Problems cited for years at drug firms

Unsafe practices at specialty pharmacies tied to deaths, illnesses

Shoddy practices and unsanitary conditions at three large-scale specialty pharmacies have been tied to deaths and illnesses over the past decade, revealing that the serious safety lapses at a Massachusetts pharmacy linked to last fall’s deadly meningitis outbreak were not an isolated occurrence, records and interviews show.

LEAH NASH FOR THE WASHINGTON POST

Christopher Long holds a family portrait with his mother, father, brother and sister. Long’s 56-year-old mother died in 2007 after receiving a toxic compounded drug made by ApotheCure.

The series of safety failures happened long before national attention focused on the New England Compounding Center, whose contaminated steroid shots were linked to 45 deaths and 651 illnesses.

A Washington Post analysis found that state and federal authorities did little to systematically inspect and correct hazards posed by specialty pharmacies, which custom-mix medications for individual patients, hospitals and clinics. In the lightly regulated industry, pharmacies were rarely punished even when their mistakes had lethal consequences.

The Post reviewed hundreds of records, including lawsuits and Food and Drug Administration documents, and interviewed dozens of government and industry officials. The review found serious problems at three of 15 largescale compounding pharmacies that dominate the industry. These multimillion-dollar companies mass-produce medications and ship them across state lines, often without individual patient prescriptions.

Three of the firms, in addition to the NECC, have experienced significant safety problems over the past decade that were tied to at least 39 illnesses. Two companies’ missteps were linked to at least six deaths. The problems included medications that were too potent or laced with bacteria.

One of the three firms identified by The Post — the California based Central Admixture Pharmacy Services — is being investigated by the FDA in connection with its Massachusetts facility, according to industry and government officials.

Executives at CAPS, a pioneer and among the largest manufacturing-style compounders, declined to comment on the investigation, which has not been previously disclosed. Federal officials would not discuss the probe, which was triggered by their ongoing investigation of the NECC and a sister company, Ameridose.

Illinois-based PharMEDium Services and Texas-based ApotheCure also had serious deficiencies, records show.

Officials at CAPS, PharMEDium and ApotheCure said their companies produce highquality products and are continuously upgrading operations to make them safe.  But when regulators have visited the firms after patient illnesses or deaths, they have sometimes found alarming conditions.

“The things they saw, they would chill your bones,” said cardiologist John Armitage, regarding the FDA’s 2005 investigation of several CAPS facilities after some of his patients died or became gravely ill.

Today, compounders supply about 40 percent of all intravenous medications used in hospitals, up from 16 percent a decade ago, according to industry estimates. They make some of the highest-risk drugs available, including steroid injections such as those linked to the meningitis outbreak. Yet they are not required to follow the safety rules that apply to commercial drugmakers.

Government regulators have failed to rein in reckless operators. State pharmacy boards, which have the primary responsibility for policing the industry, have an uneven enforcement record.

The FDA’s attempts to use its power have been thwarted by companies relying on gaps in the law and conflicting court rulings. The companies have fought enforcement orders and kept the agency out of their facilities. Some members of Congress have sought to beef up the agency’s authority, but the industry has successfully helped kill those efforts.

“You are seeing a bunch of people trying to do their best in a system that is legally and factually complicated,” said Howard Sklamberg, director of compliance at the FDA’s Center for Drug Evaluation and Research.

The FDA is again pressing Congress for greater powers.

CAPS

In 1991, health-care entrepreneur Jim Sweeney became one of the architects of the modern compounding industry when he persuaded a Southern California hospital to outsource some of its pharmacy work to him.

Across the country, nurses had made fatal errors mixing solutions in patients’ rooms, and hospital pharmacies were struggling with bacterial growths in their own drug therapies. Hospitals adopted new safety standards, but they were costly. At the City of Hope hospital, officials turned to Sweeney and CAPS “strictly to save money,” said Dale Adams, chief pharmacy officer.

