A Window on Human Research Done by Contract Research Organizations

The recent tragic and unprecedented results of a Phase I clinical trial of a monoclonal antibody known only as TGN 1412 provide a new window into the issues surrounding the now heavily commercialized world of drug testing.

The outcome of the TGN 1412 tests have received global attention. Briefly, TGN 1412 is a monoclonal antibody developed by the German company TeGenero AG. An initial test on six volunteers was arranged by Parexel International at their facility at Northwick Park Hospital in London, UK. Six volunteers received apparently the same initial dose of the drug, while two others received placebo. Within hours of receiving the drug, all six complained of fever, and severe pain in their heads. They apparently developed severe swelling of their heads and upper bodies, and then developed multi-organ system failure. All were rapidly admitted to the hospital's intensive care unit.

The particular symptom complex these patients suffered seems to be unprecedented. Previous instances in which everybody who received a new drug rapidly developed life-threatening illnesses are apparently unheard of.

The media have been doing their best to investigate what happened, while the UK Medical and Healthcare Products Regulatory Agency (MHPRA) suspended the trial and is also investigating. Based on newspaper reports available so far, though it is striking what is not known about this drug trial.

We know the company designation for the drug, and its general type (a monoclonal antibody, or protein developed to bind to a specific molecule), but nothing more specific. We do not know what the target molecule was for the antibody, the rationale for its potential therapeutic usefulness, or the results of its in vitro (test-tube) or animal testing. Some of the news reports suggested conflicting results of animal studies. For example, one report in the Times (UK) quoted the girl-friend of one of the trial subjects , "They [the drug company] said there was an oversensitivity in monkeys...." Furthermore, "a dog and some animals had died." But the Times also reported that the Chief Scientific Officer of TeGenero, Thomas Hanke, "refused at a press conference to say whether animals had died during earlier tests. 'There has been no issue on the safety of the drug oanimalsls. This is not relevant.'" In addition, Bloomberg News reported that the CEO of TeGenero, Benedikte Hatz, said "these events were completely unexpected and do not reflect the results we obtained from initial laboratory studies...." Finally, the Independent reported a claim by a lawyer for one of the research subjects that "there is confusion about whether the drug had been testsuccessfullylly and safely on animals before the tests on these volunteers."

We know very little about how the trial was designed. The Times reported "the trial protocol had been agreed with the MHPRA and was carried out 'according to strict ethical and regulatory requirements,' per Parexel. The MHPRA yesterday refused to give precise details, citing commercial confidentiality, and questions to Parexel went unanswered." Some reports suggested that all six volunteers got doses of the drug simultaneously. The Times noted that this practice was not condoned by a textbook it consulted, which instead suggested sequential dosing.

We do not know what sort of oversight or review this trial had received. The Bloomberg report quoted Parexel's claim that it uses "standardized procedures for testing a drug in humans for the first time, based on a protocol approved by ethics committees and regulatory authorities." What ethics committee approved this protocol is unclear.

We have previously posted about how clinical research on human subjects has become more and more an enterprise done by for-profit commercial contract research organizations, (like Parexel), and supervised (in the US, at least) by commercial institutional review boards (IRBs). We posted (go here and see links) about various questionable practices by US based commercial contract research organization SFBC International, which is now under investigation by a US Senate Committee and the US Security and Exchange Commission (SEC). Furthermore, a trial immunosuppressantresant drug carried out by SFBC International's Canadian subsidiary resulted in 20 patients and staff members contracting latent tuberculosis.

Current regulations of clinical research on humans in the US were developed in the days when most research was carried out and directed by faculty members at academic institutions. Now most research is funded by commercial firms, mainly drug and device companies. When such research is carried out in academic institutions, it is performed often under contracts that give considerable control to the commercial research sponsors, rather than to the faculty ostensibly principal investigators. Furthermore, most such research is now carried out by contract research organizations, under contract to the drug or device company, and supervised by commercial IRBs also paid by the commercial sponsor.

Human clinical research has profound health and safety implications both for its subjects, and for any patients who eventually take the drug or use the device under study. Given that, research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised. Such transparency was obviously not in evidence in the trial of TGN 1412. We need to revise regulation of drug and device testing on human subjects to make it sufficient to protect research subjects and patients in the current era of globalized commercial research.