Doctors decry lack of Wyeth vaccine

Health policy officials urge rationing of Prevnar, which prevents meningitis

Sunday, May 30, 2004

BY ED SILVERMAN

Star-Ledger Staff

When Barry Prystowsky heard last November about a sudden shortage of the Prevnar vaccine for meningitis, he was frustrated and alarmed.

"It was very aggravating. The explanation was never clear," said the Nutley pediatrician. "But I had to tell parents that I couldn't protect their babies against this horrible bacteria."

He was even more upset during February, when Wyeth, the only company to make the vaccine, said supplies were still hampered by unspecified production problems. Today, the medicine is being rationed, and many doctors say Wyeth should have disclosed the full extent of a series of manufacturing problems that caused the shortage.

Wyeth experienced numerous manufacturing issues for several years before the shortage was announced, according to the Food and Drug Administration. The two plants that make Prevnar were annually cited for extensive shortcomings -- most recently last September and October. And one plant avoided taking steps to improve quality control, according to a whistleblower lawsuit filed by a former employee.

A number of doctors say they were upset by the lack of timely information, because it forced them to grapple with both an unexpected shortage and an inability to plan. Doctors are rationing the widely praised vaccine, which is supposed to be administered to children four times by the age of 15 months. Instead, children are given just two shots.

"Being kept in the dark for a protracted period of time really does wreak havoc," said Tom Saari, a University of Wisconsin pediatrics professor and member of the infectious diseases committee at the American Academy of Pediatrics. "My concern is if they're going to shut down, they should've had a pretty good idea how long it would take to get up and running."

WIDER IMPLICATIONS

Beyond the immediate shortage, the episode may have wider implications for Wyeth. Prevnar is one of the Madison-based drug maker's biggest-selling products, generating nearly $1 billion in revenue last year.

Wyeth officials acknowledged manufacturing problems, but maintain they took steps to fix them. And they stressed the plant problems didn't pose a safety issue. "We're as frustrated as anybody else," said Peter Paradiso, Wyeth's vice president of scientific affairs. "We want to make sure we maximize coverage of this vaccine."

The Centers for Disease Control and Prevention, which establishes national health policy, had to issue two different advisories about Prevnar rationing during less than four months. This caused confusion and anxiety among doctors and patients, according to the federal agency.

"Had we known that the shortage was going to get much worse, we wouldn't have done things the way we did," said Lance Rodewald, director of the immunization division at the CDC, which recommended the reduction in the number of shots.

At issue is whether Wyeth should have disclosed more information sooner about manufacturing problems that may cause shortages. Although disclosure wasn't required, Wyeth didn't reveal that a team of FDA inspectors last October found numerous quality-control failings at its Pearl River, N.Y., plant. Prevnar is made at a Sanford, N.C., facility, but is packaged in Pearl River. A production shutdown occurred at the Pearl River site late last year.

BAD REPORT

The FDA inspection report, which was obtained by The Star- Ledger, detailed sloppy operating procedures, dirty work areas, instances of contamination, improper environmental monitoring and insects in a hallway outside a room where the vaccine was filled in vials. Wyeth's own internal investigations also took longer than expected and were incomplete, the report said.

"Manufacturing investigation reports are not always completed in a timely manner," the FDA inspectors wrote in reviewing Wyeth's follow-up to problems noted previously by the agency. "Further, there is a lack of evidence that product impact is addressed in a timely manner and that all batches/processes are fully investigated."

Bruce Burlington, a Wyeth executive vice president in charge of quality, regulatory and safety matters, said FDA inspectors found significant shortcomings during the inspection at the Pearl River plant last October,

Detailed inspections are routine in the pharmaceutical industry, which must adhere to strict manufacturing practices. But lengthy inspection reports aren't the norm. In this case, FDA inspectors chronicled 59 problems in their 15-page account. But FDA spokeswoman Lenore Gelb said any serious problems would be conveyed to the medical community.

In a brief interview last month, Bernard Poussot, a Wyeth executive vice president, said the stoppage at the Pearl River plant late last year took place because "the FDA shut us down." Such a step would indicate the company had no choice but to interrupt production. However, the FDA spokeswoman said the agency never took such action. A Wyeth spokesman didn't make Poussot available for further comment.

SECOND INSPECTION

This was the second time the FDA inspected the facility since October 2000, when Wyeth signed a consent decree with the federal government. As part of the decree, Wyeth agreed to correct manufacturing problems and relinquish $30 million in profit. The company still faces as much as $5 million in fines for failing to improve operations.

A consent decree results when a company repeatedly fails to comply with FDA standards. Repeated citations by FDA inspectors reflect an ongoing inability to satisfy the decree requirements, according to Suggy Chrai, a drug-industry manufacturing consultant.

