Atgam
February 1998
This is the retyped text of an undated letter from Pharmacia & Upjohn.
Dear Prescribing Clinician,
You have been identified as a possible prescriber of ATGAM for one of three lots. Two of these are being withdrawn (Lots 795YW and 45OYY) and one of these has already expired (Lot 366YB).
The reason for this withdrawal and notification is that we have been informed that one unit of packed red blood cells used in the manufacture of these lots of ATGAM Sterile Solution was from a donor who subsequently had a diagnosis of Creutzfeldt-Jakob disease (CJD). The unit of packed cells was one of many used in the manufacturing process. Although there is an extremely low risk of developing CJD from the use of this product, a theoretical risk exists and thus the decision was made to withdraw the unexpired lots in question and to attempt to notify prescribing physicians of product from all three lots.
Creutzfeldt-Jakob Disease (CJD) is a rare degenerative disease of the central nervous system. It is generally accepted that an infectious agent is involved in the etiology of some cases of CJD. This agent is an abnormal proteinaceous infectious particle, a prion. The disease has been transmitted to humans by direct tissue to tissue contact including the use of contaminated cadaveric human pituitary gland derived growth hormone, contaminated cadaveric dura mater transplantation, contaminated corneal transplantation, and the use of contaminated electrodes in the brain. There has never been a documented case of transmission of CJD from human to human by transfusion of blood or any of its components including plasma-derived products.
ATGAM is neither a human blood component or a human plasma product, but these are used in the manufacturing process of ATGAM. A stroma consisting principally of human red blood cell walls is used for immunoadsorption in the manufacturing process. ATGAM is produced from plasma from horses who have been immunized against human thymus. The human stroma is used in the manufacturing process for immunoadsorption to remove undesirable antihuman antibodies in the horse plasma.
The stroma is prepared from outdated packed red blood cells. The process for preparing the stroma involves the separation of the buffy coat containing leukocytes from the red blood cells by filtration. Filtered cell suspensions are then frozen prior to further processing. The freezing and thawing causes the rupture of the cell wall. Subsequently, this material undergoes several washings with high volumes of water, acrinol and normal saline before the final product for use in the manufacturing process is available. One lot of stroma may be used for the production of more than one lot of ATGAM. This stroma is not an active ingredient or excipient, but is only used in the purification process. The red cell stroma is used early in the ATGAM purification process and is followed by numerous additional process steps including alcohol precipitation, silica gel chromatography, diafiltration, and ion exchange chromatography.
As mentioned above, we have been made aware that one unit of packed red cells that was used to produce the stroma for the manufacture of three ATGAM lots was from a donor who subsequently had an EEG and clinically confirmed diagnosis of CJD.
There is no test to screen for the prion that is felt to be the etiology of some variants of CJD, or to validate that prions are removed or deactivated in the process. But based on 1) how blood products are used in the manufacturing process, 2) steps in the purification process, and 3) what is currently known about the transmission of the agent that may cause CJD, the risk of developing CJD from the use of ATGAM from lots which may have possibly used CJD-contaminated blood in the manufacturing process is extremely small, but there still exists a theoretical risk. Based on this extremely small but theoretical risk, the decision has been made to withdraw the lots in question.
You will need to make a determination of the medical appropriateness of notifying the patients who received the ATGAM, keeping in mind the extremely small risk of transmission of CJD, the absence of any treatment for CJD, the absence of any screening test for CJD, and the very long incubation period of this disease.
Attached is an excerpt from the letter from the blood bank who notified us of the diagnosis of CJD in the donor. You may want to consider this information as you consider the question of recipient notification. Please keep in mind that this information refers to recipients of blood or a blood products produced from a CJD donor. This would be a higher level of risk than we are discussing with ATGAM where the blood was only used in the manufacturing process.
If you have questions regarding the medical aspects of this withdrawal, please ask for Pharmacia & Upjohn Medical and Drug Information at 1-800-253-8600, extension 3-8244 or (616) 833-8244. Additional information on Creutzfeldt-Jakob Disease can be found on the internet at http://biomed.redcross.org/home/cjdfacts.htm.
Sincerely,
Dawn M. Viveash, M.D.
Chief Safety Officer
& Vice President Global Pharmacovigilance
Pharmacia &
Upjohn Telephone (616) 833-4000
7000 Portage Road
Kalamazoo, Ml 49001-0199
USA
Excerpts from Donor Blood
Bank Letter
Re: Recipient Notification
Institutions that are considering notifying the recipient about possible risks associated with blood collected from this donor may want to consider the following:
The issues surrounding notification of transfusion recipients have been carefully considered by the American Red Cross Committee for the Protection of Human Subjects, the Institutional Review Board (IRB) of the New York Blood Center, and the IRB of the Centers for Disease Control, all of which strongly discourage sharing this information with recipients of components from donors confirmed to have had CJD when these recipients are included in an ongoing collaborative investigational lookback study. This decision was influenced by the extremely low risk of CJD transmission, the tremendous stress that may be induced by this information, the lack of . any treatment, and the absence of a screening test.
The December 11, 1996, FDA memorandum, Revised Precautionary Measurements to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease by Blood and Blood Products, recommends "medically appropriate notification" and counseling of recipients.
On several occasions, at public meetings of advisory committees between 1994 and 1996, representatives of the hemophilia community strongly expressed their expectations that recipients be notified.
As stated in AABB FaxNet No. 282, Association Bulletin #96-4: Although not directly applicable, case law in the area of informed consent suggests that a physician has a duty to disclose to patients any information that is "material" as that standard is defined in each jurisdiction. The specific decision to withhold information from a patient is a professional privilege that belongs to physicians, not to institutions.
When seeking guidance from an institution's IRB or ethics committee about the need or obligation to notify transfusion recipients, AABB Association Bulletin #96-4 may be helpful in facilitating these discussions.