[Federal Register Volume 64, Number 160 (Thursday, August 19, 1999)]
[Proposed Rules]
[Pages 45383-45386]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-21294]

[[Page 45383]]



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.


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.

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 
    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 

 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 
    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 

    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 
    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

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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]