Recently, the Government Accountability Office published a report entitled, “Food and Drug Administration: Better Coordination Could Enhance Efforts to Address Economic Adulteration and Protect Public Health.”

The report describes economic adulteration as follows:

“Economic adulteration is not a new problem and ranges from simple actions, such as adding material to increase a product’s weight, to more sophisticated substitutions or additions that are designed to avoid detection by tests known to be used to authenticate ingredients or products. Economic adulteration differs from other forms of intentional adulteration, such as bioterrorism or sabotage, whose primary purpose is to cause harm.”

Once again, the heparin scandal, the poster child for the vulnerability of the U.S. drug supply, is cited in the report as a prime example of economic adulteration. In 2007-2008, heparin was discovered to contain over-sulfated chondroitin sulfate, a toxic contaminant that mimics heparin. The contamination was evidently economically motivated, and was linked to a number of serious allergic reactions and deaths in the U.S.

Economic adulteration is distinguishable from unintentional violations of current Good Manufacturing Practices, which can also cause a drug to be adulterated. For example, we have seen cases where drugs have been mislabeled, made too strong or too weak, or contaminated with microorganisms, but those problems were a result of poor manufacturing practices, not intentional adulteration with an economic motive. (See, e.g., GlaxoSmithKline statement about its failure to follow cGMP.)

According to the new GAO report, FDA officials and stakeholders cited two main challenges to addressing economic adulteration. The first:

“Globalization has led to an increase in the variety, complexity, and volume of imported food and drugs, which complicates FDA’s task of ensuring their safety. In addition to globalization, an increase in supply chain complexity—the growth in the networks of handlers, suppliers, and middlemen—also complicates FDA’s task.”

This is not the first time globalization has been identified as a problem, but it is a reminder for Congress and the Administration of the challenges facing FDA.

The second problem identified in the report was lack of information from industry. Here, there are two main issues. First, because companies regularly test ingredients from suppliers, they have information on potential adulterations that would be useful to the FDA. However, industry is reluctant to share that information when it does not have to (such as when an adulterated ingredient has entered into commerce) because of fears of exposing themselves to litigation for accusing a supplier of intentionally adulterating products if their findings turn out to be erroneous. Second, FDA would benefit if industry would share more information about what substances might be used to adulterate products. Companies develop tests to monitor products they receive from their suppliers but often are reluctant to share the information with the government because it is proprietary.

These accounts in the report highlight the necessity of involving industry in any solutions to our drug supply safety problems. Fortunately, we have seen a lot of industry support for improving the safety of the drug supply (including the generic industry’s recent agreement with the FDA to pay user fees), and hope the collaborations can continue to improve, as both industry and government will succeed only if they keep the consumer and patient’s safety as the highest priority. But in order to combat economic adulteration (and other forms of drug contamination) and protect the food and drug supply of the U.S., the FDA needs to have the tools and resources necessary to deal with these 21st century concerns.

Additional coverage of the report is available at:

• Pharmalot
• FDA Law Blog
• In-Pharma Technologist

– Anna Dunbar-Hester, Policy Analyst

Late yesterday, thirty advocacy organizations, representing seniors, labor, providers, patient safety advocates, cancer patients, and consumers joined Community Catalyst in calling for Congressional action to improve the safety of drug manufacturing.  In letters to the Senate HELP and House Energy and Commerce committees, groups urged Congress to make safe drug manufacturing legislation a priority by including new patient safeguards “in the upcoming reauthorization of the Prescription Drug User Fee Authorization Act (PDUFA).” 

Signed by advocacy groups from across the nation and in districts of some key Energy and Commerce committee members, the letters warns that the many recent drug recalls, failed inspections, and manufacturing quality breakdowns by both brand-name and generic manufacturers are likely just “the tip of the iceberg” because most manufacturing problems at overseas facilities go unseen.

The high profile manufacturing problems by Johnson and Johnson, GlaxoSmithKline, and other facilities were discovered primarily by FDA visits to the 2,500 domestic drug manufacturing plants, which are inspected once every two and a half years.  But the number of foreign drug manufacturers has doubled in the last seven years, encompassing approximately 3,800 foreign manufacturers in more than 150 countries.  

