APPENDIX B
Strategies for Gathering Information

LITERATURE SEARCHES OF COMPUTERIZED DATABASES

Because the primary purpose of this study was to examine any available information about specific adverse events associated with particular vaccines, the committee undertook an extensive search of relevant electronic databases. The initial searches were conducted by the Institute of Medicine (IOM) librarian in the winter of 1992, with follow-up searches for newly published literature carried out in August 1992, December 1992, and March 1993. Table B-1 lists the vaccine and adverse event combinations that were under consideration by the committee and that formed the basis of the search strategies.

Several database vendors1 (including Dialog Information Services, Info Pro Technologies, and the National Library of Medicine [NLM]) were used. A total of 31 individual databases were searched. Four of the databases were primarily biomedical; these included NLM's MEDLINE, Excerpta Medica's EMBASE, BIOSIS, and the Life Sciences Collection. Three databases were health sciences related: CINAHL (Cumulative Index to Nursing and Allied Health), Health Planning and Administration, and the Health Periodicals



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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality APPENDIX B Strategies for Gathering Information LITERATURE SEARCHES OF COMPUTERIZED DATABASES Because the primary purpose of this study was to examine any available information about specific adverse events associated with particular vaccines, the committee undertook an extensive search of relevant electronic databases. The initial searches were conducted by the Institute of Medicine (IOM) librarian in the winter of 1992, with follow-up searches for newly published literature carried out in August 1992, December 1992, and March 1993. Table B-1 lists the vaccine and adverse event combinations that were under consideration by the committee and that formed the basis of the search strategies. Several database vendors1 (including Dialog Information Services, Info Pro Technologies, and the National Library of Medicine [NLM]) were used. A total of 31 individual databases were searched. Four of the databases were primarily biomedical; these included NLM's MEDLINE, Excerpta Medica's EMBASE, BIOSIS, and the Life Sciences Collection. Three databases were health sciences related: CINAHL (Cumulative Index to Nursing and Allied Health), Health Planning and Administration, and the Health Periodicals

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality TABLE B-1 Vaccines and Adverse Events Studied Adverse Event T/D/Td Measles Mumps OPV IPV Hib Hep. B Encephalopathy (acute and chronic) X X X         Aseptic meningitis     X X       Subacute sclerosing panencephalitis   X           Residual (chronic) seizure disorder X X X         Guillain-Barré syndrome X X   X X X X Transverse myelitis X X   X X X X Paralytic poliomyelitis (in recipient or contact)       X       Myelitis             X Neuropathy X   X         Optic neuritis   X           Sensorineural deafness   X X         Sterility via orchitis   X X         Death X X X X X X X Anaphylaxis X X X   X X X Arthritis X           X Erythema multiforme X             Insulin-dependent diabetes mellitus   X X         Early susceptibility to Hib disease           X   Thrombocytopenia   X X   X X   NOTE: T/DT/Td, tetanus toxoid/diphtheria and tetanus toxoids for pediatric use/tetanus and diphtheria toxoids for adult use; OPV, oral polio vaccine; IPV, inactivated polio vaccine; Hib, Haemophilus influenzae type b vaccine; Hep. B, hepatitis B vaccine.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Database. Two were industry oriented: Pharmaceutical News Index and International Pharmaceutical Abstracts. Two others were primarily agricultural and included international materials: Agricola and Agris International. Seven were either business or general news databases: ABI/INFORM, Trade and Industry Index, Magazine Index, Newspaper and Periodical Abstracts, National Newspaper Index, PTS Prompt, and Newssearch. Four miscellaneous databases included Dissertation Abstracts, the U.S. Government Printing Office database, the National Technical Information Service (NTIS) file, and the Library of Congress' LC-Marc database. Monographs were searched in Books in Print Online, the Online Computer Library Center (OCLC) database, and NLM's Catline file. Current literature was found in Current Contents Online and through Conference Papers Index. Three databases covered legal and regulatory affairs: Diogenes, Legal Resources Index, and Legi-Slate. In addition, the histories of the reviewed vaccines were searched by using the History of Medicine (Histline) file on the NLM's system and the Legis-Slate