Executive Summary

Introduction

Findings and Recommendations

Appendix A: Meeting Agenda

Appendix B: Panel Members

Appendix C: Panel Member Biographical Sketches

Appendix D: Professional Societies and Patient Advocacy Groups Invited to Submit Written Comments

Appendix E: Summary and Individual Responses from Interested Groups

Appendix F: Presentation of Rebecca H. Buckley

Appendix G: Presentation of Thomas J. Lynch

Appendix H: Presentation of Mary Ann Lamb

Appendix I: Presentation of Fred Feldman (Not available at this time.)

Appendix J: Presentation of Donald Baker

Appendix K:Presentation of Sue Preston

Appendix L: Presentation of Jean-Jacques Morgenthaler

Appendix M: Presentation of Chris Lamb

Appendix N: Presentation of Paul R. McCurdy

Appendix O: Donor Pool Size for IGIV: Safety and Efficacy Considerations, Donald L. Tankersley

Antibodies have been used to confer passive humoral immunity since the early 1900s. Intravenous immunoglobulin (IVIG) to prevent serious bacterial infections in antibody-deficient individuals became available in the U.S. in 1981. It soon became apparent that IVIG possessed immunomodulatory, as well as immunoprotective properties, leading to clinical trials in a wide range of non-infectious, immune-mediated diseases. In the late 1980s and throughout the 1990s, utilization of IVIG grew rapidly, fueled largely by increasing off-label use.

In the face of rapidly increasing demand, manufacturers of IVIG "scaled up" production, increasing the numbers of plasma units pooled during the manufacture of IVIG. With some donor pool sizes(1) reported to be in excess of several hundred thousand, public attention focused on the potential effects of large donor pools on the risks of transmitting infectious agents. In 1997, growing shortages of a number of plasma products raised concerns that steps to limit the size of plasma pools might further reduce availability of IVIG.

In 1997 and 1998, the shortage of IVIG and the topic of donor pool size were discussed at meetings of the Public Health Service Advisory Committee on Blood Safety and Availability, the Blood Products Advisory Committee of the U.S. Food and Drug Administration, and the Subcommittee on Human Resources of the House Committee on Government Reform and Oversight.

In the fall of 1997, the Subcommittee requested assistance from the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health (NIH), to determine the minimum donor pool size needed for safety and efficacy of immunoglobulin products.

In April 1998, the NIAID convened an Expert Panel of federal and non-federal physicians and scientists to review published data and other information pertinent to the issue of donor pool sizes for immunoglobulin products. The panel included experts in science and public health policy, adult and pediatric medicine, infectious diseases, rheumatology, immunology, transfusion medicine, epidemiology and statistics, and medical ethics. The Expert Panel reviewed information presented by medical experts, professional societies, patient advocacy organizations, and representatives of the U.S. Food and Drug Administration and the plasma products industry.

The Expert Panel was asked to address these issues in the context of current medical indications for immunoglobulin products, including intravenous and intramuscular immunoglobulins and hyper-immune globulins(2). In the absence of data to form evidence-based recommendations, the Expert Panel was asked to address the feasibility, design, and advisability of additional studies that could form the basis for such recommendations. The findings and recommendations of the Expert Panel are summarized in this report.

1. Based on the available data, it is not possible to establish minimum donor pool sizes needed for optimal efficacy of immunoglobulin products. This is particularly true of IVIG, the product with the broadest range of medical uses. Recent recommendations concerning donor pool size deserve comment. In 1997, the source plasma industry(3) proposed that IVIG donor pool size be limited to 60,000. The FDA is now considering lower limits, i.e., ~15,000 donors per lot(4). Both recommendations appear to be based less on published evidence concerning the effects of donor pool size on efficacy of immunoglobulin products than on estimates of "tolerable" risks of transmitting infectious agents. In the absence of scientific data to establish minimum donor pool sizes, the Expert Panel recommended that the FDA ensure that donor pool sizes do not exceed current manufacturing levels. In considering this topic, the Panel’s deliberations touched on many of the issues considered earlier by the Institute of Medicine:

