[Printable PDF]
[Federal Register: August 19, 1999 (Volume 64, Number 160)]
[Proposed Rules]
[Page 45383-45386]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19au99-37]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 600
[Docket No. 98N-0815]
Plasma Derivatives and Other Blood-Derived Products; Requirements
for Tracking and Notification
AGENCY: Food and Drug Administration, HHS.
ACTION: Advance notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is announcing its
intention to propose regulations requiring that certain blood-derived
products, including certain plasma derivatives, be tracked from a U.S.
licensed manufacturer, through the distribution network, to any patient
having custody of the product. Additionally, FDA intends to require
notification of consignees and patients having custody of a blood-
derived product or an analogous recombinant product in the event the
product is associated with a potential increased risk of transmitting a
communicable disease, as determined by FDA or by a U.S. licensed
manufacturer. The regulations would also apply to any blood-derived
product which, in the future, may be routinely dispensed to the patient
and held by the patient prior to administration. FDA intends to take
this action to help ensure notification of patients having custody of
blood-derived products when such products may be associated with a
potential increased risk of transmitting a communicable disease so that
patients may make informed, appropriate decisions. FDA is soliciting
comments and information from interested persons concerning the subject
matter of the proposed regulations.
DATES: Submit written comments by November 17, 1999.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Steven F. Falter, Center for Biologics
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 208520-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
In a July 25, 1996, report entitled ``Protecting the Nation's Blood
Supply from Infectious Agents: the Need for New Standards to Meet New
Threats,'' the United States House of Representatives Committee on
Government Reform and Oversight provided recommendations to FDA on
improvement of the biologics regulations. One of the recommendations
concerned the need for the development of a more effective system to
notify patients when there are adverse events associated with blood
products.
In response to this recommendation, FDA, industry, and patient
groups have already taken a number of actions to improve the agency's
and industry's response to situations related to concerns about the
safety of blood products. FDA has improved its procedures for planning,
monitoring, coordinating, and directing FDA investigations for a range
of situations including error and accident reports, recalls, and
reports of injury or illness, including those related to plasma
derivatives. Although primary responsibility for notification of
recalls falls to the manufacturer of the product being recalled, FDA
uses a variety of electronic communications to make information on
recalls and withdrawals available to the public. These include
information on the Center for Biologics Evaluation and Research World
Wide Web home page, a Fax-on-Demand system, press releases, talk papers
(FDA briefing documents), and a ``Blood and Plasma Products'' hotline.
Interested persons may subscribe electronically to the notification
system to receive new information automatically. FDA routinely
communicates information regarding recalls and withdrawals of plasma
derivatives to consumer groups such as the National Hemophilia
Foundation and the Committee of Ten Thousand. FDA continues to work
with regulated industry to improve the safety of the blood supply,
including the development of new, safer products.
FDA has had extensive dialogue with a variety of interested persons
in evaluating the current procedures for identifying and notifying
recipients in case of safety issues related to blood products. FDA,
along with other Government organizations, held a public workshop on
November 19, 1996, to obtain public input on notification of the public
on recalls and ongoing investigations (see the notice of meeting in the
Federal Register of November 1, 1996 (61 FR 56549)). Subsequently, FDA
has met with numerous consumer groups and industry organizations to
discuss notification issues. After extensive discussions with patient
communities and within the Department of Health and Human Services, FDA
believes that there is a consensus that persons in custody of a product
that may be associated with a potential increased risk of transmitting
disease should be so notified; however, it remains unclear as to what
specifically would be the most efficient, least burdensome, process
that would ensure appropriate notification of all affected persons.
The voluntary programs for notifying recipients in cases of issues
related to the quality of blood products are fairly new and efforts
continue to recruit participation by patients who are blood product
recipients. Thus the success of the voluntary programs cannot yet be
fully assessed. However, the success of such voluntary programs will
always depend on the continued voluntary support by manufacturers of
blood products and the continued vigorous recruitment of patient/
recipients to encourage full participation. FDA is concerned that the
continued success of patient notification cannot be assured without
regulatory standards for the performance of such notification programs
and without a clear mechanism of enforcement in the event a
notification program is found deficient. FDA intends to continue to
monitor progress in the implementation of the voluntary systems and
will consider elements of the voluntary systems when developing any
regulations resulting from this notice. FDA believes there should be a
standardized notification system, clearly understood by industry and by
users of blood products, and over which FDA has clear enforcement
authority to help ensure that notification consistently and
comprehensively takes place.
