Grassley presses FDA for more information about foreign inspections, drug safety
WASHINGTON - Senator Chuck Grassley has sent another letter to the Food and DrugAdministration about its program for inspecting overseas facilities that manufacturepharmaceutical drug components.
Grassley’s new questions cover a range of issues, including the drug-safety agency’sreliance on translators provided by the manufacturing plants during foreign inspections;responsibilities within foreign chains of production; the identity of the plant that had beenconfused with the Chinese manufacturing plant that made an ingredient in the blood thinnerheparin; and other drugs on the market that may contain ingredients also manufactured by theChinese plant in question.
Earlier this month, production of heparin was suspended by its manufacturer due toconcerns that deficiencies at a Chinese manufacturing plant where the active ingredient inheparin was made may have contributed to the adverse reactions in hundreds of U.S. consumersusing the drug.
Grassley previously has asked the Food and Drug Administration about its targeting ofagency resources for inspections of pharmaceutical plants around the world, expressing concernabout the majority of inspections taking place where a minority of drugs and drug ingredients aremanufactured.
The text of all of his letters on the foreign inspection system for pharmaceutical drugsfollows here.
February 28, 2008
Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857
Dear Commissioner von Eschenbach:
As Ranking Member of the Committee on Finance (Committee), I have a responsibilityto the more than 80 million Americans who receive health care coverage under the Medicare andMedicaid programs to oversee the proper administration of these programs and ensure thattaxpayer and beneficiary dollars are appropriately spent on safe and effective drugs and devices.In December, officials from the Food and Drug Administration (FDA/Agency) briefedmy staff regarding FDA’s program for inspecting foreign pharmaceutical manufacturing plantsand ongoing questions regarding inspection funding, emerging exporters, and weaknesses in theinspection process, among other things. During that briefing, FDA officials noted that althoughthere are some employees who can speak a foreign language, they are not necessarily part of theinspection teams. Therefore, FDA sometimes relies on translators provided by the facility to beinspected. I find this problematic because, among other things, relying on translators providedby the facility under inspection creates an apparent conflict of interest, which in turn raisesquestions about the accuracy, independence, and thoroughness of FDA’s inspection of thatfacility.
Accordingly, please respond to the following questions:
1. It is my understanding that the FDA does not have designated employees who act astranslators during foreign inspections. Given our country’s increasing reliance on foreignfacilities to produce the active pharmaceutical ingredients (API) that are used in the drugssold on the U.S. market, it is troubling that the FDA does not ensure that independenttranslators are part of its inspection teams when there is a need for a translator. Since theFDA does not always have access to its own translators, what systems, if any, does FDAhave in place to ensure that the Agency is receiving truthful, accurate, and independentinformation from the translators provided by the inspected facilities? Has or would theFDA consider employing independent contractors to assist with translations during itsforeign inspections?
2. In FDA’s December 12, 2007 response, the Agency provided the Committee with thenumber of inspections conducted by country in fiscal years 2002-2007. Please identifyall of the facilities that were inspected in China, India, Brazil, Saudi Arabia, and Thailandduring that time period. For each inspection, please specify whether a translator wasrequired for the inspection. Please also specify whether the translator was an FDAemployee, an independent contractor, or an individual provided by the inspected facility.In my letter dated February 14, 2008, I asked the FDA to respond to several questionsregarding its failure to inspect a Chinese facility prior to approval of Baxter’s application forheparin. Please also provide a response to the following questions:
1. Since my Feb. 14 letter, I have learned that Changzhou SPL Co. is the Chinese facilitythat was supposed to be inspected by the FDA prior to regulatory action on BaxterInternational Inc.’s (Baxter) application. Was Baxter informed that Changzhou SPL Co.had been previously inspected and therefore did not have to be inspected again? If so,when and how was Baxter informed?
2. Was Scientific Protein Laboratories LLC, the Wisconsin company that supplied Baxterthe active ingredient in heparin through Changzhou SPL Co., informed that the facilityhad been previously inspected? If not, why not? If so, what duty did Scientific ProteinLaboratories LLC have to inform Baxter and/or the FDA that the Chinese facility hadnever been inspected? Whose responsibility is it to ensure the quality of the APIimported into this country?
3. Does Changzhou SPL Co. produce API used in other drugs that are sold on the U.S.market? If so, please identify these API and the companies that are buying them eitherdirectly or indirectly from Changzhou SPL. Is the FDA also investigating the quality ofthese ingredients?
4. Please provide the name and location of the facility that was mistaken for ChangzhouSPL Co. and specify when this facility was last inspected and what drugs and/or API areproduced at this facility.
