Finalist: The Boston Globe, by Liz Kowalczyk, Carolyn Johnson, Todd Wallack, Patricia Wen and Kay Lazar

It was Labor Day weekend when the first patients began to trickle into an Ypsilanti, Mich., hospital complaining of headaches, sensitivity to light, and neck stiffness. Laboratory tests of the patients’ spinal fluid strongly suggested meningitis and physicians started treatment.

 

But in a cluster of offices on the third floor, four of Saint Joseph Mercy Ann Arbor Hospital’s infectious disease specialists wrestled with a puzzle: Why couldn’t the laboratory identify the microbe causing the infection?

 

Later that week and some 500 miles away, a 51-year-old woman developed a powerful headache radiating into her face and headed to a Baltimore-area emergency room. She was discharged after a normal brain scan, but returned the next day with distressing symptoms: double vision, nausea, vertigo, and a loss of muscle coordination. As her condition worsened, a spinal tap provided no clues to the underlying cause.

 

And then in mid-September, Dr. Robert Latham at Saint Thomas Hospital in Nashville, Tenn., found himself perplexed by the case of a woman who returned to the hospital after a treatment for meningitis stopped working. Lab tests showed signs of a raging infection, but similarly, he could not identify the culprit.

 

At hospitals scattered across the country, it was the horror story of the waning days of summer. Teams of physicians faced the same medical mystery — patients with life-threatening infections with an unknown cause. There were subtle hints that they were dealing with a highly unusual illness, and astute clinicians and state and federal health officials worked to connect the dots. Ultimately, they would discover that these seemingly isolated cases were the leading edge of an outbreak of a fungal meningitis so rare that many doctors will never see a case in their lifetimes.

 

“The fact we had two people with strange presentations, related to the epidural injection, I hope would have been a bellwether for us,” Dr. Robert Latham said.

 

The cases would quickly be linked to three batches of an injected steroid produced by a Framingham compounding pharmacy, but by that time 14,000 people in 23 states had received the injections for back and joint pain. More than 300 have fallen ill, and 25 have died.

 

Still immersed in treating the illness, most doctors have not had time to reflect on it. But Latham compared the initial confusion, frustration, and growing alarm to the early 1980s, before HIV had been identified as the cause of AIDS. The impact of a tainted drug could never be compared to that global epidemic, but at Saint Thomas, where 38 patients have now been treated, the medical team had the same feeling of being overwhelmed by an unknown that was bigger than anyone imagined.

 

“When the HIV patients first started presenting, we were all scratching our heads, saying, ‘What in the devil is this?’ ” Latham said. “Those of us here at Saint Thomas are having an experience similar to San Francisco General in the early 1980s, when young men were walking in” with pneumonia and cancer.

 

This time, the patients walking in were mostly middle-age and elderly, with signs of meningitis.

 

The struggle for answers

Elwina Shaw of Denton, N.C., received the third of a set of epidural injections for back pain at the end of August. A vibrant 77-year-old, Shaw was generally healthy, said her daughter, Dawn Frank, aside from a little bit of knee pain and the back trouble. She wanted back surgery, but she had been steered instead toward the shots to see whether they would help.

 

Shaw was working in her garden one day in September when she got a terrible headache, Frank recalled. Shaw went to the doctor, and at first was told she was having migraines. But they didn’t go away. She went to the hospital for a brain scan, but it still wasn’t clear what was wrong. She was sent home, Frank said, and was told it might be a virus.

 

Finally, on September 25, Frank brought her mother back to the hospital, determined that doctors would not send her away until they could figure out what was wrong. Near midnight, she remembers, they did a lumbar puncture, drawing out a sample of spinal fluid.

 

Frank prayed it would not be bad. Shaw’s 80-year-old husband, Rex, needed her. A talented seamstress, eloquent writer, and a woman of great faith, she filled their home and lives with grace and love. She never drew attention to herself, and had always embraced being a homemaker and mother.

 

The test results were clear: meningitis of unknown cause. Unbeknownst to her physicians and her family, Elwina Shaw had joined the constellation of cases that were challenging doctors and wrenching families in other states.

 

In Michigan, patients who responded initially to treatment for meningitis returned to the hospital, worse. In Maryland, the 51-year-old woman’s spinal fluid was tested for bacterial infection and viruses ranging from West Nile to herpes as medical teams tried to treat her, according to a report published in the Annals of Internal Medicine . Within a week and a half of being admitted to the hospital, she was brain dead. In Tennessee, doctors were struggling to figure out how to help the woman who had seemed to recover, then relapsed.

 

Dr. Varsha Moudgal, an infectious disease specialist at Saint Joseph Mercy Ann Arbor in Michigan, said physicians there had been mulling over several unusual aspects of their handful of cases. Some patients seemed almost too well, Moudgal said, explaining that meningitis patients with the kind of sky-high counts of immune cells and extremely low glucose levels doctors measured would typically have more symptoms, such as altered mental abilities.

 

“They came in and didn’t appear to be as ill as their cerebrospinal fluid picture suggested,” Moudgal said. “They were talking to us. They were sitting up.”

 

Others had severe symptoms but their lab tests suggested their infections were not that bad.

 

The doctors turned to specialists in microbiology and pathology, asking them to rack their brains for better diagnostic methods. Physicians scoured the medical literature to see whether past cases could teach them how to treat their growing cluster of patients. Dr. Anurag Malani said he heard rumbles of a case at another hospital that echoed theirs.

 

“We knew something was wrong, but it was hard to put a finger on it,” Malani said. “In hindsight, I think a lot of other places were feeling the same frustration.”

 

Meanwhile, in Tennessee, Dr. April Pettit, an infectious disease specialist at Vanderbilt University Medical Center, had been struggling with the same disturbing pattern: A man in his 50s with what appeared to be meningitis. He initially responded to treatment, went home, and then returned, the infection careening out of control.

 

When he came back, she reported in the New England Journal of Medicine this month, he was visibly ill and his speech unintelligible. Searching for answers, she told the laboratory to test for unusual microbes, such as fungi, even though such infections are quite rare, usually occurring in people with suppressed immune systems.

 

“On morning rounds, Dr. Pettit gets a call from the microbiology laboratory,” said Dr. William Schaffner, an infectious disease specialist at Vanderbilt who is familiar with the case. “She steps out to get the call, and she receives the information the cerebrospinal fluid has grown a fungus: aspergillus. She is dumbfounded.”

 

A common denominator

Pettit reviewed her patient’s history, to see whether there was anything unusual, anything that could explain why an otherwise healthy, middle-aged man with no immune system problems could have gotten such a rare type of meningitis. Several weeks earlier, she learned, he had received an epidural steroid injection at Saint Thomas Outpatient Neurosurgery Center. It was the only thing that stood out. She contacted the Tennessee Department of Health.

 

Dr. Marion Kainer of the health department immediately got in touch with the infection prevention staff at Saint Thomas. She told them of the man in his 50s, whose disease had followed much the same trajectory as their patient — and who had also received an injection. Latham knew his patient had also gotten an epidural injection at the hospital’s neurosurgery clinic, but previously he had no reason to connect it to her symptoms.

 

“The fact we had two people with strange presentations, related to the epidural injection, I hope would have been a bellwether for us,” Latham said. But that day, they got an even clearer message that something larger was going on: Another person had been admitted with similar symptoms. That person had also had an injection at the same place.

 

Saint Thomas closed its Outpatient Neurosurgery Center on Thursday, Sept. 20, and Tennessee notified the Centers for Disease Control and Prevention in Atlanta. Latham accompanied state health officials on an inspection of the facility to see whether there were any clues as to where the infection had come from: Did the clinic have the proper infection-control policies and procedures? Was there a chance equipment had been contaminated? Could it have been a contaminated drug?

