US Pharm. 2008;33(6):53-57.
Have you ever wondered how
well the FDA is doing at protecting the American public from harmful drugs? As
pharmacists, we are educated to believe that the FDA is the oversight agency
charged with making sure we have access to drugs that are safe and effective
for intended purposes, and that pharmaceutical companies are only allowed to
market drugs in a manner approved by the FDA. We know that the manufacturer's
labeling that accompanies all drugs sold in this country has the blessing of
the FDA. We know that the FDA inspects drug plants fastidiously and that all
drugs produced in this country must be manufactured in conformance with the
FDA's Current Good Manufacturing Practices regulations.1 We
know the FDA requires pharmaceutical companies to subject new drugs to years
of arduous testing before the first drug product is sold or distributed.
However, we also know that in recent years the FDA has made tremendous
blunders that shake our core beliefs in the sanctity of the drug-marketing
system. It is therefore appropriate to look at just how good a job the FDA is
doing and what can be done to improve the odds that patients will not suffer
harm as a result of consuming FDA-approved drug products.
The real challenge is to
understand that a very large percentage of bulk medicines that go into
pharmaceutical products sold in this country originate in foreign markets. The
question then becomes, just how safe are these products, and what is the FDA
prepared to do to keep Americans from harm's way?
The FDA's Position
On April 24, 2008,
during Senate hearings on the heparin fiasco, Janet Woodcock, MD, the Director
of the FDA's Center for Drug Evaluation and Research (CDER), testified before
the Senate Education, Labor, Health, and Pensions Committee, and stated, "We
cannot be the quality-control unit for the world." She also said that the
increasingly large number of pharmaceutical ingredients manufactured abroad
makes it nearly impossible for the agency to ensure the safety of all drugs
sold in the United States. She argued that additional resources are necessary
to help improve efforts to stop contaminated drugs from coming into the
country. However, in what can only be described as a curious position, she
also stated that manufacturers must assume greater responsibility for the
quality of their products. Isn't that a bit like having the fox guard the
chicken coop? Baxter International's contaminated heparin, imported from
China, is being blamed for at least 81 deaths and scores of other serious
Overseas Drug Manufacturing
China has become
one of the world's largest suppliers of pharmaceutical ingredients, but the
country's questionable safety reputation, combined with reports of death and
serious illness associated with Chinese products in the past year, has
convinced some experts and industry members that North American governments
need a more aggressive approach to overseas inspections and safety checks.
3 Enhancing review of Chinese plants may be even more imperative given a
recent change in the way China deals with drug recalls. In December 2007, the
State Food and Drug Administration (SFDA) for the Republic of China (that
country's equivalent to the U.S. FDA) issued new guidelines that encourage
drug companies to recall unsafe drugs voluntarily.4 The new
regulation states that enterprises that voluntarily recall unsafe drugs will
be subject to lesser, or even be exempted from, administrative punishment.
Those who are aware of problems with their drugs but fail to issue voluntary
recalls will face fines up to three times the value of the recalled drugs or
even be deprived of drug-manufacturing licenses. The move by the SFDA comes in
the wake of pressure on the Chinese government to overhaul the country's food
and drug safety system following a series of drug-safety scandals over the
past few years. One of the most notorious cases of substandard drugs was that
of Anhui Huayuan Worldbest Biology Pharmacy Co., whose antibiotic injections
were blamed for six deaths in 2006.5 The problem injections were
found to be improperly sterilized, with both sterilization temperature and
time being below the state-required safety level.
To put the scope of the
potential for problems into perspective, one news agency surveyed five of the
most commonly prescribed drugs (cholesterol-lowering Lipitor, narcotic pain
reliever acetaminophen with hydrocodone, antibiotic amoxicillin, and high
blood pressure fighters Toprol-XL and Norvasc) and found that three are
manufactured overseas.6 The impending trouble may run even deeper.
