WASHINGTON, D.C. -- More than a decade ago, federal health inspectors wanted to shut down the pharmacy linked to a recent deadly meningitis outbreak until it cleaned up its operations, according to congressional investigators. 

Nearly 440 people have been sickened by contaminated steroid shots distributed by New England Compounding Center, and at least 32 deaths have been reported since the outbreak began in September, according to the Centers for Disease Control and Prevention. That has put the Framingham, Mass., pharmacy at the center of congressional scrutiny and calls for greater regulation of compounding pharmacies, which make individualized medications for patients and have long operated in a legal gray area between state and federal laws.

The House Energy and Commerce Committee released a detailed history of NECC's regulatory troubles on Monday, ahead of a meeting Wednesday meeting to examine how the outbreak could have been prevented. The 25-page report summarizes and quotes from FDA and state inspection reports and internal memos, though the committee declined to release the original documents.

The report shows that after numerous complaints over years, Food and Drug Administration officials in 2002 suggested that the compounding pharmacy be "prohibited from manufacturing" until it improved its operations. But FDA regulators deferred to their counterparts in Massachusetts, who ultimately reached an agreement with the pharmacy to settle concerns about the quality of its prescription injections.

The congressional report shows that in 2003 the FDA considered the company a pharmacy. That's significant because since the outbreak came to light in late September, public health officials have charged that NECC was operating more as a manufacturer than a pharmacy, shipping thousands of doses of drugs to all 50 states instead of just prescribed doses to individual patients. Manufacturers are regulated by the FDA and are subject to stricter quality standards than pharmacies.

The report offers the most detailed account yet of the numerous regulatory complaints against the pharmacy, which nearly date back to its founding in 1998. Less than a year later, the company was cited by the state pharmacy board for providing doctors with blank prescription pads with NECC's information. Such promotional items are illegal in Massachusetts and the pharmacy's owner and director, Barry Cadden, received an informal reprimand, according to documents summarized by the committee.

Cadden was subject to several other complaints involving unprofessional conduct in coming years, but came to the FDA's attention in 2002. Here are some key events from the report highlighting the company's early troubles with state and federal authorities:

• In March of 2002 the FDA began investigating reports that five patients had become dizzy and short of breath after receiving NECC's compounded betamethasone repository injection, a steroid used to treat joint pain and arthritis that's different from the one linked to the current meningitis outbreak.

FDA inspectors visited NECC on April 9 and said Cadden was initially cooperative in turning over records about production of the drug. But during a second day of inspections, Cadden told officials "that he was no longer willing to provide us with any additional records," according to an FDA report cited by congressional investigators. The inspectors ultimately issued a report citing NECC for poor sterility and record-keeping practices but said that "this FDA investigation could not proceed to any definitive resolution," because of "problems/barriers that were encountered throughout the inspection."

•  In October of 2002, the agency received new reports that two patients at a Rochester, New York hospital who came down with symptoms of bacterial meningitis after receiving a different NECC injection. The steroid, methylprednisolone acetate, is the same injectable linked to the current outbreak and is typically is used to treat back pain. Both patients were treated with antibiotics and eventually recovered, according to FDA documents cited by the committee.

When officials from the FDA and Massachusetts Board of Pharmacy visited NECC later in the month, Cadden said vials of the steroid returned by the hospital had tested negative for bacterial contamination. But when FDA scientists tested samples of the drug collected in New York they found bacterial contamination in 4 out of 14 vials sampled. It is not entirely clear whether FDA tested the same lot shipped to the Rochester hospital.

• At a February 2003 meeting between state and federal officials, FDA staff emphasized "the potential for serious public consequences if NECC's compounding practices, in particular those relating to sterile products, are not improved." The agency issued a list of problems uncovered in its inspection to NECC, including a failure to verify if sterile drugs met safety standards.

But the agency decided to let Massachusetts officials take the lead in regulating the company, since pharmacies are typically regulated at the state level. It was decided that "the state would be in a better position to gain compliance or take regulatory action against NECC as necessary," according to a summary of the meeting quoted by investigators.

The FDA recommended the state subject NECC to a consent agreement, which would require the company to pass certain quality tests and assurances to continue operating. But congressional investigators say Massachusetts Board of Pharmacy did not take any action until "well over a year later."

• In October 2004, the board sent a proposed consent agreement to Cadden, which would have included a formal reprimand and a three-year probationary period for the company's registration. The case ended without disciplinary action as part of a different consent agreement reached with the board in 2006.

FDA Commissioner Margaret Hamburg and Massachusetts Department of Public Health interim commissioner Lauren Smith are scheduled to testify at Wednesday's hearing.

According to the congressional report, lawmakers plan to ask the witnesses whether the FDA and state pharmacy board acted appropriately. Cadden is also scheduled to appear at the hearing, after lawmakers issued a subpoena to compel him to attend.

The NECC has been closed since early last month, and Massachusetts officials have taken steps to permanently revoke its license. The pharmacy has recalled all the products it makes, including 17,700 single-dose vials of a steroid that tested positive for the fungus tied to the outbreak. 

Related stories: 

• Fungal victim to Congress: 'It's torturous'
• Some infections thwart treatment in fungal meningitis outbreak
• FDA finds bird, bugs and filth at Ameridose plant

Photo courtesy Margaret Snopkowski

Margaret Snopkowski, 51, of Michigan, holds her 11-day-old grandson, Ethan Edward Jackson. She missed the baby's birth after becoming gravely ill with fungal infections tied to tainted drugs in a national outbreak.