This rapid globalization of overseas drug manufacturing has far outstripped the FDA’s capacity to inspect these new facilities, which today are the source of 40 percent of finished drug products taken in the U.S., and 80 percent of active drug ingredients and bulk chemicals used to make drugs domestically.  According to the GAO, under current resources, the FDA can inspect these 3,800 foreign sites only once every nine years.

The letters show that these risks are real, serious, and potentially lethal for vulnerable patients. For instance, the intentional contamination of heparin tragically led to numerous deaths and hundreds of adverse reactions amongst the hundreds of thousands of dialysis or post-operative patients treated with Heparin each year.

We also noted how these risks are not floating under the radar, but are widely known by industry leaders. A 2010 poll of pharmaceutical executives identified “raw materials imported from outside the U.S. as the greatest vulnerability” to the purity and integrity of drug products in the next five years. But progress has been made. Our letter commends how the generic drug industry has “stepped up to the plate” by “agreeing to fund inspections with user fees….” See here and here.

Reform is also widely supported by voters from across the political spectrum. In fact “81 percent of Republicans, 87 percent of Independents, and 97 percent of Democrats support increased FDA authority to issue recalls, destroy contaminated products upon import, and inspect foreign manufacturers” according to a recent poll.

The letter asks Congress to provide FDA with new authority to adequately protect US patients from the increasing risks of counterfeit drugs, a leading black-market enterprise around the world. This would include the ability to issue a recall, or to destroy contaminated, expired, or unsafely manufactured drug products that are seized at the border.

Yesterday, Rep. Michael Burgess, vice chairman of the House Energy and Commerce Subcommittee on Health, announced that reforms to end drug shortages would be included in legislation to renew the system of collecting fees from drug-makers in order to fund FDA review of new drug products. We support efforts to eliminate drug shortages, and improvements to drug manufacturing quality would certainly help. According to the FDA, manufacturing problems were the cause of over half of the drug shortages in 2010. And these problems can be quite serious, with sterile drugs found to be contaminated with “glass shards, metal filings, and fungal or other contamination” according to an FDA report last month. 

Thanks to our partners who joined us in calling for increased safety of drug manufacturing: 

Action for Boston Community Development (ABCD)
AFSCME
Alliance for Retired Americans
Breast Cancer Action
California Alliance for Retired Americans (CARA)
Center for Medical Consumers
Community Catalyst
Connecticut Center for Patient Safety
Consumers Union
Families USA
Florida CHAIN
Health Law Advocates of Louisiana, Inc.
Illinois Public Interest Research Group (Illinois PIRG)
Medicare Rights Center
Mississippi Human Services Coalition
Missouri Alliance for Retired Americans
National Education Association (NEA)
National Labor Alliance of Health Care Coalitions
National Physicians Alliance
National Research Center for Women & Families / Cancer Prevention and Treatment Fund.
National Women’s Health Network
New Hampshire Alliance for Retired Americans
North Carolina Justice Center’s Health Access Coalition
Ohio Alliance for Retired Americans
Pennsylvania Public Interest Research Group (PennPIRG)
TeamstersCare  – Teamsters Union 25 Health Services & Insurance Plan
Texas Alliance for Retired Americans
UHCAN Ohio
USAction
USPirg
Vermont Public Interest Research Group (VPIRG)

In less than a month, the FDA will convene a scientific panel to evaluate emerging evidence that some of the most commonly used contraceptives – Beyaz,Gianvi, Loryna, Ocella, Safyral, Syeda, Yasmin, Yaz, Zarah, — have greater risks than other similar products. Patients and their advocates are seeking court permission to have drugmaker’s internal studies released so that FDA can see the full picture.