 

By that Sunday, other probable cases had been identified in Tennessee, and the next day the Tennessee Department of Health contacted their counterparts in Massachusetts. Late in the evening, the Tennessee officials told the Bay State regulators of six rare fungal meningitis cases that had developed between July 30 and Sept. 18 in their state. The patients had at least four things in common: one being that they had received an injection of methylprednisolone acetate made by New England Compounding Center.

 

A day later, state regulators asked the owners of the Framingham compounding pharmacy to compile a list of all the medical centers that had been shipped medication from three batches of the steroid that federal officials had flagged as suspicious. The lots, prepared on May 21, June 29, and Aug. 10, the officials learned, had been shipped to 75 locations — and they contained 17,676 doses.

 

The next day, Sept. 26, the company voluntarily recalled the products, but there was still no firm connection between the drugs and the outbreak.

 

Then, physicians at the High Point Regional Health System in North Carolina, where Elwina Shaw was being treated, received a call from the CDC. The High Point Surgery Center was among the places that received doses of the drug. The agency official asked whether there were any patients with symptoms similar to the Tennessee cases, according to hospital spokeswoman Tracie Blackmon. High Point did have such a patient, the hospital confirmed.

 

The CDC later said in a health advisory that it was that first case outside of Tennessee that was “possibly indicating contamination of a widely distributed medication.” Frank said her family was told her mother’s case helped point the finger at the contaminated drug.

 

“The steroid was the common denominator,” Frank said.

 

The doctors in Michigan began to hear news reports of what was going on in Tennessee. They began to realize the common thread was the epidural injections their patients had received at a nearby clinic.

 

Treating an outbreak

Pinpointing the source of the infection was only the first step. Public health officials now realized that many more people were likely to be hospitalized in the coming weeks, but they had little idea how to treat them. Fungal meningitis occurs infrequently, and the circle of researchers who study such infections is small.

 

The CDC convened a panel of experts to develop advice for physicians on what symptoms to watch for, how to best treat it, and when to start antifungal medications. Complicating matters was the fact that while the initial case in Tennessee involved a fungus called Aspergillus fumigatus, the subsequent cases were mainly caused by a black mold called Exserohilum rostratum.

 

Cases of meningitis caused by aspergillus were rare, say specialists in fungal diseases, but cases caused by black mold were even more so, making the outbreak almost entirely untrodden medical ground. The large number of elderly victims was another challenge, because many had chronic conditions that could make it difficult to distinguish symptoms or that make them unable to tolerate the harsh drugs.

 

Expertise rapidly developed at the centers that were hardest hit. At Saint Joseph Mercy Ann Arbor, where 66 patients had been treated as of Friday, there was a daily 9 a.m. “huddle” of health care providers, followed by a call that drew together people from across the hospital, from the chief medical officer to pharmacists to emergency room doctors to the infectious disease specialists.

 

Drug regimens were fine-tuned to diminish side effects, and a special clinic was set up to help patients manage the disease.

 

Patients will have to take the antifungal drugs for a minimum of three months — and possibly as long as a year.

 

More staff were brought in to help manage the flood of people who came to be tested for meningitis. On their busiest day, 66 spinal taps were drawn; during the last month, a couple hundred have been performed, Malani said.

 

Three patients have died, but two fell ill before the meningitis cases were connected to a fungus.

 

By the time Rhonda Hall showed up at the hospital a week and a half ago, systems and procedures were in place and the pace had slowed. The 49-year-old bus driver from Brighton, Mich., was in an accident a year ago that still causes her pain. She had recently had surgery on her left ankle and got a steroid injection in her hip.

 

Soon after, Hall found herself clutching the side of her mattress just to get out of bed, and she realized that it wasn’t just an after-effect of the surgery. Something was wrong with her hip.

 

After hearing about the contaminated injections on the news, she called and learned she had gotten one of the bad shots. She was diagnosed with a bone infection.

 

“I was very scared in the beginning,” Hall said last week, just before going into surgery to flush out the infected joint. “Now it’s to the point . . . I want it over with so I can start healing and feeling better.”

 

The lessons learned by physicians came too late for Elwina Shaw. During her time in the North Carolina hospital, Shaw had two strokes, her daughter said, but she was able to write her name in cursive and walk afterward. Her family was hopeful.

 

But her condition worsened, and she died Friday, Oct. 19. On that day, the CDC reported that 271 people were infected, 21 deceased.

In February 2003, 11 federal and state health regulators gathered around a conference table in Boston, joined by three colleagues patched in on telemonitors from Washington, to decide the fate of New England Compounding ­Center.

 

The tiny Massachusetts pharmacy seemed too obscure to require so much firepower. But at least four patients had recently died of meningitis caused by contaminated steroid injections made by compounding pharmacies in California and South Carolina, and federal investigators were worried they could have another public health crisis on their hands, according to documents provided by a US Senate committee and the US Food and Drug ­Administration.

 

Similar steroids mixed by New England Compounding were believed to contain toxins — they had possibly sickened at least four patients. And the company was expanding — fast. Despite initially promising to sell medicines only to Massachusetts doctors, co-owner Barry ­Cadden had acquired pharmacy licenses in at least 13 states, filed applications in many more, and begun to hire a sales force to exploit the burgeoning and profitable market for custom-made drugs.

 

Before the group of regulators disbanded, they decided the state, not the FDA, would take the lead in disciplining the specialty pharmacy. That proved to be a key choice. California and South Carolina regulators took strong steps that cost the compounders involved in the earlier contamination cases their businesses.

 

But Massachusetts ultimately would take no significant ­action against New England Compounding, the company that a decade later is blamed for a national meningitis outbreak that has sickened 541 people and killed 36 — allowing it to flourish into a national distributor of thousands of steroids, painkillers, and other medicines to doctors and hospitals.

 

“Barry owned the market of pain management,’’ said Jim Nahill, who owns Pallimed Pharmacy in Woburn.

 

The Massachusetts pharmacy board did not take action against New England Compounding until October of this year. It forced the pharmacy to shut down after investigators traced the meningitis outbreak to one of its drugs — methylprednisolone acetate — one of the two steroids believed to have sickened patients in 2002.

 

Before Cadden started New England Compounding, he was a traditional retail pharmacist at a Rhode Island Walgreens store for eight years, with no experience managing a business. In his 1998 application for a Massachusetts pharmacy ­license, Cadden said he planned to customize drugs for Massachusetts doctors, particularly those in the suburbs west of Boston.

 

The Framingham pharmacy was located in the same red brick complex as a recycling business owned by his wife’s family, the Conigliaros, who helped him start New England Compounding.

 

Right away, Cadden struck others compounders, who tend to share recipes, as reticent — almost like he wanted to fly ­under the radar.

 

“They were still setting up when I knocked on the door,’’ recalled Dennis Katz, the owner of Hopkinton Drug, a compounding pharmacy 15 minutes away from New England Compounding. “I said, ‘Welcome to the area. If I can help you with a formula, let me know.’ I was not invited in, which I thought was weird.’’

 

New England Compounding was among dozens of independent pharmacies that eagerly began compounding around then, as chain drugstores and Internet mail order outfits threatened small pharmacies by taking over much of the business of filling traditional prescriptions. Insurers were ­also clamping down on payments, and by the early 2000s, the number of independent pharmacies in the United States had plunged to 23,000 from 40,000 in 1980.

 

There was also a desire among doctors and patients to more aggressively treat pain, with doses and drug combinations not supplied by big pharmaceutical companies. Patients wanted natural hormone replacement therapies, anti-aging formulas, and veterinary drugs. Consultants and compounders boasted that impossibly large profits could be made.

