We are shocked and distressed to learn of the 24 deaths and 328 illnesses caused by the meningitis-contaminated painkiller injections produced in a Massachusetts compounding pharmacy, the New England Compounding Center (NECC). Our thoughts are with the families of those patients and the 14,000 more who are waiting to learn if they were infected by their medical treatment. While the news continues to develop, we are still waiting to fully understand what went wrong, what the company should have done to prevent this, and what are the state and federal agencies with oversight responsibilities.

This tragedy reinforces our commitment to ensuring that all people have a right to trust the safety and purity of the medicines they take. As we have learned from advocating for the major drug manufacturing safety legislation passed this year by Congress, the pharmaceutical supply chain is extremely complicated. Now everyone is recognizing that compounding pharmacies are an important, additional link in that chain.

Weaknesses in the global supply chain became painfully apparent in 2007-2008 through another tragedy, when dozens of U.S. patients suffered adverse effects and some died after receiving heparin, a blood-thinner used in dialysis treatments that had been contaminated during its manufacturing in China. Many things contributed to that failure in the supply chain, including the increasingly globalized nature of pharmaceutical manufacturing and insufficient FDA resources and authority to manage it. For example, 80 percent of Active Pharmaceutical Ingredients used in drugs sold in the U.S. are produced overseas. And for a long time, the FDA has not had the resources to inspect all of these suppliers and finished manufacturing operations. Domestic plants were being inspected approximately once every two years, but foreign plants averaged once every nine years, and some were never inspected.

Fortunately, this summer, with broad support from advocates and many in industry, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) to address the problems that contributed to the heparin situation. FDASIA requires companies to implement robust “Good Manufacturing Processes,” other controls and transparency throughout the supply chain, from the raw materials to the finished products. It requires manufacturer and importer registration and risk-based inspections in both domestic and foreign plants, which should increase the frequency in foreign plants. There are new user fees for generic companies to support increased inspections, with a goal of parity between U.S. and foreign inspection rates. And there is much stronger enforcement and higher fines. While FDASIA has some weaknesses—FDA still does not have mandatory recall authority, a minimum schedule of inspections at all plants or protections for whistleblowers—the law is a huge step forward in ensuring safety of the drugs produced by registered manufacturers.

But compounding pharmacies like NECC appear to fall outside of FDASIA. They are licensed only to prepare specialized or modified drugs for individual patients with an individual prescription. Massachusetts has now ruled that NECC violated its license by selling in bulk, by acting as a typical manufacturer. For years NECC has carried out sophisticated marketing operations throughout the country, leading to big production increases and to the unfolding tragedy today. Yet compounding pharmacies have lobbied for a decade to avoid stronger regulation and as a result even more patients were potentially affected by their practices.

Ironically, compounding pharmacies have been helping to fill the gaps when drug shortages occur—and many of these shortages are a result of problems at domestic and overseas conventional drug manufacturers that have had to temporarily close plants or production lines. This is another sign FDASIA was long overdue, since company quality control systems and FDA regulation have not kept pace with the brave new world of globalized drug manufacturing. Small scale compounding pharmacies can legitimately help fill such gaps for the benefit of individual patients, although they too should be required to have strong quality assurance systems in place.

At this time there are many efforts being undertaken by state and federal lawmakers and regulators to identify precisely what legal authority currently exists for regulating compounding pharmacies and what additional oversight and resources are needed to ensure the safety of compounded drugs. We support the efforts of Congress, the FDA, state boards of pharmacy, pharmacy retailers, drug manufacturers, and other patient advocates in finding solutions to ensure the supply chain is strong and that Americans can again trust the medicine they rely on.

 – Anna Dunbar-Hester, Policy Analyst &
Marcia Hams, Prescription Access and Quality Program Director

This blog was also posted on Health Policy Hub.

Drug safety is now as American as apple pie, based on the 96-1 vote the Senate took to reauthorize the Prescription Drug User Fee Act (PDUFA). Few things pass through Congress with such overwhelming support, and we are heartened that Senators came together to pass this “must-pass” legislation.

Millions of Americans rely on medications every day, from people with chronic illness, to seniors, to anyone who takes a pill for allergies or a headache. As a member of the Alliance for a Safe Drug Supply, Community Catalyst has advocated for solutions to this critical issue. Assuming the House will also pass similar legislation and we’ll have a new law soon, one piece of the complicated health care puzzle will have been made safer. How do you spell relief? P-D-U-F-A.

