Originally tasked to inspect food and remedies made and sold in a newly-industrialized America, the FDA said today it will begin to rely on collaboration with other regulators, data-sharing and third-party auditors to safeguard the “global bazaar” of food and drugs that now feeds into U.S. homes each year.

In a report, “Pathway to Global Product Safety and Quality,” the FDA lays out the problem: cost pressures and better transportation technology have led to the move of much food and drug-ingredient production off-shore, while the agency charged with keeping that supply safe remains scaled and funded at a domestic level.

The report delineates a critical new reality: “a U.S. company” doesn’t mean necessarily made in the U.S. (of course, the J&J recall-a-palooza reminds us that U.S. operations are far from immune to manufacture safety risks.).  U.S. import of FDA-regulated products has grown 13 percent per year recently, and about 80 percent of APIs are now made overseas. And this sea change isn’t unique to food and drugs. “Some estimates predict that by the end of 2010, more than 40 percent of the final assembly in the consumer goods and life sciences industries will be performed outside of the producer’s home country, due largely to the lower cost of production,” the report says.

So to meet those radically different demands, U.S. regulators must somehow go global, too, minding significant infrastructure and resource restraints.

The report expands on the four “building blocks” FDA deputy commissioner John Taylor laid out for dealing with import safety at the Pew Health Group’s After Heparin conference in March.

Here’s a topline summary of the four-part tack:

1) Bring together global coalitions of regulators dedicated to building and strengthening the product safety net around the world.

2) Build proactive and real-time data sharing system to help these networks of regulators access important safety and monitoring info across worldwide markets.

3) Modernize its IT systems and risk analytics, and build its expert staffing capacity in those areas.

4) Leverage government, industry, and public-private partnership to expand oversight capacity, including use of third-party auditors.

The FDA called that last one “one of the most fundamental changes that FDA will undertake,” and indeed, developing and verifying systems and checks to make third-party auditors are a comparable and reliable set of eyes and ears will be a sizable challenge.

But this report is thoughtful evidence that FDA understands those challenges well, and the monumental risk of sticking with the sole-guardian approach of the 20th century.

You can read the full report here.

–Kate Petersen, PostScript blogger

At the After Heparin conference in March, Prabir Basu of the National Institute for Pharmaceutical Technology and Education spoke about the slipping security in U.S. pharmaceuticals, and ways we can use science to mitigate the risks that have come with an increasingly off-shore supply chain.

PostScript talked with Basu again recently about the true costs of making drugs overseas, and how Heparin could be an early warning sign of a much larger crisis.

PS: You’ve called the safety and quality problems in overseas drug manufacturing  “health care’s hidden crisis.” Why is that?

PB: Yes. There’s a lot of uncontrolled outsourcing of drug manufacturing, and as we know, the FDA only inspects less than 10 to 15 percent of those plants. And that doesn’t even include excipient suppliers. Being that dependent on sources outside U.S. raises the probability that one day, there could be a crisis many times bigger than Heparin. That could really set us back, and lead to a shortage of drugs in the U.S.

Here’s an analogy: For a long time people were talking about hazards of offshore drilling, but no one really took it seriously or had appreciation for the magnitude of disruption until the Gulf Coast spill. Heparin may just have been an early indication. They’ve found melamine in pet food, diethylene glycol in toothpaste, etc.

This is really the hidden crisis no one is talking about. We don’t even have capacity to manufacture life-saving vaccines in the U.S. anymore. I think pharmaceutical security is as important as defense or energy, but it’s taken a lot less seriously.

PS: How much of this problem is about cost?

PB: Well, manufacturing is about 30 percent of total cost of making a drug. The immediate reaction to lower cost is to outsource. But if we invested in science at the front end, studies have shown we could reduce the cost of manufacturing and save more money than with cheaper labor in foreign countries. Studies done by McKinsey and others have shown we could save $20 – $50 billion each year through improving the science of manufacturing and implementing Quality by Design (QbD).  We’d be in investing in our own country creating jobs and have better regulatory control, since the FDA is really geared toward domestic oversight. The natural question to ask is whether the real saving in outsourcing is coming from cheap labor, or from the savings arising from avoiding FDA inspections.

PS: One of your recommendations at the After Heparin conference was to prohibit import any drugs into the U.S. that had been made in foreign plants not inspected by the FDA.

But the fact that the average foreign plant gets inspected by FDA once every 9 years is now a commonly cited statistic, and the agency has said it doesn’t see any way its inspectorate can get to all plants, even with a huge boost in resources. Now they are considering third-party inspections. Is that an acceptable solution to your mind?