database. Each database was searched in its entirety. Years of coverage vary among databases, beginning no earlier than the mid-1960s, however. Both English- and non-English-language articles were included. When possible, the literature searches were sorted into studies of humans, studies of animals, and review articles. Much of the retrieved literature came from MEDLINE and EMBASE. The NLM's MEDLINE databases and the Excerpta Medica EMBASE database files have approximately a 40 percent overlap in the journals indexed. MEDLINE's unique content is primarily North American journals published in English, whereas EMBASE's unique content is primarily non-U.S. and non-English-language journals. Each database has unique indexing structures and thesauri. For example, some databases index Guillain-Barré syndrome as such while others use the term polyradiculoneuritis. Even such overarching terms as adverse events or adverse effects are defined as subject headings in some of the databases but not in others. This inconsistency in classification is very common and presents difficulties. To help ensure that relevant articles would not be missed, search strategies were intentionally broad. In addition to lists of synonyms for the particular adverse events being reviewed for each vaccine, more general terms such as risk, danger, and contraindication were used. A unique search strategy was thus created for each vaccine in each database. Further, the terms were searched for in the title, abstract, and descriptor fields of each database. Limiting a search to the descriptor field might have resulted in missing relevant articles if an indexer happened not to list a particular adverse event. In addition to the initial searches of vaccine and adverse event combinations (Table B-1), the committee requested searches of the following at

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality various points in the study: all vaccines and anaphylaxis, including anaphylactic shock and anaphylactoid reaction; measles vaccine and deafness or hearing loss; measles or mumps disease and deafness or hearing loss; transverse myelitis (including terms such as myelitis, myelopathy, spinal cord, brachial neuritis, neuropathy, lumbar neuritis, lumbar neuropathy, radiculopathy, radiculitis, and neuralgic amyotrophy ) and the reviewed vaccines; sudden infant death syndrome (SIDS) and the reviewed vaccines; a follow-up on the Guillain-Barré syndrome search, including polyradiculitis and the reviewed vaccines; optic neuritis, including retrobulbar neuritis, and the reviewed vaccines; diabetes and all vaccines; and serum sickness and hepatitis B vaccine. Every effort was undertaken to make the literature searches as thorough as possible. However, the results of any search are subject to the limitations of the particular databases being searched and the selection of search strategies. In addition, as a consequence of the broad search strategy as well as the eccentricities of individual databases, many citations that were not directly relevant to the desired topic were retrieved. Of the more than 8,000 citations retrieved in the course of the various searches, about 1,800 were found to be relevant to the committee's work. The limitations of using computerized databases for literature searches have been explored by Dickersin and others (Dickersin et al., 1985). Later sections of this appendix describe other steps taken by the committee to ensure a thorough review of the literature. The bibliography to this report lists the relevant material reviewed. After the literature searches were conducted, the retrieved citations were converted (using a software package called Biblio-Links) into a format readable by Pro-Cite (version 1.41), a bibliographic management program. Subject-specific working bibliographies were produced; staff and committee members reviewed the citations (including abstracts when available) and determined whether a particular article might contain information pertinent to the committee's task. Articles were then obtained for each selected citation, and copies were distributed to the appropriate committee members. Many of the articles were obtained through NLM's interlibrary loan system, DOCLINE. All or part of publications written in languages other than English were translated by professional translation services or read by committee members fluent in those languages. In all, about 150 items were translated from 18 languages. A bibliography of references cited in the report and organized both by vaccine and by adverse event entitled ''Bibliography of Adverse Consequences Associated with Childhood Vaccines'' is available from the National Technical Information Service, 5285 Port Royal Road, Springfield, Virginia 22161 (703-487-4650).