Sweeney outfitted a doublewide trailer in the hospital parking lot, hired a team of pharmacists and began making intravenous nutritional supplements for its cancer patients. Before long, CAPS was expanding to other hospitals and making intravenous drugs.

“We typically would approach hospitals and ask, ‘ What are the high-risk things you are making? How would you like us to do that for you?’ ” said Eric Steen, whom Sweeney hired from the drugmaker Baxter and made president. Sweeney sold the company in 1994.

One of the drugs in big demand was cardioplegia, a solution used in open-heart surgery to stop and restart the heart. The drug often is made from ingredients that are not sterile, so compounders must successfully sterilize them so it can be safely injected into the coronary arteries.

The pharmacies, however, cannot be compelled to test each lot or batch to check for sterility and proper potency.

In 2004, the company’s Pittsburgh facility prepared cardioplegia for Alycia Hartzell, a 2-year-old who was undergoing open-heart surgery. According to a 2007 lawsuit filed against CAPS by Children’s Hospital of Pittsburgh, the active ingredients and the sodium strengths were too strong and “the use of the CAPS cardioplegia solution led to a brain bleed, and severe permanent injuries.”

Daniel Stefko, an attorney for the hospital, said the FDA never investigated the episode. “I remember being sort of surprised to find that there was this phenomenon out there, where if I ordered something from Pfizer, it was FDA-regulated, but if I ordered basically the same thing from a compounding pharmacy, the rules were not there.”

CAPS settled with Children’s Hospital for an undisclosed amount. The Hartzell family, which sued the hospital, settled with it for an undisclosed amount. The girl’s mother, Amanda Hartzell, said she could not comment because of a confidentiality agreement. CAPS and parent company B. Braun Medical declined to comment.

A year later, CAPS shipped batches of cardioplegia from its facility in Lanham to Mary Washington Hospital, a hospital in Fredericksburg, records show.   Shortly thereafter, two patients who had undergone open-heart surgery had a devastating infection and died. Nine other heart patients ended up in the intensive-care unit for extended stays.

“It’s normal for people to have an inflammatory response following open-heart surgery, but to have a severe response that results in multi-organ failure — that’s rare,” said Armitage, who ran the cardiac unit and now lives in Oregon. “We started changing everything we could think of. Nothing seemed to work.”

In September 2005, cardiovascular specialists staged a mock surgery and found that the cardioplegia was contaminated with bacteria, according to a hospital analysis.  They repeated the mock surgery to make sure no other factors were contributing to the crisis. This time, all the cardiac team members joined in, scrubbing their hands, slipping on sterile gowns, masks and gloves as they walked through each step of an operation while the hospital’s infection-control staff watched. The only thing missing was a patient.

The cardioplegia seemed to be the only problem, the state health department concluded.

When the FDA was notified, Armitage said, it took days for investigators to arrive, and they wouldn’t tell the hospital what they were finding out about the CAPS Lanham facility.

“They said, ‘We are not a police agency,’ ” Armitage said. The hospital filed a Freedom of Information Act request and received the FDA inspection report about six months later.

The FDA found 17 safety violations at the Lanham facility. Cardioplegia was tainted with the species of bacteria that matched those found at Mary Washington. Internal tests showed “the presence of bacteria in a water container used for cleaning. . . . Likewise, sterility testing demonstrated similar bacteria in its drug products.” The Maryland Board of Pharmacy suspended the Lanham facility’s license for two months.

The FDA also found dozens of problems at CAPS’s facilities in Alabama, Pennsylvania and Missouri.  Steen, who left CAPS last year to start a medical consulting firm, said the cause of the illnesses remains a “mystery.” He noted that the facility sent the drug to a number of other hospitals that didn’t have any problems.

That might have been because Mary Washington had ordered a special formula, said Diane Woolard, director of the Division of Surveillance and Investigation at the Virginia Health Department. “It may have been a contaminated element in those ingredients,” she said.

Officials at CAPS, which has 25 locations and $500 million in annual sales, would not comment on the 2005 event. In an e-mail statement, Mike Koch, a vice president, said, “CAPS is committed to offering the highest quality admixture service to our customers and their patients.”