In addition, I request that the FDA brief my staff regarding its findings from theinspection of Changzhou SPL Co. as soon as possible after the inspection is completed.Thank you for your cooperation and attention to this important matter. Please respond tothe questions and requests set forth in this letter by no later than March 14, 2008.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
For Immediate Release
Thursday, February 14, 2008
Grassley says hold on imported blood thinner componentunderscores questions about FDA foreign inspections
WASHINGTON — Senator Chuck Grassley is asking questions about whetherdeficiencies at a Chinese manufacturing plant that’s never been inspected by the Food and DrugAdministration could be behind adverse reactions in hundreds of U.S. consumers to the bloodthinner heparin, for which production was suspended this week by the drug maker. The activeingredient in heparin is produced at the plant in question.
Grassley’s inquiry today follows on a letter he sent earlier this month to the Food andDrug Administration about where the agency has targeted its foreign inspections ofpharmaceutical plants around the world.
“The heparin case illustrates perfectly the questions about how the Food and DrugAdministration is conducting foreign inspections of pharmaceutical plants worldwide,” Grassleysaid. “It doesn’t make sense that the vast majority of inspections are happening in places thataren’t where the vast majority of drug products coming into the United States are made. TheFood and Drug Administration clearly has a demanding and high-stakes job in verifying thesafety of prescription drugs that come from all over the world. Smart and appropriate use of itsdrug-safety resources is essential to public safety.”
Grassley is Ranking Member of the Senate Committee on Finance, which has legislationand oversight responsibility for the Medicare and Medicaid programs. He has conductedextensive oversight of the U.S. drug safety system.
The text of the letters he sent today to the Food and Drug Administration and to BaxterInternational Inc., the maker of heparin, follows here, along with the text of three letters hepreviously sent to the Food and Drug Administration regarding foreign inspections ofpharmaceutical drugs sold in the United States.
February 14, 2008
The Honorable Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857
Dear Commissioner von Eschenbach:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee their properadministration. As the senior Senator from Iowa and Ranking Member of the Committee, I havea duty to ensure that the Food and Drug Administration (FDA/Agency) upholds its responsibilityto protect the public's health by properly regulating the nation's drug supply and ensuring that thedrugs Americans use are safe and effective. In carrying out this duty, I have been conducting anongoing inquiry concerning foreign pharmaceutical manufacturers and the FDA's foreign druginspection program.
As you know, Baxter International Inc. (Baxter) has temporarily suspended production ofits blood thinner heparin because of an increase in the reports of adverse events that may beassociated with its drug. According to the FDA, about 350 adverse events associated withheparin have been reported since the end of last year. It has also been reported that four peopledied after receiving heparin, but whether those deaths are related to the drug has yet to bedetermined. According to Baxter, 40% of the adverse events were classified as "serious," mostlyoccurring in patients undergoing kidney dialysis and heart surgery.
Recent news reports indicate that the active ingredient in heparin was produced at afacility in the People's Republic of China, and that "due to human error, and inadequateinformation-technology systems," this facility was never inspected by the FDA. This comes onthe heels of my earlier inquiry, which raised serious concerns that the FDA inspected only 11pharmaceutical plants in China during 2007, even though hundreds if not thousands of facilitiesare producing active pharmaceutical ingredients (API) used in drugs sold in this country.
Accordingly, I am requesting that FDA provide a timeline of events that led to thediscovery that a pre-approval inspection had not been conducted at this Chinese facility as wellas input on what can be done to prevent such situations from occurring in the future. Please keepme apprised of any developments and findings in FDA's investigation of this matter. In addition,I would appreciate responses to the following questions:
1. According to the FDA, the Agency normally conducts "pre-approval" inspections beforeapproving a drug application to determine whether establishments participating in themanufacture, packaging or testing of a dosage form or API comply with current GoodManufacturing Practices. Please describe FDA's process for identifying all foreign facilities thatmust undergo pre-approval inspection and ensuring that such inspections take place.
2. According to the FDA, the Chinese facility producing the active ingredient in heparinwas supposed to undergo a pre-approval inspection. When was that pre-approval inspectionsupposed to have been conducted?
3. Please describe in detail the "human error" that prevented a pre-approval inspection fromtaking place at this facility. What safeguards exist or need to be in place to protect against sucherrors? When, how, and by whom was the error first discovered?
4. FDA officials have previously briefed my staff on the information-technology hurdlesfacing the foreign inspection program. Please describe in detail the specific "inadequateinformation-technology systems" that contributed to this mistake.
5. Please identify the U.S. supplier and its Chinese facility that produced the API used inBaxter's heparin. How long has this facility been producing API? How long has this facilitybeen exporting to the United States, and what other drugs and/or API is produced at this facility?
