Blood and Plasma Safety

Statement of

Michael A. Friedman, M.D.
Acting Commissioner
Food and Drug Administration
Department of Health and Human Services

before

the Subcommittee on Human Resources
House Committee on Government Reform and Oversight

September 9, 1998

INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Michael A. Friedman, Acting Commissioner of Food and Drugs (FDA or the Agency). I appreciate this opportunity to discuss the General Accounting Office (GAO) report: "Blood Plasma Safety: Plasma Product Risks Are Low If Good Manufacturing Practices Are Followed" which reviewed the viral marker rates of paid versus unpaid donors. As requested, I also will update the Committee on the status of FDA's regulatory compliance program which helps assure the safety of blood and plasma derivatives through the application of good manufacturing practices (GMP) as well as the continuing shortage of immune globulin, intravenous (Human) (IGIV), the subject of the subcommittee hearing on May 7 of this year.

BACKGROUND 

For the millions of Americans with certain medical needs, whole blood and plasma derivatives are essential for preserving their life or for maintaining a normal quality of life. These patients expect that the products will be free of infectious disease and effective for their intended use. Fundamentally, it is the role and responsibility of industry to provide adequate and safe products. FDA has a responsibility to help ensure that these patients' expectations of safety and availability are fulfilled by our oversight of blood and plasma collection, processing and manufacturing facilities, as well as through product approvals and surveillance.

While the United States is recognized as having one of the safest blood supplies in the world, assuring the safety and availability of blood products still poses formidable challenges. While humans are the source of plasma, humans also are potential carriers of many transmissible diseases. From the collection of source and recovered plasma from donors, through the fractionation and manufacturing process, to the quarantine and retrieval process, there are numerous points at which safety measures are in place to minimize the risk of exposing recipients of blood products to infectious agents. FDA views the entire process as a continuum of interrelated steps. At each one of these steps, the Agency has recommended or required safety mechanisms to decrease the risks associated with the use of blood products.

The technology associated with disease detection in blood and plasma donors is continually improving, but is not perfect. The number of blood and plasma donors, while adequate to meet present needs, is not unlimited. Further improvements in efficiency, capacity and quality in the manufacturing process are possible, but often take significant time to accomplish and the commitment of major resources by an industry that often is resistant to change.

In this process, the Agency deals with competing interests in effecting its regulatory compliance program. Product safety must be maximized, but an adequate supply of lifesaving blood products needs to be available. The balance of these two interests can be very difficult to achieve and is often precarious at best.

There is no question that a shortage of plasma derivatives still exists, particularly of IGIV. This shortage situation was described in detail this past May 7 before the Committee by Dr. David Satcher, Assistant Secretary for Health and Surgeon General, Department of Health and Human Services (DHHS) and myself. Since that hearing, FDA has taken a number of actions to try and alleviate the shortage. Simultaneously, however, FDA continues to demand the highest level of compliance from the plasma industry. Actions taken by the industry have had, and will continue to have, an impact on product availability.

UPDATE ON FDA INSPECTIONS AND REGULATORY OVERSIGHT

Since 1996, FDA has strengthened its oversight of the fractionation industry. As elaborated upon last year in the June 1997 hearing held by your subcommittee, FDA transferred lead responsibility for periodic inspections of fractionators (manufacturers who further process plasma and other blood derivative products) from The Center for Biologics Evaluation and Research (CBER) to the Office of Regulatory Affairs (ORA) in 1996. Along with that transfer of the lead responsibilities in inspections and field emergency response, FDA also adopted a new model and approach, called Team Biologics, to the inspection of plasma fractionators.

Under Team Biologics, FDA has established a partnership between ORA and CBER which utilizes the diverse skills and knowledge of both ORA and CBER staffs to focus Agency resources on inspection and compliance issues in the biologics area. The goal of Team Biologics is to assure the quality and safety of biological products and bring product manufacturers into compliance. To accomplish this a cadre of investigators has been created that is more specialized and technically prepared to inspect fractionated product facilities and other biologics establishments. This specialized investigator cadre has access to a similarly specialized group of compliance officers for guidance, support and counsel on evidence development and assistance in drafting any required administrative or regulatory action documents. Likewise, a specially trained cadre of investigators has been established to inspect blood banks and plasma collection facilities.

