Regulatory Focus™ > News Articles > Legislators, FDA Outline Cases in Advance of Major Hearing on Pharmaceutical Compounding

Legislators, FDA Outline Cases in Advance of Major Hearing on Pharmaceutical Compounding

Posted 15 April 2013 | By Alexander Gaffney, RAC

Legislators and regulators alike have released previews of the arguments they intend to make at an upcoming hearing regarding a massive outbreak of fungal meningitis caused by deficient compounding practices at a Massachusetts facility, indicating that Tuesday's hearing could-once again-be a contentious one.


Pharmaceutical compounding pharmacies enjoy a relatively unusual regulatory exemption in the US whereby they can compound products without having first sought regulatory approval so long as they create the products specifically for a single patient with a valid prescription. Historically, these compounding pharmacies have largely been overseen by state-not federal-regulatory officials, and most commonly state boards of pharmacy.

The industry, once small, has expanded rapidly in recent years as the Internet has allowed pharmacies to take orders from all across the US, and drug shortages have placed an increased reliance on compounders to make up for the quality failures of federally regulated pharmaceutical manufacturers.

But that expansion has come with problems, both for the compounding industry and FDA, which has seen its authority to regulate the compounding facilities eroded by a series of court cases over the last two decades.

Industry's problems, however, seem more troubling.

In the waning months of 2012, the US Food and Drug Administration (FDA) began to receive troubling reports of patients with a rare form of fungal meningitis, which were ultimately traced back to a compounding facility in Massachusetts known as the New England Compounding Center (NECC). Inspections by FDA and Massachusetts officials found sordid conditions at the site, including rampant sterility problems. In several cases, mold was found to be located directly within the production hoods, while "white, filamentous substances" were found in autoclaves used to sterilize bulk drug products.

House GOP's Argument

The hearing, the second yet to be held, was scheduled earlier this month by Rep. Tim Murphy (R-PA), the chairman of the Energy and Commerce Subcommittee on Oversight and Investigations.

"The evidence so far demonstrates the NECC should have been shut down long before 50 people tragically lost their lives from contaminated injections," said Murphy. "With many more still sick, we will continue investigating the breakdown at the FDA so a public health disaster like this one never happens again. The FDA owes the American public the peace of mind that it will do all it can to protect the integrity of the nation's drug supply chain, and the goal of our investigation is to ensure that happens."

Now GOP legislators are indicating the crux of their argument: While they are glad that FDA is now cracking down on deficient pharmaceutical compounders, that indicates that the agency always had the authority to do so, meaning the NECC tragedy could have been avoided.

"In the wake of the deadly meningitis outbreak, it seems the FDA is finally doing its job and inspecting large-scale compounding operations with lengthy rap sheets," Murphy and Rep. Fred Upton, chairman of the Energy and Commerce Committee, wrote. "NECC and Ameridose [a subsidiary of NECC] were long on the FDA's radar screen as bad actors - years before the 2012 outbreak. FDA's inaction in the face of what the agency knew about these companies is inexcusable."

"Out of respect for the victims and their families, we need to stay focused on our mission of gathering all the facts - including those that show why the FDA failed to do something sooner and protect the public from NECC's contaminated drugs," they continued. "The documents we have gathered over the last six months paint a disturbing picture of how the FDA let the American people down."

That line of reasoning is similar to the one initially used by legislators in the initial House committee hearing in 2012, when GOP legislators in particular tore into FDA Commissioner Margaret Hamburg, questioning why FDA had not inspected the firm despite it having been on the agency's radar for more than a decade.

In a particular memorable and contentious exchange, Murphy lambasted Hamburg, accusing her of a failure of leadership. "What you have to do is easy, ma'am. Leadership is easy if you're willing to accept it, and you are not."

"Go look in the eyes of the victims and try to comfort them with that," he added, referring to Hamburg's answer over definitional complexity.

Democrats Respond

But if the 2012 hearing was notable for the apparent flat-footedness that Democrats and Hamburg seem to have been caught with, they are showing signs that they are much better prepared to defend themselves from the attacks of GOP legislators during Tuesday's hearing.

A case in point may well be a document posted by Democrats on 12 April 2013. The document, a notice from the International Academy of Compounding Pharmacists, a trade organization that advocates on behalf of the compounding industry, instructs its members of their right not to comply with requests that are basic to other areas of pharmaceutical manufacturing.

"Under no circumstances should you give [FDA] a formula, invoice or any other piece of paper," IACP instructs its members. "Ask specifically if this is a formal FDA inspection. They will reply that it is not. Regardless of the answer, tell them you are claiming your exemption as a compliant, licensed pharmacy. Look at the back of their forms, there is a place for you to claim that. Be prepared, they probably won't know what to do if you refuse to give out paperwork."

