FDA Approves Drugs Despite Suspect Safety and Effectiveness Tests

In the space of a week, ProPublica.org, the nonprofit investigative news site, published two stories about how the FDA permitted dozens of medications-including widely distributed ibuprofen-to remain on the market despite “egregious” violations at the research laboratory that was supposed to scientifically confirm their safety and effectiveness.

The first story detailed how, in 2010, FDA agents pounced on the Houston office of Cetero Research, which conducted research for drug companies worldwide. The FDA had been there plenty of times for routine inspections, but that time it was to investigate a former employee’s allegation that the company had tampered with records and manipulated test data.

So guilty was Cetero that the testing facility’s president actually acknowledged that much of the lab’s work was fraudulent. He had eight flatbed carts rolled in with documents representing five years of data from about 1,400 drug trials. The FDA concluded that the lab’s violations were so pervasive that studies conducted there between April 2005 and August 2009 might be worthless.

“The health threat,” said ProPublica, “was potentially serious: About 100 drugs, including sophisticated chemotherapy compounds and addictive prescription painkillers, had been approved for sale in the United States at least in part on the strength of Cetero Houston’s tainted tests. The vast majority, 81, were generic versions of brand-name drugs on which Cetero scientists had often run critical tests to determine whether the copies did, in fact, act the same in the body as the originals. For example, one of these generic drugs was ibuprofen, sold as gelatin capsules by one of the nation’s largest grocery-store chains for months before the FDA received assurance they were safe.”

The risks to patients, according to academic experts interviewed by ProPublica, are real, especially for drugs such as blood thinners and anti-seizure medications that must be given at very specific doses. And some generic versions of drugs act differently from name-brand products.

While the FDA investigated and ordered re-tests, European regulators pulled seven drugs from the market.

Twice the FDA said it was requiring drug makers to repeat, re-analyze or audit many of Cetero’s tests, and to submit their findings to the agency. Both times the agency allowed some companies to ignore the deadlines.

Now, six months after the last of the deadlines expired and almost three years after Cetero’s misconduct was discovered, the FDA has received the required submissions for just 53 drugs. Most companies met the deadlines but a few haven’t submitted new studies, and some companies haven’t done so because they pulled their drugs from the market altogether.

The FDA has reviewed only 21 of the 53 submissions, “raising the possibility,” ProPublica says, “that patients are taking medications today that the agency might pull off the market tomorrow.”

In its defense, FDA authorities told ProPublica that it has found no discrepancies between any original drug and its generic copy and no sign that any patients have been harmed. “It is nontrivial to have to redo all this, to withdraw drugs, to alarm the public and the providers for a large range of drugs,” Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, told ProPublica. “There are consequences. To repeat the studies requires human experimentation, and that is not totally without risk.”

She called the potential for harm from drugs tested by Cetero “quite low.” Despite requests, the FDA has not released to the public the 21 completed reviews.

Maybe the potential for harm is low. But there’s a larger issue here, and that’s transparency. “If there are problems with the scientific studies, as there have been in this case, then the FDA’s review of those problems needs to be transparent,” David Kessler, FDA head from 1990 to 1997, told ProPublica.”FDA may be right here, but if it wants public confidence, they should be transparent. Otherwise it’s just a black box.”

The medical community at large has reason to be wary. Some of Cetero’s suspect research was published in peer-reviewed scientific journals. The medical community relies on those resources. One researcher and a journal editor told ProPublica they had no idea the Cetero tests had been called into doubt.

The second story followed up the earlier piece, and confirmed that the FDA wouldn’t disclose the names of any of the approximately 100 drugs affected by the fraud at Cetero, claiming that to do so would divulge confidential commercial information. Apparently, consumer safety just didn’t figure into the decision.

Thanks to ProPublica, six of the drugs have been identified, one of which was approved after the agency had cited Cetero for misconduct. (To see the list and what is known about the drugs, link here.)

That drug is a generic version of Tussionex, a narcotic cough suppressant/anti-allergy medication manufactured by Tris Pharma. Its chemical name is hydrocodone polistirex/chlorpheniraminepolistirex.

Both of the trials that claimed to show that the generic drug was equivalent to Tussionex, said ProPublica, were analyzed in May and June 2009 at Cetero Research. Proving that a generic drug is equivalent to the brand drug is required before the FDA allows it to be marketed.

The FDA’s inspection report that spring cited Cetero’s falsified data as well as other lab violations while the drug tests were being conducted. Yet five months later, in October, the agency approved the drug for sale in the U.S.

The FDA continued to inspect the Houston lab, and July 2011 was when it deemed its misconduct so “egregious” and pervasive that five years’ worth of tests were potentially “unreliable.”

In April last year, the FDA said that studies analyzed at Cetero Houston between March 2008 and August 2009 needn’t be redone. Instead, they would require only a “verification of data integrity by an independent third-party audit.”

Tris Pharma submitted the audit later in the year, and the FDA found it “acceptable.”

The FDA has said that its risk assessment found that the chances were low that drugs tested at Cetero Houston were unsafe. And it said that the fact that it hasn’t found problems with drugs tested there “confirmed” that risk assessment. But often, side effects and other problems from new drugs and devices don’t present for a while. For example, metal hip implants can take several years to fail or contaminate their human hosts with tiny bits of metal.

As ProPublica noted, Cetero filed for Chapter 11 bankruptcy last year and emerged with a new name, PRACS Institute. This year, PRACS filed for bankruptcy. It has reported that the Houston lab has closed.

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