FDA's Regulation of Blood, Blood Products, and Plasma

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Testimony on FDA's Regulation of Blood, Blood Products, and Plasma by Michael A. Friedman, M.D.
Lead Deputy Commissioner
Food and Drug Administration
U.S. Department of Health and Human Services

Before the House Committee on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations
June 5, 1997

I. INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Michael Friedman, Lead Deputy Commissioner of the Food and Drug Administration (FDA). I appreciate this opportunity to discuss the status of FDA's regulation of blood, blood products, and plasma, as well as our notification, recall, and enforcement practices. I also would like to review the substantial progress FDA has made since the Committee on Government Reform and Oversight (Committee) issued its 1996 report 1 on blood safety and to indicate opportunities for further improvements. Accompanying me are Mr. Ron Chesemore, Associate Commissioner for Regulatory Affairs; Dr. Kathryn Zoon, Director of the Center for Biologics Evaluation and Research (CBER), the Center responsible within FDA for regulating blood and blood products; and, Dr. Jay Epstein, Director of the Office of Blood Research and Review (OBRR) in CBER. 1 Protecting The Nation's Blood Supply From Infectious Agents: The Need For New Standards To Meet New Threats, Committee on Government Reform and Oversight, H. Rept. 104-746, August 2, 1996.

II. BACKGROUND

The blood supply plays a critical role in the American health care system. While the United States is recognized as having one of the safest blood supplies in the world, assuring this safety poses formidable challenges. Each year, approximately 14 million units of whole blood are drawn from about 8 million volunteer donors to make products that are transfused into more than 3.5 million Americans. Some of this blood, and an additional 12 million units of source plasma, is further processed into products referred to as derivatives.

Plasma is the fluid (non-cellular) portion of circulating blood. Plasma contains albumin, clotting factors, and other important proteins of medical value. Plasma units intended for making derivatives are transferred to manufacturing facilities where they are pooled with other units. The fractionation process chemically and physically separates the plasma components. Derivative products are manufactured from intermediate materials obtained in the process. These products include albumin, used to restore plasma volume in treatment of shock, Factor VIII and Factor IX which are used as clotting factors for hemophiliacs, and immune globulins used to prevent and treat infectious diseases.

There is always some degree of risk in receiving blood or plasma products. For example, blood can transmit infectious disease, because blood donors may harbor undetected or undetectable communicable diseases. As this Committee noted in its 1996 report, "The public is not well served if patients are permitted to believe that there is no risk in blood transfusions or in the use of blood derived therapies." Given the finite risk 2 , and the fact that millions of Americans depend on blood and blood products, the effort to ensure the safety of the blood supply is a high priority for FDA. 2 The current CDC estimate for risk for HIV is 1:450,000; for HCV 1:10,000; and, for HBV 1:500,000.

Despite the risks associated with blood products, let me stress again that the United States blood supply is one of the safest in the world. Our role is to manage more effectively future risks and utilize modern science in maintaining the quality of the United States blood supply.

We do acknowledge, however, that there have been aspects of FDA's regulatory oversight of the blood and plasma industry which have been the subject of criticism and that have required correction. To address these problems we have instituted, and are continuing to institute, substantive changes, both procedural and managerial, in order to correct these problems and to further improve protection of the public health.

A five layer system of overlapping safeguards forms the core of the blood safety system established by FDA. This system starts at the blood collection center and extends to manufacturers and distributors of blood products. The five layers are as follows:

First, donor screening is performed. Potential donors are provided educational materials and asked specific questions by trained personnel about their health and medical history. Potential donors whose blood may pose a health hazard are asked to exclude themselves.
Second, after donation, the blood is tested for blood- borne agents such as HIV-1, HIV-2, HBV, HCV, HTLV-1, syphilis, and CMV (some collections). Donors also are excluded based on risk of malaria, CJD, and acute illness.
Third, blood establishments must keep current a list of individuals who have been deferred as blood or plasma donors and check all potential donors against that list to prevent use of units from deferred donors.
Fourth, blood products are quarantined until the products have been thoroughly tested and the donation records have been verified.
Fifth, blood establishments must investigate any breaches of these safeguards and correct system deficiencies that are found by the firms or through FDA inspection. Licensed firms must report to FDA any manufacturing problems, e.g., errors or accidents that may affect the safety, purity, or potency of their products.

In addition to these layers of protections, many plasma derivative products also are processed to inactivate viruses that may be present. At the present time, the technology to inactivate heat stable, non-lipid enveloped viruses, such as the Hepatitis A virus, while preserving the functions of the plasma proteins, is not available.

FDA regularly and frequently reviews all of its efforts to assure blood safety. Additionally, FDA works closely with the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) so that the latest science is brought to bear in the oversight of the blood supply. FDA also regularly interacts with patient groups, academicians, and industry scientists to remain current with outstanding issues of concern and technological advances.

Program safeguards are augmented by the oversight and audits of FDA's blood program provided by Congress, the General Accounting Office (GAO), and the Office of Inspector General (OIG). FDA has benefitted from outside recommendations and carefully considers any recommendations that may enhance the quality of the nation's blood supply.

