The FDA has banned imports from a factory run by Indian drugmaker Aurobindo following an inspection there in December. The ban on products from the company’s Cephalosporin facility near Hyderabad echoes an import ban on Claris Lifesciences in November after fungal contamination of IV medications made in India went unaddressed. Products from several Ranbaxy factories in India are also still under import bans after widespread manufacturing violations three years ago.

In January, Aurobindo sold its active pharmaceutical ingredients (API) division to a Chinese manufacturer, Sinopharm. China’s drug industry has been in the news in recent weeks as Congress opens an investigation into the heparin crisis that three years ago was linked to more than a hundred American deaths.

Import bans are critical to preventing drugs with suspected or known safety problems from entering the country. However, earlier action is vital as well, since such extreme and sudden blocks in the supply chain can also contribute to problematic drug shortages in hospital and other acute-care settings. To prevent such disruptions, we need to ensure that manufacturers are held accountable for Good Manufacturing Processes (GMP) through audits and sanctions. And FDA needs the authority and resources to inspect foreign plants frequently, instead of the current sometimes-to-never schedule.

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

–Kate Petersen, PostScript blogger

The House Energy and Commerce Committee is opening an investigation into the heparin crisis, in which contaminated batches of the blood thinner from China were linked to more than 100 American deaths in 2007-2008. The committee, which has trained its eye on heparin and global drug safety in the past, has asked the FDA for help identifying and pursuing those responsible for the contaminant.

According to the Wall Street Journal, the lawmakers wrote that those responsible for the adulterated heparin “pose a continuing threat to pharmaceutical products imported to the U.S.” Just last week, an FDA official involved in the ongoing heparin investigation said that the agency found contaminated batches of heparin from China as far back as 2000 and 2001.

Speaking at the American Association for the Advancement of Science meeting last week, Center for Drug Evaluation and Research official Ali Al-Hakim suggested that those involved in substituting oversulfated chondroitin sulfate, the toxic raw material found in the contaminated Chinese heparin, were likely highly educated, as the formulation of the false ingredients was finely calibrated to pass assays. He also said that updates to the U.S. Pharmacopeia and new “end-testing” requirements mean that heparin coming into the U.S. today is much safer than that in the batches that sickened patients.

According to FDANews, Al-Hakim told the audience “FDA has also moved into inspecting more of the ‘crude’ phase of production in China,” something he indicated is a daunting undertaking. Sending one inspector for one week to countries such as China or India costs $20,000 to $25,000.” And at current rates of inspection, some Chinese and foreign plants producing materials for drugs in the U.S. may never be inspected, according to a Pew Prescription Project fact sheet on the safety of the U.S. drug supply.

When inspections do occur, FDA inspectors have sometimes been denied entry, Al-Hakim said, and with such infrequent visits, it’s hard to establish that observed conditions are continuous ones. “But we need their drugs. That is a problem.” Current estimates suggest that 80 percent of the U.S. supply of heparin originates in China. In fact, estimates suggest 80 percent of active or bulk ingredients in prescription drugs that make their way to U.S. medicine cabinets originate overseas.

“The number of drug products made at non-U.S. sites has doubled in the past decade. The FDA’s ability to ensure the quality at these sites has not,” Pew’s Allan Coukell told the Journal.

Recent bills introduced in Congress would provide more resources for amping up inspections, establish systems to streamline data on a drug’s origin and manufacture path, and increase industry’s accountability for all ingredients in the supply chain. As we’ve discussed here recently, the FDA has been very vocal about the need to better protect the safety of the global drug supply, and is exploring both legislative and internationally cooperative solutions. The recent findings in the heparin investigation remind us that the stakes remain high.

–Kate Petersen, PostScript blogger

The FDA may look to outsource inspections of foreign drug manufacturing and supply plants, the agency’s acting deputy commissioner said at an industry forum last week. The resource-strapped agency has been focusing on how to execute its oversight duties in an increasingly global and fragmented supply chain.

“We recognize that third-party inspection programs need to be a bigger part of the discussion because we can’t do all the work ourselves,” Acting Deputy Commissioner John Taylor said, according to Bloomberg reports. “We’re looking at anything, anything and everything that will allow us to leverage our resources better.”

It’s good that FDA is looking at creative ways to close gaps that exist in oversight. Recent GAO reports show that thousands of foreign plants that make raw materials and APIs for American prescription and over-the-counter drugs go uninspected each year.  In a post-heparin world, the infamous stat—that a foreign drug plant gets inspected by FDA on average every 9 years, compared with an average of 30 months for domestic plants—looms large.

Here are some questions worth asking as FDA explores this idea:

• Who will pay for third party inspections?
• How will third party inspectors be certified?
• What level of recognition will these inspections receive from the agency?
• What other strategies can FDA use to leverage resources?
• To what extent can or should the agency recognize inspections by foreign regulators?

But why agree to third-party inspections when you can just wait for the FDA (and wait, and wait?) A similar system in place for medical devices now suggests the waiting game may be preferred among companies, but that could change if legislation creates new industry fees to support FDA inspections, or if inspection were tied to permission to import.

