Guarding the human guinea pigs

MINUTES after the first of six human volunteers was injected with an experimental, genetically engineered drug in London last month, the men one by one began screaming in pain, tearing their clothes off, convulsing and losing consciousness, according to media reports.

In an interview with Britain’s Daily Mirror, Nino Abdelhady, 28, who said he was offered $3,500 to participate in the study, recalled feeling the drug “ripping through” his body “like wildfire.” His head reportedly swelled to more than twice its normal size, and he didn’t regain consciousness for eight days. Other volunteers suffered organ failure, and one remains hospitalized, according to the Associated Press.

Unexpected things happen in medical research, especially when a drug is administered to humans for the first time. Eighty percent of the drugs tested on humans in the U.S. never win Food and Drug Administration approval. Still, there are several clues that the tragedy in London could have been minimized or averted -- and more clues that a similar disaster could happen in the U.S. So the cautionary tale of the experimental drug called TGN1412 deserves intense scrutiny on both sides of the Atlantic.

Developed by the German company TeGenero, TGN1412 is an antibody manufactured by fusing mouse and human cells. It was designed to activate one part of the immune system specifically to attack another. TeGenero hoped it would revolutionize therapies for diseases involving the immune system, such as some types of leukemia, multiple sclerosis and rheumatoid arthritis.

The company applied in Germany for permission to administer tiny doses (one five-hundredth of the proposed therapeutic dose) to human volunteers, but was rejected. It then received permission to do the study in Britain.

Two of the volunteers told British reporters that they were warned to expect only headaches and nausea, and had no idea that monkeys given TGN1412 had developed swelling of the immune tissue in their necks.

Inexplicably, rather than giving the drug to one man at a time and waiting to rule out any untoward reaction, the six men were injected at 10-minute intervals, according to the Daily Mirror. Waiting a day or two would have been more prudent for a new biotech drug. A company spokeswoman Thursday would not comment on the dosing interval.

Abdelhady told the Daily Mirror that by the time he got the drug, the first volunteers were already sick and a man next to him, who had been given a dose minutes earlier, was complaining of head pain, “like rockets going off” -- but that the experiment continued anyway.

British regulators said they found no evidence of drug contamination or improper practices, and that the tiny doses should not have caused such a reaction. The investigation is continuing.

But the fact that three weeks later British officials still don’t know what went wrong should raise alarms here as well. That’s because although the study involved a German drug in London, it was carried out by Parexel International, a U.S. research company based outside Boston. Parexel’s website boasts that it partners with drug and biotech companies “to accelerate time-to-market, control development costs, reduce risk and maximize return on investment.” (The London study might have achieved all of these goals, except, of course, reducing risk.)

In the United States, “institutional review boards” are entrusted with responsibility for overseeing the safety of human volunteers in drug studies. The government established these boards to prevent a repetition of the U.S. Public Health Service’s disgraceful “Tuskegee Study of Untreated Syphilis in the Negro Male,” in which poor black sharecroppers were not told they had syphilis so that the disease’s horrific effects could be studied over the next 40 years.

When the institutional review boards were created, most medical research was conducted by universities and nonprofit institutions. Now most clinical research is done by for-profit research companies such as Parexel. Similarly, oversight of the safety of human volunteers in most U.S. studies is no longer done by nonprofit IRBs, but by for-profit review companies, hired directly by the for-profit research companies. The U.S. government approves of this -- but I believe this system lacks the appropriate checks and balances to protect human volunteers.

According to Bloomberg News, the largest for-profit IRB in the U.S. oversees 17,000 studies on people, yet can spend as little as four minutes a study to evaluate whether volunteers are adequately protected. And if one for-profit ethics board doesn’t approve a study, nothing stops the company from simply applying to another -- like TeGenero moving its study from Germany to Britain. In 1998, the inspector general of the U.S. Department of Health and Human Services recommended rules to stop this practice, known as “IRB-shopping.” Ironically, just two months before the London disaster, the FDA decided that such rules were not necessary.

Moreover, the FDA recently approved “phase 0 studies” in which human beings can be given minuscule doses of experimental drugs even before animal studies are completed. Sen. Charles Grassley (R-Iowa) recently told the journal Nature that just when more oversight is needed, “the FDA is loosening the reins on drug companies. I’m concerned for those who will be receiving these experimental drugs.”

The issue isn’t simply whether the research is commercially sponsored (after all, the grotesque Tuskegee study was not for-profit), but whether there are adequate safeguards to make sure that human volunteers are not exposed to unnecessary risks, that studies are carried out as designed and that results are accurately reported.

Unfortunately, these watchdog functions are being eroded. The entrepreneurial incentive to develop new drug therapies is a great motivator. But it will not serve the greater good unless and until there is independent, noncommercial oversight of medical research.