III. FDA REGULATORY OVERSIGHT -- IMPROVEMENTS

Over the past two years FDA has made a number of substantial improvements to its regulation of the nation's blood supply. The areas which I will discuss in this testimony include: product safety, emergency response, inspection activity, dissemination of information to the public, blood banks, and future plans for the blood program within FDA.

A. PRODUCT SAFETY

In the past two years, FDA has issued new regulations and guidances to improve blood safety and deleted some obsolete regulations. Several committees have been established, or reformulated, to provide scientific and other advice to FDA to help ensure the safety of blood and blood products.

The Secretary of Health and Human Services raised blood safety to the highest levels of the Department of Health and Human Services (DHHS). The Assistant Secretary for Health was designated to be the Blood Safety Director, with overall responsibility for coordination and oversight of the Public Health Service's blood safety programs.

Reporting to the Blood Safety Director is the Blood Safety Committee (BSC) which includes the Directors of NIH and CDC, and the Commissioner of FDA. BSC has been meeting periodically since January 1996. BSC receives input from the Advisory Committee on Blood Safety and Availability (Advisory Committee).

The Advisory Committee was created in response to a commitment made by the Secretary of DHHS in her testimony before this Committee in October 1995. The Advisory Committee includes consumer representatives, scientific experts, ethicists, and representatives of regulated industry. Its purpose is to provide a forum to examine broad public health and societal implications of blood safety issues. The Advisory Committee held its first meeting in April 1997.

Since its inception in 1996, BSC has been informed of adverse events or emergency situations whenever they are likely to have broad public health impact or require increased coordination between the public health agencies. For example, an issue involving a specific incident of a product made from a donor who was subsequently diagnosed with Creutzfeldt-Jakob Disease (CJD) was brought to BSC's attention. BSC will be informed, and provide input, whenever FDA intends to take action that might be precedent setting or controversial.

FDA has made significant changes in its Blood Products Advisory Committee (BPAC). FDA has acted to eliminate any potential conflicts and possible undue industry influence by appointing new members in 1996 and revising its charter. FDA had restructured BPAC initially in 1994 expanding consumer representation through voting consultants. In 1995, the charter was revised to expand the possibility for voting representatives with consumer interests. FDA removed committee members with any appearance of a conflict of interest, except for a single non- voting industry representative. FDA also added a representative of CDC as a permanent member of BPAC. A representative of NIH is present as a consultant. This NIH representative has been allowed temporary voting privileges at BPAC meetings. BPAC plays an important role providing technical advice to FDA on scientific issues relating to safe and effective blood products and related medical devices. BPAC agendas are discussed with the Committee chairs prior to the meeting to help them prepare for the meeting. BPAC members also are sent background information on each agenda item. Since FDA's testimony before this Committee in October 1995, BPAC has met seven times covering a wide range of issues from HIV test kits to emerging new diseases to public notification issues.

FDA has provided a number of guidances in the past two years to the blood and plasma industry in an effort to ensure that the most up to date processes are utilized. In March 1996, FDA issued additional clarification of its August 1995 recommendation that blood establishments implement the HIV-1 p24 antigen test when the test was approved. FDA approved the test to screen blood donors for HIV-1 p24 antigen in March 1996 and establishments then were advised to use the test within three months of commercial availability. FDA recommended that the HIV-1 p24 antigen test be used to screen blood donors, in addition to antibody tests, thus providing additional screening. It is estimated that the use of the screening test could prevent up to 25 percent of the cases of AIDS from transfusions. These tests improve blood safety by further closing the "window period" before antibodies to HIV develop. The "window period" is the time early after infection when a person may be infectious but markers identified by testing are not yet present.

In May 1996, FDA issued further recommendations to blood establishments for the testing of whole blood, blood components, source plasma, and source leukocytes for the antibody to Hepatitis C Virus encoded antigen -- anti-HCV.

In July 1996, FDA issued recommendations for the quarantine of prior collections from donors who subsequently test reactive for HCV, HBV, and HTLV currently being screened for in blood donors.

In September 1996, FDA issued a final regulation on "Current Good Manufacturing Practices for Blood and Blood Components: Notification of Consignees Receiving Blood and Blood Components at Increased Risk for Transmitting HIV Infection." This final rule requires that blood establishments and consignees quarantine previously collected whole blood, blood components, source plasma, and source leukocytes from donors with reactive screening tests for HIV. Blood establishments also must perform confirmatory testing for donations that test reactive for HIV and notify consignees who received whole blood, blood components, source plasma, or source leukocytes from prior collections of such products so that they may take further action. FDA's rule, along with a companion Health Care Financing Administration (HCFA) rule, should result in the notification of transfusion recipients who received blood from donors who later tested positive in confirmatory tests for HIV.

In December 1996, FDA issued guidance to blood establishments on the deferral of donors who immigrated from countries with HIV-1 Group O. FDA also advised manufacturers of test kits to modify their kits to enhance sensitivity to detect HIV-1 Group O specimens.

