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Shortage of Immune Globulin Products


Statement of

Michael A. Friedman, M.D.
Lead Deputy Commissioner
Food and Drug Administration
Department of Health and Human Services

before

the Subcommittee on Human Resources
House Committee on Government Reform and Oversight

May 7, 1998

INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Michael Friedman, Lead Deputy Commissioner of the Food and Drug Administration (FDA or Agency). I appreciate this opportunity to discuss the shortage of immune globulin products and the efforts of FDA to respond to the shortages. As a public health agency, we always are concerned when medically necessary products are in short supply with the potential for negatively impacting patients' health.

My testimony will concentrate on the shortage of immune globulin intravenous (human) (IGIV) as the supply problems with immune globulin intramuscular (human) (IGIM) are addressed by Dr. David Satcher, Department of Health and Human Services, and also are discussed by Dr. Stephen Ostroff, Centers for Disease Control and Prevention.

FDA ACTIONS IN RESPONSE TO IGIV SHORTAGE

Sporadic reports of IGIV shortages were received early in 1997. During most of 1997, FDA addressed requests for information from patients and physicians about product availability primarily by calling manufacturers to assess how much material they had in inventory and informing the requester about potential sources of product.

By November 1997, however, it became clear that the availability of IGIV to patients was severely limited. In that month, FDA received hundreds of telephone calls about difficulties in obtaining sufficient amounts of IGIV. The phone calls were from many different sources, including: individual patients; distributors; major treatment centers such as Walter Reed Army Medical Center, Johns Hopkins University Hospital, and Duke University Medical Center; as well as from consumer and patient groups such as the Immune Deficiency Foundation. FDA inquiries to manufacturers, large distributors, and group purchasing organizations revealed that there was little product in inventory or available on the market nationwide.

In response to the continuing shortage reports of IGIV, during the third week of December 1997, Dr. Feigal, Mary Pendergast, then Senior Advisor to the Commissioner, and I spoke to the chief executive officers of the leading plasma derivative manufacturers tp convey our concern about the shortages and to learn more about the reasons for the shortage and to determine ways to increase supply and production. Some of the options that were discussed with the manufacturers included importing European-approved product for patient use in the United States under investigational new drug applications (IND) and setting up toll-free hotline numbers and product supplies for urgent needs and consideration of limiting exports. The companies were asked to prioritize distribution of IGIV according to patient need. All of the companies agreed to establish emergency reserves of IGIV and toll-free hotlines for the public. Two companies agreed to explore bringing in European-approved product under INDs for patient use in the United States. We also asked the companies that FDA be kept informed about ongoing production efforts.

Since those calls, FDA also has been working closely with manufacturers to facilitate increased production and distribution without compromising the safety or efficacy of the products. This involves frequent discussions with industry about its plans to come into compliance with current Good Manufacturing Practices (GMPs) without significantly disrupting production schedules. FDA also has expedited review of license supplements related to manufacturing changes for IGIV to bring available products more quickly to the market. FDA's oversight of products entering the marketplace, known as the lot release process, has been shortened from 2-3 weeks to 3-5 days.

To assure that available product was utilized most efficiently, i.e., for disease conditions known to respond to IGIV treatment, FDA sent a "Dear Doctor" letter to over 300 medical organizations on January 28, 1998. The letter alerted medical organizations and their physicians to the shortage problem and provided guidance for prioritizing the use of IGIV and limiting off-label use. The letter also included 1-800 numbers of manufacturers of IGIV so that doctors could obtain product for patient use on an emergency basis.

In response to the shortage, FDA has increased its efforts to monitor supply. FDA repeatedly has called manufacturers to assess how much IGIV is in shippable inventory. In some cases, this information has helped to identify situations where FDA could expedite regulatory review of lots pending release. On at least one occasion, there was no reported shippable inventory available from the major plasma fractionators. FDA was able to relieve the acute shortage by expediting the release of a few lots of IGIV that were pending.