 

“Anybody know what the average margin on a compounded product is?’’ businessman Mickey Letson, then president of a major compounding supply company, asked a group at a national trade show in Atlanta in 2002. “Seventy-five percent minimum gross profits. Depending on what field you’re in it can run into the thousands of percent.’’

 

Lester Nathan of Schenec­tady, N.Y., who dubbed himself the “million dollar marketing coach,’’ helped over 300 pharmacies market their compounded products. “The raw materials are cheap and the pharmacist is getting paid for a higher level of product,’’ Nathan said in an interview. “Compounding is one of the areas they should have been in anyway, in order to serve their patients better because it’s customizing medicine.’’

 

A Texas-based company called Professional Compounding Centers of America, started by a Houston pharmacist in 1981, received a growing number of calls from traditional pharmacists who wanted to learn to custom make drugs. The company mailed kits that included formulas, chemicals, and equipment. Customers included New England Compounding, which bought nonsterilized chemical powder to mix into sterile injectable drugs, the riskiest, most demanding form of compounding.

 

By 2002, the year the FDA started investigating the firm, it was clear that New England Compounding’s strategy went far beyond the local focus Cadden had promised. Yet state and federal regulators did next to nothing to slow its growth.

 

That year, the pharmacy took over a neighboring store to double its space. Cadden proudly told federal regulators he planned to sell drugs in all 50 states. And pharmacy boards — apparently largely unaware of the company’s tussles with regulators — cooperated, quickly granting New England Compounding licenses.

 

In one instance, Charles Young, then executive director of the Massachusetts pharmacy board, assured his counterparts in Florida that the pharmacy was in “good standing.’’ Young dated the letter April 10, 2002 — the same day FDA and board investigators arrived at the pharmacy to investigate potential contamination of the steroid betamethasone and found Cadden refusing to provide records.

 

During these years, the company marketed its products aggressively, borrowing techniques from large drug manufacturers. Cadden set up an exhibit booth at a national meeting of eye doctors in 2003, faxed fliers to doctors’ offices in 2004 advertising fast-acting “extra strength triple anesthetic cream,’’ and cosponsored the Eastern Pain Association meeting in Manhattan in 2005.

 

In promotional materials faxed to doctors’ offices and distributed at national meetings, the company promoted its rigorous sterility testing and attention to industry standards. One 2005 pamphlet boasted the company was licensed in 49 states, included a “state-of-the-art laboratory,” and used an independent testing firm.

 

Doctors say Cadden sometimes shipped large amounts of drugs to them on consignment, requiring them to fax patient names only as each dose was used. It is a more convenient system for physicians than providing a prescription before receiving each vial — as required by Massachusetts law.

 

“When you are good at what you do in our business, you create waves of business you can’t predict,’’ said Nahill, the Woburn compounder. It’s a competitive business, he added, and if a compounder isn’t responsive to doctors’ needs, “they will go somewhere else.’’

 

Cadden’s company got invaluable help along the way from his brother-in-law, a Florida anesthesiologist with contacts among fellow pain specialists and years of experience using compounded pain drugs.

 

Dr. Douglas Conigliaro, whose wife, Carla, was listed as the pharmacy’s majority owner, started a marketing company in 2002 that promoted New England Compounding’s products. And he introduced Cadden to a Florida pharmacist who had long supplied Conigliaro with compounded medicines.

 

“I think Doug wished Barry would do a little more volume,’’ said Sam Pratt, recalling that Conigliaro was interested in how many prescriptions he mixed per day. The men talked in 2005 at a Florida pharmacy conference, where Cadden was in high demand. Pratt said Cadden answered constant cellphone calls as they walked the convention floor.

 

Conigliaro has not responded to request for comment. Cadden has declined to comment through his attorney.

 

While Conigliaro was viewed by workers as an aggressive businessman, Cadden was friendly, they said. One former salesman, who did not want to be identified because he is afraid of damaging his career, said Cadden was “very dynamic” and loved talking about his compounding work. During his job interview, he estimated Cadden talked for 43 of the 45 minutes.

 

Beneath Cadden’s outgoing personality, however, he had a competitive nature.

 

Several years after they met in Florida, Pratt decided to call Cadden for a favor. He wanted to know how to make a certain medication, but Cadden was tight-lipped. “He said if he was going to do it for anyone, he’d do it for me,’’ Pratt recalled. “He wouldn't tell me. It was his market.’’

 

Cadden was similarly circumspect when FDA inspectors visited New England Compounding to investigate reports that several patients had developed meningitis-like symptoms after injections with the company’s drugs. He chafed and sometimes turned uncooperative, according to internal agency reports.

 

One day in April 2002, inspectors noted that Cadden had stored a 1,000-milliliter beaker of ­betamethasone — the steroid believed to have sickened at least two patients — in a protective hood while awaiting results of sterility tests, which could take a week. Cadden had covered the beaker with several sheets of aluminum foil.

 

Investigators warned the solution could become contaminated sitting out that long, but Cadden said he did not want “to waste money” on vials until he knew the product was sterile and could be sold. At a meeting a week later, Cadden told investigators the beaker did not contain betamethasone at all.

 

Federal and state officials inspected New England Compounding nine times in 2002 and 2003, and the FDA issued the pharmacy two form 483s — a formal list of concerns ­ob­served during inspections — identifying problems with the sterilization and mixing of drugs.

 

In response to one, Cadden said he had hired a consultant and taken a series of corrective actions, including sanitizing work spaces on a regular schedule and cleaning and testing the autoclave, used for sterilizing equipment.

 

The investigation occurred amid the unfolding tragedies in California and South Carolina. These cases were a key component of the FDA’s presentation to state pharmacy regulators at the February 2003 meeting.

 

The agency’s officials wanted to impress on the pharmacy board “the potential for serious public health consequences if NECC’s compounding practices, particularly those relating to sterile products, are not improved,’’ David Elder, then director of compliance for the agency’s New England office, told the group, according to a memo summarizing the meeting.

 

Thirteen patients were hospitalized, including five with meningitis, and three died, ­after receiving injections of the steroid betamethasone made by Doc’s Pharmacy in Walnut Creek, Calif. — cases that came to light in the summer of 2001. In South Carolina the next year, four patients contracted fungal meningitis from methylprednisolone made by Urgent Care in Spartanburg, and at least one died.

 

During the meeting, the FDA also pointed out that an April 2002 US Supreme Court ruling had weakened its authority over compounding pharmacies, while leaving intact its power to regulate manufacturers.

 

Though New England Compounding had begun its national expansion by that time, the regulators, for reasons that are unclear, decided the company was still a compounder, and the FDA handed over primary oversight responsibility to the state.

 

The state pharmacy board initially proposed a three-year probation and reprimand of the company, but backed off when the firm protested that the ­action would threaten its ­national business by scaring off customers. Instead, the board signed a consent agreement with the pharmacy in 2006 that required it to improve its sterile compounding procedures.

 

By that time, William Koch, a patient injected with the pharmacy’s methylprednisolone acetate in 2002 at a Rochester, N.Y., hospital, had died of bacterial meningitis, according to a lawsuit filed against the pharmacy in 2004 and confidentially settled.

 

Harold Sparr, a Massachusetts pharmacy board member from 1992 to 2006, said board members did not understand what was going on inside New England Compounding. Maybe, he said, the company “let things slide for the almighty buck.’’

 

State health officials now ­acknowledge they missed ­opportunities to ensure the pharmacy’s practices were safe and say they have now stepped up enforcement.

 

Meanwhile, the FDA remained involved, sending New England Compounding an official warning letter in 2006 detailing deficiencies it found during its inspections.

 

Cadden wrote back in 2007 that the findings were invalid because the letter came so long after the 2002 and 2003 inspections. The FDA sent a final letter in 2008 threatening follow-up inspections or even closure of the pharmacy, but never made good on those threats.