Margaret Snopkowski was supposed to be in the delivery room on Oct. 24, when her first grandchild, Ethan Edward Jackson, made his debut in Pittsburgh.

Instead, the 51-year-old Fowlerville, Mich., woman was nearly 300 miles away, lying in a hospital room in Ann Arbor, so sick with fungal meningitis that she was barely aware when the baby boy was born.

“For the most part, she wasn’t coherent,” recalled Courtney Jackson, 27, Snopkowski’s daughter. “The greatest moment in my life was being overshadowed by the worst moment in hers.”

Courtesy Snopkowski family

Tom and Margaret Snopkowski before she fell ill with life-threatening fungal infections tied to contaminated back pain shots.

As her daughter gave birth, Snopkowski was grappling with searing headaches, incessant vomiting and lower back pain so severe that a video taken in the hospital shows her whimpering and moaning, “Oh my god, Oh my god, Oh my god,” as a nurse gently advises, “Just breathe.”

Snopkowski was one of the first victims in the still-growing outbreak of fungal meningitis traced to contaminated steroid injections that have sickened 483 people and killed 32, according to federal health officials.

“It’s torturous,” said the previously healthy saleswoman for a concrete contractor, reached by phone in her room at St. Joseph Mercy Hospital in Ann Arbor, where she’s been getting treatment since early October.

Victims and their families hope that their plight will remain the focus of two congressional committee hearings set for Wednesday and Thursday, sessions expected to include Food and Drug Administration chief Dr. Margaret Hamburg and Barry Cadden, the owner and managing pharmacist of the New England Compounding Center, the Massachusetts pharmacy responsible for distributing the contaminated steroid drugs blamed for the infections.

Congressional investigators subpoenaed Cadden last week after he indicated he would not appear voluntarily.

At issue is whether federal and state regulators did enough to control NECC, or whether they let known problems dating to 2002 continue unabated. Federal and state officials have found evidence of environmental mold and fungus dating at least to January at the NECC site, documents show. The firm also was distributing drugs in bulk, contrary to regulations that require that compounding pharmacies to mix custom drugs to order for specific prescriptions.

Not only did Snopkowski contract life-threatening fungal meningitis, which causes inflammation of the membranes that protect the brain and spinal cord, but, like growing numbers of outbreak patients, she also has developed arachnoiditis, a painful, hard-to-treat infection of the nerve roots at the base of her spinal cord. Other patients -- perhaps up to a third of victims -- have also developed abscesses at their injection sites, medical experts say.

Worse, doctors aren’t quite sure what to do about it.

“We’ve never seen this disease before; it’s never been described,” said Dr. Anurag Malani, the infectious disease expert at St. Joseph Mercy Ann Arbor who is treating Snopkowski and others. “The story is being told every day and we continue to turn the page.”

Snopkowski’s trouble started on Sept. 13, when she received an epidural injection of the steroid methylprednisolone at Michigan Pain Specialists of Brighton. She’d been getting the shots every few months for five years to help ease the pain of degenerative disc disease in her lower back.

Sometimes the shots would help, sometimes they wouldn’t, but Snopkowski, an avid cook and gardener, wanted to stay active.

“It was, let’s do this as opposed to taking pills,” she said.

But Michigan Pain Specialists was among 76 clinics in 23 states to receive some 17,000 vials from three lots of NECC methylprednisolone contaminated with fungi. Nearly 14,000 people got the shots.

A week after the injection, Snopkowski said she began to feel like “something wasn’t right,” followed by low-grade headaches and then searing back pain different from anything she’d felt before.

When she got a call from the pain clinic warning that her injections were tied to an emerging outbreak of fungal meningitis, she got scared.

“Of course, I panicked,” she said. “I had all the symptoms.”

A spinal tap showed alarming evidence of infection. Within a day, Snopkowski was sent to St. Joseph Mercy. She was one of the first patients who contracted fungal meningitis caused by the black mold Exserohilum in the tainted drugs.

Snopkowski was placed on powerful antifungal drugs and at first seemed to respond. After 11 days in the hospital, she was sent home, but she was back within a week in unbearable pain.

That’s when doctors found the second infection. Malani, the infectious disease expert, said they can’t drain it, they can’t operate on it and it is responding slowly to the antifungal drugs.

Snopkowski’s treatment is also complicated because she had a bad reaction to one of the drugs, amphotericin B, and her body seems to metabolize the other commonly used medication, voriconazole, too quickly.

“We have to do some devious things to keep her levels up,” said Dr. Carol Kauffman, a University of Michigan expert in fungal infections who is consulting with St. Joseph Mercy on the outbreak, in addition to advising the U.S. Centers for Disease Control and Prevention.

Snopkowski has started taking Prilosec, an antacid, in hopes of helping her body hold on to the antifungal drug. She’s also had problems with plummeting potassium levels that caused heart trouble.

Snopkowski and her husband, Tom Snopkowski, 46, a contractor, say her days alternate between blinding pain and constant uncertainty about what the future holds.

“I’m supposed to be here two more weeks but it could be two months,” she said. “(The doctors) can’t give us anything because they don’t know.”

Courtesy Snopkowski family

Margaret Snopkowski, shown here with daughter Courtney Jackson, was vibrant and healthy before she got tainted back pain shots on Sept. 13.

Snopkowski is frustrated at the interruption in her work and her life, especially time with her daughter and the new baby. She saw Ethan once, when he was 11 days old, when Courtney brought him to the hospital chapel for a 15-minute visit.

“I started crying. She started crying,” Snopkowski said.

The family is outraged that NECC’s actions could have had such dire consequences for Snopkowski and other victims.