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality OTHER SOURCES OF INFORMATION Additional information sources used by the committee included the reference lists of the articles obtained by the committee and staff; this was particularly true with respect to vaccines in existence before about 1966, the date after which computerized reference listings are generally available. Particular attention was paid to citations in review articles and in books and reports with extensive reference lists (e.g., Institute of Medicine, 1977, 1985a,b, 1991; National Library of Medicine, 1988; Office of Technology Assessment, 1980; Plotkin and Mortimer, 1988). The American Academy of Pediatrics Red Book (1991) and the Physicians' Desk Reference (1992) were consulted for their information on adverse events and contraindications. In addition, committee members' own libraries of articles and books often provided relevant information. Committee staff regularly attended meetings of the federal Advisory Commission on Childhood Vaccines and the Centers for Disease Control and Prevention's (CDC's) Advisory Committee on Immunization Practices. In addition, in September 1992 staff members attended a session sponsored by the U.S. Food and Drug Administration (FDA), Workshop to Review Warnings, Use Instructions, and Precautionary Information for Childhood Vaccines. Relevant information, including reference material, from those meetings was provided to committee members. REVIEW OF INTERIM BIBLIOGRAPHY Midway through the project (December 1992), an interim bibliography of the more than 1,600 citations being reviewed by the committee was sent to 22 individuals representing a range of views on the topic of adverse events following vaccination. These individuals were asked to identify pertinent sources of information missing from the bibliography to ensure that no important information was overlooked by the committee. A few additional items were suggested by these reviewers, but no significant gaps were identified. INFORMATION FROM ADVERSE EVENT SURVEILLANCE SYSTEMS The committee reviewed case reports from the Vaccine Adverse Event Reporting System (VAERS), the passive surveillance system administered by CDC and FDA. VAERS was established by the National Childhood Vaccine Injury Act (P.L. 99-660) to collect reports of adverse reactions following vaccination; it began operation in November 1990. VAERS combined and replaced the two previous federal surveillance systems, the pub-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality lic-sector Monitoring System for Adverse Events Following Immunization (MSAEFI) and the private-sector Spontaneous Reporting System (SRS). The database is managed by a contractor under the aegises of both CDC and FDA. Health care providers are obligated to report specific adverse events following particular vaccines, as set out in a Vaccine Injury Table also established under the Vaccine Injury Act. Parents, other relatives, or anyone aware of the occurrence of an adverse event may also file a report with VAERS. (A blank VAERS form appears in Figure B-1.) By July 31, 1992, VAERS had received more than 17,000 reports, of which almost 11,000 concerned vaccines listed in the Vaccine Injury Table (oral and inactivated polio vaccines and the trivalent or monovalent constituents of diphtheria and tetanus toxoids and pertussis vaccine [DPT] and measles, mumps, and rubella vaccine [MMR]). Of the total number of reports, just over 2,500 were considered to be serious, that is, the patient died, suffered a life-threatening illness, suffered a reaction that resulted in or prolonged hospitalization, or resulted in permanent disability. The committee requested all available VAERS case reports (submitted up to July 31, 1992) for every vaccine-adverse event combination in its charge (see Table B-1). The committee received approximately 575 reports. The individual reports were reviewed by the committee member(s) who had responsibility for the particular vaccine or adverse event described in the report. The staff also purchased computer disks containing data submitted to VAERS for use with the Paradox (version 3.0) database software. Because of the improvements in VAERS over MSAEFI and SRS, the committee focused its efforts on case reports from VAERS. However, the committee considered summary information from the two earlier surveillance systems. The committee reviewed three publications presenting data from MSAEFI (Centers for Disease Control, 1984, 1986, 1989). It also reviewed summary information on reports to MSAEFI for 1989-1990. In addition, it reviewed information from SRS on deaths reported between July 1, 1989, and June 30, 1990. Care must be taken in interpreting information from passive surveillance systems. The extent of underreporting cannot be known. Duplicate reports of the same event for the same patient are common and are not always easy to detect, making totals questionable. Medical information provided on reporting forms is often incomplete. In general, passive surveillance systems are useful in flagging potential problems and suggesting hypotheses. See Chapters 2, 10, and 11 for further discussion.