Availability of Immune Globulin Intravenous for Treatment of Immune Deficient Patients -- United States, 1997-1998.
Reporting to FDA
Based on industry reports of IGIV distribution from all seven pharmaceutical companies handling IGIV during 1995-1998, the FDA estimated shortfall of IGIV compared with demand was 20% for 1997 and 30% for 1998. For 1997, FDA attributed approximately 60% of the decreased availability to production Impediments related to compliance and approximately 20% to withdrawals of plasma products because of the theoretical risk for contamination with the Creutzfeldt-Jakob disease (CJD) agent. The remainder of the shortage was attributed to other problems, including increased use, wastage, and export of IGIV.
To address the shortage, on January 28, 1998, FDA sent a letter to physicians reminding them of the six approved uses for IGIV (Table 1) and recommended that priority for IGIV be given to patients who have FDA-approved indications for use. In addition, a review of data from FDA, NIH, and CDC suggested that the risk for transmission of classic CJD by blood products, if it exists, is considerably lower than the risk for harm to public health from CJD-related quarantines and withdrawals. Therefore, on August 27, 1998, the Surgeon General recommended that plasma derivatives, including IGIV, be withdrawn only if the blood donor developed new-variant CJD.
In March 1998, IDF conducted a survey using its database of 1567 self-identified physicians who treat immunodeficient patients in 42 states; the physicians reported concurrently treating 23,341 primary immunodeficient patients. Of the physicians, each of 221 reported having treated 25 immunodeficient patients concurrently, accounting for 15,044 (64%) of primary immunodeficient patients in the survey. The survey, which inquired specifically about IGIV use and the effects of the shortage on immunodeficient patients during the previous 6 months, was sent to the 221 physicians and to a random sample of 265 of the physicians treating <25 immunodeficient patients concurrently. Responses were received from 151 (68%) of the 221 physicians treating 25 immunodeficient patients and from 117 (44%) of the 265 physicians treating <25 immunodeficient patients. Of the 268 (55%) who responded, 215 (80%) reported treating immunodeficient patients using IGIV. Most (184 [86%]) reported difficulty obtaining IGIV. Altered dosage schedules because of the shortage were reported: postponed IGIV infusions, 148 (69%); increased interval between IGIV infusions, 120 (56%); decreased IGIV dosages, 82 (38%); and substitution of alternative therapy to IGIV, 39 (18%). The shortage adversely affected patients of 97 (45%) respondents; adverse effects reported by respondents included increased infections, stress, anxiety, and malaise.
Reported by: M O'Day, J Boyle, PhD, TL Moran, J Winkelstein, MD, Immune Deficiency Foundation, Towson, Maryland. Div of Hematology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration. Div of Viral and Rickettsial Diseases and Hospital Infections Program, National Center for Infectious Diseases; and an EIS Officer, CDC.
Editorial Note: During the early 1980s, IGIV was developed as an infusion product that did not have large immunoglobulin aggregates and that allowed immunodeficient patients to receive enough immune globulin at monthly intervals to protect them from infections until their next infusion. IGIV is recommended for a limited number of approved or proven purposes (1). In 1990, a National Institutes of Health (NIH) Consensus Development Conference recognized the usefulness of IGIV for chronic inflammatory demyelinating polyneuropathy (Table 1) (2). In 1995, the University Hospital Consortium Expert Panel for Off-Label Use of Polyvalent Intravenously Administered Immunoglobulin Preparations (UHC) stated its position regarding IGIV use for several diseases (Table 1).
Information reported to FDA suggests that distribution and production factors contributed to the IGIV shortage, leading to the problems for patients documented by the IDF survey. However, part of the shortage has resulted from increasing IGIV administration for both approved and unapproved uses. Despite FDA, NIH, and UHC attempts to guide clinicians, >50% of IGIV use is for purposes not approved by FDA (3). If IGIV were administered only for conditions for which its efficacy is supported by adequate scientific evidence and for which no other treatment exists, then more IGIV would become available for immunodeficient patients, whose physicians have had difficulty obtaining IGIV.
The FDA analysis of information on the shortage has at least three limitations. First, reports and shortage evaluations are based on passive reporting to the agency. Second, information on monthly IGIV production (in contrast to distribution) and demand is not available. Finally, FDA has minimal information on the export of IGIV.