“It makes me sick, it honestly does, for someone to be so negligent,” Courtney Jackson said. “It’s 2012; this shouldn’t be happening.”

Snopkowski is suing NECC. Her lawyer, Elizabeth Kaveny of Chicago, also represents two other outbreak victims. She was referred through the InjuryBoard.

“NECC’s disregard for the safety of patients is unforgivable. That extends to its officers, directors and employees,” Kaveny said. “These individuals intentionally allowed filthy conditions and contamination to occur, creating a danger that NECC chose to expose to innocent people.”

Kaveny said she plans to push for criminal penalties for NECC agents. A lawyer for NECC did not respond to an NBC News request for comment.

Kauffman, the fungal disease expert, acknowledged the frustration that Snopkowski and other victims feel.

Doctors, too, are frustrated, she said. Fungal infections are rare in general, and infections with the molds involved in this outbreak are even scarcer.

“This is unlike anything we’ve ever seen before,” Kauffman said. “There’s nothing equal to this in my career.”

Unfortunately, neither she nor anyone can advise patients what to expect next. For now, they’re all trying to get through each day.

“When you’re dealing with people in pain, that’s the best thing,” she said. “We go day by day. This is all new territory.”

Related stories: 

• More die in fungal meningitis outbreak; state pharmacy chief fired
• Fallout from fungal meningitis mess: more drug shortages
• First case history shows fungal meningitis can destroy brain fast

Cj Gunther / EPA

A Food and Drug Administration agent enters the offices of New England Compounding Center, a pharmaceutical company in Framingham, Mass., on Oct. 16. The company made steroids blamed for killing 31 people and making 424 sick.

Massachusetts officials have fired the director of the state’s pharmacy board and suspended its attorney for failing to alert them that the company at the center of an outbreak of fungal meningitis was making and distributing drugs in mass quantities even though it wasn’t licensed to do so, the Boston Globe reported Wednesday.

Federal health officials say the outbreak of fungal meningitis traced to contaminated pain injections from the pharmacy has killed 31 people. They said 424 people have been confirmed sick in 19 states, including 10 who don’t have meningitis but who have infections in the ankle, shoulder or other joints.

Two congressional committees have scheduled hearings into the outbreak for next week, and will forcibly bring in the chief pharmacist at the Massachusetts pharmacy at the center of the outbreak. Meanwhile, officials have given details of the outbreak in Tennessee, where the infections were first noticed and where the alert first went out.

The Globe cited sources close to the investigation as saying James Coffey, director of the state’s pharmacy board, was fired and Susan Manning, attorney for the board, was on administrative leave. It said the Colorado Board of Pharmacy told both Coffey and the U.S Food and Drug Administration that the New England Compounding Center was distributing drugs in bulk. Compounding pharmacies like NECC are only supposed to custom mix drugs to order for specific prescriptions.

NECC has closed and recalled all its drugs. Both the FDA and the Massachusetts health officials say they didn’t have full authority to stop NECC. The FDA doesn’t regulate compounding pharmacies but it can inspect them for cleanliness. Legislation to give the FDA more authority over them foundered more than a decade ago after the U.S. Supreme Court found part of it unconstitutional.

The two committees, one in the House and one in the Senate, will look at the issue of regulation and whether the FDA did enough to control NECC. House Energy and Commerce Committee Chairman Fred Upton, a Michigan Republican, said he issued a subpoena for NECC’s co-owner and managing pharmacist Barry Cadden to appear at his committee’s Nov. 14 hearing.

“With more than 400 people infected and 30 deaths, it is critical that we hear directly from the head of the facility linked to the outbreak. Since Mr. Cadden has indicated he will not appear voluntarily, we are left with no choice but to issue a subpoena,” Upton said in a statement.

The next day the Senate Health, Education, Labor and Pensions committee will hold its own hearing, with the same panels as well as the Centers for Disease Control and Prevention's Dr. Beth Bell and interim Massachusetts health commissioner Dr. Lauren Smith; David Miller of the International Academy of Compounding Pharmacy and Kasey Thompson of the American Society of Health-System Pharmacists.

The committee also has asked the FDA for any documents from its previous investigations of NECC and other compounding pharmacies.

“Please include whether states were notified, any enforcement actions taken, including all inspections, warning letters, injunctions or seizures executed against compounding pharmacies and how such actions were coordinated with state regulatory authorities,” it asked.

The new statistics from the CDC suggest the outbreak is still related to three contaminated batches of methylprednisolone steroid distributed by the New England Compounding Center in Massachusetts between May and September. Inspections of NECC have turned up dirty conditions and more contaminated drugs, but so far, no infections have been linked to them.

And the report from Tennessee suggests that one of the batches was more contaminated than the others, because people who got injections from that lot were much more likely to become infected than people who got steroid from the other two batches.

“We found a strong association between the age of the methylprednisolone vials and the rate of infection in one clinic,” Dr. Marion Kainer of the Tennessee Department of Health and colleagues wrote in a letter to the New England Journal of Medicine. “One possible explanation for this observation is that the level of contamination in the vials may have increased over time, with subsequent higher fungal burdens present in older vials.”

The more doses of steroid a patient got, the more likely he or she was to become infected, the report found. “Patients who had multiple procedures had an increased risk of a fungal infection,” they wrote. More than 14 percent of patients who got four injections were infected, compared to 5 percent of patients who got just one. So far eight patients, or 12 percent of those infected, have died. Quick treatment seems to save lives they said.

Patients will have to undergo weeks or months of treatment with antifungal drugs, doctors say.