PB: Well, as far as I know, right now if a pharma company wants to start importing an API from a foreign source, it isn’t always obligated to have that plant inspected by FDA. I think we need to change the law, so that APIs, excipients, intermediates or finished drugs cannot be imported without having the source first been inspected by the FDA.

Today we ensure quality by inspection. But we know FDA has trouble getting resources from Congress. Many talented people have been laid off recently in the pharmaceutical industry. It would take very little effort to train these people up. We [NIPTE] could work with the FDA to develop training programs that the agency could use to certify these people to be inspectors under FDA’s supervision.

But we also have to move from quality by inspection, to quality by design.

PS: So what is NIPTE’s aim?

PB:  We believe that one of the ways to fix the quality and safety problem of our pharmaceuticals is to have proper science in place.  In some ways, the pharma industry today could be compared with the auto industry 50 years ago: pretty happy with marketing and outsourcing and not investing in manufacturing science and technology.

And what happened? The auto industry essentially disappeared in this country a couple years ago. And drugs are a critical part of our life – we are very heavily dependent on a daily basis, perhaps more so than on cars.

The science I’m talking about consists of several things: design, manufacturing, how to detect impurities, etc. The [USP] methods are pretty antiquated, actually. There are newer methods and analytical tools–predictive models that relate raw material properties and operational variables to product performance, etc.— but they are not being used to design robust processes, which will have a much lower chance of failure.

PS: But isn’t that more about drug development than problems that happen during manufacture?

PB: Development and manufacturing are extremely interrelated. The Heparin crisis has taught us that there are very, very smart people trying to adulterate our drugs. We cannot lay back: we have to be smarter, think ahead and develop state-of-the-art technologies to anticipate and deal with problems that can occur. We have to have the science and technology to stop adulteration before it happens.

PS: In the scenario you’re describing, the manufacturer incurs savings from minimum regulation and the end user–the consumer–bears the cost.  What can consumers do change the equation?

PB: Well, we need two things: to educate consumers, and to pressure our Congress to change the laws. A new bill is being proposed by Sen. Bennet to improve drug safety. Maybe it doesn’t go far enough, but it’s a good start.

When I look at my shirt, its tag tells me where it was made. Why shouldn’t I have that choice when I buy the most important things—the drugs that keep me alive? There should be labels showing country of origin for drugs, and a database where I as a consumer can go to see where each component is coming from, and better answer: do I feel safe enough to take that drug?

When an average citizen buys a drug from the pharmacy, she trusts the quality of that drug because she knows the FDA is there to ensure it’s safe. That citizen doesn’t know that the plant where an ingredient or final drug was made was never inspected by the FDA. There needs to be more education so that people are better aware of how our drugs sometimes get made in places where there is very little control and FDA supervision.

–Interviewed by Kate Petersen, PostScript blogger

The first Heparin verdict came down today on the side of an Illinois patient who died after being given the contaminated blood thinner in 2007. In the first of nearly 300 pending suits against drugmaker Baxter for its negligent role in the manufacture of Heparin, an Illinois state court jury found Baxter responsible for the death of the 63-year old patient and awarded $625,000 to the man’s estate. (Read the Chicago Tribune story here.)

After a rash of unexplained adverse reactions to Heparin in 2007 and 2008, Baxter recalled the drug and an FDA test discovered a contaminant, over-sulfated chondroitin sulfate, or OSCS. This compound was later linked to hundreds of allergic reactions, including approximately 140 that proved fatal.

Baxter and its ingredient supplier, Scientific Protein Laboratories (SPL), announced in 2008 that the OSCS contaminant was introduced intentionally by their suppliers in China. Financial motives are presumed, because Heparin costs 100 times more to make than OSCS.  In addition, Heparin which is harvested and purified from the intestines of pigs, was even harder to obtain in 2007-08 because a global pig disease epidemic had created an unexpected shortage in China and elsewhere.

The timing was right, and seems the chemistry was, too. The OSCS contaminant was not initially discovered because it mimics some chemical properties of Heparin, suggesting that it was introduced by suppliers in China who possessed the biochemical savvy to fool the standard chemical purity tests then in use by Baxter and the FDA. (The assay test has since been improved by the US Pharmacopeia.)

Congressmen Joe Barton and Michael Burgess, both from Texas, have criticized the FDA and the Chinese government for their poor investigation into the source of the intentional contamination, or adulteration, of Heparin.  The FDA has said that their continuing investigation into the source of this dangerous contaminant has been “severely hampered” by China’s unwillingness to cooperate. (See WSJ article here).