6. What is the status of FDA's investigation into the four patients who died after receivingheparin?
Thank you in advance for your cooperation and assistance on this important matter. Ilook forward to hearing from you regarding the issues and questions set forth in this letter by nolater than February 29, 2008.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
February 14, 2008
Robert L. Parkinson, Jr.Chairman and Chief Executive OfficerBaxter International Inc.One Baxter ParkwayDeerfield, IL 60015-4625
Dear Mr. Parkinson:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee their properadministration. As the senior Senator from Iowa and Ranking Member of the Committee, I havea duty to ensure that the Food and Drug Administration (FDA/Agency) upholds its responsibilityto protect the public's health by properly regulating the nation's drug supply and ensuring that thedrugs Americans use are safe and effective. In carrying out this duty, I have been conducting anongoing inquiry concerning foreign pharmaceutical manufacturers and the FDA's foreign druginspection program.
Recent press reports indicate that Baxter International Inc. (Baxter) has temporarilysuspended production of its blood thinner heparin because of an increase in the reports ofadverse events that may be associated with the drug. According to the FDA, about 350 adverseevents associated with heparin have been reported since the end of last year. It has also beenreported that four people died after receiving heparin, but whether those deaths are related to thedrug has yet to be determined. According to Baxter, 40% of the adverse events were classifiedas "serious," mostly occurring in patients undergoing kidney dialysis and heart surgery.I understand that Baxter imported the active ingredient in heparin from a facility in thePeople's Republic of China. While this facility "was supposed to be inspected," according to theFDA, the inspection was never conducted "due to human error, and inadequateinformation-technology systems." This comes on the heels of my earlier inquiry, which raisedserious concerns that FDA inspected only 11 pharmaceutical plants in China in 2007, eventhough hundreds if not thousands of facilities are producing active pharmaceutical ingredients(API) used in drugs sold in this country.
However, I understand that your company inspected the Chinese facility in question lessthan six months ago, and plans to inspect it again soon, along with the U.S. facilities, as part ofan investigation to determine the cause of the adverse events. Please keep me apprised of anydevelopments and findings in your investigation of this matter. Please also describe in detail thesteps Baxter has taken and/or plans to take to investigate the increase in adverse events. Inaddition, I would appreciate responses to the following questions and requests for information:
1. Please identify the U.S. supplier and its Chinese facility that produced the API used inheparin. Please also provide a description of Baxter's relationship with the supplier andthe facility, including the length of the relationship with the facility and a description ofall goods and/or services this facility provides to your company.
2. Please describe the results of Baxter's inspection of this facility, which was conducted"less than six months ago," as well as any previous inspections. Please provide anydocuments and reports related to those inspections.
3. Please describe Baxter's protocols for establishing a relationship with a foreignmanufacturing facility. Please also describe Baxter's process for ensuring that theproducts provided these facilities meet Good Manufacturing Practice standards.
4. When did Baxter first become aware of the adverse events related to heparin? Pleaseprovide a timeline of events that led to Baxter's investigation of the increase in adverseevents associated with the drug.
5. What is the status of Baxter's investigation into the four patients who died after receivingheparin?
In cooperating with the Committee's review, no documents, records, data, or otherinformation related to these matters, either directly or indirectly, shall be destroyed, modified,removed, or otherwise made inaccessible to the Committee.
Thank you in advance for your cooperation and assistance on this important matter. Ilook forward to hearing from you regarding the issues and questions set forth in this letter by nolater than February 29, 2008. I would also appreciate a briefing for my staff at the earliestconvenience. Please provide the requested documents and information in accordance with theattached instructions and definitions.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
February 1, 2008
The Honorable Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857
Dear Commissioner von Eschenbach:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee their properadministration. As the senior Senator from Iowa and Ranking Member of the Committee, I havea duty to ensure that the Food and Drug Administration (FDA/Agency) upholds its responsibilityto the public's safety by properly regulating the nation's drug supply and ensuring that the drugsAmericans use are safe and effective. In carrying out this duty, I have been conducting anongoing inquiry concerning foreign pharmaceutical manufacturers and the FDA's foreign druginspection program.
This past October, I wrote to you concerning the FDA's program for inspecting foreignpharmaceutical manufacturing plants and ongoing questions regarding inspection funding,emerging exporters, weaknesses in the inspection process, over-the-counter drug importation,and other pressing issues. On Thursday, December 13, 2007, FDA representatives visited myoffice to discuss these topics, and I greatly appreciate the information they provided to my staff.That same week, I received FDA's written response to my August 7, 2007 letter. I am writingtoday to review what your agency officials told my Committee staff and follow up with a numberof 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 is reiteratedbelow. I found these numbers very troubling. Since the beginning of FY 2002, the FDAconducted approximately 1,379 inspections of foreign pharmaceutical facilities, often focused incountries with few reported quality concerns. The table below contains the number ofinspections conducted by the FDA in the 10 countries with the highest number of pharmaceuticalfacilities inspected.
