1.THE SAFETY CATCH - NATURE article
2.More failings of the US FDA - NATURE editorial
3.USDA launches initiative to foster specialty biotech crops

After showing up the failings of the US FDA in the Syngenta Bt10 maize scandal, the science journal Nature in the editorial and feature article below point to the extraordinary failings of the FDA when it comes to ensuring the safety of the drugs it allows on to the market.

In the words of one of the FDA's own scientists, "The FDA as currently configured is incapable of protecting America against another Vioxx [the drug which killed tens of thousands of people in America's worst ever drug-safety catastrophe]. We are virtually defenceless."

Meanwhile, just in time for Monsanto's take-over of the fruit and vegetable seed giant Seminis, the US Department of Agriculture (USDA), which plays the part of both industry booster and regulator, has launched a public-private Specialty Crop Regulatory Initiative to help developers of GM fruits and vegetables "work their way through federal regulatory requirements into the marketplace."

Ardent GM scientist and promoter Alan McHughen is part of the initiative, and FDA and EPA scientists have been invited to send representatives to serve as consultants to the team. The initiative will look to FDA's orphan drug programme as a model.

USDA has concluded that the current regulatory framework is hindering development of GM fruit and veg so the new initiative will "help developers, obtain regulatory clearances, and work with consumer and stakeholder interests to foster market acceptance."

Here's a revealing quote from USDA: "Everything's on the table right now" to provide public research support for these crops.
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1.THE SAFETY CATCH (excerpts)
NATURE / VOL 434 / 31 MARCH 2005 /
www.nature.com/nature

The past year has seen a beleaguered Food and Drug Administration publicly denounced as unable to protect the US public.

A telling scene unfolded in the lobby of a suburban Maryland hotel on 18 February. On the third and final day of a gruelling public conference, expert advisers to the US Food and Drug Adminis-tration (FDA) held in their hands the fates of three blockbuster painkillers, known as COX-2 inhibitors.

To make their assess-ment, the experts had to balance the drugs' value in treating arthritis against mounting evidence that they cause heart attacks and strokes. Billions of dollars in revenues for drug companies ”” and the welfare of millions of patients ”” hung in the balance.

But when a mid-morning break was called and the 32 advisers wandered out for coffee, they were largely ignored by the throng of reporters at the event. Instead, the journalists clustered around a boyish-looking FDA scientist who was holding forth for a television camera. They plied him with questions about his views on the issues before the panel, diligently jotting down his every response.

In the middle of the media scrum was David Graham, a career physician at the FDA. Graham came to public prominence last November at a US Senate hearing, when he pronounced his employer "incapable" of ensuring the safety of drugs after they were approved for sale in the United States.

His scathing testimony set alarm bells ringing on Capitol Hill and raised some fundamental questions about the FDA: is the agency scientifically, structurally or politically capable of ensuring the safety of some 10,000 pharmaceuticals now used by Americans? Or has the complexity, size and pace of the business, and the power of the drug manufacturers, exceeded the regulator's ability to cope?

Graham had told senators on 18 November that just one of the COX-2 inhibitors ”” Vioxx ”” had caused at least 26,000 deaths from heart attacks in the five years before Merck withdrew it from the market last September.

An epidemiologist in the FDA's Office of Drug Safety, Graham had conducted a study using the massive database of Kaiser Permanente, a health-maintenance organization based in California. Last August, armed with its results, he warned his bosses that high doses of Vioxx significantly increased the risk of heart attack and sudden death. The agency did not act ”” and even approved the drug's use in children with rheumatoid arthritis in the weeks before Merck withdrew it.

The FDA's Office of New Drugs ”” where any new medicine must pass muster before it can be sold ”” approved Vioxx in 1999. It was heavily promoted by Merck as an alternative to standard arthritis medications because it didn't cause stomach bleeding, and it soon became a huge success, with worldwide sales of $2.5 billion in 2003 alone.

Then, last Sep-tember, a Merck-sponsored trial examining whether the pill might prevent precancerous colon tumours found that Vioxx doubled the risk of heart attacks and strokes in patients using it for more than 18 months.

Critics - including plaintiffs in the raft of lawsuits against Merck that swiftly followed the drug's withdrawal - complained that as early as 1999, studies had flagged Vioxx’s potential for causing heart attacks and strokes. They implied that the FDA should have identified the problem and pulled the medicine from the market.

In his Senate testimony, Graham endorsed that point of view. He added that Vioxx was probably far from a one-off event. It was bound to repeat itself, he said, because the FDA's organizational structure and corporate culture were biased towards approval of new drugs. Safety monitoring of drugs already out there, he said, took second place.

Graham further complained that the reviewers at the Office of New Drugs who approve therapeutics in the first place have a vested interest in the drugs' success, and are liable to ignore or overrule post-market safety concerns raised by staff scientists in the smaller Office of Drug Safety. Asked to identify other established drugs about which he had serious safety reservations, Graham named five, including Pfizer's Bextra, another COX-2 inhibitor.

"The FDA as currently configured," he concluded, "is inca-pable of protecting America against another Vioxx.We are virtually defenceless."

...the past year has been a rocky one for the FDA. In March 2004, Mark McClellan decamped after just 17 months from a commissioner's position that had sat vacant for nearly two years prior to his arrival. Soon after that, the agency came under fire for suppressing the report of a staff scientist who cautioned that popular 'SSRI' antidepressants could cause suicidal tendencies in young people. And in early October, just a few days after Merck withdrew Vioxx, the FDA's competence in ensuring the safety of vaccines destined for the US market was called into question when British authorities abruptly closed a flu vaccine plant in Liverpool owned by US company Chiron. This halved the United States' supply of vaccine for the coming winter and provoked a public uproar.

