Expert: NECC Failed to Meet Testing, Sterility Standards

By Walter F. Roche Jr.

BOSTON, Mass. A pharmaceutical expert witness says the New England Compounding Center failed repeatedly in multiple categories to meet standards for the production of sterile drugs, thus putting patients at grave risk.
Eric S. Kastango, a pharmacist who was hired by federal prosecutors to assist in the investigation of the 2012 fungal meningitis outbreak, said, "The testing was not being done. Every time a lot was done, each and everyone should have been tested."
He said that when drugs that are not sterile are injected into the body they can cause "devastating harm and death can occur."
Kastango was one of two new witnesses to testify today in the racketeering and second degree murder trial of Barry J. Cadden, the one time president and part owner of the now defunct NECC.
The outbreak sickened 778 patients. Seventy eight died.
The 15 jurors also heard from the head of the California drug company that sold NECC a chemical used in a cancer treatment drug. He said the chemical purchased by NECC in 2005 expired in 2007 even though NECC used it and shipped it to healthcare providers in 2012.
Thomas N. Tyner, vice president of Spectrum Chemical, said his company had never authorized an extension in the expiration date for methotrexate, the chemical purchased by NECC.
He said there was only one option in 2012, "Throw it out."
Kastango, who was on the witness stand for most of the session, said he was hired by prosecutors at a rate of $225 an hour and billed for 100 hours in his efforts to investigate NECC and the outbreak. He said he was being paid $350 an hour for his court testimony.
Under questioning by Assistant U.S. Attorney George Varghese, Kastango said he had visited NECC's Framingham heaquarters, examined company records, interviewed NECC employees and reviewed transcripts of the NECC grand jury.
From everything from autoclaving to sterility testing to maintaining sanitary conditions to temperature and humidity control, Kastango said NECC failed to meet the industry standards for the compounding of sterile drugs.
"They did not use validated procedures," he said.
On autoclaving Kastango said the industry standard set by the nonprofit U.S. Pharmacopeia called for
placing the drug in the autoclave for 20 to 60 minutes at 121 degrees.
But NECC was only auto-claving for 15 minutes or as low as 12 minutes, and that included no so-called ramp up time, the five minutes needed for the autoclave to reach the desired temperature.
"There was no evidence they did any testing to make sure it was properly auto-claved," he said, adding that the company also failed to use bio-indicators, another testing method to ensure sterilization.
He was also critical of NECC's practice of auto-claving drugs, like the spinal steroid blamed for the outbreak, in bulk. He said NECC stored the bulk material in beakers, leaving the opportunity for later contamination.
Kastango said NECC's sterility testing was not done consistently or correctly and when they did send out drugs for outside testing, they sent an insufficient amount. Instead of the single vial sent to an Oklahoma firm, NECC should have sent four or 20 depending on the size of the lot.
As for the use of outdated ingredients by NECC, Kastango quipped, "When in doubt, throw it out."
Varghese showed jurors and Kastango an email Cadden sent to an NECC employee regarding a testing procedure.
"What you are seeing is what we are not currently doing but should be doing," Cadden wrote. "We are not covering these things all the time in the current testing method."
Asked to comment on the email, Kastango said, "Cadden knew they weren't doing the testing correctly."
Kastango said NECC failed to comply with a number of other elements in the industry standard including a written procedure for notifying physicians and patients in the event an adverse test result came back on a drug already shipped.
He said they were using alcohol to wipe down the clean room even though it was not effective for combating fungus.
He said NECC in some categories was actually doing more testing than was recommended in industry standards, but when tests showed action levels had been exceeded, "They basically ignored that for weeks on end."
Under cross examination by Cadden's attorney Bruce Singal, showed materials from a training session Kastango hmself had conducted that included a recommendation to autoclave drugs from only 12 to 30 minutes.
Showing more of those materials, Singal asked if co-defendant Glenn Chin and not Barry Cadden, was responsible for determining clean room standards such as the length of time for auto-claving sterile drugs. Cross examination continues Wednesday.

Details Disclosed on 20 Fatal Outbreak Victims

By Walter F. Roche Jr.