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality FIGURE B-1 Form used to report adverse events to the Vaccine Adverse Event Reporting System.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality PRESENTATIONS Committee Meetings At various times in the course of the study, the committee heard presentations from Regina Rabinovich, the study's project officer from the National Institute of Allergy and Infectious Diseases; Geoffrey Evans, Chief Medical Officer of the Division of Vaccine Injury Compensation; John Mullen (CDC), Suresh Rastogi (FDA), and Stephen Gordon (Ogden BioServices Corp.), representatives of VAERS; and Dirk Teuwen, SmithKline Beecham. At its November 1992 meeting, the committee heard a presentation from Joanne Hatem, Medical Director of the National Vaccine Information Center. (Because of a scheduling conflict, Dr. Hatem was unable to present this information at the scientific workshop held on the following day.) Dr. Hatem spoke about her concerns in three areas: circumstances under which a vaccine should not be administered (i.e., contraindications), circumstances for delaying the administration of a vaccine, and potential high-risk groups for adverse events following vaccination. She asked the committee to be conscientious about reviewing adverse events that were not a part of its original charge, if the evidence should warrant such a review. Scientific Workshops The committee held a scientific workshop on September 11, 1992, in Woods Hole, Massachusetts. Notice of the meeting was sent to more than 1,000 people. Six invited speakers made presentations on the possible mechanisms of neurologic adverse events after vaccination. Approximately 90 people attended the session. Another scientific workshop took place in Washington, D.C., on November 6, 1992. Six invited speakers made presentations on the contraindications to vaccination and on the possible role of viral vaccines in the etiology of insulin-dependent diabetes mellitus. Approximately 75 people attended the session. The box entitled Presentations at Scientific Workshops Held by the Vaccine Safety Committee provides lists of the individuals who made presentations at the scientific workshops. (Transcripts of the workshops may be purchased from the National Technical Information Service, 5285 Port Royal Road, Springfield, Virginia 22161; 703-487-4650.) Public Meetings The committee held a public meeting on May 11, 1992, in Washington, D.C. Again, notices were mailed to an extensive list of interested individu-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality PRESENTATIONS AT SCIENTIFIC WORKSHOPS HELD BY THE VACCINE SAFETY COMMITTEE September 11, 1992 Robert Fujinami, University of Utah, Salt Lake City. Molecular Mimicry. Diane Griffin, The Johns Hopkins University School of Medicine, Baltimore. Measles and Rabies Encephalitis. Dale McFarlin, National Institute of Neurologic Diseases and Stroke, National Institutes of Health. Neural Antigens. Neal Nathanson, University of Pennsylvania School of Medicine, Philadelphia. The Cutter and Swine Flu Incidents. Vincent Racaniello, Columbia University, New York, New York. Polio Neurovirulence. Klaus Toyka, Neurologische Universitätsklinik und Polioklinik im Kopfklinikum, Wurzburg, Germany. Guillain-Barré Syndrome. November 6, 1992 James Froeschle, Connaught Laboratories, Swiftwater, Pennsylvania. Contraindications to Vaccination. Samuel Katz, Advisory Committee on Immunization Practices. Contraindications to Vaccination. Noel Maclaren, University of Florida, Gainesville. Possible Mechanisms of the Etiology of Insulin-Dependent Diabetes Mellitus. David Nalin, Merck Sharp & Dohme, West Point, Pennsylvania. Contraindications to Vaccination. Georges Peter, American Academy of Pediatrics. Contraindications to Vaccination. Amy Scott, U.S. Food and Drug Administration. Contraindications to Vaccination. als and organizations. Eleven individuals made presentations (in person or by telephone) at the meeting, which was attended by approximately 175 people. A second public meeting was held on January 16, 1993, in Irvine, California. Thirteen individuals made presentations (in person or by telephone) at the meeting, which was attended by approximately 65 people. The following is a brief summary of the comments of individuals who made presentations at the public meetings. Committee members were present at the sessions and were provided with full transcripts of the meetings afterward. (Transcripts may be purchased from the National Technical Information Service, 5285 Port Royal Road, Springfield, Virginia, 22161; 703-487-4650.)