Today’s verdict and the pending cases are tragic and critical reminders of the need for greater FDA resources and authority to regulate today’s global drug supply chain. China imports nearly $1.5 billion in medical products to the U.S. each year, and the FDA itself has acknowledged that another Heparin-like crisis is ‘inevitable’ unless the agency is given new authorities to inspect internationally, and to require manufacturers to follow good manufacturing practices.

Ultimately, today’s verdict is a good result for the victims of contaminated Heparin, and a wake-up call to drug manufacturers.  Consumers of all medicines—prescription and over-the-counter alike—deserve protection from harm, and manufacturers should be held responsible to make sure their products are made safely. Increasing FDA’s authority to ensure the safe manufacturing is in everyone’s best interest.

–Wells Wilkinson, Staff Attorney, Community Catalyst

The FDA is restructuring its Center for Drug Evaluation and Research to do a better job of supply chain security and manufacturing oversight, says an FDA memo from CDER Director Janet Woodcock released this week (hat-tip Pharmalot).

Elevating the current CDER Office of Compliance to a “Super Office” opens up more resources and organizational focus to monitoring manufacturing quality and supply chain problems, the memo says, and creates new capacity under the new branch, housing four offices including the brand new Office of Drug Security, Integrity, and Recalls.

In the memo, Woodcock says the new ODSIR will be “dedicated to addressing the challenges of globalization and an increasingly complex drug supply chain.  ODSIR staff will take the lead in dealing with issues such as supply chain security, counterfeit and diverted drugs, economically motivated adulteration, import operations, and drug recalls.” As Pharmalot puts it, the gist of the new Super Office status means Compliance will conduct more of “its own nerve center operations.”

The shift also suggests the agency may be preparing to exercise greater authorities, perhaps including recall and subpoena powers it has asked Congress for in recent years. Deborah Autor, current director of the Office of Compliance, will serve as acting director of the new expanded Office.

In the end, this is a bureaucratic move, but it does signal responsiveness by the agency to the new global scope and structure of the drug supply, which Deputy Commissioner John Taylor has said demands a serious refit of the way FDA does oversight.

From a practical standpoint, the move makes nuts-and-bolts sense, creating technical capacities and pathways needed to begin to modernize the way the agency monitors drug-making. And as a gesture, it reaffirms FDA’s commitment to the public health and safety aspects of its mission, a concern some FDA scientists raised with the new Administration in 2009.

More org charts? PharmaExec and PharmaTech have ‘em.

–Kate Petersen, PostScript blogger

Good news, with caveats: New enforcement numbers out from FDA and a new searchable inspection database suggest the agency has ramped up its crackdown on unsafe and substandard food and drugs.

The number of warning letters, injunctions and seizures, the agency’s three main enforcement actions, all rose in 2010: warning letters by 42% over 2009, injunctions by 55%, and product seizures by 67% in the same period. (Source: FDA Webview)

Meanwhile, the agency is moving ahead with its transparency project, unveiling a searchable database of inspections which the public can use to view inspection dates, info, and actions taken in both foreign and domestic inspections. Search entries returned don’t link to associated warning letters, which would be useful in linking inspectors’ actions with the problems they found. But a quick tour through the database suggests that the functionality is straightforward, and that here the agency has taken an important step to increase transparency around its enforcement activities, even as those activities have accelerated. It should be commended for that.

So what about these caveats? Well, enforcement volume doesn’t necessarily correlate with things that need enforcing, especially considering the wide swaths of ground FDA is working to cover in the area of foreign inspections (a recent GAO report suggests that foreign drug plants get inspected an average of once every 9 years). But as we’ve observed here before, product recalls continue to trend up on both the food and drug side. And the 2010 numbers are no exception. Being company-generated, those aren’t enforcement actions, per se, and can stand as a rough measuring stick that suggesting the number of safety and quality manufacturing problems out there is still on the rise.

The agency’s move to tighten oversight and sanctions is critical, timely, and sorely needed.  Congress should take note of the agency’s progress and the scope of enforcement work, and make sure FDA has the resources and additional enforcement authorities it’s been seeking to keep pace with the safety and quality problems here and abroad.

–Kate Petersen, PostScript blogger

House Oversight Chair Darrell Issa has been looking into the FDA’s action at a closed Johnson & Johnson medicine plant in Puerto Rico. Three months after the Justice Department took ownership of three troubled J&J plants through a consent decree, Issa is concerned that regulators and the company aren’t working quickly enough to fix the deep quality problems there.