BOSTON, Mass. - Case by case a health official today went through the names, causes of death and and other details of 20 of the patients from seven states who died in the 2012 fungal meningitis outbreak.
 Ann Burgess, who holds a Ph.D. in nursing, cited the deaths of victims from Michigan, Tennesseee, Indiana, Maryland, Virginia, North Carolina and Florida in testimony in U.S. District Court. Burgess was a prosecution witness in the case of Barry J. Cadden.
Cadden has been on trial for over a month on charges of racketeering and 25 counts of second degree murder, along with mail fraud.
In nearly all of the cases, Burgess cited fungal meningitis as the direct or secondary cause of the deaths.
The death certificate for Diana Reed, 56, of Nashville listed "fungal meningitis" as the cause. She had three injections in August and September of 2012, Burgess testified. She died on Oct. 3.
The death certificate for Thomas Rybinski of Smyrna listed "complications of aspergillus meningitis" as the cause.
As each case was detailed, jurors were shown a photo of that victim.
Pauline Burema, an Indiana victim, was 89 when she died  in 2012. "Injected with tainted steroid," records of her case state.
Godwin Mitchell, 88, died March 18, 2013 after being injected with "a tainted steroid" at a Virginia clinic, Burgess said.
Prosecutors have presented other evidence on the deaths in the indictment not included in Burgess testimony.
The jury also heard testimony from an investigator from the U.S. Food and Drug Administration about the shipment of three lots of fungus laden methylprednisolone from Cadden's company, the New England Compounding Center, to health facilities including the Saint Thomas Outpatient Neurosurgical Center in Nashville, Tenn.
Joseph Ridgley said the Nashville clinic got four shipments between June and early September of 2012. The cost of the orders, all for 500 vials, ranged from $3,270 to $3,430 vials.
Similar details were provided for shipments to Michigan Pain Specialists and an Indiana clinic, two other sites where victims were injected.
Under questioning by prosecutors, Ridgley matched a list  NECC drugs with some of the charges that have been leveled against Cadden. The drugs included some that did not have the required potency and others in which the ingredients had gone past their expiration date.
He also testified about drugs compounded by co-defendant Scott Connolly who was not registered as a pharmacy technician, as required under Massachuetts law.
The FDA investgator said Connolly compounded a drug called cardioplegia which was shipped to a Las Vegas hospital before test results came back. He said Connolly signed company records using Cadden's initials.
Ridgley also testified about a long list of other NECC drugs that did not meet specifications but are not included in the indictment.
Asked if any of those drugs caused any harm, Ridgely responded "I'm not aware of any."
FBI Agent Philip Sliney presented a chart showing NECC drugs that did not contain the required ingredients including a drug used in eye surgery that was shipped to the Massachusetts Eye and Ear Infirmary.
Another drug that didn't meet specifcations was shipped to a Tavares, Fl clinic, he said. Both of those cases were included in the indictment, he testified.
Under cross examination, Bruce Singal, Cadden's lawyer questioned how Cadden could be charged with a felony because an NECC clean room worker didn't put enough ingredients in a drug. He also noted that the long list Sliney presented included multiple entries for the same drug, an antibiotic.
His cross examination will continue Tuesday.
Contact: wfrochejr999@gmail.com

Named Victims and Dates of Death

Michigan: Karina Baxter (9/23/12), Paula Brent (11/17/12), Gayle Gipson (10/26/12), Donna Kruzich (10/8/12), Lynn Lapierre  10/17/12), Mary Pletti (8/23/12), Sally Roe (10/18/12), Emma Todd

Tennessee: Marie Hester (11/1/12), Eddie Lovelace (9/17/12), Donald McDavid (11/4/12), Diana Reed (10/3/12) , Thomas Rybinski (9/29/12), Carol Wetton (4/16/13), Earline Williams (10/15/12)

Indiana: Pauline Burema (10/10/12), Kathy Dillon (11/5/12), Alice Machowiak (12/10/12)

Maryland: Bahman Kashi (1/28/13), Brenda Rozek (9/16/12), Edna Young (12/31/12)

Virginia: Kathy Sinclair (1/19/13), Douglas Wingate (9/18/12)

Florida: Godwin Mitchell (3/18/13)

North Carolina: Elwina Shaw (10/19/12)

 

More NECC Drugs Found Contaminated

By Walter F. Roche Jr.

