When Science Goes Wrong (23 page)

In mid-2002, after critical assessments by the independent review panel, Wilson resigned as director of the Institute for Human Gene Therapy. Soon thereafter the institute itself was closed down.

The Gelsinger lawsuit and the closure of the institute were not the only woes that Wilson and his colleagues faced, however, because the FDA also sought retribution on the Penn team, and it did so with a single-minded focus and almost nitpicking attention to detail that far outdid its performance while regulating the clinical trial itself. Over months and years, long lists of allegations flew from Washington to Philadelphia, and even longer explanations and refutations flew back from Philadelphia to Washington. The core of the government’s case was that Wilson and his co-investigators had failed to stop the clinical trial or to properly notify the FDA when earlier participants in the trial developed severe adverse reactions to the infusion of the adenoviral vector, and that they proceeded with the infusion of Jesse Gelsinger when his high ammonia levels should have disqualified him from participation. Absent these misdeeds, Jesse would not have died.

Eventually, the FDA turned the matter over to the US Department of Justice. The DOJ brought a formal action against Wilson, his colleagues and their institutions, alleging that they had committed numerous violations of the Civil False Claims Act in their dealings with the NIH and the FDA.

Finally, in February of 2005, a settlement was reached. Under the terms of the settlement, none of the defendants admitted to the government’s allegations, but the University of Pennsylvania and the Children’s National Medical Center each agreed to pay a penalty of more than $500,000 and to enact numerous changes to strengthen the oversight of clinical trials. Wilson was banned from participating in clinical trials until 2010, and a special monitor was to be appointed to oversee his other research activities. He would have to undergo retraining if he ever planned to participate in clinical trials again. In addition, he was to write and publish an article describing the ‘lessons learned’ from the entire episode. Batshaw and Raper were placed under government supervision for a period of three years and would have to undergo retraining.

These were severe punishments for ambitious clinical researchers, but Paul Gelsinger doesn’t see it that way. ‘They got off easy, amazingly easy,’ he said to me. ‘It was medical manslaughter.’ The fact that Wilson never apologised or admitted any culpability for Jesse’s death was particularly galling to him.

With Batshaw and Raper it was a little different. Whereas Paul never met Wilson until after his son’s death, he had established some rapport with both Batshaw and Raper and had witnessed their efforts to save Jesse’s life. Although they may not have explicitly apologised or admitted culpability, Paul read their actions as expressing a desire for forgiveness. Raper, after all, climbed 5,000 vertical feet with Jesse’s family to scatter a portion of his ashes. And Batshaw, about a year after the settlement, sent Paul an email in which he said that his thoughts had turned to Jesse on the occasion of Yom Kippur, the Jewish Day of Atonement. Later the two men met briefly. Paul acknowledged to me that both Batshaw and Raper were genuinely torn up by what happened. ‘I’d like to see these guys find forgiveness for what they did,’ Paul told me. ‘But part of that is acknowledging what you’ve done.’

Did the tragedy of Jesse’s death, the ensuing publicity, the investigations, the legal manoeuvres and the ensuing tightening of regulations improve the safety of clinical trials – whether in the specific area of gene therapy or for drug research in general? To Robert Erickson, the University of Arizona geneticist who reviewed Wilson’s initial proposal, the answer is Yes. He said that, after it was revealed that Wilson had failed to report his volunteers’ adverse reactions, 700 such reports came in from other clinical investigators within a period of just a few days. ‘I think people are reporting adverse reactions much more quickly,’ he said.

Arthur Caplan takes a less positive view. ‘Paul Gelsinger tried to bring about changes so that the same thing wouldn’t happen to anyone else,’ he told me. ‘He went to a lot of meetings, he fought for subject rights, he gave of himself in a very powerful way, he became committed to trying to make change. But you know what I think the legacy of Jesse’s death was for human subjects reform? Almost nothing. Many of the problems that existed then still exist now: failure of informed consent to work well, IRBs still overwhelmed with work, no clarity on the animal data reports, difficulties in getting subject selection criteria properly understood. I would say no, it’s no better.’ And he went through a litany of clinical trials that have gone seriously wrong since Jesse’s death.

One particularly nightmarish episode occurred in 2006 – not in the United States, but in Britain. In March of that year, a drug-testing company named Parexel conducted the initial human trial of the immune-system modulating drug TGN1412, which had been developed by a German biotech company named TeGenero. The drug was a monoclonal antibody – an immune-system molecule that binds to a single molecular target in the body. The antibody was designed to stimulate the class of white blood cells known as T cells, and the hope was to utilise this effect in the treatment for rheumatoid arthritis and a certain form of leukaemia.

After uneventful trials in laboratory animals, Parexel recruited eight healthy volunteers – all men – for the initial human trial, which was to be conducted at Parexel’s unit at Northwick Park Hospital in North London. The volunteers included Navneet Modi, a 24-year-old business school graduate, Ryan Wilson, a 20-year-old trainee plumber and Mohammed Abdalla, a 28-year-old bar manager. Each of the eight subjects was to receive £2,000, a sum well above what is customary for participation in drug trials in the United Kingdom. In fact, some of the men were basically professional guinea-pigs. They derived a significant portion of their income from volunteering for drug trials. (Jesse Gelsinger, in contrast, was never offered any financial incentive to participate in the Penn trial.)

Two of the subjects received an inactive placebo, while the other six men were infused with the drug at a dosage of 0.1mg/kg. This level was considered safe because monkeys had tolerated dosages 500 times higher without any apparent ill-effects. Each infusion took about two minutes, and the eight infusions were done one immediately after the other, so that the whole procedure took about 20 minutes.

