Scant Oversight of Drug Maker in Fatal Meningitis Outbreak

October 7, 2012

6 Oct (NY TIMES) – Eddie C. Lovelace, a Kentucky judge still on the bench into his late 70s, had a penchant for reciting Shakespeare from memory and telling funny stories in his big, booming voice.  But a car accident last spring left him with severe neck pain, and in July and August he sought spinal injections with a steroid medicine for relief.

Instead, Judge Lovelace died in Nashville in September at age 78, one of the first victims in a growing national outbreak of meningitis caused by the very medicine that was supposed to help him. Health officials say they believe it was contaminated with a fungus.

The rising toll — 7 dead, 57 ill and thousands potentially exposed — has cast a harsh light on the loose regulations that legal experts say allowed a company to sell 17,676 vials of an unsafe drug to pain clinics in 23 states. Federal health officials said Friday that all patients injected with the steroid drug made by that company, the New England Compounding Center in Framingham, Mass., which has a troubled history, needed to be tracked down immediately and informed of the danger.

“This wasn’t some obscure procedure being done in some obscure hospital,” said Tom Carroll, a close friend to the Lovelace family, and their lawyer. “They had sought out a respected neurosurgeon who had been referred by their family doctor, at a respected hospital,” he said, referring to the St. Thomas Outpatient Neurosurgery Center. “How does this happen?”

The answer, at least in part, is that some doctors and clinics have turned away from major drug manufacturers and have taken their business to so-called compounding pharmacies, like New England Compounding, which mix up batches of drugs on their own, often for much lower prices than major manufacturers charge — and with little of the federal oversight of drug safety and quality that is routine for the big companies.

“The Food and Drug Administration has more regulatory authority over a drug factory in China than over a compounding pharmacy in Massachusetts,” said Kevin Outterson, an associate professor of law at Boston University.

The outbreak has also brought new scrutiny to the widely used procedure that Judge Lovelace and millions of Americans undergo each year.

Patients most likely assumed there was strong evidence that the procedure itself works. But the Cochrane Collaboration, an international group of medical experts, reviewed the data last year and found there was “no strong evidence for or against” the injections. Patients exposed to the drug in the current outbreak may have risked their health or even their lives for an elusive goal.

A Large Demand

Over the past two decades, pain control has become a growth industry, bolstered by the worn-out knees and aching backs of baby boomers. Pain clinics began popping up around the country.

Starting in the 1990s, spinal injections for back pain, known as lumbar epidural steroid injections, skyrocketed. They have since leveled off, but the number remains high. In 2011, 2.5 million Medicare recipients had the injections, as did an equal number of younger people, according to Dr. Ray Baker, president of the International Spine Intervention Society.

Many people seek them in hopes of avoiding surgery. The injections combine a steroid and a numbing drug in an effort to soothe inflamed and irritated nerves. Patients are told they may get weeks, months or even a year of relief.

The injections created a demand for steroids, including methylprednisolone acetate, the drug that New England Compounding was making.

To be sure, many compounding pharmacies perform well, producing formulations of drugs for specialized needs. Compounders have also provided hospitals and doctors with cheaper alternatives to F.D.A.-approved drugs.

For example, they are providing a far cheaper alternative to a drug called Makena, a new brand name version of an old drug used to reduce the risk of premature births. Once the drug got F.D.A. approval, the manufacturer of Makena began charging about a hundred times more for the drug than compounders. Officials from the F.D.A. wanted to ban the pharmacy-made versions on the grounds that Makena had met the agency’s rigorous safety standards, but senior Obama administration officials, concerned about Makena’s much higher price, stepped in to halt the ban.

In recent years, compounding pharmacies have sometimes filled gaps left by shortages of drugs made by pharmaceutical companies.

“As drug shortages have become more complex and common, pharmacies are turning to external compounding companies to help them,” said Cynthia Reilly, of the American Society of Health-System Pharmacists, referring to hospital pharmacies.

Shortages may have played a role in the large purchases of the injectable steroid now under suspicion from New England Compounding. The two manufacturers of the generic version of the drug had stopped making it.

Teva halted production in 2010 when it temporarily closed its Irvine, Calif., factory after receiving a warning letter from the F.D.A. about manufacturing quality problems.

The other manufacturer, Sandoz, stopped selling the product in the United States this year, according to the company, which would not provide a reason. Sandoz has also been reprimanded by the F.D.A. for manufacturing problems.

While the F.D.A. says the drug is not in short supply, the brand name product still available may have been considered too expensive, prompting some medical practices to turn to compounding pharmacists.

PainCare, a medical practice with 12 locations in New Hampshire, turned to New England Compounding for the injectable steroid now under suspicion when its usual supplier ran out, said the company’s chief executive, Dr. Michael J. O’Connell. The company’s two main locations alone do more than 100 injections a week.

Dr. O’Connell said he preferred compounding pharmacies because they could make the drug free of an alcohol often used as a preservative in drugs manufactured by big companies that he worried could damage nerves.

In addition, Medicare and many private insurers reimburse a fixed amount for the injections, about $300, giving doctors a financial incentive to prefer the less costly compounded versions, he said. “If you are using a more expensive product, there would be less left over,” Dr. O’Connell said.