Top Ten Total Inspections by Country, FY 2002-2007Country 2002 2003 2004 2005 2006 2007 TotalIndia 10 19 36 33 34 61 193Germany 23 14 35 25 20 18 135Italy 16 31 25 21 17 12 122Canada 27 12 17 22 24 16 118U.K. 17 22 17 18 16 9 99France 14 18 13 12 15 24 96Japan 10 13 13 21 13 12 92China 11 6 18 13 16 11 76Switzerland 11 11 11 15 9 14 71Ireland 11 5 12 14 2 7 51
In China, the world's largest producer of active pharmaceutical ingredients (API), andwhere export safety appears to be a growing problem, only 11 inspections were conductedduring FY 2007, compared to 14 in Switzerland, 18 in Germany, and 24 in France, all countrieswith advanced regulatory infrastructures. Moreover, the table shows a drop in the number ofinspections conducted in China from a peak of 18 in 2004, while inspections in countries withrobust internal controls such as France appear to be on the rise. This seems to be a misplacementof limited FDA resources. Accordingly, I am interested in learning how the United States mightutilize the advanced inspection capabilities of our industrialized trading partners to better focusthe FDA's limited inspection resources in countries where export quality is of greater concern.
On this topic, I would appreciate answers to the following questions:
(1) How many Chinese and Indian pharmaceutical plants that are currently exporting productdirectly 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 that havebeen taken each year for fiscal years 2002 through 2007. In the case of Warning Letters,please provide a copy of the letter.
(3) For fiscal years 2002 through 2007, please provide the amount of exports from each ofthe countries listed above to the United States.
(4) Please detail FDA efforts to establish any additional bilateral and multilateral agreementsthat would allow the sharing of inspection information. Please also discuss the FDA'sposition on shifting its inspection resources away from highly developed nations andtowards countries where export quality is less established.
Concerns over the quality of Chinese pharmaceutical exports were reinforced by therecent scandal involving the Shanghai Pharmaceutical (Group) Co. One of China's largestpharmaceutical companies, Shanghai Pharmaceutical is accused of producing and distributing atainted leukemia drug. Recent news reports indicate that this contaminated drug has harmednearly 200 patients in China, in some cases causing them to become paralyzed. ShanghaiPharmaceutical claims to be in partnership(s) with multinational drug companies and to activelyexport API around the globe. Please identify what products this company exports to the UnitedStates, and specify whether any of the API produced by this company is shipped to other plantswhich export to our market. If so, what is being done to ensure that these products are not alsocontaminated?
I was also disturbed by an event that occurred this past summer in Japan. When FDAinspectors visited the Tomita Pharmaceutical Company (Tomita) from July 31 through August 2,2007, they discovered significant deviations from FDA standards. These deviations includedincomplete analyst worksheets, insufficient computerized systems, a lack of written protocols,and other problems. Without these records, FDA inspectors are unable to confirm manufacturertests. Furthermore, during the inspection Tomita officials refused to provide FDA inspectorswith certain records, effectively preventing the FDA from completing its inspection. TheJanuary 14, 2008 FDA Warning Letter to Tomita asked that the company conduct an evaluationof its own facility, and threatens that the FDA will "recommend disapproval of any newapplications or supplements" from the company.
I am troubled by this response, which seems woefully insufficient. Tomita officials haverefused to allow FDA officials to complete inspection of their manufacturing facility, yet thecompany appears to still be allowed to export its product to consumers in the United States.Please confirm if this is the case. Also, I would be interested to know the full range ofenforcement measures available to the FDA when a manufacturing plant refuses to give ourinspectors full access, and how FDA officials decide what actions to take against uncooperativecompanies.
Another topic covered during the December briefing was the establishment of FDAfacilities abroad. One important step to improving the FDA's ability to inspect foreignpharmaceutical plants would be the establishment of offices in Asia, where pharmaceuticalmanufacturing is rising dramatically. In the December briefing, your staff indicated that no firmplan was in place for such an office. However, recent comments by the Department of Healthand Human Services Secretary Michael Leavitt indicate that the establishment of an office inIndia is under consideration. I would appreciate additional information regarding this effort andyour input on the resources that would be required to make an FDA office in India a reality.In addition to the inspection of foreign pharmaceutical plants, FDA representatives alsocommented during the December briefing on efforts to prevent tainted dosage forms and APIfrom entering this country. A similar problem highlighted over the last few months by theSeattle Times is the importation of unproven medical devices. The Seattle Times published aseries of articles over the last few months regarding its investigation into the sale and use ofunproven medical devices that are manufactured overseas and claim to manipulate the body'senergy fields to improve health, including curing diseases like cancer and AIDS. According tothe Seattle Times, the FDA recently took action against a network of foreign manufacturers ofsuch devices in 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 its device.Under 21 C.F.R. 812, a device manufacturer can ship and use an investigational device in aclinical study that does not involve significant risk as long as it obtains an investigational deviceexemption from an institutional review board. Consequently, as reported by the Seattle Times,the FDA does not know how many and which unproven devices are being tested in clinical trials.This week, you also testified that the problem with manufacturers importing fraudulent devicesinto the U.S. need to be stopped at the source. On this topic, I would appreciate answers to thefollowing questions:
(1) Please describe any efforts underway to improve FDA's ability to identify what devicesare involved in clinical trials as well as to identify and track foreign manufacturers and/ordistributors of non-FDA approved devices.