These drugs all contain the hormone drospirenone, while other contraceptives use a different active ingredient — progestin levonorgestrel. The FDA reports that “all birth control pills pose a risk of blood clots” but a recent British Medical Journal (BMJ) study found that contraceptives containing drospirenone were “associated with a threefold higher risk of non-fatal [deep vein blood clots]” compared to women who do not use hormonal contraception, and twice the risk of competing drugs using a hormone other than drospirenone.

On December 8, an FDA panel will likely look at the body of evidence concerning this BMJ study, and other studies listed on the FDA website. This review might tip the scales enough to add warnings to the drug’s label. Yet it remains to be seen if FDA will see all the documents it should before making a decision.

About 10,000 patients who took Yaz or Yasmin are suing the drug’s manufacturer Bayer for failing to disclose an increased risk of blood clots, and their lawyers have asked the court’s permission to submit to the FDA hearing approximately 50 documents unearthed in that litigation. The lawyers describe these documents as “internal and candid memoranda of clinical trial data and adverse event data not [before] shared with the FDA [by Bayer]”, according to a brief filed in one lawsuit.

Many readers may recall that documents concerning the safety and illegal marketing of the drug Zyprexa, the widely used antipsychotic drug, were released a couple years ago, both by a doctor retained as an expert witness, and later by the Court. This information was invaluable in alerting the public to the increased risks of death when Zyprexa is used to treat vulnerable seniors suffering from dementia. Following the pattern we saw with the pain drug, Vioxx, in 2004 and the diabetes drug, Avandia, in 2010, the Zyprexa documents showed that in the interest of maintaining the sales of their block-buster drugs, drugmakers withheld critical information from the FDA and the public — causing the deaths of tens of thousands of patients, while leaving tens of millions at risk.

The hearing on December 8 is less than a month away. We hope FDA will make sure it sees any studies that Bayer’s scientists and expert consultants did concerning the risks of drospirenone before making a decision on how to best protect the public health.

And there’s a potential conflict-of-interest issue as well. Lawyers for the injured women are concerned that some of the 13 scientific experts on the FDA panel have financial relationships with Bayer. Under the FDA rules, members of scientific advisory panels must disclose their conflicts to the FDA, and must receive a waiver in order to participate. The advisory panel could recommend that the FDA add warnings to the labels, implement other safety protocols, or even to withdraw them from the market—it should be free of industry influence.

The FDA needs complete information to do a good job, and the public needs to know who ultimately participates or votes on the FDA panel to be sure we can trust their final decision. Every day women are barraged with slick TV ads for Yaz and other contraceptives. We deserve more than marketing buzz – we need an unbiased, transparent and scientific evaluation of the drugs that makes sure women are not knowingly put risk.

(Hat tip to Pharmalot)

– Wells Wilkinson, Project Director Prescription Access and Litigation &
Marcia Hams, Director, Prescription Access and Quality

‪Pressure’s building on the Office of Management and Budget to give a status update after Nature blog reported earlier this week that OMB may have tossed a rule proposed by NIH last year that would tighten conflict of interest reporting rules for biomedical researchers and institutions. Yesterday, Sen. Charles Grassley wrote to the Administration asking for documents related to the decision, and saying to rollback the rule “flies in the face” of its own transparency promise (hat tip Pharmalot).‬

‪In the spirit of disclosure, we supported the NIH rule in public comments with the Pew Prescription Project last year, and defended it here when university associations took aim at it late last summer. Despite progress among academic medical centers in tightening individual conflict policies, many AMCs still do not publicly disclose faculty ties to drug companies, and schools and investigators are left making the call if and what to report.