Accordingly, FDA is considering rulemaking to provide for the
prompt notification of patients who may possess certain plasma
derivative products for their own use when information indicates a
potential for the product to transmit a communicable disease. FDA
recognizes that there are several alternatives as to how this
notification could best be accomplished. Any such rule would involve
the cooperation of a number of entities who must provide information to
help ensure that appropriate notification takes place, including the
manufacturers of such products, consignees who hold the product for
further sale (wholesale distributors), consignees, such as hospitals
and pharmacies, who provide the product directly to the patient, and
patients. Accordingly, in sections II. and III. of this document FDA
outlines the concepts and alternatives it is considering in the
development of these
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regulations and invites information and comments on the various
concepts and alternatives from all interested persons.
II. General Overview of the Regulatory Plan
Under the biologics licensing and quarantine provisions of the
Public Health Service Act (42 U.S.C. 262-264) and the drug, device, and
general administrative provisions of the Federal Food, Drug, and
Cosmetic Act (the act) (21 U.S.C. 351-353, 355-360, and 371-374)), FDA
has the authority to issue regulations designed to protect the public
from unsafe or ineffective biological products and to issue regulations
necessary to prevent the transmission of communicable diseases.
Biological products derived from human plasma have an inherent,
potential risk to transmit communicable diseases. Donors of the plasma
source material are screened and tested for the potential to transmit a
communicable disease. Products made from plasma may be further tested
and treated by a process intended to remove or destroy infectious
disease agents. However, despite these multiple precautions, there are
occasions when problems are identified which may increase the potential
risk that the plasma derivative may transmit a communicable disease.
Depending on the particular facts, the manufacturer may initiate a
recall or market withdrawal of the product so that consignees of the
plasma derivative may take appropriate action to prevent the further
marketing of the product (see Title 21 of the Code of Federal
Regulations (CFR), part 7 (21 CFR part 7) for additional information on
the recall and market withdrawal processes).
For some plasma products, generally those that may be chronically
administered through the lifetime of the patient, the plasma derivative
may be prescribed to the patient and held at the patient's residence
until the product is administered. (Note that although FDA is aware
only of certain plasma derivative products being routinely held in the
patient's custody, FDA intends that any regulations concerning
notification would apply to any blood-derived product which may, now or
in the future, be released into the custody of a patient.) FDA believes
that patients having custody of plasma derivatives are not consistently
notified of lot-specific product recalls or withdrawals associated with
a potential increased risk of a communicable disease or such
notification has not been timely to ensure that appropriate action may
be taken by the patient.
There are voluntary tracking and notification systems in place for
specific plasma derivatives, but these systems require patients to
register with the data base administrator in order for the patients to
be notified. In order to protect patients and to better prevent the
transmission of communicable diseases through plasma derivatives, FDA
is considering the issuance of a proposed rulemaking that would require
that patients having custody of plasma derivatives be promptly notified
of specific lots associated with a potential increased risk of a
communicable disease. Because of the importance of such a notification,
FDA is considering defining when notification should take place and
setting timeframes during which notification must be performed. The
proposed rulemaking would also include requirements for tracking of
plasma derivatives to patients who have custody of these products for
the purpose of permitting identification of such patients for notifying
them of recalls and market withdrawals.
III. Concepts of the Proposed Rulemaking
The following discussion is not intended to indicate the specific
content of the proposed rulemaking. It is meant only to describe
concepts to be covered by the proposed regulations. The discussion
identifies a number of specific topics on which the agency is seeking
additional information. However, FDA welcomes comments on any aspect
regarding the notification of patients relating to the safety of plasma
derivative products. Comments received in response to this advance
notice of proposed rulemaking (ANPRM) will be used to develop the
proposed rule. FDA specifically requests comments on the concepts that
follow.