PharMEDium Services

In 2007, a team of investigators from the Centers for Disease Control and Prevention issued an unusually blunt warning to hospitals and doctors: Compounded drugs had a higher risk of contamination than commercially manufactured drugs, and compounding pharmacies had “generally lower quality-control standards than pharmaceutical manufacturers.”

The warning, which appeared in a medical journal, stemmed from a 2005 multi-state outbreak involving another big compounder, PharMEDium Services of Lake Forest, Ill.

In January 2005, six cardiac patients at Kaiser Permanente Los Angeles Medical Center came down with a rare bacterial infection. Doctors suspected contaminated magnesium sulfate made by PharMEDium. The intravenous solution is widely used to steady the heartbeat after surgery and to treat a life-threatening condition of pregnancy called pre-eclampsia.

But neither the hospital nor PharMEDium’s Houston plant, which made the drug, had any solution left to test. Compounders are not required to keep samples for testing later on in case patients get sick.
Federal officials were stymied until they learned that five heart patients in New Jersey had developed the same infection, also after receiving magnesium sulfate made by PharMEDium. The New Jersey hospital had bags of solution left, and tests confirmed that the rare bacterial strain in the bags matched that of all patients in Los Angeles and New Jersey.

“It was almost luck that we were able to make this match,” said Esther Tan, part of the CDC team that investigated the outbreak.   Investigators said the contamination could have come from the hands of technicians who made the bags of solution. No source was identified.

One patient, Joe Chacon, a heavy-equipment operator in Los Angeles, said he was infected Jan. 12, 2005, at the Kaiser hospital during heart surgery. He became feverish, required a ventilator to breathe and eventually needed to have his pacemaker removed because of concerns about a recurrence of infection, according to his civil suit against PharMEDium.

“I was in the hospital for quite a while,” said Chacon, now 59. He said he wasn’t able to go back to work. The company settled for $25,000, his wife, Rachelle Chacon, said.
All told, at least 18 people in five states were sickened.

From 2005 to 2011, hospitals and patients raised other concerns about PharMEDium medications. In 2006, the company recalled pain medication after human error led to mislabeled drugs at its Mississippi plant, according to FDA records and company officials. An Arizona man lost consciousness after receiving morphine sulfate rather than the less powerful fentanyl citrate. In 2009, a similar incident occurred at the same plant, according to FDA records.

After the bacterial outbreak, the FDA inspected the Houston plant and found staff members had failed to fully investigate nine instances in the months before the outbreak in which PharMEDium’s own monitoring showed higher-than-allowed levels of “viable microorganisms,” according to FDA records.

The company increased environmental testing and training, officials said in an interview. The firm also developed a special barcode-scanning technology to minimize manual errors, the company said. The company said that it’s not practical to keep samples because it makes small batches of drugs with short expiration dates.

Founded in 2003, PharMEDium has four plants and annual sales of more than $100 million, officials said. The company says it uses only sterile, FDA-approved ingredients for the intravenous and epidural medications it supplies to more than 2,000 hospitals, including Johns Hopkins Hospital.
Company President Rich Kruzynski said the incidents are a fraction of the “tens of thousands of batches” provided to hospitals. The record, he said, demonstrates PharMEDium’s commitment to be the industry’s “gold standard” for quality, patient safety and regulatory compliance.

ApotheCure

While many compounding pharmacies were focusing on hospitals, others were catering to physicians who practiced experimental medicine.

One of the rising stars was Texas-based ApotheCure, which was cited by celebrity Suzanne Somers in her 2005 bestselling book, “The Sexy Years,” which extolled the anti-aging benefits of customized hormone therapies.

About the same time, ApotheCure’s owner, Gary Osborn, was quoted in alternative magazines and wrote on his company’s Web site about the benefits of using gout medication for pain relief and using lipids in “fatdissolving” solutions. He also promoted chelation therapy, which removes heavy metals from the body, as a treatment for autism.