Meanwhile, media reports and industry-based disclosures like the Propublica ‘Dollars for Docs’ database show that millions of dollars are still moving from drug company to doctors’ hands. When those doctors are also doing tax-payer funded research that guides clinical practice and prescribing, we think the NIH–and the public–should know.‬

‪I talked to Dr. Sidney Wolfe of Public Citizen yesterday about the rule, the flap around conflict of interest at FDA, and just how hard it is to find an unconflicted expert around here.‬

‪‪PS: Many academic medical centers have strengthened or implemented better disclosure policies recently. And we have the Physician Payments Sunshine Act coming down the line. So why was this NIH rule needed? Where does its rollback leave us?‬‬

‪SW: Just think about the Dollars for Docs. Before a website like that (which only has data from the eight companies that currently disclose) you needed to go to each of the eight companies’ websites, instead of being able to get all of the information on a  specific doctor at one place. Instead of having to write to every academic medical center, [the NIH rule] would put it in a user-friendly place subject to analysis.  ‬

‪And academic medicine revolted against it. They don’t want this, they don’t want medical students to easily out find what’s going on. Because if you are a med student, you may have a different view of your instructor who’s positive toward a therapy if you find out he or she is getting a considerable amount of money from the company who makes it.‬

‪There’s little doubt as to why the academy pushed against this rule. They don’t want people to believe members of their faculty have a bias. Of course, many still have to disclose it, but now it requires leafing through papers, or waiting for a FOIA request.‬

‪PS: What happened? Is this about budget woes, or pressure from industry and the universities?‬

‪SW: Nothing has happened yet.  But from what [Nature reporter] Meredith Wadman reported, it certainly pushes away from what should have been now been finalized.‬

‪No one is disputing there is a big glitch in this process. I doubt whether out of a clear blue sky, [OMB's] Cass Sunstein says, ‬Oh, that is not a good idea‪. I assume he read the letters, and he may be just more ideologically attune to academic medicine and those trying to fend off what was originally proposed by the government 15 months ago.‬

‪PS: Conflict of interest rules at FDA are also in the news after Commissioner Hamburg said at a Public Citizen meeting this week said that limiting financial conflicts has made it hard to fill advisory boards. But Health News Review and Project on Government Oversight offer lists of independent experts, and say the rule is not to blame.  Is this a real problem? ‬

‪SW: There’s no doubt that it’s more difficult to find someone without a conflict, but it’s obviously very important to do so, because these decisions are best made by people who don’t have a conflict of interest. The advisory committee I serve on, the Drug Safety and Risk Management Advisory Committee, had some empty slots, but the slots have all been filled now.

I don’t think there have been any committees that have not met because of unfilled slots.  One could argue that having tougher conflict laws and missing two or three people on a committee actually makes the decision-making better. This decision-making is too important to be polluted with a conflict of interest. ‬

‪There are two questions, and it’s not clear which Commissioner Hamburg was referring to.‬

‪Question A: Does someone get put on a committee or not?‬

and Question B is: Even if they are on a committee, should this person be recused from a given meeting? Someone with a conflict can also be given a “waiver,” but this happens much less than it used to six, eight, 10 years ago. ‬

‪PS: NIH has rules around advisors’ conflicts, too. To be an NIH reviewer, one must receive less than $10,000 from an involved company per year, as I understand it. Do you know if NIH has similar vacancies, or problems finding unconflicted experts? ‬

‪SW: NIH reviewers pretty much have a final say, whereas we are just advisors to the FDA. I doubt seriously that NIH will tell you that they have a very difficult time finding enough reviewers. And if it’s a little more difficult, remember, the whole purpose is to be as unfettered as possible. So it’s worth the extra effort.‬

interviewed by Kate Petersen, PostScript blogger

Industry user fees are one of the few ways to raise revenue it seems we haven’t heard much about over the past few weeks, as Congress has become engulfed in the debt ceiling debate. But they’re nevertheless a critical piece in funding the FDA’s system to review and approve new drugs, and may also be a key in helping the agency to meet the rapidly increasing challenges of protecting U.S. consumers from safety gaps in overseas manufacturing of drugs and medical devices.

That’s the focus of a Senate HELP committee hearing tomorrow, and the FDA Commissioner Dr. Margaret Hamburg will be there to testify. Hamburg has put these challenges out front in a recent report and public remarks (including at Public Citizen on Monday), and tomorrow’s hearing offers her an important opportunity to discuss what it will take—in resources, authorities and partnerships—for the agency to get from here to there. One industry group, the generic drug trade organization, has already publicly come out in favor of user fees to support better FDA oversight of suppliers.