A. Scope of the Regulations--Types of Blood-Derived Products
The intent of the regulations would be to help ensure that patients
possessing plasma derivative products are notified of a potential
increased risk of communicable disease so that they may take
appropriate action, such as returning the product to the distributing
establishment. Therefore, FDA intends to limit the scope of the
regulations to those plasma derivatives that may be distributed
directly to a patient. Such products include Antihemophilic Factor (AHF
or Factor VIII) for the treatment of hemophilia A, Factor IX, used for
the treatment of hemophilia B, Alpha-1-Proteinase Inhibitor (Human),
used for the treatment of alpha-1 antitrypsin deficiency and products
analogous to those listed previously, such as porcine AHF and products
made using recombinant technology. The proposed rulemaking would not
apply to plasma derivative products, such as albumin, that are not
routinely prescribed for home use.
FDA notes that occasionally patients may take custody of Immune
Globulin Intravenous (Human) (also known as IGIV) for administration at
home. FDA estimates that approximately 5 percent of the IGIV prescribed
is taken into the custody of the patient. FDA believes that such
patients should be notified in cases when the IGIV is associated with a
potential increased risk of transmitting a communicable disease. The
agency also recognizes the complexity, expense, and inefficiency of a
system which would be needed to track large volumes of product, for the
purpose of potentially notifying a small proportion of patients. It may
be more efficient to provide specific arrangements for notification at
the time the product is prescribed to the limited number of patients
who are taking custody of the product for home use. FDA invites
comments and recommendations on how appropriate information regarding
product safety can be provided to such patients and whether alternative
procedures for such a system should be codified as part of the
notification rulemaking. FDA also invites comments as to whether other
blood products should be included under the regulations, including a
discussion of the extent of the increased burdens and public health
advantages associated with such an expansion.
Currently, FDA is aware only of plasma derivative products being
released into the custody of patients. It is possible that in the
future other products, derived from other blood components, such as red
blood cells or white blood cells, may be routinely dispensed into the
custody of patients. In such a case, FDA intends that the requirements
for tracking and notification would also apply to the blood-derived
product. Because the information that FDA has so far gathered and the
information being sought by FDA pertains primarily to plasma derivative
products, this ANPRM will continue to focus upon plasma derivative
products. However, FDA invites comments on what additional blood-
derived products may be dispensed into the custody of a patient in the
future.
As discussed earlier in this document, a number of voluntary
efforts are under way to assist in the notification of persons in
custody of a plasma derivative product associated with a potential
increased risk of transmitting
[[Page 45385]]
a communicable disease. Although FDA believes that there may be innate
limitations to any voluntary system, little information is available to
the agency regarding the effectiveness of the voluntary systems in
place. FDA requests data on the effectiveness of such systems in
identifying all persons who may have custody of a plasma derivative
product and notifying them in case the product is associated with a
potential increased risk of transmitting a communicable disease. FDA
also requests comments on whether such systems may be improved and, if
so, whether regulations establishing a mandatory notification process
would remain appropriate.
B. Scope of the Regulations--Reasons for Notification
At this time, FDA intends that the proposed regulations would
require notification only for those plasma derivative lots which,
within the dating period of the product, may be associated with a
potential increased risk of transmitting a communicable disease. In
general, FDA believes that notification of end-users should take place
in the same instances for which manufacturers are now either recalling
or withdrawing plasma derivative products because of a potential
increased risk of transmitting disease. A biological product may be
unacceptable for human use due to a wide range of reasons, many not
related to communicable disease. FDA is inviting comments on how the
basis for notification should be defined in the regulations so as to
appropriately establish the criteria for determining when notification
should be required. FDA is also inviting comments and information on
whether the scope should be expanded to cover other instances, which
may affect the safety of the product but which may not be associated
with a potential increased risk of communicable disease. An established
tracking and notification system could be used in the notification of
patients having custody of plasma derivatives for all recalls and
market withdrawals. FDA invites comments on the adequacy of the current
recall process in situations, other than those related to the risk of
communicable disease, and the additional benefits that would be
provided by requiring patient notification when compared with the
additional burdens associated with the notification process.
C. Who Should Be Responsible for Notification and Related Tracking
Responsibilities?
