Regulatory Overdose

Sunday, July 30, 2000

The FDA, the nation’s most ubiquitous regulatory agency, often reacts to perceived medical crises precipitately—and wrongly. Following the recent tragic death of a teenager treated at the Hospital of the University of Pennsylvania with the relatively new and experimental medical intervention called human gene therapy, the FDA has again jumped the gun with profoundly negative consequences.

Gene therapy is the insertion of normal or modified genes into a patient in order to correct genetic or acquired disorders via the synthesis in the body of missing, defective, or insufficient gene products. Six thousand patients in three dozen countries are currently undergoing gene therapy for diseases ranging from cystic fibrosis to cancer and AIDS.

Eighteen-year-old Jesse Gelsinger, who suffered from a rare metabolic disorder (ornithine transcarbamylase, or OTC, deficiency) caused by subnormal levels of a liver enzyme, and marked by toxic levels of ammonia in the blood, was reasonably healthy when he arrived at the Hospital of the University of Pennsylvania to begin an experimental gene therapy regimen last September. But his condition began to deteriorate within hours of receiving the first treatment, an intravenous infusion of a preparation containing the normal gene he lacked, encased in an enfeebled virus called adenovirus; gene therapy uses the weakened virus as a kind of shuttle to get the genes to the right tissues in the patient. (Fully competent adenoviruses cause a number of illnesses, including conjunctivitis and colds.) Gelsinger died four days later of multiple organ failure.

In spite of intensive investigations in recent months by the researchers at the University of Pennsylvania and Children’s National Medical Center in Washington, D.C., who carried out the trial, the exact cause of Gelsinger’s multiorgan deterioration remains unknown.

The response of the FDA, which oversees the clinical testing of all new medicines, to this unforeseen, tragic event has been precipitous and inappropriate. Before and during a three-day conference convened by the FDA—and without knowing the cause of the problem—agency officials publicly blasted the University of Pennsylvania researchers. They accused them of various kinds of misconduct—having admitted Gelsinger into the trial even though he did not meet eligibility requirements, having failed to immediately report information about two other patients who (long before the death) had experienced serious side effects, and having omitted information in the patient consent form about the death of monkeys that had received a similar but much higher dose treatment. The first of these accusations is untrue. The second was misleading, in that although the toxicity in other patients had not been reported immediately after it occurred, the FDA had had that information long before the Gelsinger incident. The third was well within the usual, acceptable standards of clinical research: The results of animal studies, especially those that use a much higher dose than would be administered to humans, are not routinely mentioned in the patient consent form; the fact that 17 human OTC-deficient patients had been treated in the University of Pennsylvania trial before Gelsinger without serious and unexpected problems also argues against the importance of the monkey data. (Moreover, the consent form had received the required approval from the hospital’s Institutional Review Board, whose sole responsibility is to protect the rights of human subjects in clinical research.)

The FDA insisted on public self-flagellation by the gene therapy researchers. On the first day of the meeting, Dr. James Wilson, the lead researcher for the study, maintained that he was "fully comfortable with the clinical decision" to treat Gelsinger. Thereafter, the FDA’s senior gene therapy regulator told Wilson that he and his colleagues had better perform a public mea culpa, "or else," and the next day saw a remarkable transformation. "I really regret" the oversights, said a contrite Wilson. "We could have done better . . . and we apologize," said one of his collaborators. "We now realize we should have contacted FDA," said another.

Subsequently, the FDA shut down the University of Pennsylvania team’s seven other gene therapy protocols (not all of which involved adenovirus). Once again, the charges were unfounded or trivial, involving paperwork deficiencies unrelated to patients’ safety.

Certainly, concern by FDA officials about Gelsinger’s death is warranted. But what action is appropriate? Before all the data are in, certainly not a rush to judgment. Certainly not public humiliation—a trial by press conference—of one of the foremost gene therapy teams in the world. And certainly not the FDA’s impulsive tightening of manufacturing and quality control requirements for academic researchers—which are traditionally (and appropriately) more relaxed than in drug companies—or the FDA’s sudden freeze on the seven other University of Pennsylvania gene therapy trials.

Worse still, the FDA halted two gene therapy experiments being conducted by drug company Schering-Plough that used adenovirus—one for the treatment of liver cancer, the other for colorectal cancer that has metastasized to the liver. The FDA’s actions are difficult to rationalize in view of the testimony at the conference of two clinical researchers from the University of California at San Francisco and Cornell University that, in their respective trials with similar adenovirus preparations, in scores of patients they had each seen one instance of serious toxicity and no deaths.

The FDA’s burdensome requirements and bellicose tone have cast a chill on the entire gene therapy community. One eminent clinician speculated that the FDA has set gene therapy back five years.

The FDA’s actions, especially in view of the fact that the University of Pennsylvania program is known as one of the most advanced in the world, have already begun to inhibit the pace of clinical studies, the willingness of academics to undertake gene therapy research, and the ability of companies to support it. For example, gene therapy researchers at the Baylor College of Medicine in Houston, who recently reported success with the weakened adenoviral vector in animals, may be prevented from testing the vector in humans: The pharmaceutical company Merck and Company, which owns the rights to a technique used to produce the vector, is refusing to extend its "material transfer agreement" with Baylor, admitting that it fears claims of legal liability for any problems the vector might cause in clinical trials.

More recently, the FDA has clamped several kinds of unwarranted additional controls on gene therapy investigators. In March, FDA officials announced the requirement for all sponsors of gene therapy products to submit to the agency substantial additional information—not only about the trials themselves but also about animal studies and materials that may have been intended for use in clinical trials but were not so used for one reason or another. The new requirements and the agency’s bellicose tone have cast a chill on the entire field. One eminent clinician speculated that the FDA has set the field back five years.

The realities of clinical testing are sometimes harsh–one patient described the process as being "like willing your body to science while you’re still alive." Yet these trials can lead to significant medical breakthroughs.

The FDA’s show of toughness may have been an attempt to deflect attention from its own culpability. If there was an identifiable mistake in the University of Pennsylvania trial, it was in the choice of patients for these first attempts at gene therapy for OTC deficiency. Rather than stable adult patients, it would have been more prudent to treat OTC-deficient babies who were in coma and had a dire prognosis. That was, in fact, the original intention of the OTC researchers, but they were dissuaded by their bioethicist, who felt that parents of dying infants are "coerced by the disease of their child" and are, therefore, incapable of giving informed consent. In other words, the protocol treated and placed at risk a group that did not need the therapy, because the patients who had nothing to lose and could have benefited could not give genuine informed consent and were declared ineligible. FDA officials or the hospital’s internal review board could and should have reversed that decision.

The realities of clinical testing are sometimes harsh. One patient described the process as being "like willing your body to science while you’re still alive," and serious diseases sometimes require aggressive therapies. Also, while a treatment is still unproven and unfamiliar—the stage at which gene therapy is now—therapeutic success may be elusive. In the 1970s, for example, bone marrow transplantation was highly experimental. It was performed at only a handful of medical centers in the United States, and success rates were abysmal. But clinical research has refined the technique and identified diseases for which the technique is useful: In a genetically determined disease of red blood cells called thalassemia major, for example, more than 80 percent of the patients are now cured.

Regulators’ decisions are difficult. They affect human lives and the pace and productivity of medical research. Often, they need to be made on the basis of incomplete data, under time pressure, and in the glare of media attention. The challenge is to ensure patients’ safety but with minimum interference in the conduct of individual trials and of medical research overall. In this case, the FDA has thrown its weight around unnecessarily and prematurely. The result has been the intimidation of gene therapy researchers throughout the country and palpable costs to future generations of Jesse Gelsingers.