   "The management of a public health risk requires an evolving process of decision making under uncertainty. It includes interpretive judgement in the presence of scientific uncertainty and disagreement about values. Public health officials must characterize and estimate the magnitude of the risk…They must also develop and test public health and clinical care strategies, and communicate with the public about the risk and strategies for reducing it. …. Lack of scientific consensus becomes a kind of amplifier for the usual discord and conflict that can be expected whenever an important science-based public policy decision – one profoundly affecting lives and economic interests – must be made. First, uncertainty creates opportunities for advocates of self-interested and ideological viewpoints to advance plausible arguments that favor their desired outcome. Second, uncertainty intensifies bureaucratic cautiousness." (5)

2. Evidence is accruing that antibody dimerization may contribute to the biological activity of IVIG in immune-mediated diseases. Modeling studies and laboratory observations suggest that donor pools > 10,000 may be needed to support a high level of dimerization. However, the published studies are not sufficient to form the basis for regulatory decisions. Therefore, the Expert Panel recommended that agencies of the Department of Health and Human Services (DHHS) including the FDA, Centers for Disease Control and Prevention (CDC), and NIH support: a) additional independent, peer-reviewed modeling studies; and b) laboratory research to test hypotheses generated from such studies.
3. The Expert Panel did not recommend clinical trials to explore the effects of donor pool size on safety and efficacy of IVIG. Instead, the Panel recommended careful clinical monitoring and continued vigilance with any further reductions in donor pool size. In drawing this conclusion, the Expert Panel considered the multiplicity of off-label uses and the paucity and speculative nature of the available information on the mechanisms of action of IVIG in autoimmune and immune-mediated disorders. In the absence of more precise information on mechanisms of IVIG action, it is neither possible to establish minimum donor pool requirements, nor to design clinical trials, the results of which could be broadly applied.

   In particular, the Expert Panel felt strongly that the conclusions of individual trials would not necessarily apply to the use of IVIG in other diseases or in different clinical settings. Furthermore, because there are manufacturing and end-product differences among commercially manufactured IVIGs, panel members voiced concerns that conclusions drawn from individual clinical trials might not necessarily apply to the clinical uses of different commercial preparations of IVIG.

   A stronger argument could be made for trials to assess minimum donor pool needs for the hyperimmune globulins, due to their more narrowly focused clinical indications. However, the Expert Panel noted that these products are currently manufactured using relatively small donor pools. In addition, at least one product, Rho (D) immune globulin, is licensed not only to prevent hemolytic disease of the newborn, but also for idiopathic thrombocytopenic purpura. Because it is likely that different immunological mechanisms account for the activity of Rho (D) immune globulin in these two disorders, panel members expressed concerns about the interpretation and broader applicability of disease-specific trials of this agent.

4. Among all blood derivatives, immunoglobulin products stand out for their extensive record of safety. Advances in donor screening, viral detection, and viral inactivation have resulted in plasma derivatives that appear safer than ever, relative to known viruses. Current screening and manufacturing procedures incorporate multiple "layers of protection," which were not in place in the 1980s and early 1990s, when the transmission of hepatitis and AIDS was linked to blood products. Of note, the transmission of Hepatitis C virus (HCV) by intravenous immunoglobulin (IVIG), occurred prior to the industry-wide use of solvent-detergent treatment, a viral inactivation procedure effective against all lipid-envelope viruses (e.g., Human Immunodeficiency Virus [HIV], Hepatitis B virus [HBV], and HCV).

   Reducing the number of donors contributing to plasma pools is one important measure to decrease the risk of exposure to infectious agents, especially for infrequent users of plasma products. However, for patients requiring repeated or continuous treatments, the risks of exposure would be reduced to a lesser extent, even by large reductions in donor pool size. Therefore, in addition to efforts to reduce pool size, the Expert Panel stressed the need for continued vigilance and further improvements in donor screening and in procedures for viral inactivation and elimination.

5. The federal government should evaluate claims that reductions in donor pool size will decrease product availability. The government should provide a mechanism (e.g., a General Accounting Office review) to guarantee that the analysis is comprehensive, credible, fair, and in the public domain. Expert Panel members emphasized that neither they nor the FDA staff had sufficient information or the capacity to evaluate claims that reductions in donor pool size would have such an effect.
6. The panel strongly supported the development of recombinant therapies to replace plasma-derived products. The purification of non-immunoglobulin derivatives (e.g., clotting factors, a -1 antitrypsin) consumes source plasma and may necessitate donor pool sizes that exceed those most appropriate for IVIG. Therefore, the panel supported the development of recombinant products in order to: a) minimize overall dependence on plasma derivatives; b) diminish "competition" among different products for source plasma; and c) assure that all plasma derivatives are manufactured, to the extent possible, from donor pools of optimal size.

