Physician and blogger Roy Poses from Health Care Renewal posted a good question on PostScript ahead of the After Heparin convening, and despite the delay (apologies!), it seems worthwhile addressing here.

About the convening he wrote:

I am glad someone is putting on a conference on this topic, but am surprised that the roster of presenters is so dominated by industry. Shouldn’t there be more representation of health care professionals and consumers/ patients? Shouldn’t there be some representation of experts in ethics and law enforcement?

There’s no question, industry was a big presence around the table, but as we pointed out here, it hardly drowned out other significant voices; those of federal and state regulators, consumers, law enforcement, and independent academics and standards-makers. In fact, nearly all parties commented on what a broad range of key interests were represented.

Three representatives from national consumer groups—Community Catalyst, Consumers Union, AARP—joined the roundtable both days, and drove home the importance of better securing the drug supply for patients, whose health is their reason for being in business, and whose health it is that’s put at risk by safety gaps in the drug supply.

“As a consumer rep, I still look to the FDA,” said AARP’s Ahaviah Glaser. “But it’s got to be group accountability.”

The Pew Prescription Project itself, which convened the After Heparin roundtable, prioritizes consumer interests—its mission is to “promote consumer safety through reforms in the approval, manufacture and marketing of prescription drugs” and to conduct nonpartisan research around those issues.

The American College of Physicians was at the table, as well. I think Poses is right that prescribers and other health care providers need to speak up on this issue, as they are some of the most powerful voices able to articulate what’s at stake when they can’t guarantee the complete safety of medicines–one of the main instruments of their practice.

“If we can’t trust where our drugs are coming from, that’s so fundamental,” said Cleveland Clinic cardiologist and attendee Harry Lever. “If my patient isn’t doing well, the first thing I think about now is: maybe it’s a drug.”

In fact, the convening was remarkable for the degree of consensus forged that the system needs to change in bold ways, and fast, because public health is at risk.

And this common call for group accountability made it critical that representatives from points all along the supply chain—from raw chemical makers to the pharmacists—were there, engaged in the conversation about making our medicines safer. And that’s why, from my seat in blogger alley, After Heparin was such a positive step forward.

Change, like the products they make and sell, must originate with members of the supply chain–in the factories and audits and warehouses and ultimately the board rooms–though the conversation made it clear, too, that members of industry cannot make these fixes without a strong regulatory hand.

Yet sustaining improvements in the system will depend on them too.  So their willingness to get in the conversation with regulators, consumers and policymakers in a public way, and to agree that the drug supply risks are big and require cooperation to address, was no small thing.

And I think all that invites, rather than precludes, more patient and provider involvement and voice.

–Kate Petersen, PostScript blogger

Major chemical-makers have told FDA they’ll chip in to make sure foreign ingredient factories get inspected, and in the Capitol such a cooperative spirit to tighten up security and oversight in the prescription and over-the-counter drug supply is growing.

Last week the White House named 20 anti-counterfeiting measures it urges Congress to take, many of which are geared toward to counterfeit or knowingly contaminated medicines. And within the last week several House and Senate committees have pledged to further investigate ways to prevent fake, unsafe and substandard drugs from getting into US pharmacies and medicine cabinets.

Among the White House proposals are:

• Require importers and manufacturers to notify the FDA and other relevant agencies when they discover counterfeit drugs, including the known potential health risks;
• Adopt a track-and-trace system for pharmaceuticals and related products;
• Provide civil and criminal forfeiture under the Federal Food, Drug and Cosmetic Act (FFDCA), particularly for counterfeit drug offenses;
• Increase the statutory maximum for drug offenses under the FFDCA, particularly for counterfeit drug offenses; and
• Recommend that the U.S. Sentencing Commission increase the Guideline range for intellectual property offenses that risk death and serious bodily injury, and for those offenses involving counterfeit drugs (even when those offenses do not present that risk).

It’s key that the White House and Congress are talking about drug safety as an issue of national security, for it undoubtedly is: Ensuring that the nation’s drugs are made in sanitary facilities with materials that have been vetted and verified for safety and quality is an issue of both public health and economic security.

At the ‘After Heparin’ conference last week, regulators and legislators agreed that big overhauls are required to catch the safety system up with the pace of overseas manufacture and supply. The FDA laid out a global supply chain security plan that moves the agency toward more frequent coordinated inspections, information-sharing, targeted intelligence and overseas partnerships. And Sen. Michael Bennet pledged to expand his bill drug safety bill and secure bipartisan backing for it.