Here are some questions we think the Senators should consider asking Hamburg:

Pew’s After Heparin report and the FDA’s “Global Pathway” report both pointed again to the fact that companies that make drugs in the U.S. are inspected every 2-3 years, while those that manufacture in foreign facilities only get inspected once every 9 years.

• Shouldn’t we be ensuring that foreign drug manufacturers which operate in many countries with loose regulation have to meet the same standards as U.S. companies?
• Is weak regulation helping to foster outsourcing of U.S. drug manufacturing?
• If manufacturers continue to outsource, is increasing the level of foreign inspections one way to level that playing field? How else?’

The FDA’s report acknowledged that it is a domestically calibrated agency that in the last decade has been asked to monitor a rapidly and overwhelmingly outsourced industry – 80 percent of drug ingredients are now made abroad in countries like India and China.

• Does the law governing the FDA’s mandates and authorities—the Food Drug and Cosmetic Act—match the current challenges created by the complexity of our global drug supply?
• Does the law allow the FDA to adequately monitor and keep safe such an outsourced industry?   If not, what kind of consensus is there around what to do?

Drug counterfeits and thefts can be lucrative for criminals. Stories like the one out of Texas last year, when stolen insulin reached patients after possible mishandling, or when recalled Heparin was found in dozens of California hospitals months after the recall, suggests we sorely need a uniform way to track our drugs as they make their way through the complex chain between manufacturer to patient. And right now, we don’t have one.

• Do you believe we need such a tracing system, and what is FDA’s role in developing one?
• Does the FDA need additional authorities or a statutory mandate to ensure drug traceability becomes a reality?

–Kate Petersen, PostScript blogger

The shipment of your birthday present from distribution to delivery can be tracked. A sticker in the grocery store tells you where your pineapple was grown. A tag in your t-shirt says where it was made. Your new car lists where its component parts are from, and where it was assembled. But if you rely on anything from Tylenol to cancer treatment, you have less information about where those drugs came from and what path they took to get to you.

That’s just one startling fact in a new report released today by the Pew Health Group. After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs echoes the FDA’s recent call to overhaul the system that monitors imported drugs, and puts forward a number of recommendations to close those safety gaps.

“Consumers should be alarmed by the increasingly complex, globalized, and outsourced drug supply chain described in the After Heparin white paper,” Robert Restuccia of Community Catalyst said in a statement. Community Catalyst has teamed with Pew to advocate for many of the recommendations in the report, and leads the broad-based Alliance for a Safe Drug Supply.

“After Heparin shows that outsourcing is growing and is a business strategy for all types of prescription and over-the-counter drug producers,” he said. “As one major brand-name drug maker put it: ‘If we can buy it cheaper than we can make it then of course that’s what we’re going to do.’

And indeed, the numbers bear that out.  When it comes to drugs, the U.S. import deficit on pharmaceuticals grew to $18 billion in 2008, and it is estimated that 80 percent of pharmaceutical ingredients and 40 percent of all finished drugs in the U.S. now come from overseas.

As we’ve written about here in recent weeks and months, there’s been surprisingly broad consensus from industry, regulators and the public that the system in place to monitor these imports is broken down and in urgent need of fixing. Last year, 94 percent of pharmaceutical executives surveyed said using foreign-made raw materials was risky.  And in a different poll, the same percentage of likely voters wanted FDA to be able to recall unsafe or adulterated drugs, as it can for food. Only Congress can give the agency that power.

At the Pew After Heparin conference in Washington D.C. in March, which informed today’s report, we heard that everyone should be inspected by somebody—and that companies should be fully accountable for checking out factories and quality conditions prior to contracting with a supplier.  We heard that in this fractured supply chain, industry actors needs to work with each other and with regulators to share information they may receive on potentially dangerous or counterfeited drugs, and that a uniform tracking system to help verify a drug’s path from factory to pharmacy is sorely needed, but will most likely require the force of law to achieve.

Recently, we talked with pharmaceutical expert Prabir Basu about the importance of investing in good manufacturing science – both on the design side, and ensuring that the tests used to detect false or substandard medications are state of the art.