Related stories:

Some infections defy treatment in fungal meninigitis outbreak

More drug shortages may result from pharmacy crackdown

Bacteria found in pharmacy's drugs after fungal meningitis outbreak

Massachusetts officials said Sunday they had closed another pharmacy as part of a crackdown after an outbreak of fungal disease that has killed 25 people and made 344 sick.

They said a surprise inspection turned up unsanitary conditions at Infusion Resource,  a compounding pharmacy in Waltham, Massachusetts that prepares sterile, injectable medications. The facility was also administering injections, something it wasn’t licensed to do, said Dr. Madeleine Biondolillo, director of the state department of health’s Bureau of Healthcare Safety and Quality. Biondolillo did not say any products from the pharmacy were in any way linked to the ongoing outbreak linked to pain injections.

The Centers for Disease Control and Prevention reported six new cases of fungal disease on Saturday in the outbreak traced to steroid injections made by the New England Compounding Center in Massachusetts, bringing the total to 344 cases of infection in 18 states, with 25 deaths. Officials have closed NECC and a separate pharmacy with common ownership, Ameridose, has also closed.

The fungus causes an unusual type of meningitis in some patients who got injections directly into their spines, and patients must undergo weeks or months of treatment with antifungal drugs that themselves can be dangerous, with severe side-effects. State and federal regulators are working to find out how the drugs got contaminated and how the pharmacy managed to operate at such a large scale for so long.

“As our joint investigation with our federal partners into NECC and Ameridose continues, we have launched a series of immediate, on-site inspections of other compounding pharmacies in Massachusetts that prepare sterile injectable medications,” Dr. Lauren Smith, interim commissioner of the Massachusetts Department of Public Health, told a news conference Sunday.

“We will continue our aggressive unannounced inspections of compounding pharmacies while also focusing on our ongoing investigations of NECC and Ameridose.” Smith said the department was adding inspectors and other staff to help take on the workload.

NECC was licensed as a compounding pharmacy, which is supposed to custom-make drugs to order on a per-prescription basis. Instead, officials say, it was mass-producing and distributing drugs to hundreds of clinics treating tens of thousands of patients in two dozen states.

On Friday, the Food and Drug Administration released details of some of its inspections of NECC, and said it found greenish black matter growing in some of the products. The FDA doesn’t regulate compounding pharmacies like it does drug manufacturers, but can look for unclean conditions. The FDA said it found dirt, puddles of water and improper sterilization practices at NECC.

State health agencies are supposed to regulate compounding pharmacies but Massachusetts officials say they didn’t have the power they needed to keep tabs on NECC, which had received several state and federal warnings in recent years. Smith said her department was preparing regulations to require compounding pharmacies to submit frequent reports about sterile, injectable medications -- especially how much they are making and distributing. “This reporting will allow us to better identify large-scale operations acting more as a manufacturer, which requires federal licensure and additional scrutiny,” she said.

“We are also launching a special commission to examine best practices in other states and potential changes to state law or regulations to help us keep pace with an evolving industry and close the regulatory gray area that exists between state and federal oversight."

Infusion Resource, the pharmacy that was closed Sunday, has a branch in Rhode Island, also. "Our patients’ infusion solution needs are being serviced out of our Rhode Island pharmacy located within our main headquarters building in East Providence," Infusion Resource LLC CEO  Bernard Lambrese said in a statement.

Biondolillo said inspectors found “significant issues with the environment in which medications were being compounded, which has called into question the company's compliance with nationally accepted pharmacy standards and Massachusetts regulations.” She said while no products have been found to be contaminated, the state has closed the facility because of worries about sterility.

“Additionally, there was an adjacent space set up for giving patients intravenous medications on-site. Infusion Resource does not have an appropriate clinic license to conduct these activities, which is a violation of state regulations,” Biondolillo said.

Infusion Resource said the issues uncovered by the inspectors did not involve its products.

"The compliance issues involve such physical plant issues as a hairline crack discovered in a 4-pane window caused by settling of the anteroom, the condition of the standard clean room flooring, and a leak in a refrigerator drain hose," the company said in a statement.

"The company provides infusion therapy services to patients in home, ambulatory suite or hospital locations, with approximately 80 patients in Massachusetts served from its Waltham location. It does not provide batch compounding services -- rather it compounds for individual patient dosing needs." A spokeswoman added that the on-site space flagged by the researchers was for education, not for delivering infusions.

In a separate matter, Smith also said state pharmacy board member Sophia Pasedis, who is also a manager at Ameridose, had been asked to resign but said she had refused. Smith said Pasedis should have recused herself from any matters concerning Ameridose and NECC but it wasn’t in fact clear that she had. “Given the ongoing investigation, we believe it is in the best interest of the board to have Ms. Pasedis step down," Smith said.   “We are considering what actions to take in the interim. “

Related stories: 

• What inspectors found at NECC
• Disease risk greatest in first six weeks after injections
• After his wife dies, husband also develops fungal infection

Cj Gunther / EPA

A Food and Drug Administration agent enters the New England Compounding Center, a pharmaceutical company in Framingham, Massachusetts, linked to an outbreak of fungal meningitis.

Nine more people have been diagnosed with fungal disease linked to contaminated pain injections, federal health officials said Wednesday. They said 317 people had been sickened and 24 have died from the mold-contaminated drugs.

Of these, 312 had a rare form of meningitis that is not infectious to others but that causes very subtle symptoms and is hard to treat. They were infected by steroid shots into the spine. Five have been infected by injections to the ankle, knee, shoulder or elsewhere, the Centers for Disease Control and Prevention said.