..."It doesn't make sense to have the office that reviews the safety of drugs under the thumb of the office that puts the drugs on the market in the first place," [Senator] Grassley told the Con-sumer Federation of America last month.

Acting FDA commissioner Lester Crawford, who has been nominated by President Bush for the permanent post, told senators at his nomination hearing on 17 March that he is "open to discussing" an independent office of drug safety. Crawford has also announced that a new board for overseeing drug safety ”” an advisory board of mainly FDA employees - will publicize worrisome side effects more quickly than has happened in the past. Critics immediately assailed the board as toothless, because it will lack the power to require label changes or to pull drugs from the market. But Crawford says that it will herald a new era of public open-ness at the agency.

Still, some agency-watchers fear that the relatively low profile of Crawford's nomination and confirmation process, together with the reluctance of the conservative Congress to antagonize its allies in industry, suggest that even the tens of thousands of deaths attributed to Vioxx may be insufficient to initiate any real strengthening of the FDA.

The agency's history demonstrates that "major changes come after disasters", says Schultz. And the Vioxx case may not rise to that threshold in the public mind. At the end of the three-day advisory panel meeting back in February, the experts voted narrowly to allow Vioxx back onto the market, subject to careful constraints. They also voted to give patients continued access to Pfizer’s two COX-2 inhibitors, Celebrex and Bextra.

Graham, for one, was not impressed. "Despite the biggest drug-safety catastrophe in the history of the United States," he noted with his trademark earnestness, "people are heavily invested in the status quo."
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2.More failings of the US FDA

DRUGS ON TRIAL
EDITORIAL
Nature 434, 545 (31 March 2005); doi:10.1038/434545a
http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v434/n7033/full/434545a_fs.html

Drug safety on trial

The current US system for checking the safety of drugs already on the market is toothless. Why isn't the government doing more to strengthen it?

A revealing notice appeared last month in the Federal Register, the US government compendium of agency rules and notices. The Food and Drug Administration (FDA) was reporting on compliance by pharmaceutical companies with its requests for studies of the clinical safety and efficacy of drugs already on the market. Of nearly 1,200 such studies committed to by drug firms but not completed, some 70% have yet to begin.

This is an alarming reflection of the state of the government's vigilance. Last year, the FDA belatedly faced up to research showing that the painkiller Vioxx, which it approved in 1999, markedly increases the risk of heart attacks and strokes. It has been estimated that more than 25,000 people died before Merck pulled the drug from the market in September (see pages 554 and 557). A better approach to assessing the safety of marketed drugs is badly needed.

Under the FDA's existing system, known as MedWatch, doctors voluntarily report suspected side-effects ”” but epidemiologists estimate that this captures only 10% of adverse events. The agency used to complement this with university-run studies, but this modest effort dried up in the 1990s when it was forced to devote more resources to speeding up drug approvals.

The upshot is that the FDA depends on companies for post-market safety studies but has no legal authority to force firms to do them. The results are sobering. For instance, after 16 years of use in tens of millions of people, it is still not known whether selective serotonin reuptake inhibitors, the blockbuster antidepressants, cause an increase in suicide attempts in some adults. The FDA warned last year of such a risk in young people, but the question still hasn't been adequately explored in adults. Nor will it be if the current system prevails.

Lack of information is not the problem. After a drug comes into use, gigabytes of epidemiological data become available from governments and healthcare organizations. Nor is it a matter of sorting through the 10,000-odd prescription drugs to find one with dangerous side-effects: the most likely culprits are already well known.

What is lacking is both the money and the mandate. The United States needs a government body that can not only determine what drug safety studies are needed, but demand that they are done. It must also have the authority to dictate ”” rather than negotiate with drug-makers, as the FDA currently does ”” that beefed-up warning labels are used when evidence of new risks emerges. About $300,000 annually would pay for a high-quality pharmaco-epidemiological study. Surely the richest country in the world can find the funds for that.

It can, but will it? Congress is unlikely to implement such a change. The Republicans control Congress and the White House, and are loath to alienate an industry that has given them twice as much as it has given the Democrats in political contributions over the past decade.

Tens of thousands of people have almost certainly died because of Vioxx. Observers are left to wonder if it will take an even bigger tragedy to force the US government to do the right thing on drug safety.
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3. USDA launches initiative to foster specialty biotech crops [excerpts]
by Stephen Clapp
Pesticide & Toxic Chemical News, March 21, 2005

USDA has launched a public-private Specialty Crop Regulatory Initiative to help developers of bioengineered fruits and vegetables work their way through federal regulatory requirements into the marketplace.

Workshops in June and November sponsored by USDA agencies and private organizations found that the current regulatory framework is hindering development of small-market biotech crops (see PTCN March 14, Page 10).

"What came out of our workshop is that numerous biotech specialty crops are not being realized due to the cost of regulatory approval," William Goldner, leader of the small business innovation program in USDA's Cooperative State Research, Education and Extension Service, told a March 15 conference sponsored by the National Corn Growers Association. He noted that the last specialty crop to receive clearance was biotech papaya in the late 1990s.

Goldner said the new specialty crop initiative would help developers generate safety data, obtain regulatory clearances, and work with consumer and stakeholder interests to foster market acceptance.

The planning team is headed by Alan McHughen, a plant biotechnologist at the University of California/Riverside, and includes representatives of CSREES, the Agricultural Research Service and crop developers from private companies and academia. USDA's Animal and Plant Health Inspection Service, FDA and EPA, which jointly regulate biotech products, have been invited to send representatives to serve as
consultants to the team.

The initiative will look to FDA's orphan drug program and EPA's IR-4 minor crop pesticide program as models. Goldner noted that the IR-4 program has a budget to support development and field trials of minor use pesticides. "Everything's on the table right now" to provide public research support for specialty crops, he said.

- Stephen Clapp
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