Plasma Derivatives and Other Blood-Derived Products; Requirements for Tracking and Notification

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:

er 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

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

fied; 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

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

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

ansmission 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

duct 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

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

r 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

f 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

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

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.

ients 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

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

at 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

ss. 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

nclude 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

thdrawals 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

e 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]

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