PainCare paid New England Compounding $25 for a vial containing five 80-milligram doses, he said. A similar vial of the Depo-Medrol by Pfizer, with the alcohol preservative, costs about $40 to $46, according to the Web site of Clint Pharmaceuticals, a distributor.

About 186 of PainCare’s patients were injected with the suspect product. About two dozen have had symptoms that could indicate meningitis and have come in for spinal taps. The lab results are not back, Dr. O’Connell said, but the fluid samples were clear, rather than cloudy, as they would be if infected by a fungus.

Questions of Origins

Some physicians who work in big hospitals may not even know whether the drug they use is from a compounder.

Dr. Anders Cohen, the chief of neurosurgery and spine surgery at the Brooklyn Hospital Center, said: “We ask for the medication, it’s in stock, we use it. I don’t know if it’s coming from A, B or C. This is kind of a wake-up call about where your stuff is coming from.”

Because of the outbreak, Dr. Cohen has stopped performing spinal injections for now, and he was planning to declare a moratorium on them at his hospital until he was certain all the medicine was clean, even though his hospital is not on the list of facilities that received the potentially contaminated drug.

The size of New England Compounding appears to have reassured some doctors, who thought dealing with a large company might be safer than buying from a mom-and-pop compounder.

One pain specialist said he had heard from colleagues that the company had a good reputation and that even prestigious hospitals had used it. His practice did not buy the steroid medicine from New England Compounding but a contrast agent, a type of dye used for imaging. After he first contacted the Massachusetts company, it flew in a sales representative to meet him.

“We were impressed,” said the doctor, who spoke on the condition of anonymity because he had not yet consulted his malpractice insurer about whether he should publicly identify himself as having bought products from New England Compounding. “It seemed like big time.” The representative “assured me that all standards are being met.”

But all the dye the doctor bought from New England Compounding has had to be thrown out on the chance that it also might be contaminated, he said.

And the Massachusetts company itself has a troubled past. A series of complaints had been lodged against New England Compounding over the past decade. The State Health Department inspected in 2006. According to a warning letter sent by the F.D.A. from that year, the company was accused of illegally producing a standardized anesthetic topical cream, inappropriately repackaging a drug, and telling doctors that using an office staff member’s name was enough to put in an order, even though rules require a prescription for a particular patient.

Issues of Law

Meningitis can be caused by viruses, bacteria or fungi. Doctors say that the fungal type is the hardest to treat and devastating to patients because it can cause strokes. And indeed, some of the patients in the current outbreak have suffered strokes.

Federal inspectors last week removed samples of the suspect drug from New England Compounding to test for fungal contamination. The center, which takes in about $2.2 million a year, according to its corporate filings, is housed in a two-story brick building.

The company’s offices in suburban Boston were locked Friday, with a “no soliciting” sign on the door. The company did not respond to repeated requests for comment last week. Before it went offline, the company’s Web site said New England Compounding was licensed in all 50 states. State and federal officials said it had shipped out a prodigious amount of the potentially contaminated medicine to 75 pain clinics in 23 states.

Traditionally, the law meant compounding to be a local service in which pharmacists could tailor-make prescriptions for patients with special needs. Compounding pharmacies were not supposed to become miniature drug companies.

It is not clear how much large-scale compounding actually goes on. David G. Miller, executive vice president of the International Academy of Compounding Pharmacists, estimated that large-scale compounders represented about 10 percent of all compounding pharmacies, but he could not say what percentage of compounded medicines they made.

As state and federal authorities pored over information about New England Compounding last week, there was little agreement among experts on whether the company broke the law by making products in bulk and shipping them around the country.

Compounding falls in a legal no man’s land, between the federal government and the states. The F.D.A. regulates manufacturers, but compounders register as pharmacies, putting them under a patchwork of state rules. The F.D.A. did develop a clear set of rules for compounding, but subsequent litigation that culminated in a Supreme Court decision in 2002 struck them down, and Congress never re-established the agency’s clear authority, Professor Outterson said.

Jeff Gibbs, a lawyer in Washington who has represented compounders and drug companies, said it was unusual for a compounding pharmacy to produce large quantities of a drug that is commercially available. Policies of the F.D.A. were more concerned about compounders’ making drugs that are already approved and on the market, and not so much about compounders’ producing large volumes of medicine, he said.

But Sheldon T. Bradshaw, a lawyer in Washington who was chief counsel for the F.D.A. from 2005 to 2007, said large-scale compounders often behave like manufacturers, complete with sales teams that market their products to doctors. And they do not have to abide by the F.D.A.’s regulations, which require that problems with products be reported to the agency. In effect, he said, the companies are circumventing the regulatory process.

He contended that the F.D.A. could invoke the Food, Drug and Cosmetic Act of 1938, which makes it a criminal act “to introduce into interstate commerce an unapproved drug.” That is what New England Compounding’s products would most likely be considered because the company was doing more than traditional compounding, yet had not obtained a new drug approval, something that large drug makers spend millions of dollars and years to get. He said the agency has often sent letters to producers telling them to stop, and they usually comply, knowing there might be criminal charges if they do not.

“Some of these companies are just setting up big manufacturing shops in the guise of traditional compounding and making drugs that are, for the most part, commercially available,” Mr. Bradshaw said. “Instead of making fake Rolexes, they are making fake drugs.”