FDA Intends to Strengthen Recall Effectiveness Checks

McKinsey & Co. submitted its Recall Business Process Improvement Study to FDA last year and delivered its recommendations this April.

FDA is preparing to monitor recall effectiveness more closely as a result of pressure from Congress, the news media and the White House.

Meanwhile, drug manufacturers are talking about taking advantage of swifter communication methods that have arisen in the past couple of decades, such as email, to expedite and strengthen the recall process.

Strain from major events like the heparin recall in 2008 and the peanut butter recall in 2009 revealed flaws in the system that the agency plans to fix.

For weeks and months after it had been recalled, many hospitals in California were still treating patients with dangerous contaminated heparin, the state’s Board of Pharmacy accidentally discovered.

But it was the recall of peanut butter made with salmonella-tainted peanuts from Peanut Corp. of America that led President Obama to order a “full review” of FDA shortly after he took office (Also see "Drug GMP Warning Letters, Enforcement Could Rebound in Obama's FDA" - Pink Sheet, 1 Apr, 2009.).

Then in August 2009, the HHS Office of Inspector General faulted FDA’s monitoring of pet food recalls that resulted from a supplier’s use of melamine to boost apparent protein content. OIG concluded after reviewing those recalls “that FDA did not always follow its procedures for carrying out these activities and that FDA’s procedures sometimes were inadequate for monitoring and assessing the effectiveness of recalls.”

The OIG urged the agency to seek mandatory recall authority, which it later obtained from Congress for foods, and may yet obtain for drugs and devices. The OIG also encouraged FDA to, among other things:

• require industry to promptly check recall effectiveness and periodically report to FDA on the results of those effectiveness checks;
• make sure its own staff actually performs and fully documents audit checks; and
• follow up to make sure firms completed their recall effectiveness checks in a timely manner.

FDA’s Office of Regulatory Affairs later contracted for a comprehensive study of the agency’s recall program. McKinsey & Co. began working on the Recall Business Process Improvement Study last fall, and delivered its recommendations this April, Armando Zamora, acting director for ORA’s Office of Enforcement, said in an interview.

The study was an outgrowth of recent recalls, “some of them very complex, some of them very significant, and huge, which have mustered up a lot of interest, not only from the public’s perspective but from Congress and the media itself,” Zamora said at a recent Parenteral Drug Association/FDA Joint Regulatory Conference.

“We recognized that because of these high-profile recalls, we had to take a look at the entire recall program in general,” Zamora explained.

He noted that the agency has found it difficult to tell Congress and the news media how well recalls are going. FDA reviews some recalls with what it calls audit recall checks, but it’s a challenge, given the agency’s limited resources.

McKinsey recommended that FDA consider outsourcing recall audit checks so that it could follow up on more recalls.

Internal communication about the audit recall checks should be quicker, the report said. Zamora explained that, “as these FDA investigators go out to sites to audit recalls, they, for the most part, document their findings on a piece of paper, and that piece of paper flows back up the chain through the district and comes up to headquarters.” Now there’s an initiative to automate that process.

McKinsey also urged the agency to enhance the communication process surrounding recalls. After comparing press releases that recallers and FDA issued, “they found that the messaging was inconsistent,” he said. “So we’re looking at that from a risk communication aspect.”

The report made a few other recommendations as well, but Zamora did not describe them.

FDA is assembling workgroups to implement the recommendations, he noted.

He characterized McKinsey’s 22-week-long review as “a top-to-bottom, front-to-back study of the recall program throughout the agency” that included examining industry guidance, agency recall policy and internal procedures.

Recalls have grown more complex and information technology has advanced considerably in the years since the agency established its recall policy in 1978, Zamora noted.

Industry Best Practices

Raymond Godlewski, MedImmune’s quality and compliance VP, shared some suggestions at the PDA/FDA meeting for industry best practices to ensure recall effectiveness.

“Recall effectiveness feedback loops – what have we used traditionally? Traditionally, it’s based on the return of an attachment to a recall letter. What percentage of assignees responded to the letter sent or a follow-up phone call?”

It may be time to try new approaches, he suggested. “When you think about today’s communication channels, we still rely on sending out letters and getting people to either send things back or fax things back to us. A little arcane, I would say, so we need to look at different ways to do things as we move forward with regard to recall effectiveness.”

There are other steps companies should be taking during recalls as well to ensure their effectiveness, he said. “Are you monitoring your input sources for other signs of effectiveness? Your complaint database – are you still recovering and receiving complaints on recalled lots? Pharmacovigilance databases – are you still receiving adverse events on recalled lots? If you are, that should be telling you something.”

As part of its own effort to make recalls more effective and provide more timely information, FDA is pilot testing a program to list some recalls in advance of their designation as a Class I, II or III recall (Also see "Drug Recalls Will Be Announced Without Classification Under FDA Pilot" - Pink Sheet, 26 Sep, 2011.).

Godlewski encouraged manufacturers to make sure they have good plans for reaching everyone who needs to know about a recall. This can be difficult with hospitals, with their decentralized pharmacy services and numerous storage areas for pharmaceuticals, as California authorities discovered during the 2008 heparin recall. “So when we talk about communication, we need to make sure that we are getting to the user groups that are using our products.”

