Boston Globe page 1 article today.
Firm infects subjects to seek virus remedy
Cambridge lab starts human trial
By Stephen Heuser, Globe Staff | January 13, 2007
It sounds like a reversal of the doctor's pledge to do no harm: The Cambridge biotechnology company Alnylam Pharmaceuticals Inc. is paying 40 healthy people to get sick.
As part of a human clinical trial, the young firm has contracted with doctors to infect volunteers with a contagious virus to test the effectiveness of a drug it is developing.
Alnylam hopes to sell the first-ever drug treatment for a common disease called respiratory syncytial virus, or RSV. The disease can be fatal in infants or the elderly, but in most adults it can be hard to distinguish from a cold.
The trial, disclosed in a regulatory filing, is "state of the art for how you do clinical trials with viruses," said a company spokeswoman. It has passed review by the Food and Drug Administration and an independent oversight board. But it also illuminates an ethically thorny area of medical research: Sometimes, to learn how a disease works, you need to infect people with it.
"These studies, I wouldn't call them common exactly, but they have a very long history that goes back to before World War II," said John Treanor , a respiratory disease specialist at the University of Rochester who is not involved in the Alnylam trial.
In the test, doctors drip increasing doses of a contagious virus into volunteers' nasal passages and watch what happens next.
"They'll get runny noses; they might sneeze; they use lots of tissues," said Akshay Vaishnaw , the company's head of clinical research.
Unpleasant as it sounds, the test occupies the tame end of what infectious-disease researchers are willing to do to patients. In trials run by university doctors, subjects have been given malaria, gonorrhea, and a bloody diarrheal disease called shigellosis . In one test, people voluntarily drank water contaminated with cholera. Some trials are designed to test a vaccine, and others are run simply to learn how an infection develops.
"There's good stuff that comes out of these things, but they need to be done very carefully," said Dr. Elizabeth Hohmann of Massachusetts General Hospital, a specialist in infectious-disease human trials.
Compared with drinking cholera-laced water, Alnylam's test amounts to a walk in the park, or at least a quiet few days in the clinic. The patients remain there as doctors watch to see how sick they get. Each day, they measure the frequency of test subjects' sneezes and give them quizzes. They are asked, for instance: On a scale of 1 to 10, how blocked does your nose feel? How runny?
And then there's the Kleenex output. "We also weigh their tissues," said Vaishnaw.
Once Alnylam establishes a reliable way to get people sick, it will start testing its experimental drug to see whether it can reduce the severity of an infection.
The company would not disclose how much the subjects would be paid, or where the study is being run, but said it is already underway in a set of clinics with infectious-disease expertise, both in America and overseas. Each of the volunteers is expected to recover in a matter of days, and is prohibited from having contact with outsiders until tests show the virus is gone.
The virus in Alnylam's test causes a relatively mild illness in most healthy people, with symptoms that include coughing, sneezing, runny nose, sore throat and headaches. It spreads widely in the cold-weather months, and researchers believe that by age 2, most people have been exposed to it at least once, and thus are likely to develop a mild illness at most.
In infants or the elderly, however, the virus can invade the lungs and cause more serious diseases such as bronchiolitis or pneumonia. Alnylam's Vaishnaw says RSV sends about 300,000 people a year to the hospital, and kills 14,000. "It's an important disease," he said.
If Alnylam develops a treatment, it could be given to the elderly or the very young to shorten the course of the disease and stave off serious complications.
The type of test Alnylam plans has a name: a "viral challenge." As with many clinical trials, subjects are typically recruited through newspaper advertisements and postings on college bulletin boards that appeal to cash-strapped students. Volunteers are usually paid by the day, a rate that varies from city to city. Hohmann said that at Mass General rates run about $100 to $200 per day, depending on the extent of the testing.
Viral challenges are most commonly used for vaccine trials, in which patients are vaccinated and then deliberately infected to see whether it works. Infection trials have also been used purely for research: Scientists in Britain learned about the viruses responsible for common colds by repeatedly infecting groups of healthy patients.
But the practice has had dark chapters as well, including typhoid tests on prisoners and a long-term experiment in the 1950s and 1960s in which retarded children in New York were deliberately infected with hepatitis to study a potential vaccine after their parents signed a short, confusing consent letter.
As a result, regulators now require such trials to observe a series of precautions: Volunteers must be in good health, give full consent, and undergo careful monitoring to be sure they are virus-free before being allowed to mingle with the public.
"One question that always comes up is why would a college student or a healthy young adult do this, particularly since there's not very much compensation paid?" said Dr. Myron Levine , director of the Center for Vaccine Development at the University of Maryland. "The answer I always get from volunteers is that there's a certain type of person, the same type of person who climbs mountains or goes down grade-4 rapids."
Researchers who work with viruses say the Alnylam trial is less hazardous than so-called "first-in-man" trials of drugs whose effects are unknown.
"The risk of giving someone natural RSV is actually much better defined than the risk of a lot of other things that people volunteer in trials for," said Dr. James Campbell of the University of Maryland's Center for Vaccine Research.
For some companies, a lot rides on making patients predictably sick. Dynavax Technologies Corp., a California biotechnology company, recently lost a quarter of its value in a day after an unsuccessful trial of a potential ragweed-allergy drug. The reason for the failure: None of the trial subjects got sick during ragweed season.
Alnylam's strategy of deliberate infection should help reduce that uncertainty. But even dripping virus into people's noses, said Treanor of the University of Rochester , isn't a sure thing. He estimated that Rochester specialists have infected about 100 healthy people with RSV in tests over the years, but many never developed any disease.
"It's actually quite difficult to infect people intentionally," he said. "Most adults have a fair amount of immunity." |