 

In response to Globe questions about why Cadden was uncooperative with the FDA during the early 2000s, his attorney said, “This sort of historical retrospective sheds no light on the current issue.’’

 

“Whatever alleged conditions in the NECC lab may be dredged up from many years back simply shed no light on the mystery of what went so terribly wrong for the first time in June and August, and why,” Bruce Singal said in a written statement.

 

Its problems with the FDA apparently settled, New England Compounding embarked on the largest expansion in its history. Cadden and Gregory Conigliaro, younger brother to Doug, launched another company, Ameridose, in 2006, which focused on repackaging and custom-making medications for hospitals.

 

The pharmacy focused on small pain and eye clinics, but as a growing number of drugs became backlogged, hospitals signed on as customers and its sales exploded.

 

One former manager of its sister marketing company said that by 2008, New England Compounding was “wildly profitable,’’ earning $13 million in revenue, of which more than $5 million was pretax income. The manager wanted to remain anonymous because he is worried about being sued.

 

The company grew from about 20 employees in 2009 to 50 by the time it shut down two months ago.

 

“It was crazy, crazy expansion,” said one former sales representative who did not want to be identified because he signed a confidentiality agreement.

 

Another salesman, the one who did not want to be identified because he was afraid it would hurt his career, said Cadden wanted his pharmacy to grow, particularly after watching Ameridose become much larger. “He had sort of a love-hate relationship with Ameridose.”

 

But New England Compounding benefited from its ties to Ameridose, which frequently referred customers to its sister company for products it couldn’t supply itself.

 

FDA records for this year show that more than three ­dozen hospitals purchased drugs in shipments of 500 doses or more — even though ­Mas­sachusetts law prohibited New England Compounding from selling drugs without patient-specific prescriptions because it was not licensed as a manufacturer.

 

Gaston Memorial Hospital in North Carolina purchased 900 vials of nalbuphine, a powerful painkiller, in July alone. The hospital acknowledged it did not have individual prescriptions for each dose.

 

Hospital spokeswoman ­Dallas Wilborn said the hospital was forced to buy from the company “due to a shortage of medications from our traditional suppliers.”

 

The salesman who signed the confidentiality agreement said hospitals were desperate for medications in short supply. “They were freaking out,” he said. “If they couldn’t get these drugs, patients were going to die.”

Health officials investigating the national fungal meningitis outbreak caused by tainted steroid injections had thought that the worst was over. The number of new cases was dwindling. Then came patients like Anna Adair.

 

An avid gardener and dog-breeder, Adair was rolled into a Michigan emergency room in a wheelchair Nov. 15. She had been bedridden for days, and that morning a bolt of pain in her lower back had caused her to tumble to the bathroom floor.

 

Doctors quickly reached a disturbing realization: An infection caused by black mold had infiltrated her spine, near where she had received an injection made by a Massachusetts pharmacy, and spread into the bone. It was not the ­meningitis that sickened hundreds of others in late summer and early fall, but part of a frightening second wave of ­fungal infections caused by contaminated drugs.

 

Dozens more people have now been diagnosed with excruciating abscesses or inflamed nerves in their backs that are proving formidable to cure.

 

In a health alert issued Thursday, the federal Centers for Disease Control and Prevention said it is worried that some patients with spinal infections may not even be aware of their condition because the symptoms mimic the very back pain they originally sought to treat with steroids. The agency is now recommending that doctors consider performing MRI scans to screen all patients who have persistent back pain and received steroids from one of three contaminated batches. Previously, it advised scanning just those with new or worsening pain.

 

“People could be walking around with infections and they do not know it,’’ said Dr. Varsha Moudgal, head of infectious disease at St. Joseph ­Mercy Hospital in Ann Arbor, Mich., where Adair was hospitalized. “If they are untreated, they will cause pressure and damage to the spinal cord, and the concern then is about losing function.’’

 

Doctors at St. Joseph Mercy are scanning every patient with routine back pain who received a contaminated injection and have discovered infections among 14 percent of them. Among patients with new or worsening pain in Michigan, Tennessee, and North Carolina, MRIs have turned up infections in more than half. Since Nov. 29 alone, states have reported to the CDC at least 90 cases of spinal infections in patients who have not had meningitis.

 

The unexpected back infections add another element of worry for the nearly 14,000 ­patients across the country who received steroids laced with black mold from New England Compounding Center, amid what has been a trying 2½ months for many of them. While 39 patients have died, another 555 who have back ­infections, meningitis, or both, are facing an uncertain future. Many have relapsed and been hospitalized two or three times. Most have suffered debilitating side effects from antifungal drugs, including hallucinations.

 

At St. Joseph Mercy, where 30 patients are still hospitalized with meningitis or spinal infections, several patients have significant kidney damage caused by amphotericin, the drug Adair received during her third hospital stay. Even those who have gone home must undergo regular blood tests, electrocardiograms, MRIs, and painful spinal taps so doctors can closely monitor their condition.

 

Particularly distressing is that doctors do not know how long patients will require medication — estimates range from three months to a year — and whether the drugs will ultimately eliminate the fungus from their bodies, said a dozen patients, attorneys, and infectious disease specialists interviewed by the Globe.

 

Dr. John Perfect of Duke University Medical Center, a leading fungal disease specialist, said the medical profession “is flying by the seat” of its pants.

 

At the same time, investigators from the CDC and Food and Drug Administration are still searching for firm answers to basic questions about why the outbreak has progressed the way it has: Why did some states, such as Michigan and Tennessee, see a higher percentage of patients given the contaminated steroids get sick? And why is the number of ­patients with spinal infections still growing?

 

“The doctor has been really honest,’’ said Michael Mullins of High Point, N.C., who was diagnosed with meningitis on Oct. 5 and now has two small spinal abscesses. “We know meningitis can kind of linger. You can get sick later on in life. Whether this fungal meningitis will do this we don’t know. The only people who have lived through this kind of thing are those who are here now.’’

 

Adair, called Penny by her family and friends, had her first steroid injection from a contaminated batch Aug. 16 at a pain clinic near her home in ­rural South Lyon, about 20 miles north of Ann Arbor. She experienced terrible pain for weeks afterward, but doctors believed it was due to her degenerative disc disease, and she had a second contaminated steroid injection on Sept. 17.

 

By mid-October, Adair was in too much discomfort to walk, and her husband, a machine builder, drove her to the emergency room. It was the first of 41 days she would spend in the hospital during three stays, includ­ing Thanksgiving and her 50th birthday; they had planned to celebrate with a backyard bonfire and cookout.

 

Like many patients in the early days of the outbreak, Adair was initially misdiagnosed, with a pinched nerve, because her spinal fluid tested negative for meningitis. It was not until her second stay that doctors performed an MRI scan and found the abscess, she said. They put the mother of two on an antifungal drug called ­voriconazole and told her she would need a walker.

 

After Adair’s husband wheeled her into the emergency room Nov. 15, doctors realized the infection was eating away her vertebrae. She teared up when they told her they would have to operate to drain fluid, scrape away infected portions of bone, and remove part of a disc.

 

“If the fungus is allowed to grow and thrive, it will infect the nerves in the spine, and that has far more ominous implications for patients,’’ said Dr. Douglas Geiger, a neuro­surgeon at St. Joseph Mercy.

 

After the surgery, doctors pumped a stronger and more toxic antifungal drug, amphotericin, into Adair’s body, but had to temporarily stop the lemon-colored intravenous drip because she was showing signs of kidney damage. “I had never been so scared in my life as when I thought it was attacking my kidneys,” she said. “I almost refused this treatment at the very end.’’

 

Michigan doctors have grown particularly aggressive about screening and treating patients, in part because the state received steroids from a batch they are calling a “hot lot’’ that appears to be more highly contaminated. Like Adair, most patients in the state received contaminated injections at Michigan Pain Specialists in Brighton, which got 400 vials of methylpredisolone acetate from lot 06292012@26, made by New England Compounding pharmacists in June.