According to Bloomberg, Issa complained that regulators have not reviewed corrective action plans for the plant since the division was taken over in March, and have not visited the site since September.

Remember, that’s before a pretty bruising hearing in late September 2010 at which J&J had few answers about why it carried out a “phantom recall” to pull faulty Motrin from shelves, and the FDA said that it found quality problems in every one of J&J’s plants.

While it’s good that Issa’s subcommittee is keeping an eye on the FDA and the progress of the J&J case, the Energy and Commerce Committee has already identified some of the root problems and drawn up smart, comprehensive solutions—not just to the J&J case, but to the system failures behind some of the company’s problems.

The Drug Safety Enhancement Act (HR 1483), introduced in April, would answer some of Issa’s question by boosting mandatory inspections, and giving the FDA better enforcement tools in the form of recall and subpoena authority.

Issa is right to question the J&J aftermath and be dismayed at the larger problems in our drug safety system. He and his committee members should recognize the DSEA as an important step toward fixing those problems, and make sure this bill has the support it needs to move in Congress.

Read more on the bill at the blog, and a summary of HR 1483 here (pdf).

-Kate Petersen, PostScript blogger

Today a coalition of nine major consumer and physician groups representing millions of Americans asked Members of the House of Representatives to get behind a bill that would give the FDA broader powers and better resources to ensure the safety of the imported drug supply.

The Drug Safety Enhancement Act, HR 1483, was introduced by members of the House Energy and Commerce Committee last month and based on a similar draft circulated last year. The drug safety reforms it proposes have won wide consensus across party lines among the public, who have opened their browser windows (or newspapers) lately to near-weekly drug recalls and huge, systemic quality failures that have put the safety of drugs in every medicine cabinet on the line.

The Drug Safety Enhancement Act would give the FDA recall authority to pull drugs it believes to be risky from market, and the power to stop importation of drugs from plants that fail safety inspections or deny access to FDA inspectors. It would also up inspection resources for FDA to better align foreign and domestic oversight, and update the GMP standards industry is required to maintain to sell drugs in the U.S.

In seeking Congressional co-sponsors, Community Catalyst joined AFSCME, the Alliance for Retired Americans, Consumers Union, Families USA, Medicare Rights Center, National Physicians Alliance, Our Bodies, Ourselves, and U.S. PIRG.

The co-signers cite a 2010 poll of 820 likely U.S. voters that shows the public consensus on this issue, and the need to address it now: 81% of Republicans, 87% of Independents, and 97% of Democrats support increased FDA authority to issue recalls, destroy contaminated products upon import, and inspect foreign manufacturing facilities.

“It is essential that we protect families from contaminated and substandard prescription and over-the-counter medications,” the groups write. “We hope Congress will act this year to close the gaps in our current system for regulating the drug supply chain, gaps which make all consumers vulnerable.”

Read more on the bill here, a summary of HR 1483 here (pdf) and the letter here (also pdf).

–Kate Petersen, PostScript blogger

A year into implementation of their new Good Manufacturing Practice (GMP) guidelines, Chinese authorities have begun an investigation into safety problems of “essential medicines” after a test sample of children’s medication contained twice the allowable amount of mercury.

Today there are more than 4,700 drug manufacturers in China. Of these, nearly 3,000 produce “essential medicines” and will be subject to the investigation by the Chinese FDA (SFDA), which will also look at traditional Chinese remedies. Though the probe is targeted at drugs sold in China, it could turn up manufacturing problems for companies that also import medicines to the U.S. and other countries.

“The two-month examination will look closely at how drugs are produced and where their raw materials are sourced,” the China Daily reported. A report on the findings is expected in June.

Safety problems with Chinese-made drugs that have come into the U.S. have been in the headlines ever since contaminated batches of heparin led to illness and the death of more than 100 American patients in 2007-2008. Last month, a warning letter from the FDA called out an API supplier for falsifying inspection documents and destroying records.

But the new investigation suggests that there are huge domestic failures in China’s drug supply, too. According to the Daily, severe adverse event reports to Chinese were up 16 percent in 2010 from the year before. The new GMP quality measures are designed to bring Chinese manufacturers in line with international standards, and include stricter sterilization requirements, risk management procedures, sanctions and required reporting, audits and adverse event reporting, according to a Gold Sheet story.