FDA has required that plasma derivative manufacturers file monthly reports on adverse reactions associated with their products. Letters were sent to manufacturers in October 1996 and December 1996 notifying manufacturers that, pursuant to 21 C.F.R. 600.80, reports on any infectious disease transmission associated, or possibly associated, with any licensed biological product, be filed monthly. This is to ensure that incidents involving potential transmission of infectious agents are dealt with in an expeditious manner.

In December 1994, FDA instituted lot release testing for HCV RNA on all immunoglobulin products that have not undergone one or more validated viral inactivation or removal steps. Since then, FDA developed, and made available to manufacturers, a more sensitive assay for RNA extraction, and subsequent detection of HCV RNA by RT-PCR, in intravenous and intramuscular immunoglobulin products. FDA trained manufacturers in the use of the RT-PCR technique for use as a lot release procedure.

A Factor IX reference standard was developed by FDA and has been accepted as the world standard. A Factor VIII standard is being developed. Additionally, new lot release panels (standards) were developed for HIV, HBsAg, and HTLV-II.

In addition, FDA, in conjunction with CDC and NIH, published guidelines, such as the "U.S. Public Health Service Guidelines for Testing and Counseling Blood and Plasma Donors for Human Immunodeficiency Virus Type 1 Antigen," in the March 1, 1996 CDC Morbidity and Mortality Recommendations and Reports.

FDA has taken an aggressive stance with respect to potential new threats. FDA actions were discussed extensively in our testimony before this Committee on January 29, 1997.

FDA, in an effort to further develop its policy on CJD, formed a Special Advisory Committee on Creutzfeldt-Jakob Disease which first met in June 1995. This CJD Advisory Committee, composed of outside experts, including academic and Government representatives; consumer groups, including the National Hemophiliac Foundation (NHF); and industry groups, was rechartered in June 1996 for two additional years and is now known as the Transmissible Spongiform Encephalopathies Advisory Committee (TSE Advisory Committee), charged with advising FDA on issues related to all transmissible spongiform encephalopathies.

The risk for transmission of CJD through blood and blood products is considered to be only theoretical. Nevertheless, FDA has acted proactively to defer high risk donors and has recommended the voluntary withdrawal of affected products. 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.

There is presently 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.

Recently, manufacturers have approached FDA concerning the use of nucleic acid (PCR) tests to test plasma pools for infectious agents such as HIV. Such testing could result in donor notification, retrieval of prior collected "lookback" units and possible recipient notification. The accuracy of test results is critical since donor notification may be involved. FDA would carefully evaluate the safety and efficacy of such tests in reviewing any applications seeking approvals. The issue of PCR testing of plasma pools has been considered by BPAC and BPAC voted to adopt PCR testing of plasma pools. FDA is now preparing a Federal Register notice seeking public comment on this issue.

FDA has brought the recommendation of limiting the size of plasma pool size to BPAC for discussion on several occasions. The issue of safety in the face of unknown or theoretical threats is a difficult issue. FDA believes that restricting pool size could have some limited health benefits, including limiting the spread of rare infectious agents for which there are no screening tests and no adequate inactivation procedures. FDA, therefore, remains interested in considering setting practical upper limits for pool size and will request that all manufacturers of plasma derivatives update their product license files to include specific information regarding pool size.

FDA works closely with its sister public health agencies to ensure the safety of the blood supply. FDA receives input from CDC and NIH on issues of blood safety through several mechanisms in addition to the BSC. Employees of NIH, CDC, Health Resources Services Administration (HRSA), and the Department of Defense participate in the Interagency Working Group on Blood Safety and Availability which holds teleconferences approximately monthly to discuss issues affecting blood safety. CDC also has created a position of Assistant Director for Blood Safety in the Division of Viral and Rickettsial Diseases to facilitate interactions on these issues.

FDA collaborates with CDC and NIH on emerging public health issues through epidemiologic, laboratory, and other scientific studies. A few recent examples include: assessment of the risk of disease transmission from idiopathic CD+4 T-lymphocytopenia; ongoing surveillance study of HIV and hepatitis in clotting factor recipients; surveillance for novel strains of HIV such as HIV-1 group O; assessing the risk of transmission of CJD through blood and blood products by epidemiologic criteria and laboratory studies; studies of donor behavior related to use of voluntary deferral criteria; assessment of new donor testing technologies such as HIV-1 p24, HIV Western blot, HTLV screening, and many others.

CDC participates in product investigations on both a formal and an informal basis. CDC may assist FDA by conducting epidemiologic studies or assisting with scientific analysis.

Three recent examples are: Centeon Albuminar-epidemiologic assistance to identify products at risk for bacterial contamination; Alpha HIV antibody positive pool-scientific studies to determine whether there was an inherent problem with a licensed test kit; and Alpha Factor VIII and Factor IX epidemiologic and laboratory studies to investigate transmission of Hepatitis A virus from clotting factors. All of these efforts ensure that CDC and NIH have input at the highest levels of FDA and DHHS on blood safety matters.