   DHHS agencies and industry should support research to develop a variety of recombinant plasma proteins and monoclonal antibodies for clinical use. Furthermore, federal agencies and third party payers should make such agents available to all patients who need them.

7. Industry should collect, and make available to DHHS agencies, information on donor immunization status and the potential value and costs of measures to improve donor immunization. Efforts to improve donor immunization could potentially contribute to a reduction in the risks of viral transmission (e.g., hepatitis A and B) and to improved antibody profiles of IVIG (i.e., IVIGs that would provide broader humoral immunity to common pathogens, including influenza viruses, Hemophilus influenza type B, and pneumococci).
8. Federal agencies should assist in the development of patient databases for comprehensive surveillance and longitudinal monitoring of recipients of IVIG. Such databases would allow IVIG treatment records to be correlated systematically with information on immune function, seroconversion, and prevalence of chronic infection. Certain patient advocacy groups (e.g., the Immune Deficiency Foundation) currently support databases that could facilitate the collection and analysis of such information.
9. DHHS agencies and industry should expand support for research to develop innovative methods for donor screening and elimination and inactivation of transmissible agents. The Expert Panel believed that the potential rewards from such investments could greatly exceed the incremental gains that may be achievable with further reductions in donor pool size.

In summary, the Expert Panel: a) emphasized the safety of immunoglobulin products; b) recommended that regulatory decisions that would cap donor pool sizes below current manufacturing levels await assurances that such reductions would not result in products with substantially altered biological activities; and c) recommended various additional measures to improve immunoglobulin safety.

(1)"Donor pool size" refers to the total number of individual donors contributing source or recovered plasma to a product lot. Because multiple plasma units from a given individual may be pooled during manufacture of plasma products, the donor pool size may be smaller than the number of plasma or blood donations/units comprising each product lot.
(2)Immunoglobulin products considered by the panel included intravenous and intramuscular immunoglobulins, and hyperimmune globulins (anit-Rh immune globulin, anti-RSV immune globulin, anti-CMV immune globulin, Hepatitis B immune globulin, Varicella-Zoster immune globulin, rabies immune globulin, and tetanus immune globulin).
(3)Immunoglobulin products are currently manufactured from plasma recovered from whole blood (designated "recovered plasma") or obtained by plasmapheresis (designated "source plasma").
(4)Transcripts of FDA Blood Products Advisory Committee, December 12, 1996.
(5)HIV and the Blood Supply: An Analysis of Crisis Decision Making, L.B. Leveton, H.C. Sox, Jr., and M.A. Stoto, Eds. National Academy Press, Washington, D.C. (1995); p209-211.

Chairman

C. Everett Koop, M.D.
6707 Democracy Boulevard
Suite 107
Bethesda, MD 20817

Panel Members

John G. Bartlett, M.D.
Johns Hopkins Hospital
Division of Infectious Diseases
R. Starr Ross Research Building
720 Rutland Avenue
Baltimore, MD 21205

Henry N. Claman, M.D.
Professor of Medicine and Immunology, B-164
University of Colorado
Health Science Center
4200 E. Ninth Avenue
Denver, CO 80262-0001

Stephen C. Groft, Pharm.D,
Director, Office of Rare Diseases
Office of the Director, NIH

Bevra H. Hahn, M.D.
Chief, Division of Rheumatology
UCLA School of Medicine
Center for Health Science
1000 Veteran Avenue
Los Angeles, CA 90095

Harvey Klein, M.D.
Chief, Department of Transfusion Medicine
Warren Grant Magnuson Clinical Center
National Institutes of Health
Bethesda, MD 20892

Adel A. F. Mahmoud, M.D., Ph.D.
University Hospital of Cleveland
Department of Medicine
2074 Abington Road
Cleveland, OH 44106

Franklin Miller, Ph.D.
3910 Underwood Street
Chevy Chase, MD 20815

Frederick C. Robbins, M.D.
Case Western Reserve University
School of Medicine
Department of Epidemiology and Biostatistics
10900 Euclid Avenue
Cleveland, OH 44106

Donald Stablein, Ph.D.
The EMMES Corporation
11325 Seven Locks Road
Suite 214
Potomac, MD 20854

Leroy Walters, Ph.D.
Director
Kennedy Institute of Ethics
Georgetown University
1437 - 37^th Street, N.W.
Washington, D.C. 20007