 

Tennessee health officials have found that patients injected with the steroid from this lot were four times as likely to ­develop fungal disease as those injected with steroids from the other two implicated lots. More fungus could have gotten into this lot during mixing at New England Compounding, or it could have sat on shelves longer, giving the mold more time to grow, doctors said.

 

This lot might be one reason why a greater percentage of ­patients in Michigan got sick, or it could be that pain specialists there injected steroids in a way that made it easier for the fungus to take root and spread, Dr. John Jernigan of the CDC said in an interview. As to why the number of spinal infections is growing, specialists theorize that the incubation period could be longer than for meningitis or that it has taken longer for patients and doctors to recognize and report infections.

 

Adair is now at home, taking antifungal pills and waiting for her incision to heal. She requires morphine to get out of bed in the morning, but doctors have told her the pain should subside as her back heals. She has put breeding dogs and chickens, and tending her flower and vegetable gardens, on hold. Her husband, who depends on overtime to help make ends meet, did not get any extra pay last month while he helped care for her. They missed a mortgage payment and are working with the bank.

 

“We are just lucky I didn’t die,’’ Adair said. “I just don’t want to lose my house over this.”

 

Many of the patients stricken with meningitis early on are still dealing with the physical and emotional fallout from their disease.

 

Virginia Milne, 65, developed meningitis while traveling with her family in Europe, and after 31 days in the hospital, she is now home coping with the side effects of treatment. Milne got a steroid injection in her lower back Sept. 5 because she did not want her chronic back pain to ruin the trip. By the time she arrived in London two weeks later, she had developed a terrible headache.

 

Her husband wanted to ­return home to Virginia, but Milne insisted they go on to ­Ireland to meet a cousin. There she ended up in a small rural hospital, but they had not heard about the fungal meningitis outbreak in the United States, so she was not diagnosed until she got back. At one point, amphotericin caused such serious side effects — acute kidney failure and fluid in her lungs — that doctors pulled her off the medication.

 

“Late at night when there was no one there to talk to I would think, maybe this is how multiple organ failure occurs,” she said.

 

Now, side effects from a different drug include trouble concentrating, an unsettled stomach, swollen feet and ­ankles, and hand tremors.

 

“My doctors are not willing to say it’s the drug and it will get better,’’ she said.

 

“They are hopeful, but this is all uncharted territory.’’

KINGSTON, R.I. — The Massachusetts specialty pharmacy at the center of the deadly national outbreak of meningitis might not have existed but for a relationship that started about three decades ago on the bucolic campus of the University of Rhode Island.

 

Barry Cadden and Lisa Conigliaro were classmates in the school’s College of Pharmacy, two of 92 students who graduated in the class of 1990. ­Cadden was following a family tradition: His father was a local pharmacist and an alumnus of this state university. Conigliaro came from a family with a strong entrepreneurial bent. They would fall in love and, within a few years of graduating, marry.

 

It would be more than a wedding of two licensed pharmacists. A special alliance would evolve between Cadden and his wife’s older brother, Gregory Conigliaro, a go-getter with an eye for niche businesses. Together, they started New England Compounding Center in Framingham, as well as Ameridose, and turned them into some of the fastest-growing drug-compounding businesses in the country.

 

With Cadden’s scientific know-how and Gregory Conigliaro’s enterprising spirit, their fortunes grew. They launched a half-dozen related corporations and brought in relatives, including Lisa, as ­employees and corporate officers. Together with their wives, each built handsome homes in Massachusetts, bought vacation homes, and gave generously to their favorite charities or political causes.

 

The creative energy of the two families seemed unstoppable, until last month, when public health authorities linked an outbreak of fungal meningitis around the country to one of their injectable steroids.

 

Now New England Compounding is blamed for potentially exposing thousands of ­patients to contaminated products. So far, 19 people have died, and more than 200 people have become ill.

 

Cadden, 45, and Conigliaro, 46, and their extended families have declined comment since the outbreak began and have remained mainly out of public view. Many of their colleagues and friends also are not speaking. A spokesman for their businesses also declined comment Wednesday.

 

But public records and interviews with former employees and neighbors reveal how they created the formidable family enterprise that is now threatening to crumble.

 

Early on, Conigliaro, a civil engineer who served in the Massachusetts Air National Guard, displayed talent for high-risk business ventures. His first company, though, had nothing to do with pharmaceuticals: He made his initial fortune with trash.

 

Just a few years after graduating from Tufts University in 1987, he founded a recycling business in an old industrial building on Waverly Street in Framingham after realizing that recycling could soon become a booming business. Conigliaro started in 1990 with just a used U-Haul and credit cards, with which he racked up $42,000 in charges. But the company, Conigliaro Industries, quickly started making money by finding new uses for trash nobody wanted.

 

It converted detergent bottles into recycling bins, molded Styrofoam lunch trays into flower pots, and turned plastic computer casings into pothole filler. By 1994, Conigliaro was successful enough to be spotlighted in The Boston Globe as an up-and-coming entrepreneur.

 

Conigliaro brought many family members into his recycling business, including his mother and his father, an ­inventor who codeveloped a machine that shreds leaves. The business also includes an aunt.

 

He soon branched into real estate as well, starting GDC Holdings Inc. and GDC Properties Management LLC, which owns the large Framingham complex where the recycling business was launched.

 

It was not long before he turned his sights to the pharmaceutical business, an area his sister Lisa and brother-in-law, Cadden, knew something about.

 

Since getting married at St. Mary’s Catholic Church in Holliston, Mass., the couple had been busy raising three children in a renovated antique barn house in Cumberland, R.I., and working as pharmacists, neighbors recalled. They saw them as hard-working and devoted parents. Lisa began showing some entrepreneurial spirit of her own, filing for a patent for a product called Comfy Cuff, a cushioned sleeve for a nursing mother to wear to provide extra comfort for her baby’s head.

 

In 1998, Conigliaro and Cadden founded New England Compounding in the same Framingham building Conigliaro already used for his recycling factory and real estate businesses.

 

Like the other ventures, New England Compounding was a family affair. Gregory’s sister-in-law Carla Conigliaro, a nurse, was initially listed as the company’s president. Cadden’s wife was also on the board, listed as Lisa Cadden Conigliaro.

 

A former employee of New England Compounding, Carrie-Lee Touhey, recalled Gregory Conigliaro as the consummate businessman who provided the financial expertise, while ­Cadden was the sunny pharmacist who always had “a smile on his face.” Conigliaro normally wore a shirt and tie, while ­Cadden wore blue hospital scrubs, she said.

 

New England Compounding was not your typical neighborhood pharmacy. Instead, it ­focused on compounding, mixing the ingredients of medications in new ways for individual patients. For instance, a compounding pharmacist might create a liquid version of a pill for children or substitute an ­ingredient for patients with an allergy.

 

Richard Sawyer, who sold his Rhode Island summer home to the Caddens a few years ago, recalled Barry Cadden talking about being a pharmacist and initially specializing in cancer drugs, then broadening into other areas.

 

In fact, nationwide, the market for compounding drugs started growing because of shortages of some common drugs, such as morphine and certain antibiotic injections; increas­ing use of medications for pets; and greater diagnoses of childhood allergies. “Compounders become the only ­option,” said David A. Ball, president of Ball Consulting Group in Newton.

 

Cadden and Conigliaro soon brought in a new family member to help market their drugs and services. Conigliaro’s older brother Douglas, a doctor who specialized in anesthesiology and pain management, had been disciplined by the Florida medical board in 2002 after ­allegedly puncturing a woman’s spinal cord during surgery while inserting a catheter for pain medication. The woman was paralyzed, allegedly because of the procedure. Douglas Conigliaro was ordered to pay a $10,000 fine, but did not admit guilt.