B. EMERGENCY RESPONSE PROCEDURES

FDA has implemented fundamental changes in its internal operations to more effectively respond to emergency situations and potential emergencies. The change in emergency response procedures was necessitated by the recognition of a not sufficiently prompt response to a report of an adverse reaction to a plasma product.

On August 23, 1996, a patient in Wichita, Kansas, had an adverse reaction after receiving a plasma product. A hospitalized patient had been given Albuminar-25, manufactured and distributed by Centeon. Within 15 minutes the patient developed symptoms of septic shock. Ultimately, the patient recovered. The bottle of Albuminar tested positive for Enterobacter cloacae and the patient's blood culture also was positive for Enterobacter cloacae. The hospital reported the adverse reaction to FDA on August 24, 1996, through FDA's MedWatch 3 system and to the company. CDC was contacted about the case by the Kansas State Epidemiologist on September 4, 1996. 3 The MedWatch system is a voluntary reporting system to report adverse reactions to regulated products.

Despite the timely notification to FDA and the serious nature of the report, the MedWatch report was not identified as an emergency in its initial stages of processing. There also was a report to a field office that was not treated in an emergency fashion when reported to CBER. It was not until 27 days after the initial filing of the report that the emergency nature of the report was fully appreciated. On September 23, acting on FDA's advice, Centeon issued a voluntary recall of Albuminar and notified its consignees. Subsequent to the voluntary recall notification, CBER designated the Centeon incident as a Class I recall 4 and notified the media to publicize the matter so that affected individuals could take action. 4 A Class I recall is a situation in which there is reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequence or death. 21 C.F.R. 7.3(m)(1).

The Centeon situation brought to light differences in the way adverse reaction reports for drugs and biologics were handled by FDA. Because of these differences, the MedWatch report on Centeon's Albuminar was not acted on promptly. As a result of this incident, the following procedures are now in place for the MedWatch system.

As voluntary reports involving biologics products come into the MedWatch central triage unit (CTU) a copy is made and sent to CBER within one business-day. The original report is sent to the Center for Drug Evaluation and Research (CDER)(the Center responsible for the MedWatch program) for data processing. In addition, the contractor taking adverse event reports over the phone notifies CBER immediately when any CBER reports come in. The copy is evaluated immediately by CBER staff and forwarded as needed to appropriate CBER scientific and regulatory staff. After hours, the Medwatch answering machine greeting refers callers to FDA's Emergency Operations if no one is immediately available to take their call and they want FDA to know about an urgent problem. The overall 1-800-FDA-1088 Medwatch phone tree also was changed to refer persons making MedWatch reports to Emergency Operations if their call is urgent and they are calling after hours, on weekends, or holidays.

The mandatory reports that are sent in by biologic manufacturers, as opposed to the voluntary reports that are usually sent in by clinicians, are sent directly to CBER where a copy is kept by the safety evaluator and the original is sent to CDER for processing.

All reports associated with plasma derivative products are given the highest priority for review at all levels. To ensure rapid positive identification of plasma derivative products, up- to-date copies of CBER product lists are available at the CTU, the Telephone Unit (an outside contractor that handles adverse event telephone calls), and the CDER Division responsible for data processing (Surveillance and Data Processing Branch). All plasma derivative products involving documented, or possible, infectious disease transmission, are shared immediately with the Deputy Director, OBRR, and the Deputy Director, Division of Hematology, for evaluation to determine public health risk.

The manner in which field reports, that are potential emergencies, are handled also has been changed. Such reports, including complaints, calls, or reports, are handled by the Division of Emergency Investigations and Operations. This is now consistent with practices throughout FDA. As part of this effort, FDA has established an emergency response team consisting of members of FDA field offices, headquarters, compliance officers, and product experts to rapidly assess a situation and initiate corrective action.

While FDA did have systems in place to deal with emergency situations once an emergency was recognized, FDA has made significant improvements in its procedures for initially identifying an emergency situation. We also have established standard procedures to define the actions that need to be taken by different offices within CBER when confronted with an emergency or potential emergency situation.

CBER has finalized Standard Operating Procedures (SOP) 5 for dealing with situations that might constitute a threat to public health. The SOP details the responsible parties to whom information must be given, their accessibility at all hours, and procedures for notification when emergencies, recalls and significant adverse events are identified. 5 Emergency Operations, SOP # OD-R-17-97 (April 14, 1997).

