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‘Lone wolf’ FDA investigator says ‘clinical trial system is broken’

“Drug companies have turned into marketing machines,” Dr. Thomas Marciniak said. “They’ve kind of lost sight of the fact that they’re actually doing something which involves your health.”

FDA Laboratory Building 62 houses the Center for Devices and Radiological Health.
U.S. Food and Drug Administration

Last week, BMJ ran an article on Dr. Thomas Marciniak, an investigator with the Food and Drug Administration (FDA) who has been an outspoken critic of how clinical drug trials are conducted and overseen.

He minced no words. The “clinical trial system is broken,” he told BMJ investigations editor Deborah Cohen.

“Drug companies have turned into marketing machines,” he said. “They’ve kind of lost sight of the fact that they’re actually doing something which involves your health. You’ve got to take away the key components of the trials from drug companies.”

The state of clinical trial research is something all of us need to be concerned about. The FDA uses the findings of these studies to evaluate the effectiveness and safety of prescription drugs. Based on those evaluations, the agency then decides whether the drugs can be used to treat specific diseases and medical conditions.

Pitted against employer

Marciniak is a Mayo Clinic-trained physician who works in the cardiovascular and renal division of the FDA. As Cohen notes, Marciniak “has been embroiled in high profile controversies that have pitted him against his employer.” He has questioned the integrity of clinical data for trials involving the diabetes drug rosiglitazone (Avandia), the blood-thinning drug ticagrelor (Brilinta), and certain blood-pressure drugs known as angiotensin II receptor antagonists (losartan and valsartan), among others.

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“His career experiences have left him extremely critical of the whole research and development process — from trial design to conduct and statistical analysis of data,” writes Cohen. “Although Marciniak says he believes that most investigators are honest, there are shortcomings in the trial model to the extent that he doesn’t know what to trust anymore.”

Marciniak’s criticism of how studies are conducted — and of how the FDA evaluates them — “have seen him described as a rebel and a ‘lone wolf’ — an epithet that seems to be tagged to those who voice concerns,” Cohen adds. “However, the drug studies that he has reviewed and found problems with seem to have a knack of finding their way into the US Department of Justice’s investigations in-tray.”

A case in point: Earlier this year, Avandia’s manufacture, GlaxoSmithKline (GSK) paid a $3 billion fraud settlement with the Justice Department, in part for failing to report cardiovascular (heart attack and stroke) risk data that Marciniak uncovered in 2010.

Missing data

Marciniak’s latest concern about clinical trials is the issue of “missing data.” Writes Cohen:

By this he means participants who withdrew their consent to continue participating in the trial or went “missing” from the dataset and were not followed up to see what happened to them. Marciniak says that this has been getting worse in his 13 years as an FDA drug reviewer and is something that he has repeatedly clashed with his bosses about.

“They [his bosses] appear to believe that they can ignore missing and bad data, not mention them in the labels, and interpret the results just as if there was no missing or bad data,” he says, adding: “I have repeatedly asked them how much missing or bad data would lead them to distrust the results and they have consistently refused to answer that question.”

In one FDA presentation, he charted an increase in missing data in trials set up to measure cardiovascular outcomes.

“I actually plotted out what the missing data rates were in the various trials from 2001 on,” he adds. “It’s virtually an exponential curve.”

Marciniak puts this down to two things. “[This is] partly because subjects have become more aware of their rights to discontinue and less trustful of healthcare providers and partly because one can hide a multitude of sins in missing data,” he says.

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Safety concerns

As Cohen points out, “Marciniak has butted heads with his employers not only over ‘missing data’ but also over drug safety.”

One recent battle exposed on the pages of the Wall Street Journal earlier this year, saw Marciniak complain to [his] bosses that the agency spends longer on the approval of new drugs than it does examining the safety of new drugs after approval.

The class of drugs that ignited that dispute was the angiotensin II receptor antagonists, such as losartan and valsartan, used to treat hypertension.

A 2010 Lancet Oncology paper pooled 68,402 patients and found that people taking angiotensin II receptor antagonists had a 11% greater risk of new cancer (relative risk 1.11, 95% confidence interval 0.04 to 1.18) and a 25% greater risk of new lung cancer, compared with patients who didn’t get the drugs (0.9% versus 0.7%, relative risk 1.25, 1.05 to 1.49). The authors said their findings warranted further investigation.

A year later, regulators on both sides of the Atlantic gave the drugs the all clear. Marciniak, however, was unconvinced. In 2002, while working for the US National Cancer Institute, he had done a drug review of losartan trials in which he had noted there were more lung cancers in the losartan arm.

So Marciniak took it upon himself to plough through the patient level data of the angiotensin receptor II antagonist trials, which led him to dispute his employer’s meta-analysis. His primary hypothesis was that these drugs might increase lung cancer and filed an analysis plan with his boss. He found the drugs increased the risk of lung cancer by 24% compared with placebo or other drugs.

But the FDA did not count lung carcinoma in its cancer tally, and it relied on study level data. “I think that’s completely flabbergasting. Astounding. And it’s been totally washed over. Why?” he says.

When she asked the FDA about this, Cohen was told “the omission of a cancer term was an ‘accident’ that conveys ‘no bias’ on the results.”

Marciniak says the FDA should release all the data, so patients and doctors “can make their own informed decisions.”

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‘Regrettable’ and ‘unprofessional’

Last month, the FDA lifted the strict restrictions it had previously imposed on Avandia. The agency did so over the objections of Marciniak. He did not feel that researchers from the Duke Clinical Research Institute in North Carolina who had reexamined the original study data for the diabetes drug could be considered independent because Duke receives some financial backing from GSK.  (The institute’s associate director denies that point, reports Cohen.)

Marciniak’s objection to the lifting of the restrictions on Avandia has not won him any friends at the FDA. Agency officials claim that a memo Marciniak wrote in which he outlined his reasons for opposing it used “regrettable” and “unprofessional” language. They also claim his memo had been unsolicited. (Marciniak rebuffs both points, says Cohen.)

“If I, as a federal employee or simply as an ethical individual, see evidence of a threat to public health, I have an obligation to report it regardless of whether the issue is assigned to me or not,” Marciniak told Cohen.

One step toward helping to fix the broken clinical trial system, says Marciniak, would be to require that all raw data collected by clinical trial investigators be sent directly to the FDA, where it could be stored and evaluated. But he knows that’s unlikely to happen anytime soon.

“I’m not terribly hopeful on having it adopted just because I think the drug companies will resist tremendously because right now, 100% true, they control the data. [It’s] very, very difficult to verify whether data are complete or accurate,” he said.

Unfortunately, Cohen’s article on Marciniak is behind a BMJ paywall.