The findings of the IDF survey are subject to at least four limitations. First, physicians surveyed were from a database of physicians who self-identified as treating immunodeficient patients, and they may not represent the practices of all physicians treating patients with IGIV. Second, the response rate for the survey was low. Third, because the survey specifically inquired about difficulty obtaining IGIV, physicians having problems obtaining IGIV may have been more likely to respond. Finally, although the findings of the IDF survey suggest that the IGIV shortage may be adversely affecting physician prescribing practices and patients' health, the survey design did not permit more precise estimation of possible adverse effects. These limitations may lead to overestimation of the severity of the shortage.
FDA is using several methods to improve IGIV distribution to patients, such as evaluating products manufactured in Europe for possible use in the United States, encouraging manufacturers to set aside emergency supplies of IGIV, continuing to monitor IGIV supplies and distribution, and shortening the lot-release time for IGIV. Long-term plans include reevaluating uses of plasma derivatives and expanding plasma product production capacity.
Clinicians should review their IGIV use to ensure consistency with current recommendations, and pharmacists should facilitate appropriate use by assisting in triage of available IGIV to high priority patients as outlined by FDA, NIH, and the UHC (Table 1). IDF, in cooperation with IGIV manufacturers, is distributing a limited supply of IGIV product on an emergency basis to clinical immunologists enrolled in the program. Additional. information about this program is available from IDF, telephone (800) 296-4433, Monday through Friday from 8 a.m. to 5 p.m.
1. Buckley RH, Schiff RI. The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 1991;325:110-7.
2. National Institutes of Health Intravenous immunoglobulin: prevention and treatment of disease: NIH consensus statement. Washington, DC: US Department of Health and Human Services, National Institutes of Health, 1990;8:1-23.
3. Robert P. The fractions market in the United States. Orange, Connecticut: The Market Research Bureau, 1996.
Recommendations for use of immune globulin intravenous (IGIV), by recommending source Agency recommendations Acceptability [FDA.sup.*] [NIH.sup.+] Accepted Primary immunodeficiencies; FDA-accepted immune-mediated indications and thrombocytopenia; Kawasaki chronic syndrome; recent bone marrow inflammatory transplant in adults; chronic B-cell demyelinating lymphocytic leukemia; pediatric HIV polyneuropathy infection Equal to other therapy May be useful Not useful Acceptability [UHC.sup.ss] Accepted Post-transfusion purpura (FDA indications were not re-evaluated) Equal to other Guillain-Barre syndrome and chronic inflammatory therapy demyelinating polyneuropathy May be useful Anemia because of parvovirus B19; patients with stable multiple myeloma who are at high risk for recurrent infection; cytomegalovirus (CMV)-negative recipients of CMV-positive organs; hypogammaglobulinemic neonates with risk factor for infection or morbidity; intractable epilepsy; systemic vasculitic syndromes; warm-type autoimmune hemolytic anemia; neonatal alloimmune thrombocytopenia when unresponsive to other treatments; immune-mediated neutropenia; decompensation in myasthenia gravis; dermatomyositis; polymyositis; thrombocytopenia when severe and unresponsive to other treatments Not useful Acute lymphoblastic leukemia; acute renal failure; adrenoleukodystrophy; adult HIV infection; anemia not otherwise specified (NOS); asthma; bleeding disorders; neurologic disease or thrombocytopenia if NOS; Behcet's syndrome; chronic fatigue syndrome; congenital heart block; cystic fibrosis; diabetes mellitus; endotoxemia; euthyroid ophthalmopathy; inclusion body myositis; membraneous nephropathy; nephrotic syndrome; prophylaxis for solid organ transplantation, surgery, or trauma; recurrent otitis media; recurrent spontaneous abortion; rheumatoid arthritis (*.)Food and Drug Administration. Different IGIV products may be approved for different indications. (+.)National Institutes of Health Consensus Development Conference. (ss.)University Hospital Consortium Expert Panel for Off-Label Use of Polyvalent Intravenously Administered Immunoglobulin.
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|Publication:||Morbidity and Mortality Weekly Report|
|Date:||Mar 5, 1999|
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