As many as 14,000 people may have been given injections from three lots of steroid prepared by the New England Compounding Center in Framingham, Mass. State officials have revoked the company’s license and federal officials raided it earlier this month. Both state and federal officials say they found non-sterile conditions at the pharmacy and say it appears to have made and sold drugs far beyond what its license allowed.

CDC says 97 percent of the people who may have been affected have been told of the risk. They said the greatest risk of meningitis comes in the first six weeks after treatment; no one should have received any contaminated injections after Sept. 26, when the pharmacy’s drugs were recalled and officials first raised the alarm.

At least one consumer group says the Food and Drug Administration failed to act even though it knew of problems at the NECC. FDA and Massachusetts officials have both said they lacked the authority to move against the pharmacy and said Congress needs to pass clear legislation giving the FDA authority to regulate so-called compounding pharmacies.

Dr. Michael Carome, deputy director of Public Citizen’s Health Research Group, called it an attempt to deflect criticism.

"The claims by agency officials that the FDA lacks authority to properly regulate compounding pharmacies is contradicted by a long history of remarkably consistent statements and enforcement actions asserting the agency’s legal authority over such pharmacies," Carome said in a statement.

The FDA regulates drug manufacturers, and can inspect compounding pharmacies, which are supposed to make drugs for specific patients who need specific formulations on a prescription-by-prescription basis. NECC was one such compounding pharmacy.

"Prior warning letters from the FDA to the NECC and other compounding pharmacies appear to indicate that the agency considered these pharmacies to be engaged in drug manufacturing. The pharmacies were therefore considered subject to the safety and effectiveness standards required for approval of new drugs, as well as the rigorous manufacturing standards designed to ensure that drugs are sterile and uncontaminated with such germs as bacteria or fungi before being sold and distributed," Public Citizen said.

NECC also says regulators were familiar with its operations.

"NECC has had a long standing practice of working closely and cooperatively with the Massachusetts Board of Registration in Pharmacy and the Massachusetts Department of Public Health," the company's lawyer, Paul Cirel, said in a statement.

"It has always been the company’s practice to provide the Board with full and complete access to its facility and its records.  As is standard practice in the health care industry, the Board had numerous opportunities, including as recently as last summer,  to make first-hand observations of the NECC’s facilities and operations. Based on that history, it is hard to imagine that the Board has not been fully apprised of both the manner and scale of the company’s operations."

 Related links:

• Filthy conditions found at NECC
• Massachusetts to revoke license of pharmacy tied to fungal meningitis
• Fungal meningitis destroyed Maryland woman's brain

AP Photo/Minnesota Department of Health

Vials of the injectable steroid made by New England Compounding Center implicated in a fungal meningitis outbreak. About 17,700 single-dose vials of the steroid sent to 23 states have been recalled.

Federal health officials had good news Wednesday for some of the people injected with fungus-contaminated steroids: They don’t have an open-ended wait to find out if they are infected.

The greatest risk for fungal meningitis comes in the first six weeks -- 42 days -- after injection, the Centers for Disease Control and Prevention says. After that, doctors and patients still need to watch but they may not need to worry quite as much, the CDC said in updated guidance.

"This is the light at the end of the tunnel," Dr. John Dreyzehner, the commissioner of the Tennessee Department of Health, said at a press conference Wednesday about the new guidelines. "By Nov. 8, patients exposed in Tennessee will have passed the 42-day mark."

In Tennessee, 70 patients have been sickened and nine died -- the most in the nation -- after receiving tainted steroid injections. 

The outbreak of fungal disease has made 308 people sick in 17 states so far, and 23 of them have died, the CDC says. The New England Compounding Center in Framingham, Mass., the pharmacy that distributed the contaminated steroids, has been closed and its license has been permanently revoked.  State officials say they have found dirty conditions there. 

By Jay Lindsay, Associated Press

Water from a leaking boiler collected just outside a room that was supposed to be sterile. Floor mats used by technicians were filled with dirt and debris. Drugs were shipped out before the company even confirmed they were sterile.

State officials said Tuesday that they found these and other problems at the New England Compounding Center during a preliminary investigation into the company, linked to a deadly outbreak of meningitis.

The probe can't yet conclusively prove what caused the outbreak, a top health official said. In the meantime, Massachusetts Gov. Deval Patrick said he wants to tighten oversight at similar companies, including with surprise inspections — the first of which happened Tuesday.

The state has also moved to permanently revoke the pharmacy's operating license, as well as the licenses of its top three pharmacists.

"Those whose laboratory practices caused this outbreak should never practice pharmacy or manufacture in Massachusetts again," Patrick said.

The outbreak of fungal disease including meningitis, an inflammation of the lining of the brain and spinal cord, has sickened 308 people, including 23 who have died, in 17 states. The outbreak has been traced back to a steroid made by the NECC and given mainly for back pain. Compounding pharmacies like NECC custom-mix solutions in doses or forms generally not commercially available.

The federal government is conducting a criminal investigation.

The state said Tuesday that its preliminary investigation, which began last month after the company was first suspected in the growing outbreak, found batches of drugs ready for general distribution but not labeled for specific patients.

Its state license permits the company to fill out only specific prescriptions for specific patients, and distributing drugs in batches like a manufacturer would violate that, said Dr. Madeleine Biondolillo, director of the state Department of Public Health's Bureau of Healthcare Safety.

But company attorney Paul Cirel said it's "hard to imagine" state regulators weren't previously aware of the scale of its operations because they've worked so closely together. The state Board of Registration in Pharmacy has always had complete access to the facility, and board members were there as recently as last summer, he said.