A November 2007 Government Accountability Office report showed that the FDA
does not even know how many of these foreign plants are importing drugs and
drug ingredients into the U.S. Agency officials could not give an exact number
of overseas manufacturers, saying there were between 3,000 and 6,800.7
These companies make 80% of raw materials used to manufacture the drugs that
are sold in the U.S. Thus, even if the product is made in the U.S., the
ingredients in that drug could still have been made overseas.8
The FDA now says that the
heparin problems may be the result of a counterfeit ingredient from China that
was used in the drug. U.S. health officials had never inspected the Chinese
factory owned by U.S.-based Scientific Protein Laboratories LLC, where some of
the raw heparin ingredients were processed. When FDA inspectors finally
visited the plant in February 2008, after several deaths were linked to
heparin, they found evidence of quality control and hygiene problems.
Dr. Woodcock's remarks about
companies assuming their own quality-control accountability seems to be at
odds with long-standing FDA policy. On its Web site, the CDER is described by
the FDA as "America's consumer watchdog for medicine."9
This report describes the FDA as "one of the nation's oldest consumer
protection agencies." Employing approximately 1,700 physicians and other
scientists, CDER is the largest of five centers organized around the FDA. With
regard to protecting drug quality, the FDA states that as the pharmaceutical
industry has become increasingly global, the agency is "involved in
international negotiations with other nations to harmonize standards for drug
quality and the data needed to approve a new drug." The FDA goes on to claim
that "this harmonization will go a long way toward reducing the number of
redundant tests manufacturers do and help ensure drug quality for consumers at
home and abroad."10
The Politics of Foreign
So why is the
director of the oldest and largest watchdog agency claiming its
drug-manufacturing constituents must police themselves? Or, perhaps more
important, why is she abdicating the quality-control mission that the FDA has
It seems there are some
politics going on inside the FDA. Two days before Dr. Woodcock testified at
the Senate hearing, her boss, FDA Commissioner Andrew von Eschenbach, MD, told
the House Committee on Energy and Commerce that he rejects the idea that the
agency's foreign manufacturing-plant inspection program needs to be reviewed
and sharpened.11 He denied outright that inspection of the Chinese
plant where the heparin was produced would have caught and prevented the
contaminated drug from reaching this country because the contamination would
not have been detected by normal testing procedures. This brought forth an
angry response from Rep. Bart Stupak, chairman of the Subcommittee on
Oversight and Investigations, who charged that Dr. von Eschenbach would not
have known what the inspection would have found "because you only inspected
the plant after the deaths." He concluded that "it's time to act and fix this
program." Referring to an incidence of contaminated cat and dog food that
entered the country from China, Rep. Stupak stated, "Last year, this nation's
regulatory failures resulted in dead dogs and cats. This year, it has
tragically led to the deaths of people. If we don't make some rapid progress
on fixing the foreign drug inspection program, the next melamine [the pet food
contaminant] or heparin tragedy will soon be upon us."12
At the same time, Energy and
Commerce Chairman John Dingell challenged the commissioner to establish a
budget figure that would allow the FDA to bring its foreign drug-inspection
efforts up to par with domestic inspections. "I can't maintain my respect for
you if you keep toe-dancing around the hard facts that you can't do your job
because you don't have the resources."13 When asked by
Rep. Dingell how much money the FDA needs to conduct adequate foreign
inspections, Dr. von Eschenbach said, "I don't believe that's the solution to
the problem. It's much more complex, and the solution needs to be much more
comprehensive than simply inspecting a facility."
Earlier that same day, the
Government Accountability Office concluded that the FDA's 2009 fiscal budget
of $13 million for foreign inspections is inadequate since the agency would
need between $67 and $71 million annually to do biennial inspections of each
of the 3,249 foreign drug manufacturers registered with the FDA. This same
report indicated that in China alone it would cost $16 million per year to
inspect that country's 714 known firms exporting pharmaceuticals to the U.S.