FDA also issued an Import Bulletin (#57-B09) alerting FDA offices of the shortage of IGIV. The Import Bulletin identified two United States-licensed foreign manufacturers who may legally export IGIV to the United States for commercial distribution; provided guidance for emergency use requests for importing IGIV from unlicensed foreign sources for use in treatment of patients in the United States; and discussed FDA's enforcement discretion to release shipments of IGIV from unlicensed foreign sources that are not covered by an IND when the quantity and purpose are clearly for personal use.

FDA does not have the statutory authority to regulate the price of products that it oversees, the quantity of such products that manufacturers sell, or to whom manufacturers may sell their products. FDA is nevertheless concerned about the public health implications of sales decisions of manufacturers. The Agency does everything within its power to ensure that there are adequate supplies of safe and effective products for patients.

FDA has limited authority to compel a manufacturer to stop shipping a regulated product. FDA, of course, does have authority and has a variety of enforcement tools to take action against a company that is shipping a product that is adulterated, misbranded, or unapproved. For example, FDA has authority to seek a judicial injunction that enjoins a company from shipping a product that is adulterated because of current GMP violations.

FDA, however, does not have authority to prevent a company from shipping, including exporting, an approved product that is in compliance with the applicable laws and regulations. Similarly, FDA cannot simply compel a company to ship or sell a product domestically in lieu of export. (Even if such authority did exist, it would be difficult to enforce a "no exportation" rule down the chain of distribution.)

Although manufacturers have established 1-800 numbers for emergency purchase, the Agency has information from consumer complaints that in some cases manufacturers agreed to provide products to physicians only if the hospital has entered into exclusive contractual obligations. For a period during March, product was not available even when calling the 1-800 numbers.

The phone calls to FDA regarding the unavailability of IGIV have decreased from the November 1997 levels of 10-20 per day to the current level of 5-6 per week. Forty percent more lots of IGIV have been released by FDA per month since November 1997 than released prior to November 1997. This increase, however, was partly due to the short term effects of the actions described above to get more product on the market, rather than an increase in production.

The shortage of IGIV continues, and probably will for some time, because many of the underlying causes have not been resolved. In particular, a number of manufacturers are in the process of coming into compliance with current GMPs and are implementing corrective actions to achieve compliance that have impacted production or release of product.

Modification of current recommendations for product withdrawals due to risk of Creutzfeld-Jakob Disease (CJD) may help to alleviate the shortage to some extent, and FDA is considering such modifications. Labeling products according to CJD risk may be one way of modifying the recommendations. Thus, products at minimal potential risk may warrant a generic label, while those at higher potential risk may require a lot-specific warning label. Further modifications in our existing CJD recommendations should come about as we learn more about the transfusion risk through research and surveillance.

FDA will continue to meet with plasma fractionators on an on-going basis to investigate additional ways to improve product availability. FDA will further investigate why the 1-800 telephone numbers are not being used fully to help provide product. FDA also is considering increasing surveillance of product distribution to assess the long range potential of a product shortage before it actually occurs. This would involve receiving product distribution reports more frequently and trending the data.

AGENCY RESPONSE TO DRUG SHORTAGES

It is Agency policy to attempt to prevent or alleviate shortages of medically necessary products as best we can given our legal authorities. We are committed to assisting in making sure there is available an adequate supply of product meeting high quality standards. Each Center has a drug shortage officer who is responsible for investigating shortage reports to determine the extent and urgency of the reported shortage. The Centers evaluate potential drug shortage problems, assess the potential public health impact, and propose steps to resolve each shortage issue.

FDA's primary means of identifying whether or not a shortage actually exists is to monitor the number and persistence of inquiries from consumers, manufacturers, and distributors. FDA does not monitor the exact amount of drug products (including IGIV and IGIM) on a routine basis. Actual distribution data from manufacturers is supplied to FDA by manufacturers as part of the reporting requirement regulations found at 21 CFR 600.81. These regulations require manufacturers to report data about product distribution in the United States. While these data do not give us "real time" information, or an estimate of product available in the marketplace, the data do provide information about the amount of product distributed in the United States market.