Wyeth officials have repeatedly said the safety or effectiveness of the vaccine was never compromised. They said deficiencies were willingly disclosed to FDA inspectors and that last year's Pearl River shutdown was part of a scheduled maintenance procedure. The stoppage ran longer than expected due to ongoing manufacturing problems, they said.

"We shut it down to do a routine maintenance and because of the issues that arose, we had a pronounced shutdown," said Wyeth's Paradiso. He added the CDC and doctor groups were alerted to an impending shortage very quickly last fall, but the extent of the plant problems weren't disclosed.

In addition, Wyeth's Burlington defended the company's efforts and also noted Prevnar is a difficult product to make.

"At this point, we're where we want to be," he said. "We sent a remediation plan to the FDA and the response we received indicates our action appears to be adequate. And we'll be on a full production schedule, hopefully, later this year."

SHARED PRODUCTION

To do so, Wyeth has enlisted two companies, Cardinal Health and Baxter Healthcare, to assume part of the production process that was previously handled at Pearl River.

Normal production would cheer Wall Street. Despite the difficulties, which include a previous shortage, Prevnar has been a shot in the arm for Wyeth. Approved by the FDA during 2000, Prevnar quickly filled a medical void. Until then, pneumococcal infection each year killed 200 children under the age of 5 and caused more than 700 meningitis cases.

Last year, the vaccine generated $946 million in sales. That was much-needed revenue for a drug maker plagued by a pair of serious setbacks -- costly diet-pill litigation and plunging sales of hormone replacement treatments.

To capitalize, Wyeth has wanted to produce as much vaccine as possible, even while grappling with the consent decree. But Chrai, the manufacturing consultant, said drug makers that don't quickly fix mistakes run the risk of a financial hit and losing investor confidence.

"Prevnar is an important product for Wyeth. It's an earnings driver," said David Moskowitz, an industry analyst at Friedman Billings Ramsey. "At this point, it's a show-me story. It's very unfortunate they haven't been able to supply the product. They really need to show the marketplace they can supply it in sufficient quantities by the end of the year."

One former Wyeth employee maintains shareholders have already suffered.

In a whistleblower lawsuit filed last December in U.S. District Court in Greensboro, N.C., Mark Livingston, a quality-control expert, charged Wyeth managers at the Sanford, N.C., plant cut corners to boost Prevnar production. He also charged that his suggestions for meeting FDA standards were deliberately ignored and that he was wrongly fired during 2002.

The company's practices, according to the lawsuit, amounted to fraud and violated the Sarbanes- Oxley Act, which was designed to improve corporate governance and financial disclosure to shareholders. For instance, filings with the Securities and Exchange Commission didn't mention a negative FDA inspection report at the Sanford plant during September 2003.

MISREPRESENTATIONS

"They misrepresented the real state of manufacturing," said Joanne Royce, an attorney with the Government Accountability Project, which represents Livingston. "And so there was misrepresentation of Wyeth's financial condition. When noncompliance goes on so long, shareholders have a right to know. It's bound to reflect on the bottom line at some point."

A Wyeth spokesman, Doug Petkus, said the lawsuit was filed by a disgruntled employee and was without merit. He also said Prevnar remains safe and effective. Despite the ongoing shortage, Margaret Rennels, a University of Maryland pediatrics professor and chair of the American Academy of Pediatrics infectious diseases committee, praised Wyeth for providing weekly inventory updates, creating an effective rationing system and opening a hot line for doctors.

"They're trying to ensure that every doctor has enough vaccine to administer, and in an equitable way," she said. Yet she and other doctors say the episode is worrisome, and are concerned another shortage may occur unless Wyeth improves its manufacturing procedures. "With Wyeth, there's a pattern here, and it concerns me," said Saari of the University of Wisconsin. "The fact that these issues are still going on is disturbing, because of the impact on kids who can't get the vaccine. There are some real risks in terms of disease prevention."

Ed Silverman can be reached at (973) 392-1542 or esilverman@starled ger.com.

http://www.boston.com/news/globe/health_science/articles/2005/06/21/
childhood_vaccine_saves_lives_but_may_lead_to_other_infections?mode=PF

By Michael E. Hochman, Globe Correspondent | June 21, 2005

Since it was put on the market in February 2000, a childhood vaccine called Prevnar has reduced the rates of certain serious bacterial infections by 75 percent in American children.

But the bacterium it protects against -- pneumococcus, which causes bloodstream infections, meningitis, pneumonia, ear infections and other diseases -- is a wily organism. It comes in over 90 different strains, and Prevnar covers just the seven most common. Since the introduction of Prevnar, there has been a slow but definite rise in infections caused by strains not covered by the vaccine, and there are concerns that this trend may continue.