Truly, the bill marks a momentous occasion for consumers. Today, roughly 80 percent of ingredients used in U.S. medicines are made overseas, and there has been a historic disparity between the number of inspections conducted at U.S.-based plants and foreign plants. Under the new bill, the fees paid by name-brand and generic drug manufacturers will allow more frequent inspection of foreign manufacturing sites that produce drugs imported into the United States, addressing a critical gap in supply chain safety. As Pharmalot notes, 12.7 percent of capsule makers in China were recently found to be making unsafe capsules. While it is unclear whether those particular capsules were being introduced to the international supply chain, as Ed Silverman so eloquently puts it, “the episode underscores the larger concern that some Chinese companies that are intertwined in the pharmaceutical supply chain operate as if China is a modern-day version of the Wild West.” Of course, there’s also been a drumbeat of recalls and egregious safety problems in U.S. plants—but we only know about them due to more inspections here in the U.S. Now we’ll have parity in foreign inspections, too.

The PDUFA bill also marks the first time the generic drug industry will be contributing to the FDA’s inspection and oversight funds, pitching in nearly $1.6 billion over the next five years. We view this commitment from generic pharmaceutical producers as a notable contribution to ensuring the safety of the effective, affordable generics that we all rely on today.

In addition, the bill requires pharmaceutical companies to track each batch of drug products along the supply chain, from the factory to the pharmacy or hospital. This has been a long-sought after consumer protection, given that “track and trace” systems can be utilized to ensure counterfeit drugs are not introduced into the supply chain. Prescription drug counterfeiting is one of the most lucrative crimes in the world, and the infamous heparin contamination is believed to have been economically-motivated. And although it is relatively rare in the United States, there are far too many instances of intentionally-adulterated or counterfeit medications having breached the supply chain and been consumed by Americans, and we need to put an end to it.

One more piece of good news is the updated system to proactively address drug shortages. According to the Pew Health Group, more than 200 drugs went through periods of shortages in 2011. The bill puts in place an early warning system that manufacturers must inform FDA in advance of discontinuing manufacture of any drug. Hopefully, patients receiving cancer treatment will soon be able to cross one thing off their list of worries.

The bill was not perfect, however. Patients would greatly benefit from the earliest possible access to generic drugs when brand name patents end, so we were disappointed that the “pay-for-delay” amendment was defeated. Additionally, there are grave concerns about medical device safety, and we are disappointed that the Senate did not authorize medical device user fees to be used to evaluate the safety of devices in the market, despite the many recalls of dangerous devices in the past few years.

While there is room for improvement, we applaud the FDA, the Senate, and drug manufacturing companies for working together to pass this legislation, and eagerly await the House to follow suit.

 – Anna Dunbar-Hester, Program Coordinator and Policy Analyst

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 October, the FDA and manufacturers of finished generic drugs and ingredients (Active Pharmaceutical Ingredients or APIs) reached a ground breaking agreement that can (1) ensure the safety of generic drugs and APIs wherever they are produced globally and (2) ensure that new generic drugs become available to patients more quickly.

The drumbeat of manufacturing safety problems occurring in domestic and foreign plants that produce both brand name and generic pharmaceuticals continues must be addressed. In the last week, FDA has cited generic drug maker Mylan and German manufacturer Jenahexal for manufacturing problems, while Ranbaxy settled longstanding concerns in time to launch their generic version of the block-buster drug Lipitor.

Manufacturing failures can create obstacles to the ongoing availability of affordable generic drugs, or even serious risks to patient safety. Thus this new agreement (the Generic Drug User Fee Act or GDUFA) is critical. Addressing the lag in foreign inspections is especially significant, since 80 percent of active ingredients and bulk chemicals used in U.S. medicines now come from foreign countries. Currently, the FDA does not have the authority or resources to inspect all foreign suppliers of drug ingredients. Domestic plants are inspected by FDA on average every 2.7 years. The New York Times recently reported that at its current pace, the FDA would need 13 years to inspect every foreign drug plant exporting to the United States. 

