Letter and documents sent to the Food and Drug Administration urging them to immediately recall all lots of Abbokinase because of possible contamination with infectious agents. (HRG Publication #1473)
February 10, 1999
Dr. Jane Henney, Commissioner
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
Dear Dr. Henney:
The purpose of this letter is to strongly urge you to recall immediately all lots of Abbokinase, a widely-used clot-busting drug--$250 million in sales in 1998 for Abbott Laboratories of Abbokinase(1)--and to seize all raw materials and in-process precursors used to make Abbokinase, as recommended by FDA field officials, because of possible contamination with infectious agents. In addition, you must launch an immediate investigation into the extremely suspicious circumstances in which the kidney tissue, from which the drug is made, has been obtained in Colombia. I also urge you to investigate whether charges should be brought against the companies involved for violation of the prohibition against bringing human body parts or tissue into this country identified as "Noninfectious Biological Materials for Medical Research and Use" when, in fact, they are to be used to produce an FDA-regulated product. As FDA personnel have concluded, the law requires them to be identified as "potentially infectious." In addition, there are other apparent violations of Federal law.
From FDA inspection reports and import documents and from interviews with many FDA officials, I have learned the following:
1. Abbokinase has been derived from kidneys taken from deceased newborn babies or aborted fetuses in a hospital in Cali, Colombia (South America) without evidence of adequate informed consent from the parents (no "verification that the parents of the neonates signed the consent forms for the use of neonatal tissue."--this and other bolded quotations in this paragraph are from an FDA inspection report) and without adequate screening and testing of babies or their mothers for infections ("....no documentation of a questionnaire evaluating the suitability of the mother, nor documentation of an appropriate physical exam of the mother or neonate.") The kidney tissue is then shipped to BioWhittaker, a company in Walkersville, MD for further processing of the material. ("BioWhittaker did not provide a description of the precautions taken to prevent adventitious contamination and cross contamination during the processing of the neonatal tissues and cells--kidney, liver, lung, central nervous system cells are harvested simultaneously-- in the South American facilities.") Furthermore, the materials were then imported by BioWhittaker into the United States for further processing without being declared through customs as an FDA-regulated commodity and without being identified as "Treat as Potentially Infectious." Both of these omissions violate U.S. law. The material processed by BioWhittaker is then sent to Abbott.
2. After a July 1998 FDA inspection of BioWhittaker, which revealed the above violations in procuring kidneys in Colombia and shipping the kidney cells into the United States, (2) the FDA placed an import ban on the neonatal kidney tissue from Colombia.(3) According to FDA officials, that ban is still in effect. A September 18, 1998 FDA warning letter to BioWhittaker stated that, in violation of FDA law, "The labeling for shipments of _____states, 'These cells are NON-HAZARDOUS, NON-INFECTIOUS, and NON-RESTRICTED,' when, in fact, this material is potentially infectious." FDA investigators of BioWhittaker recommended seizure of existing in-process tissue at BioWhittaker, a recommendation which was ultimately overturned by FDA's Washington office.
3. As a result of the findings at BioWhittaker and the recommendation for seizure, the FDA conducted an inspection in October-November, 1998 of Abbott Laboratories itself, in Abbott Park, Illinois, which produces Abbokinase from the kidney tissue partially processed by BioWhittaker. At the Abbott facility, FDA inspectors found serious breaches in the testing and production of Abbokinase such as:
"Supplier's [BioWhittaker] Certificate of Analysis for Human Neonatal Kidney Cells (HNK) indicated cell lot numbers...passed the tests for Hepatitis B surface Antigen ....similar tests [on the same lot] performed by Abbott...was positive for HbsAg (Hepatitis B surface Antigen). No documentation can be located to assure the supplier was contacted [by Abbott] to determine the cause of the non-conformance and to assure corrective actions will prevent future occurrence."
Referring to separation/purification column resins that are part of Abbott's manufacturing process, the investigators found that:
"No validation studies have been conducted to assure that any virus (or other contaminant) potentially retained on the resin or column, would be adequately removed or destroyed prior to reuse, preventing cross-contamination between lots."(4)
4. Because of the risk of infection to people using the product, FDA's investigators of Abbott recommended seizure of $100 million worth of raw materials, in-process products and finished products relating to Abbokinase that were located at Abbott facilities in Abbott Park, Illinois.
