When it comes to the compounding of drugs, the one thing everyone agrees on is that something needs to be done to ensure the safety of the products. But how to do that is another matter.

The Senate Health, Education, Labor and Pensions Committee sent a bill, S. 959, to the Senate floor Wednesday that would create a new class of drugmaker, compounding manufacturers, that would be subject to FDA oversight without having to go through the drug approval process. The new class would cover large-scale drug compounders that make sterile compounded drugs in advance of a prescription and sell them across state lines. (See BioWorld Today, May 10, 2013, and May 23, 2013.)

When the House Energy and Commerce Subcommittee on Health took up the issue at a hearing Thursday, some members spoke in favor of passing a bill similar to S. 959. In light of a difference of opinion between two U.S. appellate courts over the extent of the FDA's current authority over compounders, Ranking Member Frank Pallone (D-N.J.) didn't see any alternative except a new law.

Congress needs to "step in and clarify the rules of the road," he said.

But others insisted that the FDA already has the authority it needs to go after bad actors; it just didn't do it until after contaminated drugs compounded at the New England Compounding Center (NECC) caused a meningitis outbreak that killed 55 people and sickened 740 last year. They want to know why. (See BioWorld Today, Nov. 15, 2012.)

Recently, the committee members discovered the FDA had been working on a draft guidance for three years that would have addressed the problems at manufacturers like NECC. That guidance, which was never released, reflected the agency's understanding that it had oversight of such facilities, Rep. Michael Burgess (R-Texas) said.

Acknowledging that the FDA should have been more aggressive in dealing with known problems at NECC, Janet Woodcock, director of the agency's drug center, spread the blame, saying the states could have done more and Congress could have stepped in to provide more clarity when the appellate courts ruled in 2002 and 2008.

She also made a case for new legislation tailored to fit the industry that has emerged from traditional pharmacies that compound drugs on a limited basis for individual patients.

Calling the meningitis outbreak an "appalling tragedy of a kind not seen . . . since the early 1900s," Woodcock said it was the worst of a long series of incidents involving sterile drugs compounded on a large scale. A few of those incidents involved the off-label compounding of Avastin (bevacizumab, Roche AG), as a cheaper alternative to drugs approved for age-related macular degeneration (AMD). (See BioWorld Today, March 26, 2013.)

Deficit of Quality

In the wake of the outbreak, the FDA, in conjunction with state officials, has been conducting risk-based inspections of numerous compounders. The inspections conducted to date revealed a "tremendous deficit of quality" when it comes to the production of sterile drugs, Woodcock said.

So far, 11 large compounders have been closed by state agencies, 10 companies have issued nationwide recalls of potentially contaminated drugs and 48 firms have been found to be producing drugs in unsafe or out-of-compliance conditions.

Because of the magnitude of the problem, Woodcock told the subcommittee that it's a matter of when, not if, there's a recurrence of the deadly outbreak.

To prevent that, the FDA must do a better job of communicating with the states, which have authority over pharmacies, Rep. Joe Barton (R-Texas) said, adding, "I don't want 'if' to become 'when.'"

A big part of the problem, Woodcock said, is that "we don't know the full universe of firms that are out there," because they aren't required to register with the agency. They also don't have to file adverse event reports.

Under S. 959, compounding manufacturers would be subject to the same manufacturing and reporting rules as a drugmaker, but they wouldn't have to submit applications for new drugs/biologics or generics/biosimilars. There also would be limits on what drugs they could compound.

Scott Gottlieb, a fellow at the American Enterprise Institute, testified that what the Senate bill refers to as compounding manufacturers are not compounders at all. They're drugmakers who are already subject to FDA oversight, he said.

While he thinks a clearer standard is needed, Gottlieb said if a new law is passed, it must "go hand-in-hand with vigorous enforcement by FDA of rules that prohibit compounders from making copies of FDA-approved drugs." Otherwise, it could create a "regulatory lite" pathway that would allow drugmakers to re-mask and circumvent the drug approval process.

The emergence of the large-scale compounding industry and today's lack of controls are due, in part, to the agency's inconsistent enforcement and policy changes, Gottlieb said. In its crackdown on generic firms, for instance, the FDA drove several generic drugmakers to close their facilities while they underwent remediation, creating shortages and leaving the market "to be supplied by the only outfits still capable of operating – the compounders," he explained in his written testimony.

Thus, the generic crackdown fueled further growth of compounded products that the FDA wasn't regulating.

Economic Discretion

Historically, the agency exercised its authority over compounders that copied approved drugs, requiring that the drugs be removed from the market as unapproved new drugs. But in more recent years, the agency has used enforcement discretion due to economic factors.

The FDA has, "at times, not enforced rules evenly out of concern that knocking certain violating products and firms out of the market might impose higher costs on consumers," Gottlieb noted.

For instance, responding to congressional and public pressure about the high price K-V Pharmaceuticals Co. was charging for Makena (hydroxyprogesterone caproate), the FDA refused to enforce the drugmaker's seven-year orphan drug exclusivity and allowed compounders to continue to produce the drug, which is used to prevent preterm births. (See BioWorld Today, May 2, 2011.)

Economic issues also have come into play with the FDA's acceptance of the off-label production of Avastin, even though use of contaminated product has led to serious injuries. According to testimony submitted by Gabrielle Cosel, manager of drug safety for Pew Charitable Trusts, at least 21 patients developed bacterial infections in 2011 after being injected in the eye with compounded Avastin. As a result, one patient came down with meningitis and encephalitis, four suffered a loss of eyesight and three had to have an eye removed. In a separate incident that same year, five patients were blinded when they were injected with Avastin unintentionally compounded with traces of another medication.

In her written testimony, Woodcock referred to two other incidents of bacterial infections stemming from compounded Avastin, including one as recent as March.

Despite those incidents, the FDA did not go after the compounding pharmacies for misbranding or selling an unapproved drug. In fact, several experts have pushed for broader use of compounded Avastin for AMD because of the potential cost savings to Medicare. (See BioWorld Today, Sept. 12, 2011.)

Economic issues shouldn't be a deciding factor in the FDA's discretionary enforcement of compounding manufacturers, Gottlieb told the committee, adding that they should be dealt with separately.