The report concluded, "Given the growth in foreign drug manufacturing for the
U.S. market and the current large gaps in FDA's foreign drug inspections, FDA
will need to devote considerable resources to this area if it is to increase
the rate of inspections. However, FDA's plans currently call for incremental
increases that will have little impact in the near future to reduce the
interval between inspections for these establishments."14
Rep. Dingell summarized the
hearing, stating, "Today we again explore whether FDA is adequately able to
protect American citizens from the unscrupulous or incompetent foreign
manufacturers of pharmaceutical products. Given the findings of this
Subcommittee and the recent disturbing events surrounding tainted heparin, I
believe FDA is not up to the task, as it cannot or will not undertake the
reforms needed to protect Americans from this threat from abroad."15
He went on to note that current law requires the FDA to inspect American
plants every two years, but there is no such law with respect to foreign firms
and that, on average, the foreign companies are being inspected once every 13
years. Mr. Dingell pointed out that "at least 80 percent of all active
pharmaceutical ingredients are imported, much of it from countries lacking
competent regulatory systems, such as China and India." Right now, the FDA is
only inspecting 10 to 20 Chinese drug-manufacturing plants in any given year.
"In other words, it would take FDA more than 30 years to inspect each Chinese
firm a single time, assuming no new firms are added to the list" according to
Rep. Dingell's calculations.
Apparently, it took Dr.
Woodcock only a few days to realize that her claim that more resources are
needed to do foreign inspections was at odds with her boss's assertions to
Congress that the FDA only needs to change the way it holds the foreign
companies accountable. On May 1, 2008, she backed away from asking for an
additional $255 million from Congress to fortify foreign inspections.16
Instead of stating a figure as to how much the agency would need to conduct
the foreign inspections, she would only commit to the need for additional
resources to improve the technology needed to trace shipments of drugs from
overseas. It may be a subtle change in direction, but it is nonetheless
It is also a sign
that something is wrong. Congress wants to throw money at the FDA to beef up
foreign inspections and FDA executives say "No thank you." The proverbial
Washington smoke screen must be operating at full tilt. Rep. Dingell's
committee has proposed raising hundreds of millions of dollars to finance
inspections of the offshore plants through wider use of the Prescription Drug
Users Fee Act (PDUFA). This program, now in its fourth incarnation, was
expanded when it was reenacted on September 27, 2007.17 The
proposal, being called the FDA Globalization Act, would generate significant
revenues and would require the FDA to inspect foreign drug manufacturers every
two years, as is the requirement for domestic producers. But that is the
provision the FDA objects to. Getting back on track with the party line, Dr.
Woodcock testified that "any legislation should allow the FDA to set its
priorities based on risk assessment," while explaining that the FDA might find
it a costly burden to automatically schedule foreign inspections for plants
every two years.18 She prefers that the agency make inspection
decisions based on a company's performance and other factors. In other words,
she does not want Congress telling her how to do her job or even what her job
What's going on here?
Political pundits might take the low road to explain the situation. Dr.
Woodcock works for Dr. von Eschenbach, who is a personal friend of President
George W. Bush.19 President Bush reportedly does not like the idea
of burdening members of the Pharmaceutical Research and Manufacturers of
America (PhRMA) with additional costs and, of course, PhRMA opposes the
legislation.20 That may be the skeptic's viewpoint. But there are
two sides to every story.
The FDA is undertaking major
steps to beef up its regulatory capacity. The "Help Wanted" sign has been
posted by the agency. On April 30, 2008, the FDA announced plans to hire 1,300
new pharmacists, scientists, pharmacologists, biologists, chemists, medical
officers, mathematical statisticians, and investigators.21 The
funds for doing so were authorized, in part, by the Food and Drug
Administration Amendments Act of 200722 and the Food and Drug
Import Safety Act of 2007.23 About 700 of the new positions will be
funded by increased user fees levied on companies the FDA regulates. The 1,300
new employees will add to the agency's 10,000 strong workforce and nearly
triples the number of people hired by the FDA from 2005 to 2007.24
Approximately 600 individuals will be hired in fiscal 2008.