 

The doctor led a new company in the Framingham building, now called Medical Sales Management Inc., to provide advertising and marketing services. As the sales arm for New England Compounding, ­Medical Sales promoted the compounding business at trade shows across the country, and its sales force aggressively worked the phones, cold-calling new customers and reaching out to existing ones. It also helped manage the company’s computer operations.

 

The compounding business apparently proved so successful that the families decided to ­expand their empire.

 

In 2006, Conigliaro and Cadden launched Ameridose, which was initially located in the same Framingham complex. Former workers said they found a new opportunity, selling a much-needed service to hospitals: prefilling syringes and breaking down vats of liquid medications into smaller intra­venous bags for individual treatments.

 

The new company either prepared the medications or bought them elsewhere. And unlike New England Compounding, Ameridose had a manufacturing license from the US Food and Drug Administration, allowing it to ship medications in bulk without obtaining individual prescriptions.

 

Historically, hospitals did much of that work themselves. But new federal regulations required hospitals to go through more elaborate steps to handle sterile preparations, making it more costly and complicated. Moreover, health care providers have been under growing pressure to reduce costs by outsourcing work wherever they can, creating a huge opportunity for the new firm.

 

“There is a definite need,” said Ernest Gates, president of Gates Healthcare Associates, a Middleton-based consulting company. “These standards are very difficult [for hospitals] to meet, because they lack the physical space and resources.”

 

Two years after it started, Ameridose added a second ­location, leasing a 76,000-square-foot building in Westborough. It later leased two neighboring buildings on the same block, its growth driven in part by its sales force at Medical Sales Management, who flew around the country visiting hospitals and doctors.

 

Ameridose officially changed its main address from Framingham to its new base in Westborough last year.

 

Between 2008 and this year, Ameridose went from 50 workers to close to 400, according to federal contracting records. New England Compounding ­also grew rapidly, with its head count more than doubling to about 50 employees over the last three years.

 

Meanwhile, Cadden and Gregory Conigliaro started yet another company, Alaunus Pharmaceutical in Framingham, to distribute generic drugs three years ago.

 

Both Cadden and Gregory Conigliaro seemed to thrive ­financially. In 2010, Conigliaro bought a sprawling $3.5 million home in Southborough with six bedrooms, nine bathrooms, and more than 11,000 square feet. He also bought a vacation home in Barnstable in 2008. Meanwhile, the Caddens built a $1.8 million home in ­Wrentham in 2005.

 

About three years ago, they also purchased and renovated a beach home in North Kingston, R.I., a place with stunning views of Wickford Cove that was featured in Rhode Island Monthly magazine in August.

 

Conigliaro, the more high-profile of the pair, became politically active.

 

Last month, he and his wife hosted a fund-raiser for US Senator Scott Brown at their home in Southborough. Instead of ­political donations, Cadden’s giving focused on education, includ­ing his alma matter in Rhode Island and his children’s parochial school, which he gave at least $5,000, according to the schools’ websites.

 

Some of the firms’ former workers say they saw a downside to the rapid growth. Ameridose warned prospective hires that it needed “high-energy” workers who could regularly work weekends or evenings.

 

“The environment is very fast pace,” the company said in recent help wanted ads. Several former workers said the company suffered from high turnover and pressure to meet orders. Two former co-workers said some employees spoke little English, increasing the possibility of critical errors.

 

A pharmacist who worked at Ameridose said she quit in 2009 after the company decided to try using quality control workers, rather than highly trained pharmacists, to make sure the right drugs were present before filling intravenous bags.

 

“The problem is the rush,” said the pharmacist. “You can only go so fast.”

 

Ronnie Leger, who worked in packaging at Ameridose, said he was also concerned about the hectic pace and safety. For instance, when sterile syringes and drugs fell to the ground, he said workers sometimes picked them up, quickly wiped them off, and shipped them anyway.

 

Leger said he was fired last year after he complained about the safety practices, including workers being exposed to noxious odors one day. He said he filed complaints with the FDA and the Occupational Safety and Health Administration. A spokesman with OSHA confirmed it has an active whistleblower investigation into Ameridose, but would not provide details.

 

The companies occasionally asked people in sales to help pack shipments when they got backed up with orders, according to a former Medical Sales Management sales representative.

 

The Globe interviewed a half-dozen former employees of the companies, many of whom asked not to be named because of legal agreements with the firms or fear it would harm their careers. One said the companies cared about safety.

 

Regulators also found problems. An FDA inspection of Ameridose in 2008 found ­numerous issues, including that the company did not fully test all the lots of its drugs and shipped some lots before receiving the results of sterility tests. Ameridose recalled a painkiller shortly afterward because it was overly potent. And a group purchasing company, Novation LLC of Irving, Texas, told customers it planned to sever its ties with Ameridose at the end of this month because of concerns about the company’s quality controls.

 

Novation agreed to extend the contract after Ameridose sued Novation for slander and other issues.

 

Meanwhile, New England Compounding had issues of its own. A patient in upstate New York died of meningitis after receiving a tainted anti-inflammatory shot made by the company in 2002, according to a 2004 lawsuit filed in Monroe County in upstate New York that was later settled.

 

And state and federal regulators launched an investigation after receiving complaints about the firm, leading to a consent order from the state and an FDA warning letter in 2006 detailing a number of issues, includ­ing concerns about ­potential microbial contamination from splitting and repackaging the injectable colorectal cancer drug Avastin.

 

Finally, the safety concerns exploded into the headlines this month after a growing number of people were diagnosed with fungal meningitis traced to a possibly contaminated steroid shot typically used to treat back pain. Federal safety inspectors are examining the possibility that other drugs from the company may also have been contaminated.

 

New England Compounding agreed to suspend its operations two weeks ago. Cadden has also temporarily agreed to stop practicing pharmacy in Massachusetts, though his ­license remains in good standing in neighboring Rhode ­Island. In addition, Ameridose and Alaunus agreed to temporarily suspend their operations for two weeks while federal and state inspectors review the ­operations.

 

Still, the Caddens and Conigliaros have not given up on restarting Ameridose soon. The company’s public relations firm has gone to great pains to insist that Ameridose and New England Compounding are separate companies with distinct management teams and facilities, even though they were both owned by the Conigliaros and Caddens.

 

But former employees say the companies were intertwined, even holding combined Christmas parties. The companies had adjoining booths at the National Pharmacy Purchasing Association conference in August in Las Vegas and used the same sister company, ­Medical Sales Management, for sales and marketing. They use the same public relations team. New England Compounding’s privacy policy on its website ­appeared to be almost an exact replica of Ameridose’s. It was even titled “Ameridose privacy policy.’’

 

Until recently, both companies had space in the same complex on Waverly Road in Framingham. And even today, they have adjoining mailboxes at the property. Cadden, the president and main pharmacist at New England Compounding, was also listed as comanager of Ameridose in the company’s annual report with the secretary of state in Feburary.

 

“I don’t think there was literally any difference,” said the former Medical Sales Management worker who handled sales for Ameridose, while a colleague at the next desk took ­orders for New England Compounding.

 

Now federal and state investigators are probing the ties ­between the two firms.

 

The problems appear to be taking a toll on the families, and those who know them ­insist the crisis must devastate them emotionally and financially.

 

One neighbor said the Caddens have since retreated from an offer to buy a new waterfront vacation home in Rhode Island, valued at about $1.3 million and only a few blocks from their current beach home.

Shortly before a national fungal meningitis outbreak was linked to New England Compounding Center, the Framingham company sent customers a “Quality Assurance Report Card” trumpeting the cleanliness of its labs, even as internal tests showed widespread contamination.

