Sunday, November 20, 2016

Drug Compounding Regulation Still Murky

By Walter F. Roche Jr.

A report by the U.S. General Accountability Office finds that a new federal law aimed at closing a loophole that allowed wide scale unregulated drug compounding has left many questions unanswered three years after its enactment.
The 70-page report, based largely on the responses to a survey of state pharmacy boards and other interested parties, found that neither the state boards or the U.S. Food and  Drug Administration can even determine the volume of compounded drugs being produced.
Meanwhile, the report states, the FDA, although it has collected massive amounts of data from newly authorized mass drug compounders, has not figured out how to compile that data into useful information.
The 2013 law, the Drug Quality and Security Act, was prompted by the 2012 fungal meningitis outbreak caused by a rogue Massachusetts drug compounding firm that had shipped thousands of vials of fungus laden steroids to health providers across the country.
Records in a criminal case stemming from a grand jury probe of the outbreak show 778 patients were sickened, many with a debilitating bouts of fungal meningitis. According to a filing in the criminal case 76 of those patients died. The deaths have continued, however, boosting that count even higher.
The new law authorized for the first time the licensing of mass compound drug manufacturers who can produce compound drugs without a patient specific prescription.
"Nearly all the states reported that they did not collect data on the volume of compounded drugs," the report states, adding that in 18 states regulators did not know whether, under the new law, general practice physicians could legally compound drugs in their offices.
"Notably, nearly all of the states we surveyed reported having drug  compounding law or policies for
pharmacists, but not for physicians," the report states. 
The GAO reported that as of April 22 of this year 40 of 59, or nearly 70 per cent of mass drug compounding firms had not provided some or all of the data the federal agency had requested.
And while the FDA says the new law does not allow it, 39 states reported that "anticipatory compounding of both sterile and non-sterile drugs is authorized or allowed in their state." Only one state reported that it was illegal.
In other areas, the GAO found that 21 states now require specialized training of inspectors who are assigned to inspect drug compounding facilities and inspections are conducted as often as annually or as long as five years, according to the survey results.
Thirteen states reported imposing monetary penalties on drug compounders in 2014, while a dozen did so in 2015.
The FDA, according to the report, had conducted 75 inspections at 59 mass drug compounding facilities as of April 16 and issued 24 warning letters. There were 15 voluntary recalls of compounded drugs during the same period.
Dr. Michael Carome of Public Citizen, a nonprofit advocacy group, said that while he has seen some improvement in drug compounding the violations being reported by the FDA at so-called outsourcing facilities are concerning.
What is troubling is the high percentage of outsourcing facilities inspected by the FDA that have received warning letters describing serious problems in the production of sterile compounded drugs," Carome said, noting that those warning letters have come as the FDA has "ramped up" its inspections of those mass producers of compounded drugs.

A new report by the Government Accountability Office (GAO) finds that while the US Food and Drug Administration (FDA) has taken steps to improve its oversight of drug compounders, challenges at both the state- and FDA-level remain.


Unlike traditional drugmakers, drug compounders are exempt from certain requirements of the Federal Food, Drug and Cosmetic (FD&C) Act. These exemptions allow compounders operating under section 503A of the act to produce drugs without complying with current good manufacturing practice (cGMP) and certain labeling requirements, and sell those drugs without marketing approval from FDA.
The safety of compounded drugs has been a high profile issue for FDA since an outbreak of fungal meningitis linked to a Massachusetts-based compounder killed 64 people in 2012.
In response to the outbreak, Congress passed the Drug Quality and Security Act (DQSA), which amended the Federal Food, Drug and Cosmetic Act (FD&C Act) to clarify requirements for compounders and created a pathway for compounders to register with FDA as outsourcing facilities.
Under the DQSA, registered outsourcing facilities operating under section 503B of the FD&C Act must follow cGMP requirements and are required to report adverse events to FDA for the drugs they produce in order to maintain exemptions for labeling and approval requirements.

GAO Report

Since the passage of the DQSA, GAO says FDA has made progress toward its new and clarified responsibilities with regard to drug compounding.
According to GAO, the agency has conducted more than 300 inspections of compounding facilities between May 2012 and April 2016, 75 of which were of registered outsourcing facilities. Many of these inspections led to action by FDA, including issuing numerous Form 483s and warning letters to compounders.
"These 75 inspections were at 59 of the 91 facilities that had registered with FDA," GAO writes. However, according to GAO, "many of the entities that were registered as outsourcing facilities withdrew their outsourcing facility registration submission before the agency scheduled an inspection, and others were not yet operating when the agency attempted to inspect them."
GAO says it also found that FDA generally met its obligations to publish guidance and other documents related to compounding, some of which were required under the DQSA.
In total, FDA has finalized seven guidance documents and 10 draft guidances related to compounding since 2014.
However, despite FDA's actions, GAO found that some stakeholders felt the agency was slow to publish guidance.
"Some stakeholder organizations said the amount of time it takes FDA to finalize the guidance and other documents … is challenging," GAO writes, noting that FDA cited the number of comments it received contributed to the delay.
However, overall, states appear to be content with the level of communication, with roughly three quarters of states saying they are either very or somewhat satisfied, or at least neither satisfied nor dissatisfied with the agency.
Another issue, GAO says, is that the data being collected by FDA and states paints an incomplete picture of the extent of drug compounding.
"According to FDA officials, there is no good source for data on the extent of drug compounding and who is doing it except for data on outsourcing facilities," GAO writes. Despite requirements for outsourcing facilities to provide FDA with data on the number of units of drugs they produce every six months, FDA told GAO that "not all outsourcing facilities provided these reports and the data provided were not yet collected and maintained in a standard format."
Furthermore, FDA told GAO that most registered outsourcing facilities have failed to submit all the required data to the agency. "As of April 22, 2016, 40 of the 59 outsourcing facilities had not provided some or all required reports," GAO writes.
As such, GAO says it was unable to look at aggregate data for drugs produced by registered outsourcing facilities for the report.
Going forward, FDA told GAO it plans to update its electronic reporting system so that future reports can be submitted electronically in a standardized format.
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