In a recall, the manufacturer has primary responsibility for
ensuring that the recall is undertaken promptly and that, based on an
assessment of the risk, it extends to an appropriate level, such as to
the end-user of the product. However, other persons, such as the
consignees in receipt of the product, play an integral part in the
recall process.
FDA is aware of consumer concerns that manufacturers should not
know the identity of a patient using its product. Because of concerns
about maintaining confidentiality of patients, FDA believes that the
manufacturer should not be required to directly contact patients for
notification purposes. Such notification could either be accomplished
by those consignees who provided the product to the patient or by an
independent third party contracted by the manufacturer to notify
patients in the case of a notification or withdrawal related to the
potential transmission of a communicable disease, while not divulging
patient information to the manufacturer. FDA invites comments as to
whether the consignees should be held responsible for notification,
whether a manufacturer should be required to contract with a third
party to perform notification, or whether either option should be
permitted under the regulations.
D. Tracking of the Consignment of Applicable Plasma Derivatives
FDA intends that the proposed rule would require that plasma
derivatives prescribed to patients for home use be tracked from the
manufacturer, to any consignees, and ultimately to such patients for
the purpose of permitting identification of such patients when they
need to be notified about a product associated with the potential
increased risk of transmitting a communicable disease. The tracking of
product to intermediate consignees would be necessary for notifying
them about the product risk and thus preventing further distribution of
the implicated product lot to patients for home use. Depending on the
mechanism of notification (see section III.G of this document),
required tracking information could be specific for each lot or could
simply be the ability to identify all consignees and patients who have
received that specific plasma derivative product, regardless of what
product lots they may have received. FDA invites comments, data, and
other information on the potential recordkeeping burdens that would be
associated with tracking such plasma derivative products, including any
estimates of the time it would take to prepare such records and of the
number of recordkeeping entries that would be necessary each year to
maintain these tracking records. Data are requested both for keeping
lot specific tracking information and for product specific information.
E. Initiation of Notification
In most cases the manufacturer would be the first to determine that
a plasma derivative may be associated with a potential increased risk
of transmitting a communicable disease. However, based, for example, on
consumer complaints, laboratory evidence, or information obtained
during inspection by FDA or from other public health agencies, FDA
anticipates there would be occasions when it is FDA that makes the
initial determination that notification is required. In such cases, FDA
believes the most efficient means of initiating notification would be
for FDA to inform the manufacturer by an appropriate means of rapid
communication, such as fax, electronic mail, or telephone, to initiate
notification, immediately followed by written information further
documenting why the agency deems notification necessary. The previous
description is a simplification of the process which would generally
take place when problems are perceived with a product. In most cases,
there would be considerable discussion among experts, at FDA and at the
manufacturer, to evaluate the available information and assess its
implications for the safety of the affected products before a decision
to notify would be made. Thus, the process described previously would
only be the final step in the determination that notification is
required.
FDA requests comments on what should be the required elements of
the determination that mandatory notification is to take place and what
information regarding that determination should be shared between FDA
and the manufacturer.
F. Timing for Notification
Because the plasma derivatives held by a patient may be
administered at any time, FDA believes that notification of the patient
should take place as rapidly as possible after the determination that a
notification is necessary. In some cases the first attempt at notifying
a patient may not be fruitful; the patient may be away from his or her
home or otherwise unavailable. Accordingly, FDA is also considering a
regulatory standard for the time by which full notification of patients
should be completed (or by when it is determined that the patient
cannot be notified with the currently available information). From the
time that either the
[[Page 45386]]
manufacturer determines notification is appropriate or FDA informs the
manufacturer that notification is required, FDA is considering a
standard that the initial attempt to notify all persons with custody of
the product must take place within 2 days. For those cases when the
initial notification attempt fails, FDA is considering requirements
that procedures must be in place for two additional attempts for
notification; with the final attempt in written form taking place
within 1 week from the beginning of the notification process. FDA
invites comments and information on how rapidly it is feasible to
attempt to contact patients who may possess the product subject to
notification and how much time should be allotted to complete the
notification process. If possible, the comments should describe in
detail the steps which should take place in the notification process
and the time which should be allotted for each step. FDA also invites
comments on how much time should be permitted to contact consignees,
other than the patients with custody of the product, who also may be in
possession of the product.
