February 12,2008

Grassley urges FDA to better target foreign inspection resources to improve drug safety

February 1, 2008

Via Electronic Transmission
The Honorable Andrew C. von Eschenbach, M.D.
Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Commissioner von Eschenbach:

The United States Senate Committee on Finance (Committee) has jurisdictionover the Medicare and Medicaid programs and, accordingly, a responsibility to the morethan 80 million Americans who receive health care coverage under those programs tooversee their proper administration. As the senior Senator from Iowa and RankingMember of the Committee, I have a duty to ensure that the Food and DrugAdministration (FDA/Agency) upholds its responsibility to the public’s safety byproperly regulating the nation’s drug supply and ensuring that the drugs Americans useare safe and effective. In carrying out this duty, I have been conducting an ongoinginquiry concerning foreign pharmaceutical manufacturers and the FDA’s foreign druginspection program.

This past October, I wrote to you concerning the FDA’s program for inspectingforeign pharmaceutical manufacturing plants and ongoing questions regarding inspectionfunding, emerging exporters, weaknesses in the inspection process, over-the-counter drugimportation, and other pressing issues. On Thursday, December 13, 2007, FDArepresentatives visited my office to discuss these topics, and I greatly appreciate theinformation they provided to my staff. That same week, I received FDA’s writtenresponse to my August 7, 2007 letter. I am writing today to review what your agencyofficials told my Committee staff and follow up with a number of additional questions.

In the letter and briefing, your staff provided the number of FDA inspections ofinternational pharmaceutical plants for fiscal years 2002 – 2007, some of which isreiterated below. I found these numbers very troubling. Since the beginning of FY 2002,the FDA conducted approximately 1,379 inspections of foreign pharmaceutical facilities,often focused in countries with few reported quality concerns. The table below containsthe number of inspections conducted by the FDA in the 10 countries with the highestnumber of pharmaceutical facilities inspected.

Top Ten Total Inspections by Country, FY 2002-2007
Country 2002 2003 2004 2005 2006 2007 Total
India 10 19 36 33 34 61 193
Germany 23 14 35 25 20 18 135
Italy 16 31 25 21 17 12 122
Canada 27 12 17 22 24 16 118
United Kingdom 17 22 17 18 16 9 99
France 14 18 13 12 15 24 96
Japan 10 13 13 21 13 12 82
China 11 6 18 13 16 11 75
Switzerland 11 11 11 15 9 14 71
Ireland 11 5 12 14 2 7 51

In China, the world’s largest producer of active pharmaceutical ingredients(API), and where export safety appears to be a growing problem, only 11 inspectionswere conducted during FY 2007, compared to 14 in Switzerland, 18 in Germany, and 24in France, all countries with advanced regulatory infrastructures. Moreover, the tableshows a drop in the number of inspections conducted in China from a peak of 18 in 2004,while inspections in countries with robust internal controls such as France appear to be onthe rise. This seems to be a misplacement of limited FDA resources. Accordingly, I aminterested in learning how the United States might utilize the advanced inspectioncapabilities of our industrialized trading partners to better focus the FDA’s limitedinspection resources in countries where export quality is of greater concern. On thistopic, I would appreciate answers to the following questions:

(1) How many Chinese and Indian pharmaceutical plants that are currently exportingproduct directly or indirectly to the US market have never been inspected by the FDA?

(2) From the list of countries above, please provide the number of Official Actions thathave been taken each year for fiscal years 2002 through 2007. In the case of WarningLetters, please provide a copy of the letter.

(3) For fiscal years 2002 through 2007, please provide the amount of exports from eachof the countries listed above to the United States.

(4) Please detail FDA efforts to establish any additional bilateral and multilateralagreements that would allow the sharing of inspection information. Please also discussthe FDA’s position on shifting its inspection resources away from highly developednations and towards countries where export quality is less established.

Concerns over the quality of Chinese pharmaceutical exports were reinforced bythe recent scandal involving the Shanghai Pharmaceutical (Group) Co. One of China’slargest pharmaceutical companies, Shanghai Pharmaceutical is accused of producing anddistributing a tainted leukemia drug. Recent news reports indicate that this contaminateddrug has harmed nearly 200 patients in China, in some cases causing them to becomeparalyzed. Shanghai Pharmaceutical claims to be in partnership(s) with multinationaldrug companies and to actively export API around the globe. Please identify whatproducts this company exports to the United States, and specify whether any of the APIproduced by this company is shipped to other plants which export to our market. If so,what is being done to ensure that these products are not also contaminated?