However, due to pressure on the FDA from radiologists who use the drug in procedures to break up blood clots in the peripheral arteries and veins (a use not approved by the FDA), who alleged that there is no suitable substitute for Abbokinase for this use, the FDA, without doing its own thorough, independent investigation into the suitability of alternative drugs, reversed the recommendations of its own field office and neither seized the potentially contaminated products nor recalled those already in the channels of commerce. A recognized international expert in the use of these drugs, whom I consulted, stated that urokinase (Abbokinase) and tPA, another drug for treating peripheral blood clots, were equally as safe and effective. For other conditions for which Abbokinase is approved, such as treatment of heart attacks or blood clots to the lungs (pulmonary embolism), there is not any dispute that equally safe and effective alternatives exist.
5. Instead of a recall, FDA's CBER (the Center for Biologic Evaluation and Research) Director Dr. Kathryn Zoon sent a letter on January 25th of this year to healthcare providers coincident with the resumption of Abbokinase shipments that had been on hold since December 1998. Her letter stated that:
"recent manufacturing inspections revealed deficiencies in some of the procedures used by Abbott and its supplier of the human neonatal kidney cells that could increase the risk of transmitting infectious agents...The FDA is not aware of any cases of infectious diseases that can be attributed to the use of Abbokinase. However, the likelihood that cases of infectious diseases caused by Abbokinase, if any, would have been recognized as such and reported to the FDA is probably very low. Therefore, the actual risk to patients of developing an infectious disease as a result of using Abbokinase is unknown.(emphasis added). The FDA is recommending that Abbokinase be reserved for only those situations where a physician has considered the alternatives and has determined that the use of Abbokinase is critical to the care of a specific patient in a specific situation..."(5)
6. Abbott and the FDA are making a travesty of public health by their solution to this serious problem. Instead of seizing the product made from the Colombian kidneys, Abbokinase has been relabeled with, among other information, the following statements:
"The procedures used in the manufacture of currently available ABBOKINASE raise concerns regarding the risk of transmission of infectious agents....The kidney cells used in the manufacture of this product were obtained from populations at high risk of a variety of infectious diseases, including tropical diseases....While Abbott has recently instituted a test for HCV [hepatitis C virus] in kidney cells used in the manufacture of currently available lots of ABBOKINASE, this test has not been validated."(6)
The following is a more detailed review of each of the steps leading to the present situation:
1. FDA Inspection of BioWhittaker in July/August 1998 (7/14-16/98; 7/21-23 and 8/3/98) (FDA Form 483 inspection summary, dated 8/3/98 is the source)
This suburban Washington facility was inspected in July and August, 1998. FDA inspectors made, in addition to others, the following findings:
"Audits...are not sufficient to assess safety issues in that they do not include:
-evidence that the facilities, equipment, personnel, and procedures used in the harvesting of neonatal kidneys in the South American hospital have ever been audited;
-verification that the parents of the neonates signed the consent forms for the use of neonatal tissue;
-verification into the cause of the termination of pregnancy and the causes of the neonates deaths;
-verification of the clinical history (e.g. medical records) of the mother and neonate used to evaluate the potential occurrence of infectious disease and evidence of genetic defects;"
"....there is no documentation of a questionnaire evaluating the suitability of the mother, nor documentation of an appropriate physical exam of the mother or neonate."
"BioWhittaker was unable to provide documentation of autopsies performed on the neonates despite the fact that the Human Neonatal Kidney Cells Specimen Form 0643 states the date of the autopsy."
"There is no assurance that orphans with unknown mothers are not used as a source of Human Neonatal Kidney Cells."
"BioWhittaker does not segregate Human Neonatal Kidney Cells intended for production of pharmaceutical Urokinase from the following: untested Human Neonatal Kidney Cells from potentially infectious material of human and animal origins (human tumorigenic cell lines, African Green Monkey, Buffalo Green Monkey, Rhesus Monkey, Cynomolgus Monkey, Canine, and Rabbit sources)."
"BioWhittaker failed to verify that the deficiencies noted in the audit report of 1993 for the Human Neonatal Kidney Cells supplier were corrected..."
"BioWhittaker did not provide a description of the precautions taken to prevent adventitious contamination and cross contamination during the processing of the neonatal tissues and cells (kidney, liver, lung , central nervous system cells are harvested simultaneously) in the South American facilities."
"BioWhittaker is receiving Human Neonatal Kidney Cells in the United States that are not being declared [through customs] as an FDA regulated commodity."
"BioWhittaker's shipping containers used to ship Human Neonatal Kidney Cells to ______are not labeled as: 'HUMAN SOURCE MATERIAL: TREAT AS POTENTIALLY INFECTIOUS...' according to their master file."
2. Import Bulletin [Hold] of August, 1998; Following the FDA inspection of BioWhittaker
(I have learned from FDA officials that a hold was then placed on the import into the U.S. of the Human Neonatal Kidney Cells from Colombia which is still in effect)
"Baltimore district has learned through establishment inspection that human neonatal kidney cells (HNK cells) are being imported to the United States for use in the manufacture of an FDA approved drug. Available information indicates the HNK cells are represented during importation as "Noninfectious Biological Material For Medical Research and Use."
