When cases of a potentially fatal strain of meningitis began cropping up at Princeton last year, university officials trying to stop its spread could recommend little beyond precautions like frequent handwashing and not sharing beverage containers.
Although a vaccine against the rare bacteria that was causing the illness on campus existed in much of the developed world, it was not available in the United States. Novartis, its Swiss-based manufacturer, had not applied here for licensure of the vaccine, called Bexsero, because it seemed unlikely to be used enough in the United States to offset the cost of entering the market.
In all, it took nine months after the first case was detected in March 2013 before Princeton students could be immunized and nearly a year before they had completed the two-shot course, and that happened only after extraordinary interventions from the Centers for Disease Control and the Food and Drug Administration to allow the vaccine into the country.
By the end of the outbreak, seven more students had contracted the disease on the Princeton campus, and a student at another university died after contact with Princeton students. In a second outbreak involving four students at the University of California, Santa Barbara, a lacrosse player had to have his feet amputated.
The episode highlights a drug approval process in the United States that experts say does not always take into account public health needs. Regulators typically do not seek out new treatments, but wait for pharmaceutical companies to apply for approval of new products. Drugmakers weigh their estimates of sales potential against the high costs of application. And that calculation is often more fraught in the United States than in other countries, in part because American regulators are historically loath to grant approval based solely on foreign trials, so they require expensive new studies.
“Remarkable, unprecedented action was needed because Novartis had decided there wasn’t enough of a market for it here,” said Jason Schwartz, a fellow at the Princeton University Center for Human Values and an expert in vaccine policy. He added that it did not make sense for Novartis to spend millions of dollars to license a vaccine that would most likely be used only in scattershot outbreaks in the United States.
A video made by Princeton urged students to get vaccinated.
The experience has prompted the C.D.C. to review procedures this summer for streamlining emergency entry of vaccines that have not been licensed here. Dr. Anne Schuchat, director of the National Center for Immunization and Respiratory Diseases at the C.D.C., said it was looking at how to speed up the process, adding, “What should be our threshold for initiating vaccination?”
Many new drugs and vaccines are licensed earlier in the United States than in other parts of the world, experts say, in part because companies can generally charge higher prices in this country. That was true of Prevnar 13, for example, a vaccine against pneumonia and other diseases that came to market in 2010. But in other cases, such as that of Bexsero, valuable new treatments available elsewhere are tantalizingly out of reach in the United States because of drugmakers’ assessments of the market.
Bacterial meningitis is a rare but devastating disease, which is why vaccines against the bacterium Neisseria meningitidis, a frequent culprit, have been recommended or required for years in many countries. But previous vaccines did not protect against a subtype of the germ, serogroup B, the strain that Bexsero targets and that caused the campus outbreaks.
Studies have found that around 10 percent of people sickened with that strain will die despite proper antibiotic treatment; 10 to 20 percent of survivors suffer physical or neurological disabilities.
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Novartis’s meningitis vaccine against that particular germ had far better sales prospects abroad because B strains are more common in parts of Europe, such as Britain and Scandinavia, Dr. Schuchat said. Also, because many countries vaccinate all infants with an existing meningitis vaccine (that does not include Type B strains), the drugmaker figured they might use Bexsero widely as well.
In the United States, meningitis vaccination programs instead target adolescents and particularly students living in dormitories, where disease spreads more easily in close quarters. “In the U.S., there was much more uncertainty about the development of a market,” said Daniel Carpenter, a professor of government at Harvard who studies pharmaceuticals. In 2012, about 500 cases of bacterial meningitis occurred in the United States, with about one-third caused by the B strain.
After discussion with regulators in numerous countries dating to 2008, Novartis concluded that it was not worthwhile to release Bexsero in the United States. “You don’t just throw a file at the F.D.A. and wonder — you have extensive discussions to see what kind of data they want,” said Dr. Andrin Oswald, head of Novartis Vaccines.
Instead, the company decided to work on developing a meningitis vaccine for the United States that added protection against strain B to a version of the older shot already given to college students; the new combined product will not go into final trial until 2015, Dr. Oswald said, meaning approval could be years away.
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But with new cases of meningitis still occurring last summer on the Princeton campus, the C.D.C. decided quick intervention was needed. Officials allowed Bexsero into the country as “an investigational new drug,” a pathway usually used to provide drugs still being tested to people with terminal illnesses. “This was a first, and it is hard to imagine how complex the effort was, involving the university, the state, the company, the C.D.C. and the F.D.A.,” Dr. Schuchat said.
Because it was classified as an investigational drug, unusual precautions were required. For example, C.D.C officials had to conduct extensive safety monitoring while the shots were given on campus, even though no one really doubted that Bexsero was safe or would be useful to control the outbreak, Dr. Schwartz said. “There was great confidence that it exposed people to little risk, and the benefits were off the charts.”
Novartis said it had provided nearly 30,000 doses to students and staff at Princeton and the University of California, Santa Barbara, where an outbreak occurred later in 2013. It is hard to know if a more rapid response would have prevented the associated death. Stephanie Ross, the young woman who died, was a student at Drexel University who had been out with Princeton students in March, shortly after the vaccination program was completed. Even after being inoculated, people can be silent carriers of the meningitis bacteria for some weeks; it is unclear how well the shot reduces carrier status.
This June, Novartis applied to license Bexsero in the United States, after the Food and Drug Administration indicated that it would look favorably on the application without further studies because it filled an “unmet medical need,” Dr. Oswald said. The same day, Pfizer filed an application to market a similar vaccine.
“They are willing to accept a more pragmatic approach for data submission,” Dr. Oswald said of F.D.A. officials. “From our point of view, this is a technicality, because we already had good data. This vaccine is licensed for babies from 2 months to adults everywhere else in the world.”