Congress is right to be vigilant and active on these issues, Thomas Kubic of the Pharmaceutical Security Institute wrote this week in an op-ed in The Hill, since theft and other breaches in the supply chain ultimately leave patients at risk :

[T]he second any drug leaves the carefully controlled and policed supply chain, it becomes nearly impossible for anyone to know where it’s been stored, how it’s been handled and whether or not it’s become contaminated. And this presents a health risk to anybody who takes any type of medicine.

All this means that the United States cannot let its guard down when it comes to securing the drug supply here at home…Even in a divided political environment, it’s a commonsense public safety step everyone should be able to support.

–Kate Petersen, PostScript blogger

In a sort of Capitol call-and-response, the powerful Senate Judiciary Committee pledged to take up legislation to combat counterfeit medicines as Sen. Michael Bennet pledged to expand his own bill, the Drug Safety and Accountability Act, and seek bipartisan support for it.

“Having a safe drug supply is not a Democratic or Republican issue. It’s an issue of national security and consumer safety,” Sen. Bennet said today to the After Heparin conference sponsored by the Pew Health Group.

What about drug companies that hire overseas suppliers in plants they’ve never inspected or even seen? Pew’s Allan Coukell asked (see yesterday’s post). Sen. Bennet’s bill would look to address that, he said. “The notion you could buy from suppliers without knowing who they are is shocking to people,” the Senator said, “and should be shocking to people.”

Shocking didn’t stop there. It seems we are indeed in the “Upton Sinclair period of the world,” as the US Pharmacopeia’s Roger Williams described. In California, 7,000 hospital patients were exposed to heparin after the recalls began three years ago, said panelist Virginia Herold, head of the California Board of Pharmacy. Only 18 percent of California hospitals had pulled the recalled blood thinner three months after the first recall. Telling stories of Chaucerian color—discovering counterfeits accidentally through medication errors, different-colored pills in the same bottle—Herold made a compelling argument for the first-in-nation e-pedigree law California is working to implement now, the national need for one, and better enforcement of existing monitoring systems.

Herold’s own ‘after heparin’ story also illustrated the potential dangers the current industry-led drug recall poses to the public. Both Sen. Bennet’s  bill and several others introduced last year in the House would give the FDA mandatory recall authority, which the agency has requested publicly in the past.

If yesterday’s convening generated deep agreement that the safety and quality systems that guard the US drug supply are in need of a major revamp, today’s sessions brought a different consensus: the problem of falsified and counterfeit drugs in the legitimate US drug supply is big, and has real if uncountable effects on clinical care.

It’s the economy, stupid
When it comes to why the faked and adulterated meds problem is so widespread, it seems the old maxim is true: Counterfeiters can thrive in a multi-billion dollar global market in which many cannot afford the retail price of their medicine, in which a cheaply-made talcum tab can be sold for $40 a pill, in which enforcement is irregular and lax and penalties relatively modest. And drug shortages and market interruptions are particularly ripe opportunities for such criminals to infiltrate the legitimate supply chain.

Accounting for why people seek medicines outside the traditional brick-and-mortar pharmacy model is fundamental to figuring out how to curtail counterfeiting and breaches in the legitimate drug supply, said Roger Bate of the American Enterprise Institute. “If we don’t address that people are buying from overseas, we can’t make it safer.”

Bate and Coukell said defining terms is important. Counterfeit, defined as a violation of patent and private rights, is not the same counterfeit at the center of these safety talks: any substandard, adulterated drug that violates or compromises the public health. In parts of the developing world, Coukell said, there’s concern that safety can be used as a stalking horse for intellectual property rights and may get in the way of access to life-saving medicines.

Four post solution
Proposed solutions for keeping counterfeits and substandard drugs out of US medicine cabinets clustered around four main ideas:

-Bring transparency and accountability in the supply chain, chiefly by a uniform electronic tracking system that would ID the drug and provide an unforgeable trail from supplier to pharmacy shelf (see here for more).

-Help public make good decisions. Inasmuch as we can know about the quality and safety of distributor sources, educating the public about where to get their medicines—or where to avoid getting them—is key. As Bate and others pointed out, this is made challenging by widespread use of online pharmacies and drug sellers despite U.S. re-importation laws. Panelists agreed there’s big quality disparity between the worst and best overseas factory, and the worst and best distributors, but not on how to communicate that to a public driven primarily by price.

-Coordination is key. From e-pedigree proposals, to counterfeit enforcement operations, to communicating recalls, coordination is essential, the experts said.

–More robust enforcement and stiffer civil and criminal penalties are needed to find bad actors and then hold them accountable.

