I. 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.
II. 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.
III. 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.
IV. 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.
V. 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.