There’s been a good deal of legislative action on these issues in recent Congresses and we hope for and expect strong solutions that help close oversight gaps will be brought to the table in this one.

–Kate Petersen, PostScript blogger

Those who happen to use public radio as an alarm clock know it’s a bleak week. Proposed cuts to federal funding of public radio being talked about in the House’s FY 2011 budget have unleashed a frantic country-wide pledge drive. (Health care wise, bleak ideas include Medicare voucherization, $1.3 billion in cuts to community health centers and axing the national health service core.)

And on Tuesday, the President laid out his budget, and tucked in to page 119 among the good (ie terminating “SLAMRAAM” short-range missile defense procurement, or doing more teleconferences and flying less), the bad, and the ugly (cutting low-income heating assistance) is a little Valentine for those interested in keeping prescription drug costs down and access up.

The Administration’s budget would prohibit pay-for-delay settlements, legal agreements in which brand name drug companies pay off generic companies to keep market exclusivity that have little real or purported benefit for consumers (or anyone but shareholders). [Check out this blog for more.] The President estimates $8.7 billion in savings over the next 10 years, more than the CBO’s estimated savings (~$2.7 billion) but less than the FTC’s prediction (~$12 billion).

The President’s proposal would also shorten the exclusivity period for biologics from 12 years to 7, making way for biogenerics to enter the market more quickly and saving an estimated $2.34 billion over the next 10 years.

Why are these steps important to a common-sense plan to reduce health care costs? Well, for one thing, this country has a prescription drug cost problem. A Commonwealth Fund report last year found the U.S spent $234 billion per year on drugs, and significantly more per person than other high income nations (30 percent more than Canada in 2005). But it’s not just that we’re paying too much; this cost issue means that many people can’t get adequate access to the drugs they need; according to the Commonwealth report, nearly a quarter of Americans skipped or split pills because they could not afford their medicines.  Of course, they are not the whole picture: much of the cost of prescription drugs is tied to the Medicare drug benefit, which the affordable care act sought to fix, and it remains to be seen what will happen there during the budget negotiations.

But in addition, these exclusivity tactics, if they don’t harm innovation, don’t seem to have helped it. Keeping competitors out of the market and in court with pay-for-deal may be a good strategy profit-wise, but it has not necessarily boosted a bolder R&D agenda. Without demonstrable good for access or innovation, closing up such spending drains where we can seems a smart move.

For more on pay-for-delay settlements, visit Prescription Access Litigation, and Kaiser Health News’ good roundup on the budget negotiations.

–Kate Petersen, PostScript blogger

A new report suggests that despite the economic downturn, the pharmaceutical and medical device sectors in Minnesota have experienced significant growth in recent years, mirroring similar expansion in Massachusetts. These data further drain much-repeated claims that pharma and device disclosure and gift laws passed in those states would have a “chilling effect” on industry—claims that last year worked to squelch an update to Minnesota’s law that would have required medical device companies to report payments made to health care providers in that state, as well.

The report, by the BioBusiness Alliance of Minnesota, found 20 percent growth in the state’s biobusiness jobs between 2002-2007, and within that trend, pharma jobs stood out, growing 76 percent, more than the 10 other states analyzed in the report. “Employment in the medical device industry in Minnesota increased by 4,500 jobs during 2002 to 2007,” the Minnesota Star Tribune underscored, “compared with a loss of 11,000 medical device jobs nationwide during that same time period.”

And last week brought more good news for the pharma industry in Massachusetts: Pfizer’s bringing hundreds more jobs to the Boston area, and looking to relocate two plants there from Connecticut. As you may know, since passing a first-of-its-kind gift restrictions and payment disclosure law in 2008, Massachusetts has been the epicenter of the most heated debate about the effect of state transparency regs on business. But headline after headline like this one in the years since the law passed suggest that, if anything, pharma business in the Bay State is stronger than maybe any other North American hub, and with the help of the state’s life sciences initiative, companies keep moving in and spreading out.

Here’s the Globe:

“Pfizer’s decision to increase research in the Boston area follows similar recent moves by global drug makers such as Novartis AG of Switzerland and Sanofi-Aventis SA of France, which want to plug into the area’s life sciences industry at a time when drug discovery has slowed worldwide…

‘It’s a confirmation that, when some of these companies have to make tough decisions, they continue to favor Massachusetts,’ said Susan Windham-Bannister, president of the Massachusetts Life Sciences Center, a state agency created to implement Governor Deval Patrick’s life sciences initiative. ‘It’s a good place to partner, it’s a good place to keep the finger on the pulse, and it’s a good place to tap into a skilled workforce.’’’

–Kate Petersen, PostScript blogger

Another heparin-like crisis is inevitable under the current regulatory system that monitors the global drug supply, FDA Commissioner Dr. Margaret Hamburg said at a food and drug safety symposium last week on at the Council on Foreign Relations (CFR). The global supply chain has rendered the agency’s “traditional model” of inspections and import surveillance obsolete, Hamburg said, and the global scope of the prescription drug market demands a new cooperative model in which international regulators share best practices, help build lateral regulatory capacity, and work with all stakeholders to keep substandard, adulterated, and counterfeit drugs off shelves.