Urgent Care
Many panelists expressed a common urgency that we find a way to stanch the flow of bad and substandard drugs into the U.S, and there was wide consensus that a national and uniform prescription drug tracking system is needed. But the wherefore and when’s—including the need for a federal statute, the road to implementation, and the cost outlay—are still questions.

From a systems perspective, pedigree is paramount, but former Florida drug inspector Cesar Arias said that it is also critical at a case-by-case level for investigations and needs to be implemented nationwide. “Without it, we have nothing.”

Those representing drug stores and small distributors said a level playing field was crucial and raised concerns about implementation cost and time frames of electronic tracking laws. But the when-not-if ingredients for another heparin crisis are all here, and require quicker action, many said.

“It’s really time now for some significant action, on pedigrees, and on other steps,” said Carmen Catizone, Executive Director of the National Association of the Boards of Pharmacy “They were needed yesterday, and they’re needed today.” Catizone compared it to the barcode that prevents stolen or illegitimate retail items from being returned to another store. “We need to give the same value we put on apparels and CD on the drugs we take to save our lives.”

So what’s it going to take? National Coalition of Pharmaceutical Distributors Karen Moody said to get track-and-trace adopted, federal law is needed: “If there isn’t a mandate, it ain’t gonna happen.” Rx-360’s Martin VanTrieste agreed that federal law is needed to get an e-pedigree system going: “We need a 800-pound gorilla in the room, and that’s the federal government.”

But until that happens, After Heparin showed there is much that can and must be done. “We should not make the perfect the enemy of the good,” Arias said. “We need to use the tools we have to do the job and protect the public.”

Find archived webcasts and more about After Heparin at Pew Prescription Project and Community Catalyst.

Want to read something shorter about drug safety? Try us at Twitter: @SafeRxWatch.

–Kate Petersen, PostScript blogger

In his keynote address to the “After Heparin” convening today, FDA Principal Deputy Commissioner John Taylor said the agency has not made enough progress in transforming its oversight system, but that bills before the last Congress—the Bennet and Dingell bills–could help accelerate that process.

He also laid out a global strategy plan to revamp its monitoring system that would rely more on third-party inspections, improved risk-based intelligence, data-sharing and cooperation with partners in the public and private sectors.

Taylor brought big numbers to illustrate the big gap between the domestic nature of FDA’s founding mission and the new global realities. There are 300,000+ FDA-regulated products coming into the U.S. from 150 countries. By 2008, Taylor said, the U.S. import imbalance on pharma products had increased 10-fold, to $18 billion.

The impressive range of stakeholders around the table today – from chemical manufacturers to consumers representing the patient who takes her medicine – covered a lot of ground and came to some important consensuses around needed policy reforms to close the gaps. Here are some major themes:

Info-sharing/collaboration
One common refrain from Taylor’s keynote to the closing remarks was the need to share information strategically on safety and monitoring systems. Martin VanTrieste, head of Rx-360, a non-profit industry audit-sharing organization, promoted the efficiencies his group has gained in sharing audit info and planning group audits, which offer the potential for more in-depth visits and cuts down on redundancy.

Falsifying drugs is a perfect crime, said Guy Villax, board member of the European Fine Chemicals group and CEO of Hovione, and he proposes to tackle it with info-sharing databases like the one the European Medicines Agency has developed.

Inspectorama
Inspections remain an important piece of the overall quality picture, though everyone agreed there aren’t enough resources to inspect anywhere close to all the sites that make raw materials and substances that go into U.S. drugs. The 2010 GAO update and last night’s 60 Minutes (and the PostScript archives) all have those numbers.

FDA’s Deb Autor said that gaining parity between domestic and foreign inspections are just not feasible, and in some cases, the every two years required for domestic sites would be excessive, even wasteful. But Marcia Hams of Community Catalyst reminded the group that it’s partly that very level of inspection that allowed regulators to find and monitor the flagrant quality problems at Johnson and Johnson’s three domestic factories—and to eventually take them over.

Who’s gonna pay for this?
There was, predictably, less consensus about how to pay for inspections. Though all agree that cost-savings is the major driver in the shift of supply and manufacture to emerging markets, Prabir Basu of the National Institute of Pharmaceutical Technology and Education, said that cost savings is directly linked to the low- or un-regulated climates of those markets, and can’t be accounted for by labor costs alone. But it’s unclear that the greater risk that comes with industry savings is being matched with a willingness to spend on safety and quality systems.

One solution discussed was a user fee that would go toward inspections; right now user fees go to pay for approval. But Mylan President Heather Bresch said that a user-fee system should be holistic – that is, it should support bringing safe, quality products to market and then ensure their safety once they’re on the shelves.