FDA obtains lot release data based for some plasma derivatives based on its approval of lots for release. Lot release is required only for selected products. Lot release data do not include the amount or volume of product in the lot, i.e., number of doses. Lots approved by FDA for release, however, may not be distributed by manufacturers for various reasons.

THE PLASMA INDUSTRY

As you are aware, Mr. Chairman, there were problems in the past concerning inspections of plasma fractionators. As I testified last June, FDA has addressed these problems by instituting changes, both procedural and managerial, in the inspection of these facilities.

FDA transferred lead responsibility for periodic inspections of plasma fractionators (manufacturers who further process plasma and other blood derivative products) to the Office of Regulatory Affairs (ORA). Today inspections emphasize a complete assessment of compliance with GMPs, including an assessment of the manufacturer's procedures for handling, investigating, and notifying FDA of reports of adverse experiences. This transfer of inspectional responsibilities to ORA has advanced FDA's goals of regulatory consistency and efficiency across all regulated products by making the inspection process for fractionators comparable to that for other regulated products.

The new approach to inspections of plasma fractionators has resulted in more in-depth inspections and, we believe, in production on a higher quality of product. FDA's inspectional findings (documented on the Form 483s, the form used to report findings of the inspection) contain more substantive items including items previously which may only have been discussed with a firm and not necessarily noted on the 483 in some cases. More warning letters have been issued, and two companies are presently under consent decree to ensure that the plasma products are manufactured under quality conditions.

As a result of these changes, plasma fractionators have been under increased enforcement scrutiny in the past year. We believe that such scrutiny is necessary to assure the purity and potency of plasma products. Quality is particularly important with blood and blood products. FDA can assist in speeding up the process, but we will not lower safety standards, or minimize or abolish compliance programs.

FDA can sometimes help to avert a crisis or minimize the harm to patients if a shortage does occur. FDA is sensitive to shortage issues when the Agency takes regulatory action against a company and will work with a company to avoid a shortage situation if at all possible. For example, if shutting down a plant while the manufacturer corrects problems could lead to a shortage of a medically necessary drug, the Agency might exempt a single production line from the shutdown to keep that drug available.

Plasma, as the underlying source materials used in the manufacturer of derivative products has inherent risks because many diseases are characterized by the presence of an infectious agent in the bloodstream which can be transmitted through blood and blood products. Additionally the supply of plasma can be limited by the number of available donors.

The risk of CJD transmission through blood and blood products is considered to be theoretical based on the absence of any proven transmission. Nevertheless, FDA has acted proactively to recommend deferral of donors at increased risk for CJD and withdrawal of affected products. In August 1995 and again in December 1996, FDA issued a memorandum to all registered blood and plasma establishments and establishments engaged in manufacturing plasma derivatives concerning revised precautionary measures to reduce the possible risk of transmission of CJD by blood and blood products. It is important to note, however, that FDA also allows the distribution of CJD-implicated material as long as the product is labeled accordingly. The risk/benefit of the product must be on the label. One manufacturer has used such risk labeling during this shortage period. As noted above, the decision to use risk labeling is a complex one for manufacturers.

There currently is no test available to screen blood donors for the presence of CJD. In fact, there is still scientific controversy over the nature of the causative agent. Recently there have been a number of withdrawals of plasma products because of the identification of donors who contributed to the plasma pool who subsequently died of CJD or were identified as having been at risk for CJD. These withdrawals and related quarantines are considered to have contributed to the present shortage of IGIV.

CONCLUSION

Mr. Chairman, FDA's primary concern is that no patient suffer needlessly. We will continue to do everything within our power so that patients will have safe and effective medical products needed to treat their conditions. We will maintain our commitment to GMPs. At the same time, FDA will continue to encourage companies to sustain levels of production that will provide adequate amounts of drug product to patients who depend on these medical products.