(2) Please elaborate on FDA's plans to stop importation of fraudulent and unproven devicesat the source.
(3) How will the FDA work with state, local, and other federal authorities as well as foreigngovernments to investigate and prevent the importation of fraudulent and unprovendevices 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 important matter. Ilook forward to hearing from you regarding the issues and questions set forth in this letter by nolater than February 15, 2008. I would also appreciate a written response to my previous letter,dated October 30, 2007.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
For Immediate Release
Tuesday, October 30, 2007
Grassley delves further into FDA review of foreign-made pharmaceuticals
WASHINGTON — Sen. Chuck Grassley is following up on his initial inquiry of theFood and Drug Administration regarding its work to ensure the safety of foreign-madepharmaceutical ingredients and medicines with a series of questions about foreign inspectionfunding, FDA registration of foreign plants, newly emerging exporters of pharmaceuticals, andweaknesses in the foreign inspection process.
The text of the letter he sent today to the FDA Commissioner follows here, along with thetext of his August letter. FDA officials briefed Grassley staff following the first letter.
October 30, 2007
The Honorable Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857
Dear Commissioner von Eschenbach:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee the properadministration of the programs. As Ranking Member of the Committee, I have a duty to ensurethat the Food and Drug Administration (FDA/Agency) upholds its responsibility to the public'ssafety by properly regulating the nation's drug supply and ensuring that the drugs Americans useare safe and effective.
On August 7th of this year, I wrote to you concerning the FDA's program for inspectingforeign pharmaceutical manufacturing plants. This is because these plants produce a largeamount of the active pharmaceutical ingredients (API) and dosage forms that make up America'spharmaceutical supply, and I wanted to know more about the problems confronting the FDA inits efforts to ensure that the products coming out of these facilities are safe for Americans. OnAugust 23, FDA representatives briefed my committee staff about the FDA's ongoing efforts andthe challenges the Agency faces. This briefing was very informative, and I would now like totake this opportunity to review what your agency officials told my Committee staff and followup with a number of additional questions.
The pharmaceutical industry, like many sectors, has experienced rapid globalization inrecent years. Today, it is estimated that nearly 80% of the pharmaceuticals used in the UnitedStates are manufactured overseas, including both active pharmaceutical ingredients and dosageforms. The responsibility for ensuring the safety of these drugs is placed on the FDA, whichinspects plants where API and dosage forms are manufactured both at home and abroad. I nowunderstand that most foreign inspections occur in China and India, which are the largestexporters of pharmaceutical products to the United States, followed, in order, by leadingexporters Italy, France, Germany, Israel, Spain, the United Kingdom, Ireland, and Japan. Iunderstand many of these Western European countries, as well as Israel and Japan, have robustregulatory systems and dependable drug safety protocols, while other exporters are lessdependable and demand more of the FDA's inspection resources. I also understand that the FDAconducts inspections of pharmaceutical manufacturing plants in these countries on the basis offree trade agreements, bilateral agency-to-agency memorandums of understanding, and informalletters.
The FDA is in an understandably difficult position, in that it is charged with ensuring thesafety of America's pharmaceuticals, which are produced in nearly every corner of the globe.Understanding this challenge, I sought to learn more about how the FDA accomplishes this task.Through discussion with the director of the FDA's Division of Field Investigations and others,my staff learned that the FDA employs roughly 1,300 Consumer Safety Officers (CS Officers) toconduct the Agency's national and international inspection activities. Of these, there areapproximately 600 CS Officers, usually senior investigators, qualified to conduct foreigninspections. On a voluntary basis, these inspectors travel abroad for about three weeks at a time,during which they aim to inspect three manufacturing facilities.
With an annual foreign inspection budget of about $3.5 million, and an estimated cost of$3,100 to $3,500 per inspector per inspection, the FDA aims to conduct approximately 1,000foreign inspections annually. Because this budget includes inspections of foreign foodproducers, medical device manufacturers, and makers of veterinary medicine, pharmaceuticalmanufacturing plants only make up between a third and half of the inspections conducted in mostyears.