Cheating to the test
The culprits responsible for the adulterated heparin linked to the American death developed a molecule that fooled up more than a dozen different country’s and companies’ tests, including the US Pharmacopeia, which now has an updated heparin assay. USP’s CEO Roger Williams said that a thoughtful updated test is a critical factor in assuring safety and quality, and called for legislative support for such standards.

But physical audits are absolutely key, said Philippe Andre, a China-based auditor whose photos bore that out. Andre and Brant Zell, past chair of the Bulk Pharmaceuticals Task Force, both underscored that when it comes to working with overseas suppliers, knowing what you’re getting ahead of time is critical. Andre said he’s surprised by how many companies contract with suppliers in China without ever visiting the plant. And Zell pointed out the importance of companies doing proactive physical audits. “If you just test, you don’t get all the answers,” he said. “Quality’s built-in, and if you visit, you get an idea about how things are being done.”

National Security Rx
Drug safety is, at its core, a national security issue. An industry in which bad actors are economically motivated and able to infiltrate the legitimate supply chain with a relatively low risk of penalty is ripe for exploitation, and in this way, heparin is a shadow of the bioterrorism threats that captivated the nation a decade ago and caution for the bigger crises inevitable if the system goes unfixed. Attendee Laurie Garrett from Council on Foreign Relations pointed out that one of the lesser-hyped documents in the Wikileaks case was a State Department memo listing of overseas sites of national security interest to the U.S.: more than 30 percent were drug, vaccine and biological manufacturing sites.

Nearly all the parties around the table agreed that the safety gaps in the pharma supply pose a great and growing threat to public health, and that incremental scale-ups won’t solve the sort or scope of risks that the new globalized drug supply chain pose.

This has got to be a paradigm shift. And we fail to make it at the patient’s peril.

“We just need to figure this out, we just need to step it up,” said AARP’s Ahaviah Glaser. “As a consumer rep, I still look to the FDA, but it’s got to be group accountability.”

“If we can’t trust where our drugs are coming from, that’s so fundamental,” said Cleveland Clinic cardiologist Harry Lever. “If my patient isn’t doing well, the first thing I think about now is: maybe it’s a drug.”

Allan Coukell of the Pew Health Group, which hosted the convening, said he was encouraged by the caliber of the discussion: Significant common ground was gained, wide agreement forged on some policy reform proposals, and all with very little finger-pointing.

Hams asked FDA’s Taylor how he saw the role of the consumer: How do we engage the people taking the medicines around safety, and communicate the need to be both vigilant and compliant?

To a degree it’s good, Taylor said, when consumers take the FDA for granted. When their aspirin is safe, and works, then the agency is behind-the-scenes and doing its job. But he agreed of the need to figure out how to engage the public: “We’re going have to explain why we think these changes are necessary…in a way that actually affords consumers an extra level of confidence that the world is changing,” and that the rules must change to meet it.

“We can’t take for granted that folks know that [this] world is changing.”

Tune in tomorrow for Day Two, and follow @SafeRxWatch on Twitter for short, live tweets from tomorrow’s sessions.

–Kate Petersen, PostScript blogger

Can current safeguards in our medicine supply prevent another heparin crisis, and how do we confront quality problems so extensive that the government must seize factories because of the risk to public health? On Monday and Tuesday Mar. 14-15, the Pew Health Group will bring together members of industry, policymakers, regulators and consumers to tackle these and other key questions about overseas drug manufacture, distribution and safety.

“After Heparin” comes at a critical moment. Since adulterated batches of the blood-thinner heparin from China were linked to more than 100 American deaths in 2007 and 2008, a spike in drug recalls and manufacturing violations signal breakdowns in internal quality and oversight systems. Just yesterday, the FDA took over three Johnson & Johnson plants after endemic quality problems that led to near-weekly recalls went unfixed.

The FDA and Justice Department’s seizure, known as a consent decree, “is a strong, but necessary, step to ensure that the products manufactured by this company meet federal standards for quality, safety and purity,” Director of FDA’s Office of Compliance Deborah Autor told CNN. Autor will speak Monday at the “After Heparin” conference.

And on this Sunday’s 60 Minutes (7 ET on CBS Mar. 13), Dr. Sanjay Gupta will look at the problem and proliferation of counterfeit medicines, and how they can make their way back into the legitimate U.S. drug supply. (Here’s a preview). Experts believe the cost-incentive of using adulterated materials was a driving factor in the tainted heparin from China.

