Even one of the researchers involved in evaluating injectable Temodar didn't know that the FDA had flagged Cetero's analysis as potentially unreliable until contacted by a reporter for this story.
Dr. Max Schwarz, an oncologist and clinical professor at Monash University in Melbourne, Australia, treated some brain-cancer patients with the experimental injectable form of Temodar and others with the capsule formulation. Blood from his patients was sent to Cetero's Houston lab for analysis.
Schwarz said he still has confidence in the injectable form of the drug, but said that he was "taken aback" when a reporter told him that the FDA had raised questions about the analysis. "I think we should have been told," he said.
Suspect research conducted by Cetero Houston was not only used to win FDA approval but was also submitted to peer-reviewed scientific journals. Aided by the FDA's silence, those articles remain in the scientific literature with no indication that they might, in fact, be compromised. For example, based on Cetero's work, an article in the journal Cancer Chemotherapy and Pharmacology purports to show that Temodar for Injection is equivalent to Temodar capsules.
Edward Sausville, co-editor-in-chief of the journal, said in an email that the first he heard that something might be wrong with the Cetero research was when a reporter contacted him for this story. He also said the publisher of the journal would conduct a "review of relevant records pertinent to this case."
'There's Always Something Missing'
During his years of inspecting the Houston lab, the FDA's Stone said he often had the sense that something wasn't right. When he went to other contract research firms and asked for data on a trial, they generally produced an overwhelming amount of paper: records of failed tests, meticulous explanations of how the chemists had made adjustments, and more.
Cetero's records, by contrast, showed very clean, error-free procedures. As Stone and his colleagues dug through the data, though, they often found gaps. When pressed, Cetero officials would often produce additional data — data that ought to have been in the files originally handed over to the FDA.
Stone said, "We should have looked back and said, ‘Wait a minute, there's always something missing from the studies from here. Why?'"
One reason, the FDA would determine, was that Cetero's chemists were taking shortcuts and other actions prohibited by the FDA's Good Laboratory Practice guidelines, which set out such matters as how records must be kept and how tests must be performed.
Stone and his FDA colleagues might never have realized Cetero was engaging in misconduct if a whistleblower hadn't stepped forward.
Cashton J. Briscoe operated a liquid chromatography-tandem mass spectrometry device, or "mass spec," a sensitive machine that measures the concentration of a drug in the blood.
He took blood samples prepared by Cetero chemists and used mass specs to perform "runs" — tests to see how much of a drug is in patients' blood — that must always be performed with control samples. Often those controls show readings that are clearly wrong, and chemists have to abort runs, document the failure, recalibrate the machines, and redo the whole process.
But Cetero paid its Houston chemists based on how many runs they completed in a day. Some chemists doubled or even tripled their income by squeezing in extra tests, according to time sheets entered as evidence in a lawsuit filed in U.S. District Court in Houston by six chemists seeking overtime payments. Briscoe thought several chemists were cutting corners — by using the control-sample readings from one run in other runs, for example.