Saturday, November 29, 2014

Big Pharma Plays Hide-the-Ball With Data

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The problem with data in all science is that negative results are rarely disclosed for any number of good reasons.  My argument though is that all data needs to be disclosed as a matter of course.  I will; go further than that.  All data needs to now be saved electronically and delivered to a records depository with a cover submission letter.  That at least establishes a working protocol that preserves data at low cost.
The data can be withheld for sensible time periods before it is released.  The first huge benefit is that all new researchers to an area of work will have the raw data to review in order to make their own judgement. That matters as experimental weaknesses can bias an interpretation unnecessarily.
This applies to all science.  The more serious problem is medical research were weak or deliberately biased interpretation can lead to serious harm.  Worse, we cannot trust the often partly naive or the simply greedy to get it right.
Big Pharma Plays Hide-the-Ball With Data

By Ben Wolford / November 13, 2014 6:54 AM EST

On the morning of March 2, 2005, a 14-year-old Japanese girl woke up scared. At first she thought someone was outside the house watching her, but then she decided the stranger must be inside. She wandered restlessly and, despite the cold weather, threw open all the windows. Later, over a meal, she declared, “The salad is poisoned.” Two days later, she said she wanted to kill herself.

This teenager with no history of mental illness was diagnosed with delirium. The night before the hallucinations started, she began taking an anti-influenza drug called Tamiflu (generic name: oseltamivir), which governments around the world have spent billions stockpiling for the next major flu outbreak.

But evidence released earlier this year by Cochrane Collaboration, a London-based nonprofit, shows that a significant amount of negative data from the drug’s clinical trials were hidden from the public. The Food and Drug Administration (FDA) knew about it, but the medical community did not; the U.S. Centers for Disease Control and Prevention (CDC), which doesn’t have the same access to unpublished data as regulators, had recommended the drug without being able to see the full picture. When results from those unpublished trials finally did emerge, they cast doubt over whether Tamiflu is as effective as the manufacturer says.

The revelation of hidden data bolstered a growing movement against what’s referred to within the research community as “publication bias,” in which scientists squirrel away mostly negative or inconclusive findings and broadcast only their positive ones. Concealing trial data—for which patients accept the risks of untested treatments for the greater good—is routine. As many as half of all clinical trials are never published, PLOS Medicine reported last year.

That Japanese girl, whose case was detailed in an FDA report, did not kill herself. But at least 70 people have died, many of them by suicide, after Tamiflu-induced episodes. The deaths were almost surreal: A 14-year-old who took Tamiflu jumped off a balcony, and a 17-year-old on the drug ran in front of a truck. Scientists documented other cases of “psychopathic events,” including a South Korean girl who temporarily developed bipolar disorder and an 8-year-old Japanese boy who wouldn’t answer to his name and began to growl.

Tens of millions of people have taken Tamiflu without incident, and you are far more likely to die from the flu than you are to have a dangerous reaction to the drug. And it’s true that with many medicines a minuscule chance of death is usually tolerated—as long as the benefits far outweigh that risk.

But if Tamiflu does nothing, and there’s even a slight chance of life-threatening side effects, why was it approved? And why continue to prescribe it? That’s what the Cochrane Collaboration argued in a report it published in April. Cochrane is widely considered one of the most rigorous reviewers of health science data. It takes results of multiple trials, looks for faults and draws conclusions. It doesn’t accept funding from businesses with a stake in its findings. And in April, Cochrane took Tamiflu’s maker, Roche, to task about many of its claims.

Gavin Morrow, Principal Scientist of Immunobiology, shows data to Karl Mullen, Research Assistant, at the AIDS Vaccine Design and Development Laboratory at the laboratory's campus in the former Brooklyn Army Terminal, Dec. 1, 2008 in New York City.

Questionable Findings

The influenza virus infects by hijacking healthy cells in the respiratory tract, taking over the nucleus—the cell’s brain—and ordering up copies of itself. Then these new viruses burst out of the cell membrane like an enemy horde to infect more cells. The drug oseltamivir is thought to work mainly by trapping those virus copies inside the cell. With a lower “viral load,” the symptoms won’t last as long, and there’s a lesser chance of developing complications, like pneumonia, and infecting other people.

That was the theory. Roche paid for dozens of clinical trials to prove oseltamivir worked in practice. Afterward, the scientists produced lengthy “clinical study reports” and turned them over to the FDA, which approved the drug in 1999. Some of those reports were condensed into short articles published in medical journals. Most of us have access only to these published findings.

But the full clinical study reports from those trials were locked away. There wasn’t even a list of what trials were conducted; Cochrane initially figured there were about 36 and sought to read them all. It began negotiating with the drugmaker, filing freedom of information requests to the FDA and the European Medicines Agency (EMA), Europe’s FDA equivalent, and backing pressure campaigns in the media. At one point early on, Roche offered to give Cochrane 10 reports, but only if it signed a confidentiality agreement keeping everything secret—including the existence of the agreement. Cochrane refused to sign.

After five years, Roche and the EMA opened up (the FDA has not, and did not respond to requests, both from Cochrane and Newsweek, to explain why). What Cochrane uncovered was more than 70 Tamiflu trials and well over 100,000 pages of unpublished reports. Among them were many trials where the results were negative or inconclusive. With this more complete picture of the testing, Cochrane concluded the trials don’t prove that Tamiflu prevents hospitalizations, contagiousness or complications. The only thing it definitely does do, Cochrane said, is shorten the duration of symptoms, by about a day.

Many agencies, including the CDC, did not change their positions after the report. In response to questions from Newsweek, a CDC spokeswoman referred to an article from April in which the agency says it still believes Tamiflu is “an important adjunct to influenza vaccine.” It cites, for example, a large study published in May in The Lancet, which found that the odds of dying from the flu rose each day without Tamiflu.

As the Cochrane Collaboration was conducting its investigation, the BMJ was conducting its own. It found that neither the FDA nor the EMA “logged any specific psychiatric harms when they licensed oseltamivir.” No one could have predicted the bizarre suicides, but Cochrane’s disclosures revealed indications in the unpublished study reports of the potential for psychiatric side effects. Roche and the regulatory agencies have said there was no proof that the delirium and hallucinations were caused by the drug. As the number of deaths mounted, that position became increasingly difficult to hold.

Since the Cochrane report, many groups have urged companies and regulators to open up trial data, particularly if public money is being used. The U.S. government spent $1.3 billion to develop and stockpile antiviral medication, including Tamiflu. “All trials should be published or at least have their results available somewhere,” says Agnes Dechartres of Paris Descartes University, who led the PLOS Medicine stud

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