 

Charts sent to customers and obtained by the Globe show that in the first half of 2012, there were no instances of contamination exceeding the accepted standard on surfaces in the “clean rooms,” where the company produced sterile injectable medications such as the steroid now linked to 28 deaths.

 

But during that same period, the company’s own internal testing showed that 33 surface samples from the clean rooms contained bacteria or mold at levels requiring corrective action to remove contamination, according to company records. These test results were disclosed in a report released Friday by federal investigators.

 

Pharmacy and laboratory safety consultants said New England Compounding’s report card, sent to the Globe from a hospital that bought from the pharmacy, directly contradicts the findings of the company’s internal testing. The hospital provided the pharmacy report card on the condition it not be identified.

 

Three consultants who were shown the report card by the Globe said it lacks basic scientific data — such as how many tests were conducted to detect bacterial and mold contamination — that hospitals and other health facilities should have requested from the compounder to determine whether the company’s facility and products were up to the industry standards. They described it as a promotional brochure rather than a technical report.

 

“Their marketing material is baloney. They are just saying what they want to say,” said Stephen Runge, president of nanoCLEAN Decontamination Services, a Quincy company that decontaminates laboratory clean rooms after impurities are detected.

 

A New England Compounding spokesman said the company would have no comment.

 

Two of the three lots of steroids that have been linked to 363 cases of meningitis and joint infections across 19 states were produced during the period covered by the company’s report card, which was sent to an unknown number of its more than 3,000 customers. Those customers include hospitals, clinics, and doctors’ offices.

 

The report card stated that the company’s “extensive” testing of finished products for sterility and microbial contaminants had a 100 percent success rate from January through June 2012, though the report did not include the number of tests conducted. The customer report, adorned with a picture of a lab technician covered head to toe in protective clothing, stated in a cover letter that its quality systems and facilities are “in a state of control.”

 

“The results of our internal review . . . demonstrate that NECC meets and is in continued compliance with all applicable requirements and standards,” said the report, signed by Barry Cadden, a co-owner of the company and its former lead pharmacist. Cadden encouraged customers to keep the report on file to show the Joint Commission, a private accrediting agency, and government regulators during inspections.

 

Elizabeth Zhani, spokeswoman for the Joint Commission, said that the agency’s inspectors do not specifically ask hospitals for a copy of sterility reports from their outside compounding pharmacies. Instead, inspectors typically review copies of contracts a hospital signs with outside contractors, including compounding pharmacies. The commission’s regulations do not specify whether those contracts must include reports from pharmacies about sterility testing.

 

New England Compounding closed earlier this month and state regulators have sought permanent surrender of its pharmacy license, as well as permanent revocation of the licenses of the company’s three pharmacists, including Cadden and his wife, Lisa Conigliaro Cadden. The Food and Drug Administration, which is among several federal and state agencies investigating New England Compounding, released a report Friday depicting lax safety practices and widespread contamination inside the company’s labs between January and September.

 

Federal investigators found visible mold, including 83 vials from one lot of the tainted steroid used to treat back pain that contained “greenish black foreign matter.” That lot was produced in August.

 

The FDA report said that the company’s own environmental testing showed bacteria and mold in numerous spots in two clean rooms that were at levels above New England Compounding’s own “action limits” — the level at which remedial action should be taken to remove contaminants. But there is no evidence that the company investigated further or took corrective measures, the report said.

 

And, the company did not assess whether products made in the rooms on the days samples were taken could have become contaminated.

 

According to the FDA report, every one of the 62 surface samples taken in two clean rooms contained bacteria or mold, and more than half exceeded the action level.

 

By comparison, New England Compounding’s report to customers stated that between January and June, there was no contamination found on surfaces in the clean rooms that was outside the norm — what the company called an “excursion rate.”

 

It reported a 0.25 percent excursion rate for air monitoring in the clean rooms. The FDA report said the company’s internal documents showed two of five air samples taken during the same period exceeded the action level, or 40 percent.

 

The company’s customer report also stated that its “media fill success rate” — routine tests that certify staffers are correctly preparing sterile medications — found 100 percent success.

 

New England Compounding “has established an extensive environmental monitoring program for surface and air samples for clean room areas to ensure preparations are compounded in the cleanest environment possible and to document compliance with [industry] requirements,” the company’s report card stated.

 

Eric Kastango, president of Clinical IQ, a New Jersey-based pharmacist and safety consultant to the industry, said he has found that health care organizations often don’t know what questions to ask compounders to determine whether the companies are complying with industry standards.

 

“If you have a nice glossy brochure, and you represent that you can fill a need with all the drug shortages, nobody really wants to ask the hard questions,” he said. “You are led to believe by these vendors they are legitimate, but it’s not really independently vetted out.”

Compounding pharmacies started as small mom-and-pop stores that mixed hard-to-find medications for local doctors and their patients who had allergies, difficulty swallowing, or otherwise could not take mass-produced drugs.

 

But amid growing drug shortages in the pharmaceutical industry, some large compounders such as the New England Compounding Center stepped in and expanded their business far beyond the industry’s homespun roots.

 

State pharmacy regulators on at least two occasions in the past decade displayed indifference in their oversight of a troubled Framingham specialty pharmacy that has now been blamed for a national fungal meningitis outbreak, according to documents ­obtained by the Globe Tuesday.

 

At the same time state and federal regulators were investigating New England Compounding Center for problems with sterile drug preparation, the company’s lead pharmacist, Barry Cadden, was chosen to serve on a state pharmacy board task force to write new rules for compounding pharmacies.

 

Cadden, who also co-owns New England Compounding, was appointed in June 2002, two months after the Food and Drug Administration and the pharmacy board began looking into complaints about his company — now blamed for the outbreak that has killed 32 and sickened more than 400.

 

The documents also show that three top pharmacy board administrators learned in 2006 that an Illinois company chosen to monitor New England Compounding was led by a man convicted of fraud involving a product blamed for blinding people. But the officials apparently did not tell board members before they voted the following month to accept the Illinois firm’s findings that New England Compounding had made satisfactory improvements.

 

The revelations come as lawmakers convene hearings Wednesday in Washington and on Beacon Hill to investigate the causes of the meningitis outbreak and whether it could have been prevented. Cadden has been subpoenaed to testify before the US House Committee on Energy and Commerce, Oversight and Investigations Subcommittee .

 

The FDA began investigating Cadden’s company in April 2002, in response to reports of dizziness, shortness of breath, and a sudden drop in blood pressure suffered by about five patients treated with an injectable steroid made by New England Compounding, according to a memo prepared by the House committee staff.

 

That memo says the FDA invited the Massachusetts Board of Registration in Pharmacy to join in the investigation, and that Cadden, after initially cooperating, stopped answering questions and providing records.

 

But that didn’t keep the state from inviting Cadden to join three other compounding pharmacists on the panel that would draft rules for their industry.

 

Precisely who chose Cadden is unclear, and the 99 pages of documents on the task force, released under the state open records law, do not reflect his role in the committee’s work.

 

Harold Sparr, president of the board at the time, said in an interview and follow-up e-mail that he appointed fellow board member Karen Ryle to chair the task force and that she chose the pharmacists for the group.

 

But Ryle, an associate chief of pharmacy at Massachusetts General Hospital and a current board member, said in a statement that she did not choose the task force members. She added that they “were chosen for their knowledge and experience in the field” but did not say who picked them. She declined to be interviewed.

 

Ryle is slated to testify Wednesday before three state House leaders.

 

Records show that Ryle’s task force met for more than a year and drafted rules that were later weakened after industry complaints, but never adopted.

 

The task force initially proposed extensive testing of drugs for contamination and potency before they could be sold, and also stipulated that compounders could produce drugs only for individual patients. But the International Academy of Compounding Pharmacists, a trade group, objected to these and several other proposals, citing the “prohibitive” costs of end-product testing. The final draft from the task force dropped these provisions.