G. Who Should Be Notified
FDA's public health objectives would be met if only those patients
are notified who possess the product lot(s) with an increased potential
for transmitting a communicable disease. However, a possible
alternative would be to notify all patients who have been dispensed the
brand of plasma derivative in question during the time period that the
product lot subject to the notification has been in distribution. This
method would negate the need to track plasma derivative products to the
end-user by lot number. FDA invites comments on the comparative
advantages and disadvantages of notifying only those patients who may
possess the product lot in question versus notifying all patients who
may possess the indicated brand of the plasma derivative. Under any
system, the information provided to patients would be lot specific.
H. Information Included in a Notification of Patients
Required information to include in a notification of patients could
include specific lot information, a statement to describe the risk
potentially affecting the product lot, and instructions for further
action to be taken by the patients who have custody of the product lot
in question. FDA invites comments on whether the previous information
is appropriate and adequately comprehensive for notification.
I. Adequacy of the Notification Process; Quality Assurance
FDA recognizes that, even with a standard mandatory process,
notification of every patient may not be successful. For example, the
patient may have moved or may be away from his or her home for an
extended period of time. FDA is considering a requirement that the
manufacturer have a process in place to evaluate, in cooperation with
its consignees or any third party involved in notification, the
effectiveness of its notification process, such as through the selected
sampling of patients who should have been notified, and, with such
information, determine how its notification process could be improved.
FDA invites comments on the most appropriate means for evaluating the
effectiveness of the notification process and who (the manufacturer,
consignees, a third party) should be involved in such an evaluation.
J. Relationship of Notification With Product Recalls and Withdrawals
In most, if not all, situations for which FDA is considering
requiring notification, manufacturers, under current procedures, would
subject the product to recall or market withdrawal. Procedures for
product recalls are presented as guidance in 21 CFR part 7. ``Market
withdrawal'' is defined in Sec. 7.3. Product recalls and market
withdrawals are similar functions for the removal or correction of a
marketed product. In the case of recalls the product is considered to
be in violation of the law and may be subject to a regulatory action by
FDA, such as seizure of the product. A market withdrawal may be
performed for a distributed product associated with a minor violation
or for products that are not in violation of the law. Many of the
procedures described in this ANPRM as potentially appropriate for the
notification process are identical or similar to procedures generally
performed in a product recall or market withdrawal (see, for example,
the procedures for development of a recall strategy (Sec. 7.42(a)(1)),
conducting effectiveness checks (Sec. 7.42(b)(3)), and recall
communications (Sec. 7.49)). FDA invites comments on the
interrelationship among product recalls, withdrawals, and the
notification process described in this ANPRM. What recall/withdrawal
procedures would continue to be appropriate in the event FDA requires
patient notification? How may the process best be integrated to ensure
effective notification and product removal?
K. Informing Patients of the Notification Process
FDA believes that a patient taking custody of a plasma derivative
should be informed that she or he will be notified in the event the
plasma derivative is associated with a potential increased risk of
transmitting a communicable disease. This information should be
provided, in writing, when receiving delivery of the plasma product or
before, such as at the time the product is prescribed. FDA invites
comments on whether such information can best be provided in the form
of patient labeling accompanying the product or should be delivered by
other means. FDA also invites comments on whether such information can
be standardized for all plasma derivative products and, if so, who
should be responsible for preparing such information.
IV. Request for Comments
Interested persons may, on or before November 17, 1999, submit to
the Dockets Management Branch (address above) written comments
regarding the general and specific issues presented in this ANPRM. Two
copies of any comments are to be submitted, except that individuals may
submit one copy. Comments are to be identified with the docket number
found in brackets in the heading of this document. Received comments
may be seen in the office above between 9 a.m. and 4 p.m., Monday
through Friday.
This ANPRM is issued under section 201 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321 et seq.) and under authority of the
Commissioner of Food and Drugs.
Dated: June 15, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-21294 Filed 8-18-99; 8:45 am]
BILLING CODE 4160-01-F