The draft GDUFA agreement is a major commitment by the industry to solve this problem by “ensuring that industry participants, foreign or domestic, who participate in the U.S. generic drug system are held to consistent high quality standards and are inspected biannually, using a risk-based approach, with foreign and domestic parity.” The industry has backed up this commitment by agreeing to provide $300M annually in user fees to provide FDA with the resources to increase inspections and to speed the review of new generic drugs. The fees would supplement FDA annual funding. 
 
Guaranteeing the availability and safe manufacturing of generics is not only critical to patient safety, but also to access to care and to the financial stability of families, health plans and public programs. Today 78 percent of all prescriptions dispensed in the U.S. are generics. In 2008, the average cost of a generic drug was nearly four times less than the brand name equivalent ($35.22 vs. $137.90). Thus, while 78 percent of prescriptions are generics, the total spending on generics accounts for just 25 percent of the total U.S. drug spending, and generics drugs have saved more than $824B over the last decade.

GDUFA can play a role in solving the problem of drug shortages, as well. Shortages can be catastrophic for patient safety, and often affect generics since they account for 78 percent of prescribed drugs. Stepped up inspections at foreign plants can prevent manufacturing problems that can lead to shortages of medically necessary drugs. Health system pharmacists, who confront these problems every day, point out that “user fees can result in faster approval processes for generic drugs” while not sacrificing  patient safety concerns. 

The FDA-industry draft agreement is now being reviewed by the Office of Management and Budget. When approved, it will be sent to Congress for action, probably to be included in the renewal of the Prescription Drug User Fee Act (PDUFA), which deals with user fees for brand-name drug approvals.

- Marcia Hams, Director of Prescription Access & Quality

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

The buzzword at a Sept. 14 hearing on securing the pharmaceutical supply chain was one not often heard in the current congressional climate: “consensus.” There was general agreement among witnesses that our laws are outdated in a world where the drug supply chain stretches around the globe through a network of suppliers in countries such as India and China.

In 2007 and 2008, the pharmaceutical industry and regulators got a wakeup call when a batch of the blood thinner heparin was adulterated by a Chinese manufacturer, sickening and even killing American patients who took it.

“I believe that adulterated drugs coming into this country is criminal. I think it’s a form of murder,” said Sen. Barbara Mikulski of Maryland. “So we’ve gotta get real, we’ve gotta get serious, and we have to have a sense of urgency.”

The hearing, organized by the Senate Health, Education, Labor and Pensions Committee, is a part of lawmakers’ fact-finding effort for the 2012 reauthorization of legislation on drug user fees.

In testimony, the Generic Pharmaceutical Association supported Health and Human Services Secretary Kathleen Sebelius’ call for congress to update the U.S. Food and Drug Administration’s authorities.

“GPHA is in agreement with the secretary and FDA that it is essential to modernize the laws governing the U.S. supply chain,” Gordon Johnston said. “As noted in my opening remarks, the responsibility of ensuring safety is a shared one that rests with all of us in industry and not just FDA.”

Johnston also referenced the Pew Health Group’s report, After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs:  “As my colleagues at Pew noted in their recent report, it’s also critical that manufacturers continue to go beyond good manufacturing practices and assure that their supplier qualification tools are used as well as a risk based assessment to assure the quality and integrity of suppliers abroad.”

In his testimony, Allan Coukell, director of medical programs at Pew Health Group used a photograph of a factory in squalor to demonstrate the horrible conditions of facilities where some drug ingredients are manufactured.

“A couple of speakers have mentioned the need for manufacturers themselves to ensure supplier quality. That’s crucial,” Coukell said. “Sometimes substandard facilities sell to so-called “show” factories – a high-quality facility that sells product that it did not make itself.”

Coukell quoted a China-based pharmaceutical auditor who said American and European companies are misinformed about the identity of all, or part, of their supply chain more than a third of the time.

Potential solutions discussed included strengthening industry quality management, increasing regulatory oversight, and making sure the FDA has the tools it needs, such as the ability to order the recall of drugs.

Sen. Michael F. Bennet of Colorado noted how the testimony at the hearing reflected the notion that updated policies are a necessity.

“I find remarkable the degree of consensus around a lot of the issues we face,” Bennet said. “The lack of a regulatory regime that reflects reality is bad for our consumers and bad for our business. I think that’s why we need to be urgent in fixing it.”

– Marcia Hams, Community Catalyst, Director of Prescription Access and Quality

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