report has made national news, all sorts of industry insiders are coming out of the woodwork and saying it’s common knowledge that Big Pharma hires ghost-writers — pays for the use of academic names — for research and development reports.

For example, in the In The Pipeline blog this week, Derek Lowe says there’s little doubt that the practice goes on. “I’ve never been in a position to see it happen, but it’s been reported for years,” he says.

Lowe points out that no one is suggesting the articles contain bad science or that conclusions drawn in them are faked, even if they written by Merck people.

“I haven’t seen anyone suggesting that the Merck studies themselves are bogus – they had damn well better not be – but by playing games with the external author list, the company invites suspicion,” Lowe says. The practice is driven by what he suggests is a need to bolster a drug’s image because of the money involved. Developing a new drug and shepherding it to market is enormously expensive.

Lowe gets close to the truth when he concludes that the only way to win back public trust, which he says “we’ve lost, in case anyone hasn’t noticed”, is to cut out the shortcuts and double-talk and “act as if what we’re doing — drug discovery — is something to be proud of.”

Calling for ethical changes in Big Pharma’s approach to its business is right on the money. But Lowe shows a lot of altruistic optimism when he says if such practices aren’t curtailed, the industry could face serious price controls, lots and lots of marketing restrictions, the FDA raising the bar for approvals to never-before-seen levels, and “flocks of lawyers beating their wings, circling around our every move” — as if Big Pharma can, on its own, accomplish the fundamental changes it needs to make.

Seeing as Big Pharma’s shady practices are so ingrained and so widespread, it seems to me that one of the measures Lowe warns of — the FDA revamping its approvals process and raising the bar – will almost certainly not be enough incentive to get Big Pharma’s ethics levels demonstrably high enough to warrant a return of public trust.

And while we’re talking about public trust, let’s face the flip side. The FDA itself has a long way to go in that department, too. The public wouldn’t be forced to resort to lawyers and the legal system if the FDA was really on the job.

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It’s been more than two years since FDA scientist David Graham told a Senate panel that the FDA was “incapable of protecting America against another Vioxx.” Now he tells a House panel that “nothing has really changed.”

20-year veteran FDA scientist told the House Subcommittee on Oversight and Investigation recently that the FDA is “incapable of protecting America against another Vioxx, and that since then nothing has really changed” in the FDA’s approvals process.

The subcommittee, chaired by Bart Stupak (D-MI), has been engaged in a series of hearings to evaluate the FDA’s ability to safely approve new drugs and provide post-marketing surveillance, with a jaundiced eye aimed at Big Pharma as well. The hearing was titled: “Ketek Clinical Study Fraud: What Did Aventis Know?”

Dr. David Graham told panel members that the FDA’s Center for Drug Evaluation and Research (CDER) “regards industry as the agency’s main client” rather than considering broad public safety as its mandate. It was Graham’s testimony in 2004 that helped lead to Merck’s arthritis drug Vioxx being pulled off the market in September of that year. Asked about other drugs that the FDA has mishandled, Graham told the subcommittee that atypical anti-psychotic medications to sedate nursing home residents kill roughly 15,000 people a year, and that the weight gain and diabetes dangers posed by Zyprexa, used to treat schizophrenia and bipolar disorder, was known for years to Eli Lilly, the drug’s maker.

Another physician, Dr. David Ross, who has worked on the CDER’s pre-approval side for a decade, said that the antibiotic Ketek, made by Sanofi Aventis, was approved in spite of the fact that the FDA knew it could “kill people from liver damage and that tens of millions of people would be exposed to it.” Ross testified that his FDA bosses forced him to ease back on his unfavorable review of Ketek.

The antibiotic Ketek, approved in April 2004, has been linked to liver failure and other adverse side effects, and the FDA announced in February that Ketek was no longer approved to treat sinusitis or bronchitis because its potential risks outweigh any benefits for these fairly benign conditions. It remains on the market to treat only pneumonia acquired outside a hospital or nursing home.

Mark Senak in his EyeOnFDA blog says the FDA is “in the stew”, and that the FDA leadership “may not believe that they are running for office. They are mistaken. They are running for an office called public confidence. And right now, as for the past few years, the agency is losing that essential race.”

Clearly there are problems with the FDA’s approvals policies and post-marketing controls. When you add Big Pharma’s propensity for unethical practices into the mix, such as withholding or altering clinical trial data, there is no question but to bring about serious changes in the way drugs are tested, reported and approved for public use.

Anything else continues the betrayal of public trust.

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Reacting to reports of deaths, injuries and continuing law suits due to prescription drugs, Rep. Rosa DeLauro, D-Conn., is calling for major improvements to the drug review system at the Food and Drug Administration.

Congresswoman Rosa DeLauro, D-Conn, plans to use her clout as chairwoman of the House appropriations panel responsible for FDA funding, to improve drug safety — and it’s about time someone took the situation seriously.

Calling top agency officials simply “incompetent” over the recent crisis involving the blood-thinner drug heparin in which at least 19 people have died, DeLauro said real change can occur only with a new administration.

DeLauro was quoted in the media saying the FDA “is an agency that is charged with safeguarding the public health, but it’s being run like the keystone cops.”

In the heparin crisis, caused by contaminated ingredients from a Chinese factory, the FDA became aware of the problem only after hundreds were sickened and deaths had occurred. Of course, Congress announced an investigation.

This whole affair shows how little has changed at the agency in nearly a decade. In 1999, a contaminated antibiotic manufactured in China killed at least 17 people before the FDA took notice, and, as usual, Congress investigated. Ho-hum.

Mark Senak, commenting in a recent blog on the terrible first quarter the FDA is having, included DeLauro’s “Keystone cops” quote as one of the indications of trouble at the agency — a heavily funded, understaffed and apparently under-talented federal agency who’s single mandate is to protect the health of Americans, a job it is failing to do effectively enough.

The FDA has itself admitted it violated policy by failing to inspect the plant in China. But according to a New York Times report, drugs imported from China have soared since the last China drug scandal, while the FDA’s inspections of overseas drug plants have dropped significantly. Of the 566 plants in China that export drugs to the US, the agency inspected only 13 of them last year. The story is the same in India and other countries that make drugs or drug components for Big Pharma.

Last week Congress called on the FDA to move faster in forcing drug companies to include in their “direct-to-consumer” advertisements that flood TV every night ways for consumers to report drug side effects to the FDA. The agency tracks so-called “adverse drug events” — meaning drug side effects — and uses reports from doctors and patients to address safety problems with drugs already on the market. But because the system is voluntary, agency scientists complain, it misses the vast majority of drug reactions that occur.

“When only a fraction of adverse drug reactions are reported to the FDA, that means the system is failing,” DeLauro said. She stated her priorities are: Improving the FDA’s handling of post-market drug safety reviews; direct-to-consumer advertising; sufficient funding for generic drug reviews; addressing the agency’s advisory committee conflict of interest policies; improving device oversight; handling drug importation; and renewal of agency user fees.

Let’s keep our fingers crossed that DeLauro and company remain in place through and after this November’s election.

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