We talked with California Board of Pharmacy Director Virginia Herold, who illustrated the importance of having a national tracking system for drugs that enter our homes and hospitals.

We heard from API manufacturer Brant Zell, who said the FDA has had its hands tied for years when it comes to fulfilling its mission to ensure the safety of foreign-made drugs. Zell said he thought that the heparin crisis in 2008 would be the straw that broke the camel’s back, and moved Congress to act. To date, that’s not been the case.

We’ve seen the FDA go before Congress to ask for the authorities and tools to do a better job of ensuring the quality and safety of drugs before they get to U.S. shores, and keeping ones that don’t meet quality standards out and off the shelves.  So far, Congress has yet to act on those requests.

At a hearing last week, some in Congress again pledged to take action and pass a law that would guide the building of these industry quality rules and give the FDA the authorities it needs to oversee a terribly complex and global supply chain. Today’s report reminds us that there are enough gaps in the supply chain to exploit and economic incentives to do so that the clock is surely running on another heparin-like crisis. The time to act is now.

You can read the full report or watch a webcast of the March conference here.

–Kate Petersen, PostScript blogger

Virginia Herold is the executive officer of the California State Board of Pharmacy. In her role there, Herold works closely with and advises the 13 Board of Pharmacy members in the development of policy and in the administration of the board’s enforcement, licensing and regulatory programs to further the board’s consumer protection mandate. The Board regulates over 130,000 licensees in 13 separate regulatory programs including pharmacists, pharmacies and drug wholesalers.

Herold talked at the Pew Health Group After Heparin conference in March about finding recalled heparin in California hospitals during the 2008 heparin crisis and how the state has moved to prevent future safety failures. I caught up with her again last week to talk about how recalled drugs get back into the drug supply, why counterfeits can be so hard to track down, and how we might begin to fix the system.

PS: Your talk at the After Heparin conference in March showed a recall system that is really broken – nearly 8,000 patients in California were exposed to heparin after the recalls began. How did such a broken system become the standard, and how do we start to fix it?

VH: I’m not certain what the solution is. However, we do know wholesalers and pharmacies do not track drugs by lot number or expiration date, which is how manufacturers issue recalls. The manufacturer will release the lot number and expiration date—info that isn’t really available to the wholesaler and pharmacist except by a visual check. That is very difficult given the large number of drugs moving through the pharmaceutical supply chain, and especially considering number of recalls we’re having now.

Secondly, the distribution systems are relatively complex, especially in a hospital setting. Some drugs are in the pharmacy. Some are outside the hospital pharmacy on the floor in carts. Some are on Pyxis machines.

A perfect example of the complexity of a recall call is [last week’s] recall of Tylenol, which is an over-the-counter product, but the recall complexity is similar.  Right now, some of those products are in transit — in boxes, crates or pallets on trucks. Two days from now when those trucks unload those drugs, unless they are caught on the other end, may not be pulled as part of the recall (because the recall occurred Wednesday, and the receiver of the drugs missed the search review that happened Wednesday or figures the recalled drug product would not have been shipped.)

And we’ve learned that even when recalled drugs are returned to the wholesalers as part of the recall, they may be inadvertently placed back into active stock and then reshipped to new pharmacies.  We saw three instances of this with the heparin recall, where a batch of the returned drug isn’t quarantined, and then, because it is still part of active stock, the recalled product was shipped to another hospital.

Another problem is the use of the world “voluntary” on a manufacturer’s recall notice.   The manufacturing companies initiate these recalls, sometimes after the FDA finds a problem and asks them to recall a drug, more often on their own.  If a problem appears and the manufacturer doesn’t act, the FDA can take action, but it rarely does this.

Typically the manufacturer “voluntarily” recalls the drug from the supply chain. Recalling a drug is perhaps the most sensitive thing companies will do. And so recall notices are carefully worded, and often use the word voluntary.  But when that recall notice lands on the pharmacist’s desk, he or she doesn’t always recognize that it doesn’t mean voluntary on the part of the pharmacy to take action. It means the pharmacy should take action to remove it, and not dispense it to patients.

