Published online 22 July 2010 | Nature | doi:10.1038/news.2010.370

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FDA investigation at Columbia University serves as warning to other centres, say experts.

PET scans use compounds tagged with radioactive isotopes to reveal the inner workings of the brain. SCIENTIFICA, VISUALS UNLIMITED /SCIENCE PHOTO LIBRARY

The work of a leading brain-imaging centre has been suspended after an investigation found that researchers had injected impure psychiatric drugs into clinical-trial volunteers.

Experts say that the episode should prompt other centres to review their practices, and it highlights the shortcomings of an oversight system in which academic labs are largely self-policing.

Researchers at Columbia University's Kreitchman PET Center in New York used radioactive isotopes to label trace amounts of drugs and other compounds, inject them into human volunteers, and track their radioactive decay with positron emission tomography (PET) to visualize how the compounds bind to neural receptors.

However, the chemicals used by researchers at the Kreitchman Center repeatedly failed purity tests and were not correctly authorized by the US Food and Drug Administration (FDA).

Permissive approach

Most experimental drugs in the United States are regulated through an Investigational New Drug (IND) application to the FDA. But radioactive drugs used in research pilot studies do not require an IND, and can rely instead on approval from the research institution's Radioactive Drug Research Committee (RDRC). Researchers are typically expected to file for IND status after 30 trial injections have allowed them to refine their procedure. Even when IND status has been granted, however, the FDA only audits research laboratories in response to complaints, and such complaints are exceedingly rare.

Marc Laruelle, a psychiatrist at Imperial College London who worked at the Kreitchman Center from 1996 to December 2005, says that its problems can in part be traced to the autonomy granted to PET investigators in the United States. Laruelle says that he saw researchers at Columbia taking a permissive approach to regulations, injecting several hundred patients with compounds that only had RDRC approval, rather than filing the necessary IND application. In 2003 he complained about the lax oversight to officials including radiologist Ronald Van Heertum, then director of the centre, but nothing was done. Van Heertum did not respond to Nature 's requests for an interview.

After discovering a problem with the centre's radiolabelled compounds used in his own research, Laruelle contacted the FDA with his concerns in 2004 and, when the FDA audited the centre the same year, it found a slew of problems. For example, radiolabelled compounds that had failed quality-control tests were not properly investigated by researchers, and were still injected into patients.

As a result of FDA sanctions following the audit, production of radioligands — the radioactive molecules that bind with receptors in the body — was shut down for nine months. Laruelle's grants were frozen, and he had to dismiss technicians he could no longer pay.

Gordon Frankle, a psychiatrist who was a junior faculty member at the Kreitchman Center at the time, says that he was not confident that the problems with the lab's procedures were being solved after the audit. He moved to the University of Pittsburgh, Pennsylvania, in June 2006. "It was not clear when and how the questions the FDA was raising were going to be addressed," he says.

Repeated violations

FDA inspectors returned to the centre on 3 June 2008. They found that it was repeating the old violations — and making some new ones, such as injecting volunteers with drugs that were not sufficiently sterile. In the aftermath of that visit, Columbia brought in Chester Mathis, a radiochemist who directs the PET facility at the University of Pittsburgh, as a consultant to advise on their production of fludeoxyglucose, a commonly used radiolabelled compound. He says that he made several recommendations, but does not know if they were incorporated into the centre's protocols.

At the time, Mathis also noticed that radioligand records relating to a drug trial in which he was involved were inconsistent, and production methods did not comply with the paperwork that the sponsoring drug company had filed with the FDA. Mathis declines to name the drugmaker but says that he "brought it to the company's attention".

In January this year, the FDA went back to the centre to check on its progress. Investigators found that technicians had given researchers ten batches of drugs that exceeded impurity limits, sometimes more than doubling them, according to FDA documents seen by Nature. The lab was also using a faulty equation to calculate impurity levels, and an impurity signal found in the computer record of a gas-chromatography test on a radiolabelled compound had mysteriously disappeared from the filed printout. The results of the investigation were reported in The New York Times on 16 July.

Fundamental reorganization

In a 6 July letter responding to the FDA, Columbia said that it had reviewed patient records and found no evidence of harm. Paul Harris, a Columbia biochemist who has used the Kreitchman Center's services for research into insulin-creating β-cells and diabetes, claims that most of the 'impurities' reported by the FDA were simply the radioligands' decay products, which are expected to form following injections. And although experts contacted by Nature agreed that the violations were alarming and a breach of patient trust, they were less certain whether the impurities would have caused any negative health effects or affected the outcome of studies. "With brain receptors, we really must be careful," says radiologist Barry Siegel of Washington University in St Louis. "But my gut feeling is that we have a large margin of safety."

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Columbia declined to answer Nature's specific questions about the case. David Hirsh, Columbia's executive vice-president for research, told The New York Times that the university is now "fundamentally reorganizing the lab's management and operations". The university has hired an external consultant to guide this process, and the Kreitchman Center's radioligand lab is expected to restart production in January.

Some Columbia researchers have been able to obtain their radiolabelled compounds from commercial sources or other institutions, but research depending on short-lived isotopes, such as carbon-11, has been suspended. Van Heertum and psychiatrist John Mann are no longer co-directors of the centre, according to Harris and Laruelle.

Abass Alavi, a radiologist at the University of Pennsylvania in Philadelphia, says that imaging centres across the country should take note of the case. "This is a big lesson for all the major institutions that they are going to have to tighten their internal reviews."