Another problem brought to light with the Centeon recall was the attempt by certain plasma derivative manufacturers to characterize recalls as market withdrawals. 6 There have been several manufacturers who have initiated multiple product retrievals that were characterized as market withdrawals which FDA subsequently determined to be recalls. Two of these recalls were assigned Class I Recall classifications by FDA. The characterization of any recall, and particularly Class I recalls, as "market withdrawals," can be serious. Given the seriousness of the situation, the manufacturers re-issued letters to consignees properly designating the actions as recalls and provided instructions to secondary distributions for extension of the recalls to their customers. FDA has dealt with each plasma derivative manufacture involved in such recalls on an individual basis to assure that product removals were properly conducted. In addition, FDA recently addressed a letter to all plasma derivative manufacture specifically calling attention to their responsibilities concerning the classification of product recalls and market withdrawals. FDA also has engaged in discussion with trade associations and other organizations to encourage industry- wide attention. 6 Market withdrawals are defined as a firm's removal or correction of a distributed product which involves a minor violation that would not be subject to legal action by FDA or which involves no violation, e.g., normal stock rotation practices, routine equipment adjustments and repairs, etc.(21 C.F.R. 7.3(j)).

FDA also has formed a task force to continue reviewing all current procedures for handling reports of adverse events. This task force is examining ways that FDA receives reports and how to improve internal communication and handling of these issues so that the public health is better protected.

C. INSPECTION ACTIVITIES

Based on internal assessment of inspection activities, and consistent with outside recommendations, FDA has 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). Along with a transfer of the lead responsibilities in inspections and field emergency response, FDA has adopted a new model and approach to the inspection of plasma fractionators. This new approach emphasizes a complete assessment of compliance with good manufacturing practices (GMPs). In addition, the approach includes an assessment of the manufacturer's procedures in handling and investigating reports of adverse experiences and subsequent notification of these adverse experiences to FDA. Transfer of the lead to ORA will advance FDA's goals of internal consistency and efficiency as the inspection process for fractionators is now comparable to inspections for other regulated products.

ORA conducts inspection activities through FDA's five regional .offices and multiple district and field offices. The field inspectors are trained to inspect primarily for GMPs. Prior to April 1992, CBER alone had responsibility for inspections of plasma fractionators. In April 1992, CBER and ORA agreed to conduct joint inspections of plasma fractionators with CBER serving as the lead. In December 1995, CBER and ORA issued an SOP for joint inspections that had CBER and ORA sharing the lead on inspections. In Fiscal Year 1997, ORA assumed the lead for periodic inspections of plasma fractionators including evaluation of inspection findings and recommendations for appropriate regulatory action. To ensure the capabilities of the field to take the lead for these inspections, FDA intends to provide field staff more intensive training in biologic product manufacturing and, at the same time, provide CBER product specialists with more intensive training on inspection techniques with an emphasis on documentation of GMP deficiencies. OIG's analysis of prior CBER inspections concluded that CBER inspectors "were first and foremost scientists whose primary duties were not the inspection of plasma fractionators." 7 The inspections by CBER "were not designed to support post market obligations -- primarily assuring compliance with GMPs. Conversely, ORA inspectors were full time inspectors with more experience in conducting GMP inspections." 8 7 Department of Health and Human Services, Office of Inspector General, Review of the Food and Drug Administration's Inspection Process of Plasma Fractionators (Discussion Draft, May 1997) at p. 12. The OIG provided FDA with a Discussion Draft and has permitted FDA to cite from that draft for purposes of this testimony. 8 Id., at p. 12-13.

In the wake of the Centeon incident, FDA decided that an intensive review and inspection effort was needed to assure ourselves, and the public, of the safety of plasma manufacturing. FDA adopted a plan to conduct a compressed schedule of inspections of all plasma fractionators. There are a total of 26 licensed plasma fractionators. Twenty-two of these plasma fractionators currently are supplying product for the United States market. As of the date of this testimony, we have reinspected 100% of the plasma fractionators currently supplying product to the United States market in Fiscal Year 1997. Four manufacturers, all foreign firms, were not inspected as they are not currently producing product for the United States market. Three of these firms are renovating their facilities and one firm is temporarily shut down but expects to resume operations in the near future. Upon resuming production and prior to distribution of product to the United States, all four foreign firms will be inspected.

A review of the results of establishment inspections from Fiscal Year 1993-1996, and those in Fiscal Year 1997, emphasizes significant inspection differences. In general, inspections under the lead of ORA have resulted in more in-depth inspections. 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. The final Establishment Inspection Report (EIR) is received in the CBER Office of Compliance (OC) on a more timely basis. To date, there have been five Warning Letters issued in Fiscal Year 1997, one Notice of Intent to Revoke, and one injunction based on a consent decree related to plasma fractionation inspections. The following table provides some comparative figures:

ORA and CBER have formed a Biologics Program Committee (BPC) to address the roles of each office and to identify points of differences between CBER and ORA inspections which need additional clarification, coordination, and resolution. In as much as all blood product reinspections are led by ORA, it is anticipated that ORA will assume the lead role in periodic inspections for other CBER biological products over the next three years.