My staff learned further that inspections of foreign pharmaceutical plants are arranged inadvance, and conducted by FDA teams of two CS Officers. I understand that once the FDAteam arrives, inspections do not actually cover the API or dosage forms. Rather, the FDA teamsinspect the plants for overall integrity and ask the manufacturing plants being inspected to sendsamples of their products to the United States for testing. These products are then tested by theFDA's Forensic Chemistry Center.
Once an inspection is completed, my staff was told that there are three possibleoutcomes: 1) No Action, 2) Voluntary Action, and 3) Official Action. I understand that the"Official Action" can take two forms: an "untitled letter" if the plant is not yet shipping productto the United States, and a "warning letter" if it is and some concern has come to FDA's attentionas a result of the onsite review or the testing of the samples provided. A "warning letter" servesto put the plant on official notice of a deficiency and requires corrective action in a timelyfashion. FDA's briefing provided also revealed that, upon recommendation, the FDA can alsodetain the product from entering the United States until corrective action is taken.I thank the FDA for briefing my staff on the Agency's inspection process, and wouldappreciate further discussion on this process. There are a number of other matters regarding theFDA's ability to monitor and ensure the safety of the API and dosage forms produced andmanufactured abroad that are of interest to me. I will outline these matters below, and lookforward to an additional briefing on these points.
Inspection Funding
Following the briefing, it is clear that fiscal constraints are a major reason behind theFDA's inability to inspect foreign pharmaceutical manufacturing plants as widely as is needed.My staff was told that other countries, including the United Kingdom and Australia, may chargehost plants the cost of inspection, and that European Union members may charge host plants orhost governments for their inspections. The August briefing did not cover this issue at greatlength, but I would like to revisit it and discuss ways to make certain that the FDA has theresources it needs to ensure the safety of API and dosage forms imported to the United States.
FDA Registration
One reason the FDA's task is so daunting is that the pool of registered foreign plants isever expanding. Exacerbating this problem, many foreign plants register with the FDA whilehaving no intention of exporting to the United States. This registration process has the effect ofincreasing the costs and inspection pool of the FDA while having no benefit at all to theAmerican consumer. I am under the impression that many plants register simply to bolster theircredentials internationally, as opposed to being interested in exporting their products to theUnited States. For example, in China there are approximately 578 companies registered with theFDA, but only 200 to 300 actually ship product to the United States. One possible explanation isthat FDA registration is free to foreign companies and gives them the imprimatur of having anFDA "seal of approval," However, this seal of approval comes on the American taxpayer's dime,as it is their tax dollars that fund the foreign inspections. I am interested in learning what, ifanything, the FDA may be considering to address this problem.
Emerging Exporters
The FDA's limited resources to conduct these inspections results in another problem.Some emerging exporters have never been inspected. According to your staff, most of the FDA'sinternational inspection efforts focus, understandably, on China and India. Other emergingexporters, such as Bangladesh, sparked my interest because there appear to be few, if any,inspections of pharmaceutical plants in emerging exporter countries. I am interested in learningmore about efforts to inspect emerging pharmaceutical exporters.
Weaknesses in the Inspection Process
I am also concerned with the ease with which foreign manufacturers can get around FDAregulations. Due to the FDA's lack of extraterritorial authority, FDA teams must arrangeinspections far in advance, and have no authority to conduct surprise inspections. Drug samplesare not always collected on site, but are often sent to the United States for testing by themanufacturer. This system seems to allow room for foreign manufacturing plants to get aroundFDA's efforts to protect American consumers, and I look forward to hearing your ideas on howto better approach these issues. I would also like to know whether this policy of "mailed-in"samples is FDA's policy, or that of the foreign plants. In other words, are foreign manufacturinglimiting our ability to obtain samples on site or in any way prohibiting samples from being takenon site by FDA's inspectors.
In addition to the issues presented above, I would like to continue our discussion fromlate August, focusing more on the following areas:
1. How does the FDA identify all of the foreign pharmaceutical manufacturing plants thatexist in a given country?
1. How does the Agency monitor which plants export to the United States and whichdo not?
2. How does the Agency monitor keep this list up-to-date?
2. Beyond pre-approval inspections, how frequently do FDA teams inspect a typical foreignpharmaceutical manufacturing plant?
1. Does FDA conduct follow-up inspections only after a specific complaint isreceived, or is there another system for conducting follow-up inspections?
3. How does the FDA select plants for inspection?
1. Does it conduct a pre-approval inspection at every facility before the facility shipspharmaceutical products to the United States? If not, why not?
2. What process does FDA use to decide whether and when to conduct follow-upinspections?
4. After the FDA takes "Official Action" by way of an untitled letter or warning letter, howdoes the FDA ensure that problems are corrected?
1. Does an FDA team conduct a second inspection in every case? If not, howfrequently does the FDA conduct second inspections?