BOSTON, Mass. - A parade of microbiologists from the U.S. Food and Drug Administration detailed today how they found contaminants in a variety of drugs produced by the now defunct New England Compounding Center.
Testifying in U.S. District Court the scientists from New York, Denver and San Francisco described in brief detail how they tested the drugs, some collected at NECC's Framingham offices along with others from Tennessee, Florida and West Virginia.
The drugs found contaminated included the spinal steroid blamed for dozens of death, but also other drugs not previously identified such as triamcinolone, betamethasone and cardioplegia.
At the Saint Thomas Outpatient Neurosurgical Center in Nashville, Tenn. 78 vials of methylprednisolone acetate were collected.
Haydee Romero from FDA's New York office, said 28 of the vials contained yeast, while 20 had two different kinds of mold.
NECC vials found at the Specialty Surgery Center in Crossville, Tenn. also were contaminated.
Romero also tested 25 vials that were collected directly at NECC. All 25 were contaminated with yeast or mold.
The testimony came in the case of NECC's one time president and part owner, Barry J. Cadden. He has entered not guilty pleas to charges of racketeering and second degree murder. The murder charges stem from the death of 25 of some 78 patients who died after being injected with fungus ridden steroids from NECC.
In other testimony Stacey Degamo, an FDA investigator, testified that while they found several varieties of fungus when they inspected NECC in October of 2012, they did not find either of the two specific fungi, aspergillus fumigatus and exserohilum rostratum found in victims of the 2012 outbreak.
Other microbiologists to testify under questioning from Assistant John Claud, a U.S. Justice Department attorney, included Patricia Stanke from FDA's Denver office. She said one of 10 vials of betamethasone she tested had a bluish mold, which turned dark grey with aging.
Henry Lau from FDA's San Francisco office said he also tested betamethasone produced by NECC. Five vials were found to have bacteria, which he said could be "very harmful."
He also tested triaminclone and three vials showed the presence of bacteria, bacillus lentus.
A third drug he said he tested was cardioplegea, a drug used to stop the heart from beating during surgery. He said three vials contained bacteria.
On cross examination Lau said that he became aware that some of the drugs collected from NECC went missing, but he said he didn't know whether they were ever found.
The vials that turned out to be tainted came from health facilities in Florida, West Virginia and Kentucky

FDA: NECC Steroids Not Properly Sterilized

By Walter F. Roche Jr.

BOSTON, Mass.-An investigator from the U.S Food and Drug Administration testified today that the fungus ridden steroids shipped from a now defunct compounding firm had been sterilized for less than half the recommended time.
Testifying in U.S. District Court Stacey Degarmo said that records she reviewed at the New England Compounding Center in 2012 showed the steroids were placed in an autoclave for only 15 minutes. She said with the volume of drugs being treated the manual for the autoclave called for 31 minutes in autoclave.
She said NECC didn't even follow its own instructions, which called for 20 minutes inside the autoclave at a temperature of 121 degrees.
Degarmo, the lead FDA investigator assigned to the 2012 fungal meningitis outbreak was testifying for the prosecution in the second degree murder trial of Barry J. Cadden. He was one of 14 people connected to NECC who were charged in a 2014 indictment.
The indictment followed a two year probe of the 2012 fungal meningitis outbreak, which sickened 778 patients, killing 78 of them.
The FDA investigator said she asked NECC for validation that a 15 minute treatment in the autoclave was adequate but she never got a response. She said her review of NECC records showed that the practice of sterilizing the steroid, methylprednisolone acetate, for only 15 minutes dated back to 2009.
Another problem area, she said, was the fact that NECC was testing its steroids in bulk, not the individual vials later shipped to health care providers. She said the records showed NECC had shipped out vials before the sterility tests came back.
Degarmo said that one of the first things she noticed when she got to NECC was a big pile of deteriorating mattresses piled up near the building. She said heavy equipment was being operated in the area creating a cloud of dust and particulates.
"All this was flying around," she said.
She said that set of  "red flags" because she had learned that one of the seven outbreak victims in Nashville, Tenn. had been diagnosed with aspergillus fumagatus, which grows in the soil.
Degarmo said that she also performed environmental sampling tests when she arrived at NECC's Framingham, Mass. facility on Oct. 1, 2012.
She said 11 of 41 samples tested positive for mold, bacteria or both. Yeast was also detected in key areas including the air conditioning and heating unit atop the brick structure.
The 11 positive findings for mold or bacteria included specimens from  a pass through from the clean room to the warehouse or packing area, inside the glove of a glove box used to prepare sterile drugs, on a mat at the entrance to the clean room and around a boiler sitting in a pool of leaking water.
The FDA investigator said she also learned that when NECC prepared lots of the steroid only one sample was sent out to an independent laboratory to test for sterility. She called that "inadequate."
Under questioning by Assistant U.S. Attorney George Varghese, Degarmo said that when they examined vials of the steroid that had not been shipped out before a quarantine was imposed some had "clearly visible black mold."
She said 12 of 45 vials examined had visible mold.
At that point in time, she testified Cadden "still didn't believe there was a problem with the NECC product."
She also said she got conflicting information when she asked Cadden if NECC was compounding the drugs from sterile or non-sterile components.
Under cross examination by Bruce Singal, Cadden's lead attorney, Degarmo was questioned repeatedly about why the agency waited several days after learning about the outbreak before sending a team to NECC.
Citing internal FDA emails and documents, Singal asked why the FDA was worried about whether it had the legal authority to join an investigation already begun by the Massachusetts Board of Pharmacy.
Degarmo said she was aware that the FDA's authority over compounding pharmacies had been challenged in the past, but it was not a major factor. She said the agency clearly had the authority to investigate any cases involving adulterated drugs.
She said her team accompanied the team from the Mass. Pharmacy Board on the initial inspection because that agency had clearer authority to order NECC to produce records in the event the company refused to do so.
Singal, however, noted that FDA still hadn't acted even after it learned that seven patients in Nashville, Tenn. had been stricken with an additional case reported in North Carolina.