This new approach emphasizes a more complete assessment of compliance with GMP. In addition, the approach includes a more detailed assessment of the manufacturer's procedures in handling and investigating reports of adverse experiences and subsequent FDA notification of these adverse experiences. FDA has taken strong steps to assure compliance of the plasma industry with GMP through court injunctions and warning letters.

Product Availability/Shortages

As part of the FDA enforcement program, FDA carefully considers the impact of regulatory actions on product availability. FDA takes regulatory action when it believes that products are violative and could compromise the public health. FDA will exercise enforcement discretion when appropriate. For example, if the Agency determines, after balancing all the factors, that halting the manufacture of a "medically necessary product" could cause harm to patients, FDA can permit continued manufacture of the critical product even while regulatory action against the firm proceeds. Each case has to be evaluated on its own merits weighing the need for the medical product versus the risk of use of a product manufactured outside the parameters of GMP. In no instance, however, would FDA authorize release of a product known to be contaminated or potentially unsafe.

In the case of plasma manufacturers, FDA faces a very difficult task. In many cases, the plasma industry lags behind the drug industry in compliance with GMP. As FDA has acknowledged over the past year, and in testimony before this committee, past regulatory efforts with the plasma industry were not as rigorous and exacting as they could have been with respect to GMP. Not all plasma fractionators have accepted FDA's increased surveillance and oversight. Until the plasma industry accepts that GMP are essential to safe, high quality products, the manufacturing operations will continue to be out of compliance, often necessitating enforcement actions that potentially threaten product supply.

In May, I testified that FDA anticipated some relief in the shortage of IGIV based on the assumption that Centeon would resume production of IGIV at its previous capacity. Centeon is subject to a court order in the form of a consent decree with FDA that requires significant improvements in GMP. Pursuant to the consent decree, the company resumed production based on its initial efforts to comply with the consent decree, which required improvements to quality assurance, including the hiring of third-party consultants to evaluate and improve Centeon's quality assurance programs. Despite FDA's belief that the company was on the road to compliance, the first comprehensive inspection of the company to determine compliance with the consent decree revealed otherwise. The inspection revealed inadequacies in several critical areas including: quality assurance, failure investigations, laboratory controls, equipment and process validation, and production and process controls.

Consequently, it was necessary for FDA to require Centeon, by notice dated August 13, 1998, to take specific action under the consent decree to correct these violations. As this testimony was being prepared, the Agency was evaluating the company's response to FDA's August 13 letter and the plans to address the specified violations.

Although Centeon continued to be out of compliance, FDA has advised Centeon that it can continue to produce medically necessary products for the time being, including IGIV, under certain conditions. At this time, FDA is still working with the company to determine the company's final response to FDA's August 13 letter and the ultimate impact on the availability of the products it produces.

IGIV Supply

At the present time, FDA continues to be aware of IGIV shortages as well as shortages and possible shortages of several other plasma derivatives, including albumin and clotting factors. FDA anticipates that the IGIV shortage will not be alleviated and will continue as long as production levels do not meet or exceed previous years' levels. FDA has acted affirmatively to assist the plasma industry to alleviate shortages and is exploring other alternatives to address shortages. FDA has continued to expedite lot release for IGIV; monitored the shortages through data submissions; and worked with health professionals to identify needed supplies.

FDA believes that the plasma industry also needs to act more aggressively to comply with GMP while maintaining adequate production to meet medical demands. FDA will not and can not relax GMP standards for this industry. While FDA would prefer not to allow products manufactured under inadequate GMP to be distributed in the marketplace, the Agency appreciates the risk to patients of not obtaining product and, where the safety of the product can be assured, will exercise enforcement discretion in a manner that accommodates both priorities.

On April 28, 1998, the DHHS Advisory Committee on Blood Safety and Availability (Advisory Committee) considered the issue of shortages of plasma derivatives and issued a number of recommendations. One recommendation was that FDA and industry should collect and disseminate standardized information on production, distribution and demand for a number of plasma derivatives. FDA has asked industry for monthly data on product supplies, although there has not been final agreement about the terms and extent of data collection and sharing. Another Committee recommendation was for FDA and industry to explore the possibility of importing supplies of IGIV and Immune Globulin Intramuscular (IGIM). FDA has explored this issue and various concerns need to be resolved involving GMP and plasma collected abroad.

