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 complications.2
Overseas Drug Manufacturing and Heparin
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 Inspection
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 traditionally embraced?
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 significant
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 is.
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 et seq.
2. Carey MA. Drug safety rests greatly with pharmaceutical makers, FDA official says. Congressional Quarterly HealthBeat. April 24, 2008. www.cqpolitics.com/wmspage.cfm?parm1=1&docID=hbnews-000002710903#. Accessed May 2, 2008.
3. Drug recall puts overseas inspections in spotlight. Canada Pharmacy News. March 8, 2008. www.canadapharmacynews.com/2008/03/drug-recall-puts-overseas-inspections.html. 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 4, 2008.
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, 2008.
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 4, 2008.
9. CDER Report to the Nation: 2000. April 27, 2001. www.fda.gov/cder/reports/RTN2000/rtn2000.htm. Accessed May 2, 2008.
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. http://healthcenter.bna.com/pic2/hc.nsf/id/BNAP-7E5JF4?OpenDocument. Accessed 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. http://online.wsj.com/article/SB120969159705761551.html?mod=dist_smartbrief. 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. www.biojobblog.com/2008/03/articles/rants-and-raves/changes-at-fda-janet-woodcock-chosen-again-to-head-cder/. Accessed May 3, 2008.
20. Taylor N. Legislation proposed for FDA foreign inspections. April 22, 2008. www.in-pharmatechnologist.com/news/ng.asp?n=84815-fda-phrma-glycerol-heparin-dingell. 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 3, 2008.
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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