The statement appears on records accompanying the shipments, but not on the product container labels. The product container label states "WARNING: Human Source Material. Treat as Potentially Infectio[u]s."
"Serious safety issues per Section 361 of the Public Health Service Act were raised during Baltimore's inspection which cause concern for the following reasons:
* Inadequate medical history exists for the mother.
* Virology testing procedures have not been validated.
* Inadequate testing and documentation exists to demonstrate adherence to the Drug Master File.
* Audits of the foreign firm are not adequate to ensure compliance with all Drug Master File requirements."
3. FDA Warning letter to BioWhittaker September 18, 1998
Following the inspection described above, a recommendation for seizure was made by the Baltimore FDA Office but it was not implemented. A Warning Letter from the FDA to BioWhittaker was sent on September 18, 1998. Included in the letter were the following:
"Investigation of Quality Control Initial Test Failures" is not followed in that, for at least___ lots of ____that initially failed sterility testing, there was no investigation into the cause of the contamination..."
"The labeling for shipments of _____states, 'These cells are NON-HAZARDOUS- NON-INFECTIOUS, and NON-RESTRICTED,' when, in fact, this material is potentially infectious."
"....labeling which routinely accompanies shipments of ___________ from your supplier was found by the agency to contain false and misleading statements."
4. FDA Inspection of Abbott in October/November 1998
Following the BioWhittaker inspection, the FDA conducted an inspection of Abbott in the Chicago area. This inspection was done from 10/26 to 11/20/98: Excerpts from FDA form 483 are listed below:
"Human Neonatal Kidney Cells used for the production of urokinase during 1997 and 1998 manufacturing campaigns...have not been tested for the presence of Hepatitis C virus".
"Human Neonatal Kidney Cell culture supernatant is harvested daily and placed into a chilled tank where it is stored for up to one week prior to further processing. There are no tests performed to evaluate the level of bacteria, endotoxin, mycoplasma or adventitious virus in the in-process bulk at the end of this hold period."
Referring to separation/purification column resins which are part of Abbott's manufacturing process, the investigators found that: "No validation studies have been conducted to assure that any virus (or other contaminant) potentially retained on the resin or column, would be adequately removed or destroyed prior to reuse, preventing cross-contamination between lots."
"Supplier's [BioWhittaker] Certificate of Analysis for Human Neonatal Kidney Cells (HNK) indicated cell lot numbers...passed the tests for Hepatitis B surface Antigen....similar tests [on the same lot] performed by Abbott...was positive for HbsAg (Hepatitis B surface Antigen). No documentation can be located to assure the supplier was contacted [by Abbott] to determine the cause of the non-conformance and to assure corrective actions will prevent future occurrence."
Based on the findings of this inspection, FDA's Chicago office recommended seizure of $100 million worth of raw materials, in-process products and finished products relating to Abbokinase that were located at Abbott facilities in Abbott Park, IL. This recommendation was overturned by the FDA in Washington.
5. FDA Statement of December 11, 1998
Two days following an Abbott 12/9/98 letter to doctors concerning the shortage of Abbokinase, the FDA released a statement concerning what was to be a temporary hold (not a seizure) of Abbokinase.
"FDA Center for Biologics Evaluation and Research (CBER) will not release lots of Abbokinase until CBER's review of the inspectional findings and information recently submitted by Abbott is complete. During inspections of Abbott, the FDA observed significant deviations from Current Good Manufacturing Practices."
6. Letter of January 25, 1999 from CBER Director, Dr. Kathryn Zoon to Health Professionals.
Instead of acting on the recommendations of FDA's field office in Chicago and seizing Abbokinase finished and in-process products, the FDA was persuaded by physicians who use Abbokinase that it has unique advantages for the treatment of peripheral (leg) clots, even though it is not approved for this purpose and there is no scientific evidence of its superiority over other thrombolytic (clot-busting) drugs for this purpose. Thus, instead of seizure and recall, the company changed the labeling of the drug and the FDA sent a letter to physicians and other health care providers:
" recent manufacturing inspections revealed deficiencies in some of the procedures increasing the risk of transmitting infectious agents....The FDA is not aware of any cases of infectious diseases that can be attributed to the use of Abbokinase. However, the likelihood that cases of infectious diseases caused by Abbokinase, if any, would have been recognized as such and reported to the FDA is probably very low. Therefore, the actual risk to patients of developing an infectious disease as a result of using Abbokinase is unknown. The FDA is recommending that Abbokinase be reserved for only those situations where a physician has considered the alternatives and has determined that the use of Abbokinase is critical to the care of a specific patient in a specific situation...."
