FDA official: “clinical trial system is broken” – BMJ

By MB   Dec 11, 2013

If you trust the safety and effectiveness of drugs and vaccines that are prescribed by your doctor or drug store, you don’t understand the process by which those pharmaceutical products are tested and approved.

For a candid, inside look at the sordid world of drug trials and and how top FDA officials actively conceal and censor drug safety red flags, read this exposé by FDA investigator, Thomas Marciniak.

They say it’s safe and effective, but the Supreme Court objected.
They made Big Pharma protected, ‘cause their products are defective!

FDA official: “clinical trial system is broken” – British Medical Journal

December 5, 2013

The clinical trial system is broken and it’s getting worse, according to longstanding Food and Drug Administration investigator, Thomas Marciniak …

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

The Mayo Clinic trained doctor is based in the FDA’s cardiovascular and renal division, analysing industry data. 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 …

MISSING DATA CRUSADE
there are numerous examples that Marciniak cites as evidence to support his concerns about how drug trials are conducted and overseen.

His latest concern revolves around “missing data.” 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 be 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.” …

“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 says the problems he spotted included misrecording of the dates of adverse events, leading to events not being counted; failure to submit potential adverse events for adjudication; and not counting events because of withdrawal of consent despite the events occurring beforehand.6

“In PLATO the missing data for events was about 13%,” he says …

SAFETY CONCERNS
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 bosses that the agency spends longer on the approval of new drugs than it does examining the safety of new drugs after approval …

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 1.04 to 1.18) and a 25% greater risk of new lung cancer …

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 …

But his bosses were not impressed by his endeavours. When Marciniak had told the director of the office of drug evaluation that he was intending to conduct the review, he responded, “This would represent a lot of man-hours, so I have to assume that there is a paucity of work in the [cardio-renal] division at this point.”

To which Marciniak replied: “You are faced with a serious, unanswered question of whether drugs taken by millions of Americans increase cancer rates and you’re concerned about 62 to 93 man-days for my entire plan?” …

While many of Marciniak’s concerns about data integrity have not garnered headlines, that all changed with GlaxoSmithKline’s blockbuster diabetes drug, rosiglitazone (Avandia). It was partly the result of his probing of the raw data in 2010 that led to the drug receiving such a high profile suspension in Europe and severe prescribing restrictions in the US because of concerns over its cardiovascular safety …

“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,” he says. Marciniak contests that his employers want to discredit him, and his paranoia is perhaps supported by an article in industry trade publication, the Pink Sheet.

“The advisory committee’s lukewarm response to Marciniak’s critique of Avandia suggests that his concerns about ARBs [angiotensin-II receptor antagonists] are unlikely to gain broad traction,” an article in June said …

To make his point, Marciniak highlights one particular instance in the RECORD trial. An investigator reported that one participant had had a heart attack but later changed his mind.

“Sixteen or eighteen months later he [the investigator] suddenly supposedly woke up and decided it wasn’t a heart attack. I rather doubt it,” he says. “That’s a good example, I think, of something that should never happen.”…

“I think what could be done is actually to have all of the data provided from the sites, from electronic clinical study reports directly into the regulatory authority as well as directly to the sponsor,” he says. The FDA would then be able to store them.

“With what the investigator initially sent in I think we would be miles ahead in terms of them being able to verify whether the data are complete or not,” he says. He also says that randomisation should be taken away from the companies and done by the regulator.

But the chances of success are small.

“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 says.

Read the BMJ article

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