"NECC's transparency in dealing with the board since inception in 1998 demonstrates its good-faith intention to operate in compliance with the requirements of its license," Cirel said.

Besides possible state license violations, Biondolillo said the inspections also revealed "several health and safety deficiencies" at the NECC facility in Framingham, just west of Boston.

Three lots of steroids produced by the company are suspected in the outbreak, and the company shipped orders from those lots 13 times before receiving the results of its own tests to confirm those lots were sterile, Biondolillo said. Some medication was shipped as long as 11 days before the company received test results, she said.

Biondolillo also detailed signs of flawed sterilization procedures, including black specks of fungus in sealed vials of the steroids, which were returned to the company during a recall.

Investigators found the company didn't sterilize its products long enough and didn't adequately test whether its sterilization equipment was working, she said.

In addition, mats on which people wiped their shoes to remove contamination before entering a sterile environment were "visibly dirty and soiled with assorted debris," she said. And a leaking boiler adjacent to a pharmacy clean room left an unsanitary pool of water around it and the adjacent walls, she said.

As the investigation continues, Patrick's moves to increase oversight at the state's 25 compounding pharmacies have started.

The first of the unannounced inspections, to take place at least annually, was done on Tuesday, health department spokesman Alec Loftus said. He wouldn't give the inspected facility's name and said the results are being reviewed.

Patrick also said compounding pharmacies will now be required to file annual compliance reports that could help regulators determine if they are acting as manufacturers.

 Related stories:

• Massachusetts to revoke license of pharmacy tied to fungal meningitis
• Fungal meningitis destroyed Maryland woman's brain
• Clues predict who will get sick from fungal infection

By The Associated Press

New state documents detail problems found in 2006 by an outside firm hired to do an assessment at the company at the center of a deadly meningitis outbreak.

The state documents, obtained by The Associated Press under a public records request, say that in 2006 investigators found inadequate contamination control and no written standard operating procedures for using equipment, among other problems, at the New England Compounding Center. The problems were corrected that year, and a state inspection in May 2011 as the company prepared to update its facilities found no such issues.

The outbreak of meningitis, an inflammation of the lining of the brain and spinal cord, has sickened nearly 300 people, including 23 who died, in more than a dozen states. Each victim had received a steroid shot, mostly for back pain. Federal health officials matched the shots produced by the company to the outbreak after finding a deadly fungus in more than 50 unopened vials there but have not said how the shots were contaminated.

A congressional committee on Monday sought a decade's worth of records from the company.

In a letter sent Monday to a lawyer for NECC, the House Committee on Energy and Commerce seeks nearly 10 years of documents about safety and quality issues at the company. It indicates that as far back as 2002 and 2003 officials from the Food and Drug Administration and the state conducted joint probes of the company after receiving a report about a steroid shot. Those probes preceded a 2004 joint investigation of the center by FDA and the Massachusetts Board of Registration in Pharmacy.

In January 2006, based on several complaints, the company signed a consent agreement with state regulators in which it agreed to a full inspection of its drug compounding practices by investigators.

The company's encounters with regulators have been reported since the outbreak began, but state pharmacy board documents released Monday offer a new level of detail. They show the inspection by Illinois-based Pharmaceutical Systems Inc. found "significant gaps" in procedures and a lack of required documentation at the NECC facility in Framingham, just west of Boston.

In a letter to pharmacist Barry Cadden, who co-founded NECC in 1998, PSI said it was "the opinion of the auditors that your operation needs to be upgraded and enhanced to be in substantial compliance" with federal pharmacy regulations.

"The auditors observed some of the compounding activities and although the technicians appeared to be performing the operation adequately, without a written procedure to follow it is not known if the activity is repeatable and reliable; and as noted throughout the report much of the documentation for the activities that is performed is inadequate," wrote Mick Moriva, vice president of quality operations for PSI.

The report found insufficient documentation that proper sterilization procedures had been followed.

Inspectors who looked at the company's non-sterile compounding procedures found potential contamination problems ranging from uncovered and unlabeled containers to a large hole in a ceiling panel above a workbench. The exteriors of some equipment were visibly dirty with buildups of residue.

In April 2006, George Cayer, then-president of the state pharmacy board charged with regulating the compounding industry, sent a follow-up letter to Cadden praising the company's progress in responding to the inspection.

"As you are aware, PSI states that NECC has made significant improvements over the past months and demonstrated the ability to be compliant with state and federal regulations. The Board commends NECC on the progress to date," Cayer wrote.

As part of the consent agreement, the company was placed on probation for one year, but the probation was stayed as part of the agreement, and no fines or other punitive action were ordered.

But the letter from the congressional committee indicates that the company got a warning letter from the FDA in December 2006.

Among the issues cited was NECC's manipulation of a sterile injectable product that led the FDA to be "especially concerned about potential microbial contamination."

The committee said NECC's actions "call into question whether the NECC was operating as a traditional compounding pharmacy or on a commercial scale as a drug manufacturer."

Compounding pharmacies, regulated primarily by states, specialize in customizing doses for patients who have allergies to ingredients in FDA-approved drugs or who might need smaller dosages than what's available commercially. But some pharmacies have pushed into full-scale manufacturing.

Committee members say they want to know "how long NECC has been operating in this manner and why, six years after the FDA's warning letter and 10 years after an inspection relating to methylprednisolone acetate produced and distributed by the NECC, the company was able to continue to do so."

In its letter, the committee also said Cadden had declined to speak to it, although he was not invoking his rights under the Fifth Amendment. Criminal investigators have raided the company, but no one has been charged with a crime.

NECC spokesman Andrew Paven said he hadn't seen the committee's letter but the company continues to cooperate with the ongoing investigation.