This Committee in its 1996 report recommended that in conducting inspections, FDA cease pre-notification of plasma manufacturers of planned inspections. Prior to 1996, CBER would request production schedules of plasma fractionators immediately prior to scheduling an annual or biennial inspection but would not pre-notify the manufacturer. The request, however, resulted in some manufacturers accurately guessing when an inspection was about to occur. To avoid this result, CBER implemented a new SOP 9 in November 1996 which directs that letters be sent on a periodic basis to all manufacturing firms to obtain production schedules. (Pre-license approval inspections are conducted by pre-notification as is consistent with other FDA Centers.) The OIG report noted that in the recent reinspection process, FDA had not precisely followed the SOP but had instead called the firms to obtain the production schedules. 10 The phone calls were necessitated by the abbreviated time frames associated with the compressed inspection schedule for the 22 inspections this calendar year. In the future, this SOP will be implemented as written. 9 Request for Industry Production Schedules for the Purpose of Planning and Scheduling Biennial Inspections, # OD-R-12-96. 10 Supra, at 18.

D. DISSEMINATION OF INFORMATION TO THE PUBLIC

This Committee made a recommendation in its 1996 report that FDA "develop an effective system of recall notification for blood and plasma products." In response to the Committee's concerns and other recommendations, FDA has provided enhanced public access concerning recalls and withdrawals of blood and blood products and has increased public input in the discussion regarding policy development on withdrawals and notification of plasma products.

FDA has made information concerning recalls and withdrawals widely available to interested and affected parties. A voice information system with toll free lines has been set up with information on fractionated product recall and market withdrawal information. A fax information system has been put into place allowing "fax-on-demand.11 FDA's Home Page on the Internet's World Wide Web contains information about recalls and market withdrawals of fractionated blood and plasma products. An automated e.-mail system has been created to provide information to those requesting notice of such actions and other CBER information.

In November 1996, the Pubic Health Service (PHS) held a workshop, "Informational Meeting: Notification of Plasma Product Withdrawals and Recalls," to discuss and obtain public input on notification of the public on recalls and ongoing investigations.

Participants included employees of FDA, NIH, CDC, consumer groups, and industry. This meeting was organized to obtain input from consumers and industry on when and under what circumstances notification of end users should be made.

FDA has been working with industry and consumer groups to determine when consumers should be notified and the best method for notification. FDA's current position, discussed at the public meeting in November 1996, is that the manufacturers and blood establishments should carry the ultimate responsibility for public notification. The manufacturer is in the best position to notify end users because they are the most knowledgeable about their consignees. Nevertheless, FDA recognizes its role and the important public health need to make consumers immediately aware of product recalls and withdrawals.

FDA has initiated a dialogue with manufacturers, distributors, and consumers about designing a notification system that will serve all users, especially consumers who maintain personal custody of the derivative product. The manufacturer presently only notifies its consignees of the recall or withdrawal. FDA communicates by telephone about product recalls, withdrawals, quarantines, and other matters of safety interest to consumer groups such as the NHF and the Committee of Ten Thousand (COTT), as appropriate.

To improve communication and cooperation, FDA employees have participated in NHF annual meetings and at meetings of NHF's Medical and Scientific Advisory Council twice yearly. NHF and COTT were asked to participate in national and international meetings sponsored by FDA including: the November 1996 "Information Meeting: Notification of Plasma Product Withdrawals and Recalls" and the "International Conference on the Virological Safety of Plasma Derivatives."

Consumer groups, including NHF and COTT, participate as members of BPAC. In addition, consumer groups have been invited to present information to BPAC on issues such as consumer notification and warning labels. FDA also has discussed its interest in the development of warning labels on plasma derivative products.

Informational meetings between consumer groups and FDA have been held periodically to discuss issues of patient concern. Recently, NHF has been invited to meet with FDA on a quarterly basis over the next year to improve communication about FDA practices and procedures.

At the first meeting of the Advisory Committee in April 1997, the issue of Hepatitis C (HCV) lookback and notification of recipients was considered. The notification of transfusion recipients potentially infected with Hepatitis C was another recommendation of this Committee in its 1996 report. A final decision has not been made on HCV lookback by the Advisory Committee, however, all aspects of this recommendation are being examined.

HCV lookback has been extensively discussed at meetings of BSC in 1996. At the request of-BSC, an Inter-Agency Working Group on Blood Safety and Availability analyzed this issue. Issues dealing with the feasibility of personal notification; potential percent of recipients unable to be notified, alternative means of notification for the most at-risk recipients and other issues were considered. The Working Group developed several options and recommendations. DHHS adopted two of the Working Group's options including physician targeted outreach and a public information campaign to identify HCV infected persons. It is important to recognize that DHHS has taken an active role in recipient notification encouraging the dissemination of information through other means than personal notification. CDC is working with voluntary and professional organizations, such as the American Liver Foundation, to educate providers and the public through advertisements and other communications about viral Hepatitis-related liver disease, with an emphasis on Hepatitis C. Also, CDC, in partnership with the Hepatitis Foundation International, on November 22, 1997, will air an interactive satellite teleconference entitled, "Hepatitis C: Diagnosis, Medical Management and Prevention." The program will feature presentations by nationally recognized experts and will provide supplemental printed materials to facilitate patient identification, diagnosis, medical management, and counseling. The Advisory Committee has the matter of "directed lookback" under active consideration.