Judge Seeks Limits on Next NECC Trial

By Walter F. Roche Jr.

With the current trial winding up its eighth week with no end in sight, the federal judge presiding over the criminal trials stemming from the 2012 fungal meningitis outbreak is moving to limit the length of the next scheduled case.
In a six-page order issued this week U.S. District Judge Richard G. Stearns has instructed lawyers for the defendant, Glenn Chin, and federal prosecutors to submit proposed time limits for the jury trial.
The action comes as the case against Barry J. Cadden is approaching a third month and the prosecution has yet to wrap up its side of the case.
The charges against Chin mirror those against Cadden, racketeering and 25 counts of second degree murder among other charges.
They were among 14 people connected to the New England Compounding Center indicted following a lengthy probe of the 2012 fungal meningitis outbreak. Two of the 14 have pleaded guilty to lesser charges. Two others have had all charges dismissed.
Cadden was president and part owner of NECC. Chin was a supervising pharmacist.
The remaining defendants are slated to go on trial after the Chin case is completed.
In the order issued by Stearns he cited the advantages of setting such limits and noted there are precedents for such a process.
"It enables the court to efficiently manage its docket" and "improves the quality of jury comprehension," Stearns wrote.
Stearns wrote that he had additional concerns about "the phenomenon of mega-trials, that is trials, the duration of which are measured in months not days."
He also expressed concern of the effect on jurors in trials that "consume an inordinate amount of the court's time and focus."
The outbreak, caused by fungus riddled drugs shipped by NECC to health care providers across the country, sickened 778 people and killed 78 of them.

FDA Raced to Find Outbreak Cause

By Walter F. Roche Jr.

A microbiologist for the U.S. Food and Drug Administration testified that he had never seen sterile drugs as contaminated as the ones he rushed to analyze in October of 2012 from the New England Compounding Center.
"I've never seen a sterile product so contaminated," Philip F. Istafanos told jurors.
He said samples of NECC drugs were shuttled from Massachusetts to FDA's National Research Laboratory in Jamaica, New York on Oct. 3 where he and others worked into the night to begin a detailed analysis.
Because of the urgency, the FDA official said staff from New York met counterparts from Massachusetts at the halfway point to collect the samples.
Istafanos was testifying for the prosecution in the trial of Barry J. Cadden, the one time president and part owner of NECC. He has been charged with racketeering and 25 counts of second degree murder. The outbreak sickened some 778 patients across the country, killing 78 of them.
Istefanos said nearly 100 vials of drugs from NECC were brought to his laboratory followed by more than two dozen swabs taken from key locations in NECC's Framingham, Mass. headquarters.
The samples arrived on Oct. 3, just as a formal announcement of the fungal meningitis outbreak was becoming public.
He said a first look at the vials of methylprednisolone acetate showed nine had visible black spots and he removed the stringy mass from one vial to examine it.
"I took out the black material and put it under a microscope," he said, adding that he had never seen anything like what he found in the vials.
He described black threadlike material bundling together, some of which clung to the sides and bottom of vials.
He said half of the samples were sent to the U.S. Centers for Disease Control and Prevention and analysis of the remaining vials began with testing of the dust cover to exclude it as the source of the fungus.
He said they then began testing the actual drugs using three different media or growth agents, instead of the usual two.
Though the full process normally takes 14 days, Istafanos said,"It was urgent. We needed a faster result."
He said they began examining the samples and began to see results in four or five days when a blackish mold became visible. In addition to the mold, analysis showed the presence of yeast, which Istafanos described as a "very unlikely" combination.
"It was contaminated, very contaminated, very bad," he said.
He said 49 of the 50 samples had yeast and mold and one had only yeast.
He said as a control they replicated the testing process with substances known to be sterile. Those produced no growth.
Describing blackish and white-ish mold found in the NECC drugs, Istafanos said, "This is a sterile drug. It should have nothing in it."
He said 11 of the environmental sample swabs also tested positive.
Earlier in the day Roger Edwards, a forensic accountant hired by the FDA, testified that Cadden and his wife collected $19.5 million in salary and profits from NECC between 1998 and the company closing in October of 2012.
Each owned 17.5 percent of the company. Barry Cadden collected $10.9 million in salary and profits while Lisa Cadden collected over $8.6 million.
A third witness, FDA investigator Kristina Donohue, testified about inspections of NECC she conducted in 2002 and 2003. She said the agency had received complaints that even though it was only licensed as a pharmacy, NECC was acting like a drug manufacturer, which would make it subject to stricter FDA regulation.
On her first visit in 2002 she said she observed a beaker of betamethasone covered with tin foil. Calling it "problematic," Donohue said the situation raised concerns about sterility. She said they also noted NECC was not doing end product testing and there were concerns about expiration dates of some products.
She said that when she returned in 2003, the physical size of the NECC operation had doubled and staff had jumped from eight to 12.
She said Cadden told her NECC was issuing drugs only with patient-specific prescriptions, as required by law. She said staff from the Massachusetts Board of Pharmacy accompanied her on the NECC visits because that board licensed the company.
At that point, Donohue said, the FDA considered NECC to be acting as a pharmacy, subject to state regulation and not the stricter FDA standard for drug manufacturers.
Contact: wfrochejr999@gmail.com