"NECC worked cooperatively with the Massachusetts Board of Registration in Pharmacy to resolve to the Board's satisfaction any issues brought to the company's attention," he said by email.

Related stories:

Clues predict who may develop fungal meningitis

Fungal meninigitis probe may worsen some drug shortages

Nearly 300 sickened in fungal outbreak

U.S. and Massachusetts state health regulators were aware in 2002 that steroid treatments from the pharmacy at the center of a deadly meningitis outbreak could cause adverse patient reactions, congressional investigators said on Monday.

The U.S. House of Representatives Energy and Commerce Committee said complaints about preservative-free methylprednisolone acetate were partly responsible for joint state and federal inspections of the New England Compounding Center's (NECC) Framingham, Massachusetts facility in 2002 and 2003.

It is the first indication that health officials knew of potential problems with the specialty pharmacy's production of the drug before tainted versions were linked to fungal meningitis earlier this year.

The House committee is investigating the meningitis outbreak amid calls for tighter FDA scrutiny of pharmacies like NECC, which produced large quantities of drugs for sale nationwide while operating outside federal safety and efficacy regulations for drug manufacturers.

Officials at NECC and FDA were not immediately available for comment.

Steroid treatments are now implicated in 294 fungal meningitis cases, 23 of them fatal, that have so far been reported for patients who received the drug for back and neck pain, according to federal officials. As many as 14,000 people may have been exposed to the treatment. Health officials are also investigating other problems that may have been caused by additional drugs from the same pharmacy.

The House committee, which has oversight of drug safety issues, said Massachusetts public health officials informed its staff about the 2002 and 2003 inspections during a closed-door October 18 briefing.

In a letter to an attorney for NECC, Republican committee Chairman Fred Upton and other panel members said NECC signed a January 10, 2006, consent agreement as "settlement of complaints related to an adverse complaint report investigated by the (FDA) for methylprednisolone acetate preservative free."

FDA issued its own warning letter to NECC in 2006, pointing to potential health risks from other products.

The House committee did not provide details about the adverse incident except to say that it was reported via the FDA's MedWatch system, which collects reports of problems with drugs and medical devices. But it said inspections called into question whether NECC was operating as a traditional compounding pharmacy or as a drug manufacturer.

"The committee seeks to determine how long the NECC has been operating in this manner and why, six years after FDA's warning letter and 10 years after warnings relating to methylprednisolone acetate ... the company was able to continue doing so," lawmakers said in an October 22 letter to NECC attorney Paul Cirel.

The committee sent a similar letter to NECC co-owner Barry Cadden.

The lawmakers said NECC and Cadden failed to respond to an earlier request for a briefing with committee staff and called on the company to produce records dating back to 2002 no later than November 5.

The list of requested documents includes state and federal inspection reports, consent agreements, communications between regulators and NECC as well as the companies Ameridose LLC and Alaunus Pharmaceutical LLC, which share similar ownership.

Related stories:

Fungal meningitis clues may predict who gets sick

Fungal meningitis outbreak tied to steroid shots isn't the first

The quest for relief from pain has now resulted in the deaths of 19 people and a total of 247 confirmed infections of fungal meningitis from tainted steroid injections. Thousands more who got the injections, made by the New England Compounding Center in Massachusetts, are worried that they too may wind up sick or dead. 

The horrific outbreak has resulted in the outrage about a lack of oversight of the compounding pharmacy.

But, this tragedy has another aspect that is not getting sufficient attention. Why are so many Americans getting spinal injections?

Most people in the United States will experience low back pain at least once during their lives. Back pain is one of the most common reasons people go to the doctor or miss work. It has also spawned a lucrative industry of spinal injection treatments whose efficacy, safety and long-term utility are mixed.

Epidural steroid injections are a common treatment for many forms of low back pain such as bulging discs, sciatica and leg pain. Experts agree that injections should be a last resort after patients in pain have tried anti-inflammatory medications and physical therapy. Millions of Americans get shots but far too many as a first attempt at relief, rather than a last resort.

The use of spinal injections, which have been around for 50 years, has been growing rapidly with one study reporting a 629 percent increase in Medicare expenditures for epidural steroid injections over the last decade.

Back pain injections can cost as much as $600 per shot. Insurance will pay much of the cost and there are often a lot of shots given. Sadly, there are lots of programs all over America that advise you on the Internet and in newspaper ads to come in and get a shot for back pain before trying anything else – that’s just lousy medicine.

Do the shots work? Many patients who get them say they do. But  the evidence is not convincing that people do better with shots than pain relievers and anti-inflammatory drugs. One recent, blinded study, published in the British Medical Journal, showed that patients reported as much pain relief with saline placebo shots as those who got epidural steroid injections.

Another study, published in 2007 in the medical journal Spine, showed that shots are most useful for people with herniated disks and pain radiating into their legs or arms but fewer than half of the injections given are for these conditions.

The explosion in back pain injection treatment closely parallels the explosion of obesity in the United States. Not surprisingly, the treatments that have the best evidence of helping relieve back pain are losing weight, exercising more and maintaining better posture. We are becoming a society that relies on symptom relief for health issues, not fixing the underlying problem.

No one should have to fear getting a fungus that might kill them when they go to get treatment for their back pain. Our legislators and regulators have let us down when it comes to keeping an eye on mom and pop drug makers. But, too many of us are using spinal injections as the first response to back pain. And too many doctors and clinics are pushing that treatment as an easy fix. Nothing is easy when it comes to pain. Medicine needs to stop promoting quick and very lucrative fixes for back pain when for a lot of people who suffer an alteration in lifestyle should be what the doctor orders.