FDA continues to utilize its Office of Public Affairs (OPA) to disseminate information to the press and media on issues of concern, including recalls and market withdrawals. FDA's Regulatory Procedures Manual, Chapter 7, Emergency Procedures (May 1997) provides that OPA is "responsible for issuing publicity and preparing answers to press inquiries about emergencies." Questions have been raised as to the nature of press notification and the best method of disseminating the necessary information -- i.e., whether there should be a press release, press advisory or an FDA Talk Paper. 11 OIG reviewed one particular incident related to blood and blood products -- the recall involving Centeon. During the Centeon crisis, FDA prepared several Talk Papers and provided information immediately on its FDA Home Page on the Internet. FDA communications, including Talk Papers, resulted in Associated Press coverage of the Centeon recalls. FDA also arranged press interviews with its blood experts. The OIG concluded that: 11 FDA Talk Papers provide background information for use in responding to inquiries.

We do not believe that FDA's use of talk papers in lieu of a press release adversely affected the Centeon recall process especially in light of the press conference with the Associated Press and Internet distribution. 12 12 Supra, at 25.

FDA is firmly committed to providing accurate and timely information to the public about recalls and market withdrawals. The timing of such public notification is a delicate balancing act as definitive information is often lacking at the initial stages of a potential emergency situation. For example, until lab tests are conducted, the exact product that may have caused an adverse reaction can not always be determined. Until manufacturing records are examined and traced, the specific lot number of a distributed product may be difficult to ascertain. FDA continues to work on improving the dissemination of important information to the public.

This Committee's 1996 report recommended that DHHS disseminate more clinically useful information on blood safety issues. The Interagency Working Group on Blood Safety and Availability formed a subcommittee to look at how to carry out this recommendation. A survey of the blood industry for educational materials is presently underway.

Several sources have recommended that FDA must articulate its requests or requirements in forms that are understandable and implementable by regulated entities since regulators must rely heavily on the performance of industry to accomplish blood safety goals. In particular, when issuing instructions to regulated entities, FDA agrees that it should specify clearly whether it is demanding specific compliance with legal requirements or is merely providing advice for consideration. To assist in this determination, in February 1997, FDA published a notice in the Federal Register, 62 Federal Register Vol.39, 8961 (February 2, 1997), announcing a new FDA document entitled, "Good Guidance Practices," which sets forth FDA's policies and procedures for the development, issuance, and use of guidance documents.

FDA is working to implement, as regulations, those recommendations that it believes are necessary for public safety. Historically, as new scientific information was gathered, FDA would develop recommendations based on this information to assure the safety of the blood supply. Recommendations were made, in lieu of regulations, because of the length of time needed to develop regulations and the importance of moving quickly to protect the public health. These recommendations, however, usually have been adopted by industry as part of their standard operating procedures. Once part of their standard operating procedures, they must be adhered to by the manufacturers. if not, such failure would be noted in an inspection.

In June 1994, FDA announced that it was conducting a review of all blood regulatlood products across state lines. Unlicensed facilities do not ship across state lines but must follow the same safety procedures as licensed facilities. Licensed facilities are required to file error and accident reports (EARS) with FDA in the event of errors and accidents in their procedures and facilities which may result in an unsuitable unit of blood being available for distribution.

To provide more protection for donors and recipients of blood, FDA is developing a proposed rule to require unlicensed establishments to report errors and accidents to the Agency. In addition, a National Heart, Lung, Blood Institute (NHLBI) grantee is studying blood banking errors from a systems perspective, drawing on the experience of other fields where zero tolerance for errors is the norm. NHLBI and FDA will review the results periodically to see if implementable improvements over present practice are discovered.

In 1996, the CBER Errors and Accidents Reports System (CEARS) was established. This database made all EARS, including a brief description of the incident, electronically available to field personnel. CEARS is a menu-driven computer program which provides for the display of information from the CBER database containing EARs relating to biologics. This system is an invaluable asset to field personnel because they are able to download the data in various formats (i.e., summaries, key problems, etc.) for review prior to inspections of blood collection facilities.

The blood industlood products across state lines. Unlicensed facilities do not ship across state lines but must follow the same safety procedures as licensed facilities. Licensed facilities are required to file error and accident reports (EARS) with FDA in the event of errors and accidents in their procedures and facilities which may result in an unsuitable unit of blood being available for distribution.

The blood industry has evolved from a loosely organized medical service into a major manufacturing industry - an industry which must conform to high standards and quality control requirements comparable to those of pharmaceutical companies or other regulated industries. FDA can provide support and guidance, but it is fundamentally the blood bank's responsibility to comply with the rigorous standards that are necessary to protect our blood supply.

FDA is committed to holding blood banks to these standards. In the past few years, there have been a number of legal actions designed to hold blood collection facilities to strict standards.

FDA sought and obtained a Consent Decree for Permanent Injunction for the American Red Cross in May 1993 because of problems found during inspection of those facilities. American Red Cross collects approximately 45% of all whole blood donations in the United States.