I was also disturbed by an event that occurred this past summer in Japan. WhenFDA inspectors visited the Tomita Pharmaceutical Company (Tomita) from July 31through August 2, 2007, they discovered significant deviations from FDA standards.These deviations included incomplete analyst worksheets, insufficient computerizedsystems, a lack of written protocols, and other problems. Without these records, FDAinspectors are unable to confirm manufacturer tests. Furthermore, during the inspectionTomita officials refused to provide FDA inspectors with certain records, effectivelypreventing the FDA from completing its inspection. The January 14, 2008 FDA WarningLetter to Tomita asked that the company conduct an evaluation of its own facility, andthreatens that the FDA will “recommend disapproval of any new applications orsupplements” from the company.

I am troubled by this response, which seems woefully insufficient. Tomitaofficials have refused to allow FDA officials to complete inspection of theirmanufacturing facility, yet the company appears to still be allowed to export its productto consumers in the United States. Please confirm if this is the case. Also, I would beinterested to know the full range of enforcement measures available to the FDA when amanufacturing plant refuses to give our inspectors full access, and how FDA officialsdecide what actions to take against uncooperative companies.

Another topic covered during the December briefing was the establishment ofFDA facilities abroad. One important step to improving the FDA’s ability to inspectforeign pharmaceutical plants would be the establishment of offices in Asia, wherepharmaceutical manufacturing is rising dramatically. In the December briefing, yourstaff indicated that no firm plan was in place for such an office. However, recentcomments by the Department of Health and Human Services Secretary Michael Leavittindicate that the establishment of an office in India is under consideration. I wouldappreciate additional information regarding this effort and your input on the resourcesthat would be required to make an FDA office in India a reality.

In addition to the inspection of foreign pharmaceutical plants, FDArepresentatives also commented during the December briefing on efforts to preventtainted dosage forms and API from entering this country. A similar problem highlightedover the last few months by the Seattle Times is the importation of unproven medicaldevices. The Seattle Times published a series of articles over the last few monthsregarding its investigation into the sale and use of unproven medical devices that aremanufactured overseas and claim to manipulate the body’s energy fields to improvehealth, including curing diseases like cancer and AIDS. According to the Seattle Times,the FDA recently took action against a network of foreign manufacturers of such devicesin response to that investigation. In addition, FDA regulations do not require that adevice manufacturer always obtain FDA’s approval in order to initiate a study of itsdevice. Under 21 C.F.R. 812, a device manufacturer can ship and use an investigationaldevice in a clinical study that does not involve significant risk as long as it obtains aninvestigational device exemption from an institutional review board. Consequently, asreported by the Seattle Times, the FDA does not know how many and which unprovendevices are being tested in clinical trials. This week, you also testified that the problemwith manufacturers importing fraudulent devices into the U.S. need to be stopped at thesource. On this topic, I would appreciate answers to the following questions:

(1) Please describe any efforts underway to improve FDA’s ability to identify whatdevices are involved in clinical trials as well as to identify and track foreignmanufacturers and/or distributors of non-FDA approved devices.

(2) Please elaborate on FDA’s plans to stop importation of fraudulent and unprovendevices at the source.

(3) How will the FDA work with state, local, and other federal authorities as well asforeign governments to investigate and prevent the importation of fraudulent andunproven devices into this country?

(4) What oversight and enforcement actions can be taken by the FDA to protect patientsagainst fraudulent and unproven medical devices manufactured overseas?

Thank you in advance for your cooperation and assistance on this importantmatter. I look forward to hearing from you regarding the issues and questions set forth inthis letter by no later than February 15, 2008. I would also appreciate a written responseto my previous letter, dated October 30, 2007. Any questions or concerns should bedirected to Christopher Armstrong at (202) 224-4515. All formal correspondence shouldbe sent via electronic transmission in PDF format to Brian_Downey@financerep.senate.gov.

Sincerely,

Charles E. Grassley
Ranking Member