''I think this is a very good vaccine," said Dr. Gordon Schutze, a professor of pediatrics at the University of Arkansas for Medical Sciences. ''But I'm concerned because we're seeing a rise in disease caused by strains not covered by the vaccine." Pneumococcus -- which is also referred to as Streptococcus pneumoniae -- was first identified in 1881, and has been a scourge of humanity since long before that. Studies have shown that roughly half of all children carry pneumococcus in their noses and throats at any one time. It's mostly harmless, but when the bacterium is inhaled into the lungs, or gets into the bloodstream, it can cause serious illness.

Prior to 2000, pneumococcus was responsible for close to 200,000 hospitalizations and several thousands deaths annually in the United States in both children and adults. The rates have dropped since the introduction of Prevnar -- one recent study in Michigan showed a 50 percent reduction in hospitalizations in young children since 2002 due to the vaccine -- but pneumococcus continues to be one of the most important causes of infectious disease worldwide.

Children receive Prevnar in three doses at 2 months, 4 months and 6 months of age, followed by a booster dose at about a year old. The latest federal data shows that about two-thirds of American infants are receiving all of their doses on time.

The only previously approved vaccine against pneumococcus -- called the pneumococcal polysaccharide vaccine, which is still given to high-risk adults -- is not effective in infants and young children. While Prevnar is very effective in infants and young children, it only protects against a limited number of strains because it stimulates an immune response against pneumococci's outer shell, which varies from strain to strain.

Prevnar seems to be reducing pneumococcal disease not just in children but in adults as well because children are now less likely to pass on the bacterium to others. This so-called ''herd effect" has been a somewhat unexpected benefit of the vaccine.

According to Dr. Cynthia Whitney of the US Centers for Disease Control and Prevention, serious diseases such as meningitis and bloodstream infections due to strains of pneumococci not covered by Prevnar have risen by about 50 percent since its introduction, though the amount of disease due to these strains is still low. The rise has been more substantial for less-serious diseases such as ear infections and pneumonia. The strains not covered by Prevnar seem to be better at causing these less-serious diseases for reasons that are not entirely clear.

Recent studies have also found that strains of pneumococci not covered by Prevnar multiply in the noses and throats of children after they are given the vaccine. Although Prevnar reduces the amount of the seven strains it covers, other strains completely fill in the gap -- so the total amount of pneumococcus found in children's noses and throats is not reduced by vaccination.

This ''replacement" phenomenon is something that occurs commonly throughout nature. For example, when timber companies chop down the largest trees in a forest, it creates room for smaller trees and bushes to increase in number. Likewise, when doctors give antibiotics to treat an infection, new bacteria that are resistant to the antibiotic quickly fill in the space left by the susceptible bacteria.

And it is not just other strains of pneumococcus that are filling in the gaps. New evidence is showing that ear infections due to other species of bacteria are on the rise now that ear infections caused by pneumococcus have decreased. This may make it necessary to treat ear infections with different antibiotics than those currently used because the bacteria filling in the gaps are not always susceptible to the currently used antibiotics.

According to experts, extensive replacement has not happened with other widely used vaccines, likely because many other bacteria exist in only a small number of disease-causing varieties. The rise in nonvaccine strains of pneumococci has been especially concerning in high-risk patients -- those with HIV or sickle-cell disease, for instance -- whose immune systems are weaker.

Dr. Stephen Pelton, a pediatric infectious disease physician at Boston Medical Center, explained that the strains not covered by Prevnar are weaker than the strains that are covered. Therefore, high-risk patients -- who have weaker immune systems -- are most susceptible to these less-virulent strains that healthy people usually can fight off.

The rise in nonvaccine strains of pneumococcus is likely to continue. ''We do need to keep our eyes on the nonvaccine type disease in case it starts becoming more of a problem," Whitney said.

Experts say that the best way to curb such a rise would be to develop new vaccines to cover more strains. This will be especially important for the developing world where, according to Pelton, pneumococcal strains not included in Prevnar have always been a more important cause of disease than in the United States.

Wyeth Pharmaceuticals, which makes Prevnar, is currently working on a product that would cover 13 total strains of pneumococci -- six more than the current version. And GlaxoSmithKline has new vaccines in development as well.

According to Pelton, researchers are also developing vaccines that would cover all 90 strains of pneumococci. Several groups are working on a vaccine that would stimulate a response against a protein common to all strains. The best candidate proteins are hidden inside the outer shell, however, and the immune system has trouble recognizing these proteins when pneumococcus enters the body. ''I think we can ultimately win the race [against pneumococci]," Schutze said. ''But I think we'll probably have to do better than covering seven strains. I think we'll have to find a vaccine that covers 20 strains or so."