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Testimony on Immune Globulin Shortage by David Satcher, M.D., Ph.D.
U.S. Surgeon General
Assistant Secretary for Health
U.S. Department of Health and Human Services

Before the House Committee on Government Reform and Oversight, Subcommittee on Human Resources
May 7, 19988

Mr. Chairman, members of the Subcommittee, I am Dr. David Satcher, Surgeon General of the United States and Assistant Secretary for Health in the Department of Health and Human Services. Thank you for the opportunity to appear before you today and testify about the shortage of immune globulin products. This is a serious public health matter and clearly worthy of our attention.

As you know, I am the Chairman of the Blood Safety Committee of the Department of Health and Human Services. The Committee was formed by Secretary Shalala in 1995 because she has made the safety and availability of whole blood and blood products a priority.

The Blood Safety Committee is currently reviewing the immune globulin shortage. Only a week ago, our Advisory Committee on Blood Safety, comprised of a variety of medical, legal and ethical experts, conducted two days of hearings on the immune globulin situation. Their recommendations are currently under review by the Department.

Immune globulins are one of several classes of proteins derived from human plasma, the fluid (non-cellular) portion of circulating blood. Other important plasma-derived proteins of medical value include albumin used to treat burn victims and clotting factors used to treat hemophiliacs.

My focus today is on the two types of immune globulins used to prevent and treat infectious and inflammatory diseases. They are immune globulin intravenous (IGIV) and immune globulin intramuscular (IGIM).

Among the well documented, FDA-approved uses for IGIV are treatment of Primary Immunodeficiency (PID), Immune-mediated Thrombocytopenia (ITP), Kawasaki disease, Bone Marrow Transplantation, B-cell Chronic Lymphocytic Leukemia, and Pediatric HIV-1 infection. There has been an increase in off-label uses of IGIV that includes treatment of a large number of neurological disorders, autoimmune diseases, and hematological disorders.

IGIM is primarily indicated for post-exposure prophylaxis against Hepatitis A. (It has also been used to a limited extent for travelers requiring Hepatitis A prophylaxis, although the hepatitis A vaccine, approved for use in 1995, is now recommended instead of IGIM). IGIM is routinely needed by every local health department when dealing with a sporadic case of hepatitis A and is particularly critical in the setting of an outbreak, such as in 1997, when individuals in Michigan developed hepatitis A after eating contaminated frozen strawberries. It also is used in children with primary immune deficiency, but IGIV is usually preferred to avoid administration of large volumes intramuscularly.

Drug shortages arise from a variety of causes, such as the unavailability of raw materials or packaging components, marketing decisions, increased demand, manufacturing problems and enforcement issues. Throughout much of 1997, we received sporadic reports about shortages of clotting factors, immune globulins and albumin.

It is the Department's policy to attempt to prevent or alleviate shortages of medically necessary products as best we can given our legal authorities. We are committed to providing assistance to ensure that there is available an adequate supply of product meeting high quality standards.

The Centers for Disease Control and Prevention (CDC) was first alerted to shortages of IGIM in October 1994, when a State health department was having difficulty locating sufficient quantities of the product for a large number of people who had been exposed to a food handler with hepatitis A. CDC assisted the State in meeting its IGIM demand. Upon contacting Armour Pharmaceutical Company, now Centeon, CDC learned that most of the company's production was going to the Department of Defense, which was routinely using IGIM as a prophylaxis for soldiers stationed around the world.

Sporadic outbreaks of disease and large-scale use of immune globulin products by the military are two causes of the shortages we have identified. There were other factors as well, including new viral testing requirements for IGIM that caused withdrawal of untested lots and the cessation of production by one major manufacturer.

Our public health agencies, CDC and FDA, worked with industry to facilitate IGIM availability. In October 1997, we recognized the potential for another IGIM shortage and requested all IGIM manufacturers to increase production. In addition, FDA worked with one manufacturer to perform testing on tetanus immune globulin so the product could be used as a substitute for IGIM. FDA also worked with two companies to file applications to produce additional product. These applications were reviewed expeditiously -- both in approximately one month -- to facilitate increased production. Presently, the amount of IGIM being produced is enough to meet routine public health needs, but because inventories remain low, we are concerned that IGIM reserves would not be sufficient to meet the demands of unanticipated public health crises.