The most important action, however, has been the recommended change in policy on plasma derivative product withdrawals because of concern regarding transmission of Creutzfeld-Jakob (CJD) disease. On August 27, Dr. Satcher announced at the DHHS Advisory Committee that he supported a modification of the current recommendation on quarantine and withdrawal of blood and plasma derivatives due to the theoretical risk of CJD. The new policy recommends withdrawal of plasma derivatives only if the blood or plasma donor develops new variant CJD (nvCJD). FDA presently recommends the withdrawal of blood and plasma derivatives when there is any evidence in a donor of classical CJD or CJD risk factors. The policy change was deliberated carefully and extensively within DHHS and was the subject of two meetings of the Public Health Service (PHS) Blood Safety Committee. The scientific deliberations considered a number of factors before recommending the policy change. Most importantly, epidemiological studies of humans over the past few decades have failed to demonstrate a single case of blood transfusion causing CJD infection. Based upon that, the risk is thought to be very low, and possibly non-existent. Conversely, withdrawal of plasma derivatives has caused harm to the public health due to product shortages.

FDA's policy regarding CJD has been a contributing factor to the shortage of IGIV. Multiple IGIV lots have been quarantined or withdrawn because of donors who, after donation, were identified as being at risk of, or as having developed, CJD. Substantial amounts of intermediate product, not yet processed into final products, also were affected by the withdrawals and placed in quarantine.

The Agency anticipates that this new recommendation, once implemented by industry, should help minimize the present shortages of IGIV and other plasma derivatives, although the change will not resolve the shortage situation.

VIRAL MARKER RATES/DONOR SCREENING 

Although the final safety step of viral inactivation/removal is the most important mechanism which assures the safety of plasma derivatives, the initial step in the process, namely donor collection, also plays a critical role in product safety. GAO evaluated this first step to determine the risk of infectious agents including human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) from unpaid versus paid donors being incorporated into the manufacturing process. The Agency generally agrees with the findings relating to the viral marker rates of donors made by GAO in its report. In particular, FDA agrees that the data presented demonstrate that the paid and unpaid donor populations, whose plasma is used for manufacture of fractionated products, have different viral marker rates. FDA believes, however, that GAO's analysis shows that within the error of estimation, the risk of contamination of plasma pools from paid versus unpaid donors is comparable as a result of donor screening and testing, and inventory hold procedures implemented by the source plasma industry.

There have been various studies conducted to assess the extent of the differences in the viral marker rates of paid versus unpaid donors. As might be expected, the studies show different results depending upon the design of the study, the region where the study was conducted and other variables. Various differences between procedures for collection of source plasma versus recovered plasma make direct comparison of marker rates difficult. For example, the differences in frequency of donation of whole blood versus plasma affects the calculation of the viral marker rates. While the various studies are instructive, none should be interpreted as an absolutely accurate measure of viral marker rates nationwide.

The implications of viral marker rates in paid donations have been considered by FDA for a number of years. On June 28, 1993, FDA sponsored a Workshop on Safety of Plasma Donation as part of the June 28 and June 29 Blood Product Advisory Committee (BPAC) Meeting. FDA asked committee members to review whether source plasma and recovered plasma were comparable with regard to the safety and efficacy of plasma derivatives produced. The safety of plasma derivatives also was reviewed at the International Conference on the Virological Safety of Plasma Derivatives in November 1996. FDA again brought the issue of viral marker rates to the BPAC on March 19 and 20, 1998, and asked for a similar review based upon additional data and changes in the plasma industry, including implementation of PCR testing and new donor management practices.

Direct comparison of viral marker rates, therefore, does not measure either the differences in the underlying donor populations or the residual risk to plasma pools. FDA concurs with GAO's models for estimating the incidence of infections in the populations and the risk after donor selection and screening. It needs to be recognized, however, that these calculations have a wide margin of error.