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Presentations, May 11, 1992, Washington, D.C. Shannon Dixon, Honolulu, Hawaii Mr. Dixon explained that he developed poliomyelitis in 1962 following receipt of oral poliovirus vaccine. He made a complete recovery and lived an active life until the early 1980s, when he began to develop symptoms that have been diagnosed as postpolio syndrome. He is now severely physically disabled and requires attendant care. Mr. Dixon urged the committee to recognize that recovery from polio is not always the end of medical problems for patients with polio. He noted that the National Vaccine Injury Compensation Program must take into account the possibility of postpolio syndrome when developing compensation plans for those who contract polio from the oral vaccine. Jesse Ferguson, Milwaukee, Wisconsin Mr. Ferguson described health problems that began shortly after receipt of tetanus toxoid following a work-related injury. These health problems culminated in the loss of use of his right arm and a diagnosis of brachial neuritis. More than a year later, he was still unable to return to construction work and had been told that his medical condition would not improve. Mr. Ferguson urged the committee to ensure that the public is made more aware of the possible side effects of vaccines and to consider new guidelines for the implementation of vaccination programs. Barbara Loe Fisher, Dissatisfied Parents Together, Vienna, Virginia Mrs. Fisher expressed concern about the concurrent administration of multiple vaccines to children—particularly the possibility that multiple vaccination might result in a greater risk of adverse reactions and/or interference with proper immune response. She maintained that large-scale definitive scientific studies of the effects of simultaneous administration of vaccines have not been carried out and that, in the absence of such studies, it is not possible to make decisions about safety. James Froeschle, Connaught Laboratories, Swiftwater, Pennsylvania Dr. Froeschle gave information about adverse events following diphtheria and tetanus toxoids (DT) that had been reported to Connaught. From a comparison of spontaneous reports with postmarketing surveillance data, the company estimates about a 50-fold underreporting of adverse events in the passive reporting system. The distribution of types of events, however, was found to be approximately the same; in both cases, the majority of reported events were local reactions or fever. The company has seen a marked decrease in adverse event reports since the inception of VAERS late in 1991, because physicians are now requested to send reports directly to the VAERS contractor.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Joanne Hatem, National Vaccine Information Center, Vienna, Virginia Dr. Hatem stressed the importance of reviewing case reports submitted to FDA, CDC, and VAERS. She reported that her review of measles and mumps vaccines shows inaccurate medical evaluation and a trend toward minimizing reported injuries on the part of manufacturers and FDA. Dr. Hatem also addressed the issue of concurrent administration of multiple vaccines, stating that adequate research has not been carried out to establish its safety. Walter Kyle, attorney, Franconia, New Hampshire Mr. Kyle maintained that, because of incomplete inactivation, the inactivated polio vaccine (IPV) manufactured in the 1950s caused polio disease in addition to those cases reported as part of the well-known Cutter incident. He suggested that polio following IPV should be an adverse event listed in the Vaccine Injury Table of the National Vaccine Injury Compensation Program. He also asked the committee to look into the possibility of seizures following administration of the oral polio vaccine (OPV) or the simultaneous administration of DPT and OPV. Susan Maloney, Rowley, Massachusetts Mrs. Maloney told the committee about the death of her 15-week-old son 4 days after receiving his second dose of OPV. The death was initially classified as sudden infant death syndrome. She described the 7-year process that took place before the family received the results of pathology tests. Ultimately, it was revealed that vaccine-strain poliovirus had been isolated from the child's tissue, including the heart. Mrs. Maloney urged the committee to recognize death as a potential adverse outcome after administration of OPV. She also called for improved autopsy protocols following infant deaths. Ann Millan, National Vaccine Information Center, Vienna, Virginia Mrs. Millan expressed concern that doctors do not always report adverse events after vaccination, as required by law. She criticized the federal government for not following up the case reports presented to the National Vaccine Advisory Committee by her organization. She was also concerned about the simultaneous administration of multiple vaccines. She stated that, with regard to the safety of vaccines, the burden should be to prove or disprove a relationship rather than to assume safety in the absence of data. Mrs. Millan expressed particular concern about the possibility of delayed death or injury caused by live virus vaccines. John Mullen, Division of Immunization, Centers for Disease Control, Atlanta, Georgia Mr. Mullen, project officer for VAERS, briefly traced the history of adverse event reporting in the U.S. Public Health Service.