The letter goes on to concede that while FDA has the right to inspect a pharmacy, "The investigator does not have free rein to go everywhere in your facility or to see everything."

"Although FDA has broad powers to inspect drug manufacturers, the Federal Food, Drug and Cosmetic Act restricts the scope of FDA inspections of retail pharmacies," it adds. "Unlike with a drug manufacturer, it does not have the right to inspect …"records, files, papers, processes, controls" or other related documents of a pharmacy that meets certain criteria."

The letter alludes to many to the arguments made by Democrats during the last hearing: While FDA has the authority to inspect facilities in principle, in reality this authority is often met with fierce opposition, even when an inspection is properly conducted. While FDA has the authority to inspect a pharmaceutical manufacturing facility that may make a product, it lacks the authority to request the same documents from a compounding facility that makes the very same product as the pharmaceutical manufacturer.

FDA Responds

FDA, too, has highlighted similar arguments in recent weeks.

"It may surprise some people to know that, even in light of the recent tragic events, some of the firms we inspect still challenge our authority to conduct full inspections of their facilities," Hamburg wrote in a 12 April 2013 blog posting on FDA's website. "Our inspections have been delayed or the inspectors were denied full access to records at some of these facilities. At least four of our recent inspections were delayed by such resistance; and in two other instances, we had to get administrative warrants from the courts, resulting in U.S. marshals accompanying FDA inspectors back to the firms so FDA could complete the inspection."

"These challenges and others highlight the need for clearer authorities for FDA to efficiently protect public health," she added.

Hamburg also noted that even exercising its limited authority to regulate compounders was exacting a toll on its now-tightened resources. "To carry out this proactive inspection effort, FDA had to shift resources from other areas, and this is not a sustainable approach for the longer term," she wrote.

The same argument was presented earlier that same week by FDA's Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), and Howard Sklamberg, director of CDER's Office of Compliance (OC).

'No Way to Regulate an Industry'

"This is no way to regulate an industry," explained Woodcock in an interview with Ed Silverman of the industry blog Pharmalot. "Sure, we could have gone out and done more inspections like this and battled each one in court. But there are 28,000 compounding pharmacies of any type and we don't know who's who, because they don't send us anything or tell us. So how would we regulate that industry when we go there and have to get a warrant from a judge to walk in the door? You could say we could battle in court and get in the firm, but what about the other 27,999? We have to have a scheme - these firms we regulate or we don't."

In response to a later question, Woodcock expanded on that point again: "We could get totally tied up in lawsuits and we would have to stop inspecting the drug industry. And that would be great for some people. Any time we have to go to court, we have to get warrants; we have to do all these things. It isn't to say we weren't doing it before. It was done for cause. During those 10 years, we were getting court rulings partly because we were active in that space. So nothing would prevent us from having ongoing reactive programs"

Sklamberg, too, elaborated on this point, saying that there are, "realistically, with the government, limited resources."

"We made this a top if not the top priority for the drug inspection program over the last few months," he continued. "The agency can always choose to target a specific thing as opposed to something else. And when we go through this process and have the resistance and have people having us get warrants and challenge our legal authority, it's a bigger resource expenditure and bigger opportunity cost for the agency."

Few Good Options

But for now, FDA has few other good options. In the wake of the NECC tragedy, which has so far killed 53 and injured hundreds more, the agency has been scrambling to inspect compounding pharmacies.

In a report issued on 12 April, FDA wrote that it has completed 30 of the 31 priority inspections it sought to conduct. Of those 31 companies, 29 received Form 483 inspection reports indicating major deficiencies. One inspection had not yet been completed by the time of its report, while just one pharmacy completed its inspection without receiving a 483. That pharmacy, it should be noted, was not compounding sterile drugs; every other pharmacy that received a 483 was compounding sterile products.

FDA's report notes that it was forced to obtain a warrant in two of its inspections, while another four companies didn't allow access to records without first undergoing a lengthy process of legal negotiation.

The inspections, in other words, are onerous to conduct, particularly for an agency that has seen its funding cut by sequestration. But the alternative-not inspecting facilities regularly-no longer seems to be a valid option, particularly in light of legislator's concerns and FDA's own inspectional findings.

What remains to be seen, then, is how legislators will address the problems. Will FDA be given more authority-authority it has repeatedly requested-to conduct inspections more easily? Will legislators argue that it already has sufficient authority to act, and force FDA to make do with its present resources? Or will new options, such as user fees floated last month by Hamburg, emerge as viable options?

For now, the future is as murky as some of the compounded sterile injectable drugs recalled by FDA.

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