Accountant Cites $32.4 Million NECC Revenue

By Walter F. Roche Jr.

A forensic auditor testified today that the New England Compounding Center's revenues soared in its final ten months of operation hitting $32.4 million and pushing the company's total sales since its inception in 1998 to $153 million.
Roger Edwards, a forensic accountant, was called as a prosecution witness in the trial of NECC's one time president and part owner Barry J. Cadden. Cadden has been charged with racketeering and 25 counts of second degree murder following a grand jury probe of the deadly 2012 fungal meningitis outbreak.
In other testimony Tuesday, Cadden's attorney Michelle Peirce continued to sharply question a key prosecution witness, NECC's quality control manager, Annette Robinson.
Robinson acknowledged in a later exchange with prosecutors that she testified before the grand jury investigating NECC under a grant of immunity and she had legal counsel at the time. Robinson was not charged in the 2014 indictment.
Edwards testified that he had examined the books of NECC and at first the now defunct company had the appearance of a small family business. That changed in 2007 when there was a dramatic increase  in revenues.
He said there was another "significant" jump in 2012 when revenues hit  a record $32.4 million, even though the company was only in business for a little over nine months. NECC shutdown in early October after the outbreak became public.
Edwards also will be testifying later this week on a report he compiled showing Barry Cadden and his wife, Lisa, collected $18 million in profits from NECC from the 1998 startup till the 2012 closure. The accountant's report lists payments of $8.5 million to Lisa Cadden and $9.5 million to Barry Cadden between 1998 and October of 2012.
The cross examination of Robinson took most of the Tuesday session as Peirce repeatedly questioned apparent differences between the witness's statements in court last week and testimony she gave before the grand jury and in interviews with federal investigators.
Peirce focused on Robinson's statement about the fact that bioindicators were not being used when drugs were being sterilized in an autoclave. Robinson testified last week that Cadden told her in 2012 that they should have been using bioindcators all along.
Peirce cited Robinson's grand jury testimony in which she said Cadden "may have" made that statement.
Peirce also asked Robinson about how many times she had been questioned by federal officials and whether she was discussing her upcoming testimony with prosecutors during a break in the day's court session.
U.S. District Judge Richard G. Stearns cut off that line of questioning.
"I'm sure nothing untoward happened," he said.
Robinson testified earlier that when she was about to be questioned by officials from the U.S. Food and Drug Administration in 2012, Gregory Conigliaro, an NECC part owner, told her to just tell the truth.
Asked if Cadden hadn't said the same thing, Robinson agreed that may have happened.
Peirce also challenged Robinson's statement that she notified Cadden whenever test results from an independent testing firm showed any NECC drugs were out of specifications or when she discovered mold in the clean rooms.
"I would go in and say, 'Barry there is a lot of mold,'"Robinson responded. "I went to him when I thought there was a problem."
Several of Peirce's questions related to Robinson's admission that she thought she might have caused the outbreak because she mishandled a glove box while collecting environmental monitoring samples.
"Did you clean it," Peirce asked.
"No," Robinson responded.
She also acknowledged she did not report the incident at the time it occurred.