While these moves will enhance
the agency's ability to regulate drug makers, there still seems to be
significant debate as to whether the FDA is prepared to bolster its foreign
inspection efforts. As pharmacists, we should demand more accountability in
the quality-control measures used to produce the drugs we dispense.
1. 21 CFR § 820.1
2. Carey MA. Drug safety rests
greatly with pharmaceutical makers, FDA official says. Congressional
Quarterly HealthBeat. April 24, 2008.
May 2, 2008.
3. Drug recall puts overseas
inspections in spotlight. Canada Pharmacy News. March 8, 2008.
Accessed May 4, 2008.
4. China issues new recall method,
encouraging voluntary drug recalls. China View News. December 12, 2007.
http://news.xinhuanet.com/english/2007-12/12/content_7235616.htm. Accessed May
5. Health ministry demands daily
reports on suspect antibiotic. Embassy of the People's Republic of China in
Australia. August 9, 2006. http://au.china-embassy.org/eng/xw/t266786.htm.
Accessed May 28, 2008.
6. Officials question safety of
overseas drug manufacturers. April 1, 2008.
www.nbc4.com/health/15765666/detail.html. Accessed May 4, 2008.
7. Audit: FDA hampered in review of
imported drugs. USA Today. November 1, 2007.
www.usatoday.com/news/health/2007-11-01-fda-imports_N.htm. Accessed May 4,
8. Schlafly P. It's still the
economy, stupid. Free trade in dangerous drugs. The Phyllis Schlafly Report.
February 2008. www.eagleforum.org/psr/2008/feb08/psrfeb08.html. Accessed May
9. CDER Report to the Nation: 2000.
April 27, 2001. www.fda.gov/cder/reports/RTN2000/rtn2000.htm. Accessed May 2,
11. Edney A. FDA chief defends
agency's work before House panel.
www.govexec.com/dailyfed/0408/042208cdpm2.htm. Accessed May 2, 2008.
12. House members criticize FDA
failures in inspection of foreign drugmakers. Pharmaceutical Law & Industry
Report. April 25, 2008.
May 2, 2008.
13. See note 4, supra.
14. Drug safety. Preliminary
findings suggest recent FDA initiatives have potential, but do not fully
address weaknesses in its foreign drug inspection program. April 22, 2008.
www.gao.gov/new.items/d08701t.pdf. Accessed May 28, 2008.
15. See note 6, supra.
16. Mundy A. Democrats, FDA official
at odds over inspection plan. The Wall Street Journal. May 2, 2008.
Accessed May 2, 2008.
17. Prescription drug user fees.
www.fda.gov/oc/pdufa/. Accessed May 2, 2008. The Act has a sunset provision
requiring Congress to renew it every 5 years. HR 3580 (2007).
18. Goldstein J. Should drugmakers
pay FDA to inspect foreign factories? May 2, 2008.
http://blogs.wsj.com/health/2008/05/02/. Accessed May 28, 2008.
19. Mintz C. Changes at FDA?--Janet
Woodcock chosen (again) to head CDER. March 11, 2008.
Accessed May 3, 2008.
20. Taylor N. Legislation proposed
for FDA foreign inspections. April 22, 2008.
Accessed May 3, 2008.
21. Mundy A. FDA to hire additional
scientists to expand drug safety operations. The Wall Street Journal.
April 30, 2008. http://online.wsj.com/article/SB120956615942356319.html.
Accessed May 3, 2008.
22. HR 3580 and S 1082. FDA
Amendments Act of 2007. www.govtrack.us/congress/bill.xpd?bill=h110-2900. Law
strengthens FDA. www.fda.gov/oc/initiatives/advance/fdaaa.html. Accessed May
23. HR 3610. Food and Drug Import
Safety Act of 2007. www.consumersunion.org/pub/core_food_safety/004809.html.
Accessed May 3, 2008.
24. See note 15, supra.
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