 

Ryle said her task force submitted its draft regulations to the state public health department in 2003, but that US Pharmacopoeia, a nonprofit that sets drug industry standards, was revising its regulations regarding compounding pharmacies at that time.

 

“These regulations were moving along toward implementation, and they would supersede the regulations that we had drafted, so the work we had been doing went no further,” Ryle said.

 

The Globe previously reported that Illinois-based Pharmacy Support Inc. was chosen by the Massachusetts pharmacy board in January 2006 to review operations at New England Compounding.

 

The board was responding to several complaints that New England Compounding was mass-producing drugs and operating like a manufacturer, in violation of its state ­license. Those complaints included the 2002 report of ­patients suffering health problems.

 

It had been unclear whether the board at the time was aware of the legal troubles of Ross Caputo, who founded Pharmacy Support Inc. after being indicted in federal court in 2003.

 

Newly released documents show that the board’s attorney saw a news story about Caputo’s conviction from a Chicago newspaper in April 2006 — a month before the pharmacy board voted to accept Pharmacy Support’s findings that New England Compounding had met the requirements of a consent agreement, which helped the Framingham company avoid a one-year probation.

 

An April 24, 2006, e-mail from board attorney Susan Manning about New England Compounding issues included an attachment labeled “2 guilty of selling bad sterilizers to hospitals.”

 

The attached article detailed Caputo’s conviction for fraud involving the marketing of faulty sterilization equipment by another company that he formerly ran.

 

Manning sent the e-mail to Jean Pontikas, director of the Massachusetts Division of Health Professions Licensure, board executive director Charles Young, and assistant director James Coffey, but the head of the agency that oversees the pharmacy board said the board was apparently never informed.

 

“We have found no evidence to indicate that the Executive Director or staff attorney of the Board provided this crucial information to the Board,” Dr. Lauren Smith, interim commissioner of the Department of Public Health, says in testimony prepared for the US House hearing Wednesday.

 

A spokesman for the administration of Governor Deval Patrick said Tuesday that Pontikas was placed on administrative leave last Thursday.

The top executives of New England Compounding Center are likely to be criminally prosecuted on federal charges that carry possible prison sentences, according to former prosecutors who cite the large number of people harmed, allegedly by contaminated steroids made by the Framingham pharmacy.

 

US Attorney Carmen M. ­Ortiz, whose Boston office is known for aggressive prosecution of health care companies, acknowledged in a statement last month that she is probing New England Compounding, but has declined further comment. Agents from the US Food and Drug Administration’s ­Office of Criminal Investigations were seen last month combing through the company’s Framingham offices.

 

“If there is a federal charge, there is probably going to be jail time” sought, said Todd Graves, a former Missouri US attorney who in 2002 prosecuted Robert Courtney, a Kansas City pharmacist on several federal counts related to diluting chemotherapy drugs for thousands of ­cancer patients. Courtney, who pleaded guilty, was sentenced to 30 years in jail.

 

Graves said public outrage at the time bolstered his leverage in the case, a factor he ­believes will give prosecutors an edge this time, too.

 

“There is a lot of anger and not just among those who are hurt, but anyone who looks at this situation, and judges, juries they are all affected by these types of things,” Graves said. “The wind would be at your back” as a prosecutor appealing to the jury.

 

Thirty-four deaths have been blamed on pain injections made by New England Compounding, and 490 patients have developed fungal meningitis or other infections after getting the steroid shots in their backs or joints, according to the federal Centers for Disease ­Control and Prevention.

 

Barry Cadden of the now-closed New England Compounding Center invoked his Fifth Amendment rights against self-incrimination and declined to answer questions.

 

Graves and other former federal prosecutors and legal specialists interviewed by the Globe said the US attorney’s ­office is likely to focus on three charges against New England Compounding: selling adulterated (in this case contaminated) drugs in violation of the federal Food, Drug and Cosmetic Act; fraud; and false claims, for defrauding Medicare and ­Medicaid through the company’s sales of medications that were unsafe to thousands of hospitals and pain clinics nation­wide that, in turn, billed the government for treatment of patients insured through these programs.

 

Penalties for those charges typically range from a maximum of three to 20 years in prison, though federal guidelines allow for a life sentence in cases of health care fraud involv­ing death.

 

Companies prosecuted ­under these provisions typically reach settlements with the government, agreeing to pay multimillion-dollar fines and to change their practices to comply with the law. Prosecutors are often satisfied with fines because of the difficulty of proving company executives intended to commit a crime, and jury verdicts are unpredictable.

 

But in this case, the former prosecutors say the government is likely to seek jail time for New England Compounding’s top executives under a seldom-­used provision of the law known as the responsible corporate officer doctrine.

 

This doctrine allows federal prosecutors to hold a company’s executives criminally respon­sible for wrongdoing of employees, even if the executives did not participate in or know anything about the criminal activity. Conviction carries a maximum one-year prison sentence.

 

“The government has gone after a lot of big companies and gotten a lot of money, but I don’t think they feel they are having the deterrent effect if people don’t go to jail,” said ­Stephen Huggard, a Boston ­attorney and former federal prosecutor in the Boston US ­attorney’s office.

 

In 2011, federal prosecutors in Pennsylvania won convictions and jail time for four former Synthes Inc. executives for their roles in the medical-

device maker’s promotion of a bone cement for back surgery. The product was not approved for that use by federal regulators, who had warned about its safety in spine surgeries. Prosecutors said the company did not stop marketing the product until after three elderly patients died in surgery. The executives’ prison sentences ranged from five to nine months.

 

But last month, the owner of a Texas compounding pharmacy avoided prison, instead receiv­ing probation and a $100,000 fine after pleading guilty to charges involving an overly potent gout drug that led to the deaths of three patients injected with the medication.

 

The threat of criminal charges led Barry Cadden, co-owner and former managing pharmacist at the now-closed New ­England Compounding Center, to invoke his Fifth Amendment rights against self-incrimination and decline to answer questions last week during a congressional hearing on the outbreak. His attorney, Bruce Singal of Boston, sought immunity from prosecution for ­Cadden in exchange for his testimony, but said he has not heard back from lawmakers.

 

He said it was irresponsible to speculate on criminal charges against Cadden. “Criminal defense lawyers and former prosecutors . . . should know the perils of speculating on the outcome of a hypothetical criminal case without the benefit of the facts,” Singal said by e-mail.

 

An attorney for the company’s other principal owner and top officer, Greg Conigliaro, ­declined to comment through a company spokesman. The company’s attorney, Paul Cirel, said in an e-mail that “it is premature, if not irresponsible, to speculate on the likelihood of criminal charges, let alone sentences that might ensue.”

 

The Globe reported earlier that shortly before the fungal meningitis outbreak was linked to New England Compounding, the company sent customers a “Quality Assurance Report Card” trumpeting the cleanliness of its labs, even as internal tests showed widespread contamination.

 

Federal regulators investigated New England Compounding a decade ago after patients treated with injectable steroids made by the company, including the same medication implicated in the current outbreak, reported health problems. The FDA also sent the company a 2006 warning letter about mass producing drugs and operating like a manufacturer, which state officials have said violated its state license.

 

Investigators will be seeking these types of documents to demonstrate that company officials knew there were problems yet continued to promote its products as sterile, said Robert M. Thomas Jr., formerly a federal prosecutor in Maryland and now a Boston attorney representing employees in whistleblower cases against their former companies.

 

“It’s e-mails, it’s warning letters that were received,” said Thomas. “You show knowledge of the risk, you show lower employees telling higher employees of problems. You start with lower-level employees. You may have to give them immunity to talk.”