5. If a particular foreign pharmaceutical manufacturing plant uses subcontractors or importsAPI or dosage forms from other plants, does the FDA inspect these subcontractors orother plants before the primary plant is approved to export to the United States? If not,why not?
1. If so, does the same FDA team that inspects the primary plant also inspect thesecondary?
6. My staff was told that FDA inspectors used to take drug samples during the course of aninspection, and that these samples would be kept in the custody of the FDA until tested.According to the briefing in August, I understand that this is no longer the practice.Instead, the FDA reportedly permits foreign pharmaceutical manufacturing plants to shipthe samples to the Forensic Chemistry Center themselves, allowing for limited, if any,assurance that the samples are indeed from the plant that is the subject of inspection. Ismy understanding of the current procedures correct?
1. If so, why has the FDA changed its approach, and how does it ensure the integrityof its inspection process?
7. It has been reported that generic and over-the-counter drug importation is a majorconcern. I would like to receive more information about this issue, and to explore withyou what additional tools the FDA needs to ensure that these pharmaceuticals are safe forAmericans.
I look forward to your cooperation and assistance on this important matter. Please haveyour staff contact my Committee staff to schedule the requested briefing by November 16, 2007.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
For Immediate Release
Thursday, Aug. 9, 2007
Grassley Seeks FDA Briefing on Steps to Ensure Safety of Foreign-made MedicineWASHINGTON – Sen. Chuck Grassley, ranking member of the Committee on Finance, isasking the Food and Drug Administration for an explanation of its steps to ensure the safety offoreign-made medicine. In a letter to the agency commissioner, Grassley said he is disturbed byreports of the inadequacy of FDA inspections of foreign pharmaceutical manufacturing facilities,especially given the growing predominance of overseas manufacturing of such products.
The text of Grassley’s letter follows here.
August 8, 2007
The Honorable Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857
Dear Commissioner von Eschenbach:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee the properadministration of the programs, including the payment for prescription drugs regulated by the Foodand Drug Administration (FDA). As Ranking Member of the Committee, I have the duty to ensurethat the FDA upholds its responsibility to the public’s safety by properly regulating the nation’s drugsupply and ensuring that the drugs Americans use are safe.
I have been troubled by a number of recent articles discussing the FDA’s failures ininspecting foreign pharmaceutical manufacturing plants. In fact, in a recent Washington Post article,William Hubbard, a former FDA associate commissioner, characterized the problem as “dire anddeteriorating.” Given the fact that nearly 80 percent of the active pharmaceutical ingredients usedin the U.S. are manufactured abroad, this is a significant problem that needs to be addressedimmediately.
Even more troubling is that this problem is not a new one. Congress has expressed concernsabout the FDA’s oversight of foreign drug manufacturing facilities in the past. In 1998, theGovernment Accountability Office prepared a report to the United States House Committee onCommerce responding to concerns about the FDA’s “ability to ensure the safety and quality of theincreasing volume of foreign-produced drugs imported daily into the United States.” The fact thatthis problem persists nearly ten years after this report was published is unacceptable.
Accordingly, I am requesting that the FDA provide information about how it is handling thisserious problem. I would like to know the measures the FDA has in place today to inspect foreigndrug manufacturing facilities, as well as how it intends to improve these measures in the future.Specifically, I ask the FDA to brief my staff and provide formal responses to the followingquestions:
1. What protocols does the FDA currently have in place regarding inspection of foreignpharmaceutical manufacturing facilities? What specifically does the FDA do when it inspectsa foreign pharmaceutical manufacturing facility? Please include copies of the protocols inyour response.
2. How many on-site visits of foreign pharmaceutical manufacturing facilities has the FDAperformed since 2002 and who performed them? In what countries were these inspectionsperformed? How many inspections were performed in each country? What were the results?When an inspection results in negative findings, what kind of follow-up occurs? How muchdoes the FDA spend on foreign inspections annually? How many of these inspections werefor pre-approval purposes rather than ongoing inspections of existing sites? How many werefor facilities producing generic drugs, and how many were for those producing brand nameones? In India, what number were for PEPFAR Aids programs?
3. What kinds of cooperative relationships does the FDA have with its foreign counterparts orother foreign regulatory bodies? How does the FDA measure the efficacy of the inspectionsperformed by these foreign agencies? By those measures, how well are these agenciesperforming the function of thorough inspection of drug manufacturing facilities?
4. What strategies is the FDA developing to improve the inspection of foreign pharmaceuticalplants, and what is the timeline for the implementation of these strategies? What, if any, arethe barriers to implementing these strategies?