But Chinese sites have a 5-year grace period to comply with the 2010 GMP updates, and how the SFDA will staff or enforce the tightened rules is unclear. Regulators in China and abroad must be vigilant in ensuring the process stays on track, and that already-established firewalls keep unsafe and substandard medicines out of both the domestic and international supply chain.

For more on imported drug manufacturing safety, follow SafeRxWatch on Twitter or visit the Pew Prescription Project.

–Kate Petersen, PostScript blogger

Outlining its priorities for the next four years, the FDA asked clearly last week for new authorities and resources to help the agency move to a proactive, preventive model aimed at keeping the global drug supply safe, rather than the border-busting and warning-letter mode it often relies on now.

In a bold and long-vision document that Community Catalyst backed in alliance with major medical, manufacturer and consumer groups, the agency says it will need nothing less than a ‘’paradigm shift” to make the ever-expanding global drug supply safer as it makes its way to American pharmacy shelves and medicine cabinets.

The agency said it needs:

• resources for boosting inspection and testing efforts
• innovative 21st-century compliance and enforcement tools
• a “global alliance of regulators” who share standards and goals for what safe drug manufacture looks like and how to achieve it
• better information systems to collect, track, and manage safety data
• better coordination with standards-setting agencies (such as the USP) and foreign and state regulators.

A new bill before Congress would go a long way to helping the agency get there. The Drug Safety Enhancement Act, introduced earlier this month, would increase resources for inspections and information systems, as well as add muscle to the agency’s enforcement arm with important recall and subpoena authorities to get risky drugs off the market faster and get the information it needs when things do go wrong.

The agency wrote:

The growing challenges of globalization have far outstripped the FDA’s resources for inspection and quality monitoring, and the inability to maintain adequate oversight means potential risk to consumers grows every year. Addressing these challenges will require a paradigm shift — to a focus on prevention, on stopping threats before they ever become reality. The border must be viewed as a final checkpoint for preventive controls, rather than the primary line of defense against unsafe imports.

You can read about our comments of support and our campaign for safer drugs at this earlier post, and watch FDA Deputy Commissioner John Taylor talk about FDA’s five-year plan and priorities at the Pew Health Group’s After Heparin conference in March.

–Kate Petersen, PostScript blogger

Longtime drug safety watchdog Rep. John Dingell and other members of the powerful Energy and Commerce Committee today introduced a new version of the comprehensive Drug Safety Enhancement Act, which would strengthen the FDA and close critical gaps in the safety of the U.S drug supply.

A drug safety hearing of the E&C Subcommittee on Oversight and Investigations tomorrow will provide an early opportunity to look at the ways this new bill addresses some of the complex risks that spring from an increasingly fractured and global drug supply chain.

Brought by Rep. Dingell, Ranking Member Henry Waxman, Health Subcommittee Ranking Member Frank Pallone, and Oversight Subcommittee Ranking Member Diana DeGette, the Drug Safety Enhancement Act, comes less than a month after the agency told industry, consumers and policymakers at the After Heparin conference that it needed to make bold updates and obtain new regulatory tools to keep pace with the expansion of the drug supply. The bill reflects past agency priorities and recommendations, as well.

According to a Committee statement, the bill:

• gives the FDA important new enforcement tools it’s been asking for, including recall and subpoena authority
• boosts inspections by generating funds for GMP inspections and requiring parity between inspections of US and foreign drug-making plants and suppliers
• builds a higher barrier between unsafe drugs and US medicine cabinets, prohibiting drugs from sites that cannot prove or have refused, failed, or falsified inspection from entering the country
• improves tracking by establishing a registry and unique ID numbers of all drug facilities and parties supplying the US, both foreign and domestic

“A few years ago, thousands of American lives were jeopardized by contaminated heparin stock imported from China,” said Rep. DeGette in a statement. “As pharmaceuticals and their ingredients are increasingly imported from the global marketplace, we must ensure our families can trust the medicines they rely upon by empowering the FDA.”

“We must address the deficiencies uncovered by recent recalls,” said Rep. Dingell. “The Drug Safety Enhancement Act is a strong and effective response to the troubles we face with an increasingly global and complex drug supply.  I look forward to working with my colleagues on both sides of the aisle, consumer advocates, and the regulated industry to ensure we address the safety of the nation’s drug supply in a meaningful way.”

For updates on drug safety legislation and news, follow SafeRxWatch on Twitter.

For summaries of previous drug safety legislation, a consumer survey on drug safety, and other resources, visit Community Catalyst and Pew Prescription Project’s Securing a Safe Drug Supply.

–Kate Petersen, PostScript blogger