As the number of raw materials and ingredient suppliers in low-cost economies mushrooms, knowing where our drugs come from has gotten harder to determine. Eighty percent of all ingredients in medicines brought into the U.S. are now made overseas, and though FDA foreign inspections have increased, an inspectorate designed for a much smaller domestic market has not been able to keep pace.  Congress has proposed legislative solutions to address these safety gaps, and Americans—nine of ten—overwhelmingly support such fixes.

FDA acting Deputy Commissioner John Taylor and U.S. Senator Michael Bennet from Colorado will deliver keynote addresses at “After Heparin,” and roundtables made up of major industry associations, consumer groups – including Community Catalyst – regulators and scientists will look at the major questions and potential policy solutions around quality systems, inspections, and counterfeit detection and deterrence.

For a conference agenda and more information, visit the Pew conference page.

Check back at PostScript Monday and Tuesday for conference exclusives, watch the live webcast here starting Monday at 8:30 am Eastern, and follow SafeRxWatch on Twitter for live updates from the conference.

–Kate Petersen, PostScript blogger

Despite a heightened awareness of the need for transparency of financial relationships in clinical medicine and research, a new review of meta-analyses in JAMA found that among a sample of high-impact publications, very few of the reviews acknowledged industry-backing of the source trials.

According to the review, only two of 29 of the meta-analyses selected from recent editions of influential journals identified industry-backed trials as such, even though nearly two-thirds of the trials with declared funding sources were sponsored by drug companies.

A considerable body of research suggests that industry-backed trials tend to portray the drug more positively, favor the drug over placebo, and downplay side effects more often than in non-industry trials (see the JAMA bibliography). This 2006 BMJ article found industry support tended to lower the rigor of meta-analyses.  It seems, then, a matter of some import to have an understanding of trials’ funding sources, both in their original publication and when they are aggregated in reviews.

Of course, blame for this dearth of financial disclosure doesn’t rest solely with the reviewers of the trials – the lack of standard documentation of industry funding and relationships in trials published in major medical journals is a complex and compound problem. For instance, among the Randomized Control Trials (RCT) included in the 29 meta-analyses, only a quarter included financial disclosures for authors, and only two-thirds listed sources of trial backing. In such a landscape, then, it’s tricky–if not impossible–for a meta-analysis to accurately or completely describe the shape and scope of the funding behind the findings.

The researchers call for a standard policy:

The results of the present study highlight a major gap in the reporting of COIs and suggest that, without a formal reporting policy, COIs from RCTs are unlikely to be reported when results are synthesized in meta-analyses. The PRISMA statement should be updated to require authors of meta-analyses to report funding sources of included RCTs or report that funding sources were not disclosed.

There’s much agreement that transparency of potential COIs is important in clinical care and prescriber settings. But progress toward transparency in the clinic may be diluted, if not undermined, without a more unanimous foundation of disclosure in the medical literature, which serves to set the therapeutic standards and practice guidelines used there.

–Kate Petersen, PostScript blogger

More than half of all domestic drug manufacturing plants inspected by the FDA failed inspection last year, a new analysis by Bloomberg revealed. Looking at almost 10,000 inspection records from the last 10 years, the report shows that inspection failures jumped 20 percent from 2007 to 2010, and 80 companies failed more than half of their inspections in that timeframe, according to Pharmalot’s account.

Though the failure rate wasn’t broken down by quality indicators, the trend is worrisome. These domestic sites are being inspected at a rate of .9 times per year; plants overseas are only getting checked out by FDA once every three.

Meanwhile, Roger Bate of the American Enterprise Institute looked at samples manufactured in a series of emerging economies and found that drug compounds manufactured in Africa had the most variability, followed by China, Vietnam and other emerging markets. A higher variability can signal drug quality problems. In a statement, Bate said that loopholes in regulation of these emerging markets make the difference in quality among producers hard to determine.

“China is an unusual country—they have some good producers and some shoddy producers. Some of those problem suppliers have to do with the fact that in China you don’t have to be registered as a drug producer in order to sell your chemicals or compounds—instead, you can register as raw chemical producer and the regulations are less strict,” Bate said.

But drug pedigree today, said PhRMA spokesperson Mark Grayson, is not as clear cut as borders. “Saying something is made somewhere is no guarantee that it is made there. For instance, a country produces some raw chemicals for a compound, then ships it to Ireland, and they might combine five more ingredients there and stamp it ‘Made in Ireland.’ Then it could be shipped somewhere else,’ Grayson said. ‘The end result is that even though [the label on] a drug says it was made somewhere, the component parts are made all over the world.”

For more on the safety of the drug supply, visit Community Catalyst and the Pew Prescription Project.

–Kate Petersen, PostScript blogger