I think we need to recognize upfront that the recall system needs to be in the hands of the FDA as the regulator.   You don’t want every state to set up its own separate system. Drug distribution is national, it needs a national solution.

PS: There’s been a lot of talk in the last week or so about drug shortages and FDA’s role in them. How do shortages figure into this equation?

VH: Sometimes the recall of a drug could cause a shortage of a drug for practitioners and patients.  Other times a shortage may be due to other factors.  One issue here is an ethical question: what if a recalled drug is the only drug appropriate for treatment and there is no other substitute drug available?  If the removal of the drug from the market is done for a health care reason, and it’s a necessary drug, is it better to have a contaminated drug, or no drug at all? Should the recalled drug be provided in such circumstances, and what type of consent should occur if this is the only lifesaving solution?

How do you decide? Should there be some consent form for patients facing a severe condition and their providers that says: this drug has been recalled but there are not other options available? These questions are way out of my pay grade–the FDA should be deciding that.

The FDA’s in a tough spot, too. They are expected to keep the drug supply safe, but with all the manufacturing of drug products and ingredients off-shore, they don’t have the resources to inspect everything worldwide.  If you are the patient that needs a drug or a treatment, you want anything that’s available anywhere in the world that will help you. But in the U.S., the FDA has to approve the drug before it is sold.

PS: In the case of heparin, I understand FDA asked Baxter to wait on a full recall until enough alternative supply could be procured.  How do you think about potentially contaminated drugs that may have still been in circulation?

VH: In April or May 2008, we somehow heard that 50 percent of the total heparin products were unavailable due to the multiple recalls. Actually, we discovered recalled heparin still in California hospitals after the recalls because we were beginning to have concerns about the shortage of this drug.

In late March 2008, a pharmacy director told me they had received a fax in the pharmacy offering heparin at $130 for an amount they used to pay $8 for. Such offers concern us as regulators, because it immediately connects – we probably have unlicensed activity and possibly counterfeit or diverted drugs.  If the licensed wholesalers cannot obtain a drug, where is this supplier getting the drug?

So we started off by inspecting 40 hospitals.  We thought we were going to find counterfeit heparin in the hospitals and unlicensed sales to hospitals. Instead, we found recalled heparin in 40 percent of them. We never even got around to searching for counterfeit drugs because we were so concerned about the recalled supply still in hospitals, and a climbing death count nationwide from exposure to it.

PS: As I understand it, right now pharmacies and distributors don’t have to tell the FDA when they suspect a drug has been stolen or adulterated.

VH: In California, if someone has knowledge of, or reason to believe a drug has been adulterated or counterfeited, they are required to report that to the Board of Pharmacy.

PS: And at the Board, are you required to tell the FDA?

VH: I am not aware of a specific law requiring this, but by practice we tell the FDA everything of such a nature that we find. They have bigger field of vision — and if it’s happening in California, there’s a pretty good chance it’s not just in California.

In terms of counterfeit prescription drugs, we have had some rare problems here stumbling upon a couple of counterfeit drugs.  It is hard to detect a counterfeit drug. There’s nothing in a pharmacy that shines for us with neon light saying:” This is a counterfeit, come over here!”   In some cases, a patient will stop responding to a medication. Usually when that occurs, no one even suspects the efficacy of the drug itself.  More typically the therapy is no longer working, switch to a new one.

Right now California, like the rest of the nation, has a problem with prescription drug abuse.  This means there is high demand for certain types of prescription drugs, which leads to drug diversion from the supply chain.

And the economy is bad.  So some of our licensees may get offered a great deal on a drug from someone they don’t normally do business with.  Nobody stops to think ‘Why am I getting this good deal?’

People trust the drug supply in the U.S.  But when drugs are bought and enter the supply chain by any of the supply-chain partners through unauthorized means, it’s hard for the other partners to identify this.  It is like buying that TV out in the Wal-Mart parking lot: It’s a good deal! But we need to ask why it is a good deal.