7. Lack of Scientific Evidence that Abbokinase is Safer or More Effective Than Other Thrombolytic (clot-busting) Drugs
The FDA did not actively seek opinions from independent experts on the evidence for the relative benefits of various thrombolytic agents for the treatment of blood clots. Instead, the FDA listened to radiologists who like the drug despite the absence of objective data that it is superior in safety or effectiveness to other drugs. The FDA contacted the professional organizations representing doctors who use the drug for breaking up blood clots in the legs, all of which are likely to have strong ties with Abbott and who similarly liked the drug. Apparently, no effort was made to seek out experts who are not so strongly affiliated with the product.
I wrote to Dr. Victor Marder, a noted hematologist at the University of Rochester, who has published more than 200 medical journal articles, mostly concerning treatments for blood clots, and who has written a chapter on the use of these thrombolytic (clot-busting) agents soon to be published in Hoffman's textbook, Hematology, which reviews 230 papers on the use of drugs for clot-busting purposes. I asked him to comment on whether or not there was any scientific basis to support the alleged superiority of Abbokinase, even if it were not possibly contaminated, for the treatment of peripheral blood vessel clots. He replied that in the only published large head-to-head study of Abbokinase vs. tPA, the other clot-busting drug used for peripheral arterial occlusion,(7) "both were equally safe and effective." In his response to me, he also pointed out that "any plasminogen activator [clot-busting drugs such as urokinase, tPA and streptokinase] is equivalent to another until proven otherwise by direct comparison in a properly-performed randomized and blinded trial."(8) The list of alternative drugs for all of the uses of Abbokinase, including peripheral blood clots, is included in Dr. Zoon's letter.
Given the extraordinary number of gross breaches from the collection and processing of kidneys, and in Good Manufacturing regulations governing the manufacture of Abbokinase, there is a significant likelihood that these products are contaminated. If cases of infection have occurred, the likelihood that they would have been reported to the FDA is, according to the agency, "probably very low." In the absence of evidence of the superiority of Abbokinase over other available products, there is no excuse for these products to stay on the market.
If the FDA does not recall these products, considering the unknown risk of infection and the knowledge that equally effective products exist for treating all of the diseases for which Abbokinase is approved and the unapproved uses as well, what assurance do Americans have for the safety of many other FDA-regulated biologics, such as the blood supply? If blood were collected and processed in the extraordinarily dangerous and sloppy process which has been found to characterize the production of Abbokinase from kidneys obtained under highly suspicious circumstances from infants at high risk of Hepatitis C and other diseases including tropical diseases, and processed in the dangerous way Abbokinase has been, there would be a massive outcry. If the FDA waits until the first documented case of Abbokinase-induced infection occurs to act, it will be making a mockery out of the notion of preventive public health action.
A double standard seems to be operating in this case. The questions raised about the kidney tissue taken from deceased babies in Colombia were serious enough to merit a now six-month hold on importing this tissue. Yet patients are being exposed to potentially contaminated Abbokinase manufactured from kidney tissue imported before the hold which was collected and processed under equally questionable and dangerous methods. It is difficult to come up with a more dangerous scenario for an FDA-regulated biologic.
However, the recent record number of non-biologic drugs which have been recalled in the past two years because of serious safety problems (Duract, Posicor, Redux and Seldane) demonstrates that the problem of inadequate--too late--regulatory action is not limited to biologics.
An immediate recall of all Abbokinase products should be instituted and prosecution of the companies involved for violation of federal laws should be immediately undertaken.
I look forward to a prompt response to this letter.
Sidney M. Wolfe, M.D. , Director
Public Citizen's Health Research Group
1. Abbott Abbokinase Use Should Be Limited Due to Infection Risks From Donors. Food Drug and Cosmetic Reports, February 1, 1999, page 6.
2. FDA Form 483: Summary of Inspection of BioWhittaker, Walkersville MD, July 14-16, 21-23 and August 3, 1998. Issued August 3, 1998.
3. FDA Import Alert: 8/11/98 (IA # 57-B10).
4. FDA Form 483: Summary of Inspection of Abbott Laboratories, Abbott Park, IL. 10/26-11/20/98. Issued 11/20/98.
5. Letter from Dr. Kathryn Zoon, Director of CBER in FDA, 1/25/99 to Health Professionals. "Important Drug Warning."
6. Current FDA-approved labeling of Abbokinase.
7. Annals of Surgery 1994; 220:251-268.
8. Letter from Victor Marder, M.D. to Sidney M. Wolfe, M.D., February 5, 1999.