In a round table discussion following her speech, Dr. Hamburg expanded on the idea of this global alliance:

I think the time has come that we really need to create and formalize a global alliance of regulators that are committed to solving these problems together, to sharing information in new ways, sharing best practices in new ways, even sharing the workload in new ways, and importantly, working with industry and other stakeholders because it is a shared responsibility that goes beyond government….

She tied these efforts to the “critical central role of the consumer,” and said that “at the end of the day, it’s all about serving them and protecting and promoting their health and well-being.”

To us, “role” suggests action, but in such a splintered drug supply chain involving 300,000 facilities in 150 countries–and 150 different regulatory systems–sometimes it’s hard to see what this consumer role or action might look like. At a CFR panel later in the week, Caroline Smith DeWaal from Center for Science in the Public Interest offered one vision:

We really need consumers to demand safe food and safe drugs from their government. And the industry plays a major role, but consumers can demand from their political players that these systems be implemented. But systems shouldn’t be stovepiped just for exports. They really need to benefit the consumers in those countries.

You can watch the symposium, and find links to the transcripts and backgrounders here. This expert round-up published after the symposium does a good job of identifying some ways to get at the safety challenges posed by the global drug supply, including:

• thinking about counterfeits through a safety lens, not just a patent-based one

• considering affordability as a potential driver of or toward growing counterfeit markets

• developed nations’ involvement in helping to build regulatory capacity in manufacturing hubs in the developing world

• meaningful international regulatory cooperation/communication

• the place of inspections in a resource-limited drug safety system

Though the whole CFR round-up’s worth a read, Charles Clift, a consultant for the Centre on Global Health Security, Chatham House, does a good job of framing the big questions:

The drug safety issue is a problem that has two components. One is, how do we protect the legal supply chain? If all my active ingredients and many of my finished products are produced overseas, I can’t possibly inspect all those plants that are producing them, so what is the answer to that? We have to take different approaches, collaborate more, share more information, and generally have a global alliance of regulators who will try to get a grip on this very complex supply chain.

The other aspect is: What do we do about drugs, which are essentially illegal [because they are complete fakes or contain fake components that can sicken or kill people]? They are not submitted to regulators, they come into the country illegally or they are produced in the country illegally, and they can do enormous harm to individuals.

These CFR conversations  provide potential answers to what is a daunting web of policy questions. Encouragingly, so do some  recent U.S. legislative efforts.  For more on those proposals to protect the drug supply, visit the Pew Prescription Project and SafeRxWatch.

–Kate Petersen, PostScript blogger

A couple of interesting bits around the blogosphere on the pipeline problem NIH aims to tackle that we wrote about last week.

Over at Corante’s “In the Pipeline,” Derek Lowe points to a new paper out of the Tufts Center for the Study of Drug Development. Analyzing patent history over the last 50 years, the paper posits that oftentimes copycat compounds were in the pipeline before the original was approved: in other words, the “me-too” drug phenomenon may be a case of a race to market, rather than sequential imitation of already successful therapies. Lowe writes:

I’ve been in the drug industry since 1989, and for every drug class that’s been introduced during my career, at least one of the eventual follow-on drugs has already been synthesized before the first one’s been approved by the FDA…

So the mental picture you’d get from some quarters, of drug companies sitting around and thinking “Hmmm. . .that’s a big seller. Let’s hang a methyl off it now that those guys have done the work and rake in the cash” is. . .inaccurate. As this paper shows (and as has been the case in my own experience), what happens is that a new therapeutic idea becomes possible or plausible, and everyone takes off at roughly the same time. At most, the later entrants jump in when they’ve heard that Company X is working in the same area, but that’s a long time before Company X’s drug (or anyone’s) has shown that it’s going to really work.

If you wait that long, you’d be better off waiting even longer to see what shortcomings the first drug has out in the real marketplace, and seeing if you can overcome them.

Lowe’s take on the Tufts review suggests we re-examine where we place the emphasis when we talk about a pipeline that lately has created more me-toos than breakthroughs.

But even if similar compounds went into the pipeline at relatively the same time, how do we re-incentivize risk on the front end, and minimize risk in the post-market phase? And what do we do about a marketing model that’s finely tuned to this R&D trickle, pushing each kissing-cousin compound as the Next Big Thing?

George Miller over at Fierce Pharma Manufacturing wonders whether there’s some middle ground between blaming industry vs. regulators for process-change sloth:

Forbes magazine editor Steve Forbes excoriates the FDA in a recent editorial, blaming a government regulation failure—rather than a market failure, as Congressman Henry Waxman does–for the lack of new antibiotics. Although his chief complaint is with the agency’s “increasingly horrific bureaucratic roadblocks” to drug development, his arguments extend to some extent to manufacturing regulation…

I’m not willing to buy into his moving-backwards scenario. But perhaps there’s some middle ground that our two political parties might explore between Forbes’ doomsday vision and quarter-century guidance updates.

There’s something here, too, for those of us asking how to thaw a pipeline to produce safe, innovative therapies when the players and the rules look different from political season to political season.

–Kate Petersen, PostScript blogger