In April 1996, FDA obtained a Consent Decree for Permanent Injunction for Blood Systems, Inc. (BSI), doing business as United Blood Services, because FDA's inspections revealed continuing problems with adherence to GMPs. BSI collects blood at 17 licensed facilities and multiple blood collection sites in 13 states.

In December 1996, FDA obtained a Consent Decree for the New York Blood Center (NYBC). NYBC agreed to strengthen its quality assurance/quality control programs; improve management and supervision of technicians performing blood screening tests and to make improvements in its records management. NYBC recently announced it would contract out certain testing operations.

FDA recently suspended the license of Intermountain Health Care (IHC) blood center in Utah because of numerous GMP violations. This action stopped the interstate movement of IHC's products. At the same time, FDA asked IHC to cease its intrastate operations, and the firm agreed. American Red Cross recently announced its plan to assume responsibility from IHC for serving the needs of the citizens of Utah for blood and blood products, but all such changes must be approved in advance by FDA.

A question was raised previously regarding FDA procedures for checking the origin of blood from other countries and whether FDA could identify whether blood diversion was occurring from a high risk country to a low risk country. The February 3, 1997, revised Import Alert #57-01, "Automatic Detention of Blood and Blood Components including Human Plasma and Serum," provides guidance to FDA staff to eliminate improper entries of blood and blood components. The Import Alert specifically addresses items that must appear on the immediate container label for imported blood products that are not covered by an unsuspended and unrevoked United States license or valid short supply agreement. Among other items, the label must include the names and address of the establishments that are collecting, preparing, labeling, or pooling the source material.

In addition, CBER's OC is currently developing a revised compliance policy guide for imported blood products for use by the district offices. FDA conducts inspections to audit foreign blood establishments to verify licensure for those products exported to the United States when licensure is required and to ensure no product diversion.

IV. FUTURE PLANS FOR IMPROVING FDA BLOOD PROGRAM

FDA is committed to vigilant regulation and monitoring of blood and blood products in the United States. A number of critical changes have been implemented that already have yielded significant improvements as will future plans.

FDA intends to make significant organizational and management changes at CBER. The Director of CBER has announced recently the selection of a Medical Deputy Director. The Medical Deputy Director will be responsible for direction and coordination of all the offices and components within CBER that deal with blood and blood products. Presently, the responsibility for blood is diffused through OBRR, OC, and the Office of Establishment Licensing and Product Surveillance (OELPS). The Medical Director will now have the ultimate authority and responsibility to ensure that all of the essential regulatory functions are coordinated and carried out in a timely fashion. The Medical Director will have access to all individuals within CBER who work on blood-related issues and will be able to reassign these individuals to those tasks deemed most important to the regulatory oversight of the blood supply. One of his first priorities will be to develop a list of those regulatory actions that need the most immediate attention. We are confident that this management change will have a significant impact.

FDA, and the new CBER Medical Deputy Director, will continue the reinvention of blood and blood regulations with the goal of simplifying paperwork and the movement to a standards based approach to regulation. The Biologics License Application (BLA) implementation is proceeding and will provide a single application in place of the establishment license application (ELA) and the product license application (PLA) that are now required. Efforts to develop standard manufacturing operating procedures for specific blood products will continue. The emphasis will remain on quality assurance.

FDA intends to continue its identification and prioritization of its rule-making needs. Those guidelines previously issued in the form of guidances and recommendations will be evaluated to determine which are essential to the safety of the blood supply and need to be issued in the form of regulations. Concurrently, regulations for donor suitability, product standards, and compatibility testing need to be updated. outdated regulations, such as GMPs for blood and standards for recovered plasma, need to be revised. Lookback issues on several levels will be evaluated. Regulations to require manufacturer of plasma derivatives to incorporate manufacturing procedures for viral inactivation or removal will be considered.

The effort to improve ORA/CBER cooperation and communication will continue through its TEAM BIOLOGICS. Joint training and rotating details of personnel will be continued, as well as inspection coordination and report evaluation.

FDA needs to improve its evaluation and analysis of its 483s, EIRs, and EARs. Attention to trends in these reports will assist FDA in developing policies and procedures for implementation, as well as possibly identifying new threats to the blood supply.

Research activities also will aid in the identification of new threats to the blood supply. FDA will continue to develop a paradigm for identifying and addressing emerging infectious diseases with CDC and NIH.

To better leverage limited resources, FDA intends to work to better coordinate blood and plasma regulatory activities with State and other regulatory authorities on accredited inspections and harmonized requirements.

V. CONCLUSION

FDA faces significant challenges in helping to assure the safety of the blood supply. We must strive for zero tolerance for errors in the regulation and management of the blood and blood products industry. At the same time, there has to be sufficient information for the public to understand the risks associated with using blood and blood products. All of this must be done without compromising the supply of blood and blood products that is vital to the health of the American people. We already have done a great deal. Major changes have been made in product safety, our response to emergencies, inspection activities and inter-agency cooperation.

Now, efforts must continue to improve our internal operations.

We are absolutely committed to these efforts and we will not rest until we are assured that the blood supply is as safe as is possible.

Thank you for the opportunity to testify.