The Agency believes that management and analysis of viral marker rates should be considered in the broader context of implementing strategies for reducing risk, including developing improved donor screening processes, additional and more sensitive testing methods, improved viral clearance procedures, and reducing pool size. If an opportunity exists to make the ultimate product safer by addition of tests in the initial stages of plasma collection these tests should be utilized. More importantly, plasma fractionators must adhere to GMP to ensure the safety of products. Presently, however, it makes no sense to further restrict the donor pool to unpaid donors given the need for plasma for manufacturing needed products when there is no evidence that safety of the products would be enhanced. This same conclusion was reached independently by experts in 1993 and 1996 at national and international workshops.

It is, of course, highly desirable to collect plasma from disease-free individuals, whether paid or unpaid. Collection establishments assess for risk factors for blood borne diseases by interviewing potential donors for high-risk behavior and for symptoms of disease. Based on this information, donation facilities eliminate individuals with higher risks for disease, although this process also eliminates many healthy potential donors. Donor screening criteria identify behavior that correlates with higher risk for disease and higher risk of contaminated blood. For example, FDA has recommended that prisoners not be used as donors because it has been found that a high percentage of all prisoners are drug users. Thus, although in the past blood and plasma were allowed to be colleted in prisons, that is no longer the case. It is difficult, however, to identify and isolate other large segments of society that may be high risk, thus selection must be done on an individual donor basis.

PLASMA POOLS

In order to manufacture sufficient quantities of plasma derivatives, most manufacturing facilities are designed to work on a large production scale, using large plasma pools. These plasma pools are derived by combining units from thousands of individual donations. The number of units combined into a common mixture for processing is known as "pool size."

A major recent advance in assuring safety of plasma derivatives is gene amplification based testing by polymerase chain reaction, or PCR. After individual units are collected and the marker positive units eliminated, the plasma industry now combines several hundred units into mini-pools for further testing by newer methods that are not yet feasible to use on individual donations. These mini-pools are tested with a very sensitive means of detecting infectious agents -- nucleic acid techniques. While there are a variety of nucleic acid techniques, the most promising is PCR testing. This technology can detect very minute levels of nucleic acids, which are genetic building blocks for infectious agents such as HIV and HCV and for all organisms. If this testing detects the presence of an infectious agent in the mini-pool, the individual positive unit can be identified and eliminated from further processing. Units that are marker negative based on testing in mini-pools are then combined into a larger pool. This larger pool is used as the starting material which will be separated, or fractionated, into various components that will eventually become finished products such as albumin, clotting factors, immune globulins, among others. Because this technology is more sensitive than some current screening, PCR testing leads to better detection and elimination of most window period donations from the plasma pool. This greatly decreases, if not eliminates, the viral load, or the number of infectious virus particles, in a plasma pool. Although current viral inactivation/removal techniques have a capacity that greatly exceeds the anticipated viral load in a plasma pool, further reductions in viral load only can be viewed as positive measures, which add to assurance of safety.

Another means of managing risk is to limit the pool size. The potential benefit of limiting pool size is that the infectious risk for infrequent users would be reduced in instances where the prevalence of the infectious agent is low. Reduction in pool size also might lessen the impact of recalls and withdrawals on supply of the products. In setting upper limits on pool size, however, potential adverse consequences also must be considered. With small size batches, quality monitoring and release testing could consume a large portion of the batch. Smaller pool size, and therefore smaller batch size, in existing plants may result in sub-optimal processing and decreased overall product availability.

This Committee has considered issues related to plasma pool size in its ongoing oversight activities concerning blood safety issues and recommended limitations on pool size. FDA is now developing guidance on limitations to plasma pool size which is expected to be issued in the near future.

VIRAL INACTIVATION

Since the initial safety steps of eliminating blood possibly contaminated with infectious agents is imperfect, the most critical safety step remains viral inactivation. The risk to a patient from any particular agent may vary with the particular plasma derivative. Thus, FDA believes that all human plasma derivatives should undergo viral inactivation or removal procedures to ensure safety. FDA has been moving progressively toward this goal even for products that never have been documented as transmitting viral agents. Most plasma derivatives already are processed specifically to inactivate or remove many viruses. There are highly effective mechanisms for removing or inactivating lipid enveloped viruses such as HIV, HBV, and HCV. The technology to inactivate heat stable, non-lipid enveloped viruses, such as the Hepatitis A virus, or agents such as CJD while preserving the functions of plasma proteins, however, currently is not available.