As ApotheCure branched out, nearly doubling its $6 million in annual sales during the mid- to late 2000s, patients began getting ill after using some of its products. FDA records from a 2007 inspection show ApotheCure did not alert the agency about many of the incidents.

However, the FDA was notified by local health officials about a 2004 episode in which nine people in Pennsylvania got sick after receiving infusions of an ApotheCure solution that the pharmacy said would dissolve fat, records show. Symptoms included abdominal pain, nausea, vomiting and renal complications, according to state health records.

When FDA officials showed up to investigate the Dallas facility that had made the solution, Osborn turned them away, saying they needed an inspection warrant, FDA and court records show. They never returned with one, the records show.

FDA officials said that although they did not secure a warrant, they worked with Texas State Board of Pharmacy officials, who inspected the facility. The state board did not take any disciplinary actions, said Allison Benz, the board’s director of professional services.

In 2005, a 5-year-old autistic boy died after being treated with ApotheCure’s chelation compound. Using this treatment for autism “is not evidence-based, and it has the potential for being very toxic and fatal,” said FDA’s Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research.
The company kept promoting chelation therapy, records show. Osborn did not make any public statements about the incident at the time and did not respond to The Post’s requests for comment.

Two years later, three patients at an Oregon pain clinic died after injections of Apothe Cure compounded colchicine, a medication for gout marketed by alternative compounding pharmacies for neck and back pain. The solution was eight times as strong as what was ordered by the treating physician, records show.

The Oregon state attorney general’s office investigated the company after the three deaths. David Hart, who prosecuted the case against ApotheCure for the attorney general’s office, said he thinks the FDA missed a critical opportunity in 2004 when it didn’t get the search warrant.

“Arguably, if action had been taken earlier by the FDA, this could have been prevented,” he said.
When the FDA was notified of the 2007 deaths, this time the agency got a warrant for the facility. Records show that the agency identified 13 deficiencies and that Texas authorities found 80 deficiencies and violations.

In its report, the FDA noted that products were not tested for potency prior to shipping — something that could have prevented the deaths. But that didn’t violate the law because testing for potency and sterility is not required of compounders, noted ApotheCure attorney James J. Doyle III in a written comment.

The agency’s and state board’s findings became the backbone for state complaints in Texas and Oregon and a Justice Department lawsuit filed against Osborn and his company, state and federal records show.

At the time of the fatal incidents, Osborn told the Associated Press that the colchicine mishap was due to “human error.” Osborn declined interview requests from The Post. His attorney, Lawrence J. Friedman, said he thinks his client was unfairly singled out.

“They decided to make an example out of ApotheCure,” Friedman said.
After the 2007 incident, Friedman said, his client hired consultants and “doubled, even tripled,” safety precautions.

However, a Dec. 20, 2010, internal audit of ApotheCure, obtained by The Post, showed that three years after the FDA investigated, the pharmacy was still riddled with unsanitary conditions.
Insect body parts were found in “clean rooms” where sterile products were compounded. A suspended ceiling, with exposed pipe, wiring and duct work, allowed “contaminants to flow over the sterile suite and fall through the suspended ceiling.”

The Texas pharmacy board returned last year and found a few minor problems. All of them have since been corrected, said Gay Dodson, the board’s executive director.

In 2012, Osborn pleaded guilty to misdemeanor criminal violations of the federal Food, Drug and Cosmetic Act for the colchicine-related deaths. Osborn was ordered to pay a combined $400,000 in fines to settle the DOJ, Texas and Oregon complaints directed at him and his company. The terms of settlements with victims’ families are confidential.

Osborn’s company — which has about $10 million in annual sales — is still in operation.

“People make mistakes, but there is nobody watching over these people,” said Christopher Long, whose 56-year-old mother died after receiving the toxic colchicine made by ApotheCure. “The regulatory piece of this, nothing has changed. I realize it takes a long time to rein things in, but my mother is dead, ApotheCure is still in operation, and people have died again.”