5. How long do FDA inspectors typically remain abroad? How long do inspections of foreignfacilities usually last?
6. Does the FDA currently have any plans to create an agency outpost in India? If so, what isthe status of these plans?
7. A report by PriceWaterhouseCoopers recently stated that, in the near future, pharmaceuticalmanufacturers will make a large shift from domestic facilities to ones in Asia. How is theFDA preparing to respond to this possibility?
I look forward to your cooperation and assistance on this important matter, and would greatlyappreciate a briefing for my staff. Please have your staff contact my Committee staff to schedule ameeting.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
For Immediate Release
Thursday, Aug. 9, 2007
Grassley Seeks FDA Briefing on Steps to Ensure Safety of Foreign-made Medicine
WASHINGTON – Sen. Chuck Grassley, ranking member of the Committee on Finance, isasking the Food and Drug Administration for an explanation of its steps to ensure the safety offoreign-made medicine. In a letter to the agency commissioner, Grassley said he is disturbed byreports of the inadequacy of FDA inspections of foreign pharmaceutical manufacturing facilities,especially given the growing predominance of overseas manufacturing of such products.The text of Grassley’s letter follows here.
August 8, 2007
The Honorable Andrew C. von Eschenbach, M.D.CommissionerU.S. Food and Drug Administration5600 Fishers LaneRockville, MD 20857Dear Commissioner von Eschenbach:
The United States Senate Committee on Finance (Committee) has jurisdiction over theMedicare and Medicaid programs and, accordingly, a responsibility to the more than 80 millionAmericans who receive health care coverage under those programs to oversee the properadministration of the programs, including the payment for prescription drugs regulated by the Foodand Drug Administration (FDA). As Ranking Member of the Committee, I have the duty to ensurethat the FDA upholds its responsibility to the public’s safety by properly regulating the nation’s drugsupply and ensuring that the drugs Americans use are safe.
I have been troubled by a number of recent articles discussing the FDA’s failures ininspecting foreign pharmaceutical manufacturing plants. In fact, in a recent Washington Post article,William Hubbard, a former FDA associate commissioner, characterized the problem as “dire anddeteriorating.” Given the fact that nearly 80 percent of the active pharmaceutical ingredients usedin the U.S. are manufactured abroad, this is a significant problem that needs to be addressedimmediately.
Even more troubling is that this problem is not a new one. Congress has expressed concernsabout the FDA’s oversight of foreign drug manufacturing facilities in the past. In 1998, theGovernment Accountability Office prepared a report to the United States House Committee onCommerce responding to concerns about the FDA’s “ability to ensure the safety and quality of theincreasing volume of foreign-produced drugs imported daily into the United States.” The fact thatthis problem persists nearly ten years after this report was published is unacceptable.
Accordingly, I am requesting that the FDA provide information about how it is handling thisserious problem. I would like to know the measures the FDA has in place today to inspect foreigndrug manufacturing facilities, as well as how it intends to improve these measures in the future.Specifically, I ask the FDA to brief my staff and provide formal responses to the followingquestions:
1) What protocols does the FDA currently have in place regarding inspection of foreignpharmaceutical manufacturing facilities? What specifically does the FDA do when it inspectsa foreign pharmaceutical manufacturing facility? Please include copies of the protocols inyour response.
2) How many on-site visits of foreign pharmaceutical manufacturing facilities has the FDAperformed since 2002 and who performed them? In what countries were these inspectionsperformed? How many inspections were performed in each country? What were the results?When an inspection results in negative findings, what kind of follow-up occurs? How muchdoes the FDA spend on foreign inspections annually? How many of these inspections werefor pre-approval purposes rather than ongoing inspections of existing sites? How many werefor facilities producing generic drugs, and how many were for those producing brand nameones? In India, what number were for PEPFAR Aids programs?
3) What kinds of cooperative relationships does the FDA have with its foreign counterparts orother foreign regulatory bodies? How does the FDA measure the efficacy of the inspectionsperformed by these foreign agencies? By those measures, how well are these agenciesperforming the function of thorough inspection of drug manufacturing facilities?
4) What strategies is the FDA developing to improve the inspection of foreign pharmaceuticalplants, and what is the timeline for the implementation of these strategies? What, if any, arethe barriers to implementing these strategies?
5) How long do FDA inspectors typically remain abroad? How long do inspections of foreignfacilities usually last?
6) Does the FDA currently have any plans to create an agency outpost in India? If so, what isthe status of these plans?
7) A report by PriceWaterhouseCoopers recently stated that, in the near future, pharmaceuticalmanufacturers will make a large shift from domestic facilities to ones in Asia. How is theFDA preparing to respond to this possibility?
I look forward to your cooperation and assistance on this important matter, and would greatlyappreciate a briefing for my staff. Please have your staff contact my Committee staff to schedule ameeting.
Sincerely,
Charles E. GrassleyUnited States SenatorRanking Member of the Committee on Finance
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