The Other Heparin Story

Godlewski was referring to the widespread use of recalled heparin that Virginia Herold, executive officer of the California State Board of Pharmacy, recently described at a Pew Charitable Trusts meeting.

She called it “the other heparin story.”

The issue came to Herold’s attention purely by chance, she told Pew’s “After Heparin” roundtable March 15 in Washington. The early 2008 recall of tainted heparin came as she was working to build support for the pedigree requirement the state was trying to establish to keep counterfeits out of the drug distribution chain.

During a break at a large public meeting on the state’s effort to establish drug pedigrees, the director for a large chain of pharmacies told her they were low on heparin. They’d been hoarding it, but were nervous about possibly running out. That’s when they received a fax from someone who wanted to sell them some heparin.

“So the hospital makes a phone call, tries to buy it,” Herold told the Pew meeting. “And the price at the time had been $8 before for heparin, and this was $130 for the same size order, a huge increase in price. And when they decided maybe they would try buying some, they couldn’t buy any, because it wasn’t available anymore.”

Herold realized there was a great deal of pressure at the time for supporters of the pedigree law to show demonstrated cases of counterfeit drugs infiltrating the legitimate distribution chain.

She figured there was a good chance that the anonymous wholesalers profiting from the heparin shortage might be introducing counterfeit heparin into hospitals. Little did she know then that the crisis actually resulted from counterfeit ingredients in heparin.

“We went into 40 hospitals, just as a survey, towards early April,” looking for counterfeit heparin, she said. “In 40% of those hospitals, we found recalled heparin still in patient care areas after the last recall. Keep in mind, the last recall in this case was March 28. We’re now two weeks in, and we’re finding recalled heparin in patient care areas still reaching patients.”

Realizing this was a public health crisis, the state pharmacy board took action. “We contacted the FDA, we contacted the hospital association in California, we contacted the California Department of Public Health, which regulates hospitals. And then we ourselves went through all 533 licensed hospital pharmacies.”

The pharmacy board’s 22 pharmacist inspectors inspected every pharmacy. The board sent out notices. The Department of Health even sent an all-facilities letter, which Herold described as “a really serious letter,” ordering the hospitals to find any recalled heparin and get it out of the supply. And the Board of Pharmacy alerted hospitals about it at “every speaking gig we did,” she said.

“In the end, we located recalled heparin in 94 of the 533 hospital pharmacies, 18 percent, sometimes as long as three months after the last recall,” Herold said. “It shows a complete failure of the recall system in California, and I suspect California wasn’t the only state where this occurred.”

By pulling patient records, the state’s Department of Public Health determined that 7,000 patients had received recalled heparin after the recall, she said.

What Caused The Problem

Herold attributed the failure to a combination of issues.

There were five heparin recalls in a short period of time from various manufacturers for various reasons, three of them unrelated to the economically motivated heparin adulteration issue. Hospital staff would get confused, thinking they were receiving additional notices about recalls they had already addressed. One of the recallers changed names from Tyco to Covidien during its recall, further confusing the situation.

The recall notices identified product by the manufacturer’s lot number, but invoices did not. “Wholesalers don’t track by lot number, they don’t sell by lot number. Pharmacies don’t buy by lot number, they don’t track lot number,” Herold said.

There was no way to tell where hospitals, particularly the large ones, were storing heparin. In some cases, recall notices went to the offsite warehouses where some hospitals receive drugs, and never actually made it to the pharmacy. Often, recall notices went to hospitals in totes with drug products, and never made it to pharmacy directors.

“We found one of the problems with recall notices themselves was the use of the term ‘voluntary’ on it,” Herold said. “Pharmacists thought voluntary meant ‘we don’t have to pull this out, it’s voluntary. It’s not a mandatory recall.’”

The ubiquity of heparin in hospitals was a big issue. “It’s stacked everywhere all over the hospital. It was stuck in Pyxis (automated dispensing) machines, in drawers, in pockets, God only knows where my staff found it. Although they were only in any given hospital fewer than two hours, we were able to find these drugs.”

There were also mix-ups with returns. “Some pharmacies returned the heparin to the wholesalers as a quarantined drug, which is what you do with a recall frequently,” Herold said. “Unfortunately, in three cases, we were able to document that recalled heparin ended up being reshipped to other customers because the wholesaler didn’t identify it as recalled.”

What California Did About It

The board of pharmacy cited and fined the pharmacies and the pharmacists in charge, Herold said.

“We also created a statutory change in our law to require all licensed sites in California to be part of our email list so that we can immediately send a notice to you.”

In a series of meetings with hospital stakeholders, the board developed a set of best practices, which it published in January 2010 in its “Addressing Drug and Device Recalls in Hospitals” report.

Herold added that “there’s not a hospital pharmacist in California that I believe was deliberately not pulling that recalled heparin out of the supply. They truly didn’t realize it was still there. Otherwise we would have treated it a little differently.”

[Editor's note: this story was excerpted from "The Gold Sheet," which provides in-depth coverage of drug manufacturing policies and quality control. For information, contact customer care at 800-332-2181.]