‘An hour after the drug entered my body, I was suddenly gripped by pain,’ Modi later told
The Times
. ‘I felt my head swelling up like an elephant’s. I thought my eyeballs were going to pop out. I screamed out, “Please, doctor, help me. Help me,” but he told me to lie down, and then came back with a single paracetamol tablet. It felt like a terrible nightmare.’

All six of the subjects who received the TGN1412 became extremely ill. They were experiencing the same kind of ‘cytokine storm’ that had killed Jesse Gelsinger.

Their heads and bodies grotesquely swollen, they were rushed into intensive care. Within 12 hours, their lungs, kidneys and other organs were starting to fail, and their blood pressure fell to dangerous levels. The subjects were treated with massive doses of steroids and other immune-suppressing drugs, and they underwent dialysis in an attempt to remove the TGN1412 from their bodies.

Four of the men began to recover within two days, but two men – Wilson and Abdalla – became critically ill with cardiovascular shock and respiratory distress syndrome, and were maintained on respirators and other life-support systems for many days. Eventually, all of the subjects recovered sufficiently to be discharged from the hospital, but they have had serious ongoing medical problems, including blackouts. Wilson had to have gangrenous toes and fingertips amputated, and all of the subjects are considered to remain at high risk of cancer and immune-system disturbances; in fact, one of them was already reported to show early signs of lymphoid cancer four months after the drug trial. ‘It’s a really bizarre feeling when you discover you might be dead in a couple of years or even in a couple of months,’ said Modi. ‘I feel like I’ve given away my life for £2,000.’

Initial investigations into the cause of the medical disaster have failed to identify any human error, such as in dosage, that might have caused the drug trial to go so seriously wrong. Nor does it seem that the drug was contaminated with bacteria or with other toxic agents. Rather, it appears that this was an unforeseen reaction to TGN1412 in its intended dosage. Nevertheless, two aspects of the way the trial was conducted seem to have played key roles in causing the harm to be so severe. First, and most obviously, the researchers did not wait to observe the reaction of the first volunteer to the drug before infusing it into the other five. ‘To me, that was insane,’ commented Robert Erickson. Second, the researchers infused the drug at a very high rate – much faster than it had been infused into the monkeys. Adverse reactions are typically worsened by high infusion rates, so a slower rate might have caused lesser harm or none at all. Nevertheless, the investigation when complete may identify other more important causal factors.

Of course, a lawsuit is now in the works. But TeGenero, a recent biotech start-up, filed for bankruptcy in July 2006, citing the drying up of investment capital after the drug-trial story broke. Each subject reportedly received £10,000 in compensation from TeGenero before it went bankrupt, but the company’s insurance policy was for only £2 million, meaning that there will not be nearly enough money to adequately recompense the six men should the company be found liable. At time of writing, I understand there have been talks between the victims’ representatives and Parexel, but the outcome of these negotiations has not been disclosed.

Gene therapy took a terrible blow from the Gelsinger tragedy. Clinical trials came to a halt and were only restarted in the most restrictive and cautious fashion. In 2006 the ‘father’ of the field, USC’s William French Anderson, was convicted of child molestation and (in the following year) sentenced to 14 years’ imprisonment. Then, in July of 2007, another death occurred. This happened during a clinical trial of a genetically engineered vector designed to treat rheumatoid arthritis and related conditions. The vector, developed by a Seattle-based company named Targeted Genetics, employed a type of virus different from (and supposedly safer than) the adenovirus that killed Jesse Gelsinger. The trial was also thought to be safer because the vector was injected locally into the affected joint, rather than into the bloodstream. Yet the patient, who has never been identified, died after receiving a second dose of the vector. An NIH inquiry concluded that the injection of the gene therapy agent was not the cause of the patient’s death. Nevertheless, the event was a blow to Targeted Genetics. Its founder and CEO resigned in 2008, and the company is now in financial difficulties

In spite of these setbacks, Inder Verma sees a bright future for the field. He points to a dozen or so SCID-affected children who are alive today because of gene-therapy procedures that they underwent in France. ‘It will become a successful therapy,’ he says.

NUCLEAR PHYSICS: Meltdown

THE TOMBSTONE OF Richard Leroy McKinley looks no different from hundreds of others in Section 31 of Arlington National Cemetery. It’s a plain stone slab, decorated with a simple cross. It lists McKinley’s date of birth (December 2, 1933) and death (January 3, 1961), states his rank (Army Specialist 4), and mentions his service in Korea.

If you were to dig beneath the stone, however – an act which is forbidden by a special order from the office of the US Adjutant General – you would find something out of the ordinary. You would have to dig through three feet of earth, then drill through a foot-thick slab of concrete, then break open a metal enclosure that reaches ten feet into the ground, and then work your way through another concrete casing before you got to the metal casket, which is lined with lead sheeting. If you finally managed to get the casket open, you would find what appeared to be a mummy, wrapped in successive layers of lead, plastic, and cotton sheeting. After unwinding these wrappings, you would finally see the mortal remains of Richard McKinley himself. You would notice that his belly and chest have been roughly sliced open and his internal organs removed, along with his left arm and most of his skin. While pondering this macabre scene, you would be absorbing enough nuclear radiation to put your own life in peril.

McKinley was one of three men – the others were John Byrnes and Richard Legg – who died in a night time explosion at the National Reactor Testing Station (now the Idaho National Laboratory) on Idaho’s Snake River Plain. The cause of the explosion, in a scientific sense, was quickly figured out. But the human cause of the accident – if, indeed, it was an accident – remains a mystery 45 years after the event.

The Testing Station opened in 1949. Throughout the 1950s and beyond, it was ground central for America’s effort to develop controlled nuclear fission as the basis for power generation, both for military and civilian applications. The Station’s first reactor went critical in 1951, and a couple dozen more were constructed during the remainder of the decade.