While all the above safety measures enhance the reduction of risk, without adequate viral inactivation, the other safety measures will not provide the measure of assurance that is necessary for public safety. The application of GMP to this process is particularly important. If viral inactivation and removal processes are not carried out in accordance with GMP standards, the companies will not be able to provide the necessary level of assurance that the finished product is safe.

EMERGING INFECTIONS PLAN

The greatest threat to the blood supply is posed by unknown or emerging agents that may not be inactivated or removed during processing. Realizing that there constantly will be emerging infectious agents which pose threats to the safety of the blood supply, FDA is committed to developing a strategy for each identified emerging infectious agent. The Agency is engaged in the scientific investigation of emerging infectious agents, which includes surveillance, methods and standards development and regulatory controls.

In 1997, DHHS organized a Committee on Emerging Infectious Diseases (Committee) comprised of representatives of the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and FDA. The Committee has developed a plan for evaluating and managing any emerging infection with the potential to threaten the blood supply. The Committee also has developed a database of known emerging infectious agents that might threaten the blood supply. This database is updated as new information is obtained. The response to a potential threat falls into four phases. First, epidemiologic characteristics of the agent will be identified and its transmissibility by blood ascertained. This process may involve field investigations, seroprevalence studies (if it is a known agent) using banked and acquired specimens, literature reviews and consultations with outside experts. Second, the Agency will undergo extensive laboratory investigations, including, as necessary, attempts to grow the agent, to infect laboratory animals, and contribute towards the development of serologic and gene based amplification assays. In addition to the laboratories of the PHS agencies, assistance may be requested from outside laboratories that have the appropriate expertise either through collaborations or by supplementation of existing grants. Third, FDA will issue recommendations to blood establishments for donor screening and deferral. Fourth, PHS will establish emergency communications to enhance coordination and interact with State and local health departments and blood organizations.

The Committee has been holding regular quarterly teleconference meetings and ad hoc meetings. The FDA BPAC and PHS Blood Safety Committee have been informed on a regular basis of updates and initiatives undertaken by this Committee. FDA also regularly interacts with patient groups, academicians and industry scientists to remain current with outstanding issues of concern and technological advances.

There are a number of examples of emerging threats for which FDA has been actively involved in developing a response. For example, Chagas disease, caused by the parasite Trypanosoma cruzi, while endemic in South and Central America, has become an emerging threat in North America. This parasite is transmitted through blood transfusion, although fortunately there only have been four cases of this disease caused by transfusions in North America. FDA is monitoring several large-scale clinical trials being conducted in blood banks in the United States using experimental assays to detect infection of the parasite.

Some emerging threats do not come from newly characterized infectious agents, but rather from variations of well known infectious agents. An example of this is HIV-1 Group O that was identified for the first time in 1996. In July 1996, FDA requested manufacturers of HIV test kits to modify their kits for enhanced sensitivity to Group O. Later that year, FDA advised blood and plasma establishments to add to their donor deferral criteria histories of risk factors associated with geographical areas in which Group O is endemic.

Identification of a new emerging infection will depend heavily on the recognition by the epidemiology community of new trends in data. While it is possible that viral marker rates may assist in identifying certain trends there is no present identifiable correlation that will assure that certain viral marker rates will lead to the identification of presently unknown infectious agents. It is just as possible that there will be no correlation. Populations at increased risk for known agents, however, are appropriate to monitor for emerging agents.

CONCLUSION

FDA maintains as one of its highest priorities assuring the safety of the blood supply and blood and plasma derivatives, including vigilant oversight of GMP compliance by the plasma fractionators. The Agency also will continue to do everything within its power to help alleviate product shortages. Unless industry moves forward aggressively with its quality improvement and assurance efforts, however, shortages and occasional disruptions in the distribution of needed products will continue to occur. We will continue our efforts to assure the safety and availability expectations of patients who need these critically important products.