I will now turn to our concerns about another immune globulin product: IGIV. The current IGIV shortage is the result of many factors, including increased demand for product, decreased production by the manufacturers, as well as increased quarantines, withdrawals and recalls due to manufacturing problems and CJD issues. Also, manufacturers have stated that they have diverted their resources to quality assurance programs from manufacturing, thus reducing production capabilities. Overall, we estimate that supply of IGIV fell short of demand by about 20% in 1997.

The demand for IGIV has been increasing by about 10% per year since 1994. This increased demand results from both new approved indications and an increase in off-label uses of IGIV. Although hard data are not available, off-label use is estimated by the Immune Deficiency Foundation and physicians at major centers to represent 50-70% of current IGIV use. It is worth noting that alternative therapies are available for many of the diseases for which IGIV is being used off-label.

As I said, there was reduced production in 1997. One major manufacturer, Centeon, distributed a significantly reduced amount of product that year. As a result of a consent decree entered into because of regulatory violations and the release of contaminated products, Centeon decided on its own that it would shut down production and did not distribute product. Centeon's production shut down went beyond corrective actions required or suggested by FDA. We estimate that although FDA did require a temporary cessation of distribution prior to May 1997 this lack of product from Centeon alone accounted for 60% of the total 20% product shortfall. While FDA made every effort to allow manufacturers to continue operating while they addressed regulatory problems, some companies with compliance problems made decisions to stop release and distribution of product and to shift resources to the compliance correction.

CJD is another contributing factor to the shortage. Multiple IGIV lots have been quarantined or withdrawn because of donors who, after donation, were identified as being at risk of, or as having developed, CJD. Many of these lots were distributed and largely consumed before the withdrawals went into effect. Substantial amounts of intermediate product, not yet processed into final products, however, also were affected by the withdrawals and placed in quarantine. We believe that the manufacturer's decision not to process CJD-implicated intermediates into products released with special labeling is the primary impact of CJD on product availability. We understand that other manufacturers, American Red Cross and Baxter, did not reach 1996 distribution levels in 1997 because of quarantined CJD implicated in-process intermediates resulting in a reduction of final product, accounting for about 20% of the total product shortfall. While other manufacturers reached or surpassed their 1996 distribution levels in 1997, it is likely that they could have produced more had they not been affected by compliance or CJD issues, again reflecting decisions made by the companies and not required by the Federal Government. CJD product could be distributed as long as it is risk-labeled, a complex marketing decision for many manufacturers. Other factors that contributed to the total 20% product shortfall in distribution include decisions to retain product for later distribution to cover periods of planned plant shutdown, and potentially, not packaging IGIV in vial sizes most efficient for use of product.

Export of IGIV is another factor that affects the amount of material available for domestic distribution. FDA does not monitor how much product is exported and does not require foreign distribution data to be provided. Manufacturers, however, voluntarily have told FDA that exports are not a major factor responsible for the shortage although the amount exported could relieve the shortage in the United States. Exports account for 0 to 29% of distributed product, depending on the manufacturer, according to information received by FDA. It was recently disclosed by an industry trade group, the International Plasma Products Industry Association, that exports from the major United States fractionators increased from 1996 to 1997 and accounted for about 20% of their marketed IGIV products.

We do not have quantitative information about the fate of the IGIV product once it is outside of the direct control of manufacturers. There may be product released to the market but held up in the distribution chain. That data is not captured by any FDA analysis.

Mr. Chairman, we have identified shortages of immune globulin products, and to a reasonable extent, we know how these shortages occurred. But I will not be satisfied until we have assurances that the shortage will be resolved and that future shortages will not readily occur. As I said earlier, we are reviewing recommendations of the Advisory Committee on Blood Safety, which call for greater collaboration between government and industry to reduce and prevent immune globulin shortages. At minimum, this collaboration will occur. I look forward to learning more about the problem through the information presented here today, and as always, I look forward to working with you and the other members of the Subcommittee. Thank you.

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