Arthur Caplan is the head of the Division of Medical Ethics at NYU Langone Medical Center.

Related stories:

Deadly fungal meningitis outbreak tied to shots isn't the first

First case history shows fungal meningitis can destroy brain fast

Four more die in fungal meningitis outbreak

NYT: Quality lapses in drug factories add to dangers

Pouya Dianat / AP

Shawn Lockhart looks at the meningitis-causing fungus Exserohilum rostratum at the mycotic lab at the Centers for Disease Control and Prevention in Atlanta. Federal health officials have been working around the clock on the outbreak that has killed at least 19 and sickened 247 people. A review of data shows tainted drugs have caused fungal meningitis infections before.

The growing number of illnesses and deaths blamed on tainted pain shots from a Massachusetts compounding pharmacy may be the worst such outbreak of fungal meningitis in U.S. history -- but it’s not the first tied to the injections.

Five people were sickened and one died in 2002 after receiving epidural injections of the steroid methylprednisolone contaminated with the fungus Exophiala, a new review of public health records shows.

“It’s playing out about the same way, but the order of magnitude is so much greater,” said Dr. Jeffrey Engel, an epidemiologist who grappled with the outbreak that started in North Carolina and spread to four other states a decade ago.

“This is a total catastrophe.”

Methylprednisolone is the same drug initially implicated in the current outbreak tied to at least 20 deaths and 257 confirmed infections in 16 states, according to federal health officials. In recent days, two more drugs and two additional types of fungi were added to the initial concerns. Nearly 14,000 people received the potentially tainted steroids, which were distributed in 23 states, federal health officials said.

They came from New England Compounding Center of Framingham, Mass., one of several hundred compounding pharmacies in the U.S. that custom-mix drugs for individual patients.

A decade ago, some 870 patients in North Carolina got similar shots, according to press accounts at the time. A 77-year-old woman who was being treated for low back pain developed fungal meningitis and died more than four months after an epidural injection, the Centers for Disease Control and Prevention reported. Four other women ages 52 to 71 were also sickened by the tainted shots, either in their aching backs or in arthritic joints, but they recovered.

That outbreak was traced to contaminated bulk drugs and to faulty sterilization practices at the Urgent Care Pharmacy in Spartanburg, S.C., recalled Engel, who is now the executive director of the Council of State and Territorial Epidemiologists. The Food and Drug Administration issued a nationwide alert about the company's drugs and the South Carolina Board of Pharmacy issued a cease and desist order to halt all sales of the firm's products. 

Engel has been watching the current outbreak closely, dismayed that the problem continues.

“Haven’t we done anything nationally to prevent this?” he said.

That case is among some 20 incidents since 1990 of recalls, serious illnesses and deaths linked to faulty compounding practices across the U.S., all gleaned from public reports. Some occurred in hospital pharmacies; others happened in compounding pharmacies that aren't required to report adverse events to regulators. 

Eric S. Kastango, chief executive for the health consulting firm Clinical IQ, along with staffers at the Institute for Safe Medication Practices, a nonprofit medication advocacy group, compiled the reports and published them in a newsletter Wednesday.

Food and Drug Administration officials say they’ve logged at least 200 adverse events from 71 compounding pharmacies in the past two decades, but FDA officials did not respond to NBC News requests for a complete list of those incidents.

According to the ISMP report, the problems varied widely: Some 19,000 patients with chronic lung diseases were endangered in Missouri in 2003 by bacterial contamination of at least two batches of a compounded inhalant solution. In 2005 in Maryland, 10 patients died after receiving contaminated compounded medication used to stop the heart during surgery.

And just last year, nine patients in Alabama died and 19 were sickened by bacterial-contaminated IV nutrition solutions. In California, 16 patients developed severe eye infections after contaminated ocular injections of compounded Avastin. One patient was blinded; another developed a brain infection. 

The new fungal meningitis outbreak has reignited calls for stricter oversight of compounding pharmacies, which are generally regulated by state boards of pharmacy, and exempt from regulations by the FDA.

“Ultimately there’s going to have to be a crackdown on these compounders,” said Engel.  

Compounded drugs aren’t FDA-approved and they haven’t been tested for quality or safety. The pharmacies are not required to register with FDA, to disclose what products they are making, or to report problems such as illnesses and deaths that those products might cause.

On Tuesday, FDA enforcers raided the NECC’s facility; earlier in the day, the agency officials had said inspections of the facility raised questions about the sterility of any of the company’s products.

At the same time, members of Congress  said they wanted answers about how the problem occurred. Massachusetts  Rep. Ed Markey, a Democrat, said that NECC distributed controlled substances including morphine and fentanyl without a license.

But lawmakers have demanded stricter control over the industry before, in the early 1990s. Those efforts were stymied by compounding pharmacists, who resisted regulation. Now the industry is governed by a patchwork of state laws -- some enforced, some not -- and general uncertainty about the FDA’s role.

There are well-known steps to ensure that compounded drugs are made safely, particularly the USP 797 guidelines from U.S. Pharmacopeia, the international nonprofit that sets standards for drug safety worldwide.

The trouble occurs when some compounding pharmacies, even only a minority, fail to follow them, Kastango told NBC News.

“We’re not doing good processes, we’re not using good aseptic technique,” he said. “You look at the data and most of these events are starting with non-sterile compounding.”

Related stories: 

• Four more die in fungal meningitis outbreak
• FDA: Check all who got suspect pharmacy drugs
• Congress seeks probe of pharmacy in fungal meningitis outbreak