PS: How does California’s e-pedigree law fit in?

VH: We believe that this will greatly aid all supply chain partners in ensuring the visibility and lineage of where a particular drug container has been: who has owned it at every step, back to the manufacturer.  The system requires a certification of each sale and purchase down to the pharmacy level that will make it harder to introduce drugs at any transaction in the pharmaceutical supply chain.  This information will be available by reading a code on the container.  There is a need to review information readily, and in a certified way, that holds everyone accountable. A weak link in the supply chain undoes all the security, compliance and care that’s been used by other supply chain partners.

We don’t want the quality of the drug supply in the U.S.  to come into question the way it has in some other countries.  The U.S. still has a strong secure drug system, but we see some faults in it, and we are working to plug these.

The public doesn’t need to be afraid or overly suspicious of their drug supply—they just need to be a bit cautious.  And to beware of Internet drug buys where you can obtain drugs without a prescription or from an unlicensed pharmacy.  A great deal of counterfeit medication is obtained this way.

–interview by Kate Petersen, PostScript blogger

Ohio Senator Sherrod Brown says he’s disturbed that 80 percent of active pharmaceutical ingredients in U.S. drugs are foreign-made, saying that has allowed drug companies to “skirt existing regulations” and “outsource drug safety standards.”

“Drug company profits cannot come at the expense of consumer safety,” Brown said. He framed his concern around three constituents who died after taking contaminated Heparin imported from China in 2008. The attention on the practical implications of FDA’s ability to protect American patients and consumers is laudable, especially in the midst of anti-regulation fervor on the Hill.

Responding yesterday to the FDA’s recent report on import safety, Brown issued a series of serious follow-up questions and recommendations.

Some of the recommendations, such as exploring import fees to make up the cost difference between domestic and foreign inspections, were discussed at the Pew Health Group’s After Heparin conference in March, a forum where regulators, industry and policymakers gathered to discuss a forthcoming set of recommendations on global drug safety. Brown asks FDA Commissioner Margaret Hamburg her thoughts on import and facility fees, as well as assessing penalties to companies responsible for recalled, counterfeit, or substandard drugs.

Some of Brown’s other suggestions, such as giving FDA authority to deny product entrance to any company that’s turned away inspectors, exist in a House bill introduced earlier this year, the Drug Safety Enhancement Act. (More on the DSEA here!)

We’re glad to see a Congressperson taking up the FDA’s new report so quickly and thoroughly. Brown’s questions to the agency are good ones, and it’s worth highlighting some of them here.

• What steps can your agency take to ensure that key exporters are not only included in the coalitions, but also abide by the resulting comparability and information sharing standards?
• How often are FDA inspectors denied access to foreign pharmaceutical or API facilities either by the company or government officials?
• Does your agency have the authority to refuse entry into the United States of pharmaceutical products or APIs from foreign entities if the FDA has been denied access to manufacturing facilities? If it does not have such authority, is further legislation necessary?
• What role do import refusals from China – and other countries – play in the in the drug shortage crisis in the United States? Specifically, what percentage of drug shortages result from imported refusals as compared to consolidation of pharmaceutical companies, economic decisions of a company to cease production, and problems in manufacturing?
• The report also notes that some countries, including Mexico and Costa Rica, consider the FDA seal of approval equivalent to approval from their respective oversight agencies.  What countries does the FDA believe have stringent enough regulations to be equivalent to FDA-approval?
• Which APIs or pharmaceutical products are at the greatest risk for adulteration or counterfeiting?
• Are the pharmaceutical companies that manufacture these products or utilize these APIs aware of these risks and what oversight activities do these companies perform themselves at contracted facilities?
• The report states that the FDA may be unable to fully and completely share data across the coalition due to legal restrictions.  What restrictions are currently in place and what sort of legislative change is necessary to facilitate the FDA’s exchange of information with foreign counterparts?

Read the FiercePharma story or Brown’s full statement here.

–Kate Petersen, PostScript blogger

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