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Separate surveillance systems for vaccines administered in the private sector and the public sector existed until 1990, when the congressionally mandated VAERS system began operation. Mr. Mullen outlined the limitations of passive surveillance systems. He expressed the belief that VAERS can serve as a useful complement to other mechanisms of postmarketing surveillance for vaccines. Mary Pearce, Philadelphia, Pennsylvania Mrs. Pearce spoke about her daughter, who became ill following receipt of the measles-mumps-rubella vaccine (MMR) at age 15 months. The child was diagnosed with febrile seizures and, ultimately, with diabetes. Mrs. Pearce urged the committee to consider the possibility of a link between MMR and diabetes. Susan Weinberg, Baltimore, Maryland Mrs. Weinberg detailed the symptoms of her daughter, who was diagnosed with diabetes mellitus several weeks after receiving her first dose of MMR at age 15 months. At age 11 years, the child now leads an outwardly normal life and requires insulin twice a day. Citing research indicating that viral illness may be linked to the onset of diabetes, Mrs. Weinberg expressed concern that MMR can cause diabetes in children with a genetic predisposition for the disorder. She suggested that, when it becomes possible technologically, all infants should be tested for such genetic tendencies before receiving the vaccine. Presentations, January 16, 1993, Irvine, California John Brydon, attorney, Long Beach, California Mr. Brydon expressed concern about whether the inactivated polio vaccine produced in the 1950s adequately inactivated the poliovirus. He believes that the vaccine was capable of producing polio in a small number of children who received the vaccine. Mr. Brydon also spoke about transverse myelitis following receipt of MMR, calling for studies of the possible relationship. Christine Buhk, Sturgeon Bay, Wisconsin Mrs. Buhk related the case of her 18-month-old daughter, who became ill 3 days after receiving MMR and Haemophilus influenzae type b (Hib) vaccine. The child became progressively ill with a rash, fever, diarrhea, and vomiting and died approximately 2 weeks later. Eight months later, Mrs. Buhk had not yet received an autopsy report. Kim Chapman, Colorado Springs, Colorado Mrs. Chapman described the case of her 18-month-old daughter, who developed a high fever 4 days after receiving DPT, Hib vaccine, and OPV and who eventually was hospitalized with dehydration, disseminated intravascular coagulation, encephali-

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality tis, and renal failure. The child has severe residual brain damage. Mrs. Chapman questioned the rigid use of the 72-hour guideline for vaccine reactions listed in the Vaccine Injury Table of the National Vaccine Injury Compensation Program. She expressed further concern about the incomplete understanding of contraindications to vaccination among physicians and parents. She also questioned the wisdom of concurrent administration of multiple vaccines without adequate research into their safety when administered in combination. Mark Geier, medical/legal consultant, Silver Spring, Maryland Dr. Geier expressed concerns about the National Vaccine Injury Compensation Program: that it is more adversarial than intended by Congress, that plaintiff's expert testimony is too often dismissed as biased, and that decisions made under the program are inconsistent. He criticized the 1991 IOM report (Institute of Medicine, 1991) on pertussis and rubella vaccines for contributing to the problems of the compensation program by not making clear the level of certainty required to make decisions about causal relations between vaccines and adverse events. Cynthia Goldenberg, Laguna Niguel, California Mrs. Goldenberg spoke about her son, who was diagnosed as autistic as an infant. She subsequently discovered that he had a very high rubella antibody level and very low immunoglobulin G (IgG) levels. She stated that intravenous IgG treatments have been followed by marked improvement and that, at age 4, her son attends a regular school and no longer meets the criteria for autism. She urged parents of children with autism or similar diagnoses to seek advice from an immunologist. Marjorie Grant, Determined Parents to Stop Hurting Our Tots, Beaver Dam, Wisconsin Mrs. Grant expressed strong concern about the safety of administering combination vaccines to infants. She cited the case of her son, who received a combined DPT-polio vaccine (Quadrigen) at the age of 6 months and subsequently suffered seizures, paralysis, and severe mental retardation. She urged the committee to consider the evidence with regard to the safety of combined vaccines in carrying out its work. Michael Hugo, attorney, Boston, Massachusetts Mr. Hugo questioned the arbitrary time criteria used by the compensation program for determining the relationship between a vaccine and an adverse event, noting that events that fall outside the guidelines by only a few hours are not compensated, are returned to the jurisdiction of the civil courts, and thus result in more lawsuits. He called for the biologic variability of individuals to be taken into account so that the Vaccine Injury Table guidelines would not be considered as rigid rules.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Marcel Kinsbourne, Winchester, Massachusetts Dr. Kinsbourne, a neurologist, questioned some of the new criteria being proposed by the federal government for the vaccine compensation program. He further questioned the conclusions of the 1991 IOM report on pertussis and rubella vaccines (Institute of Medicine, 1991), particularly in regard to a differentiation between acute and chronic encephalopathy. He concurred with Dr. Geier (see above) that the confidence level for making decisions about vaccine injury should be more lenient than is usual for strictly scientific decisions. Andrea Martin, Woodland, California Mrs. Martin spoke about her daughter, who became ill following receipt of DPT and OPV at ages 2 and 4 months and who was ultimately diagnosed with transverse myelitis. Mrs. Martin was told by her doctors that the child should not be immunized further. Sandy Mintz, Parents Concerned About the Safety of Vaccines, Anchorage, Alaska Mrs. Mintz took exception to elements of the 1991 IOM report (Institute of Medicine, 1991) and expressed a wish that the current committee would avoid the same problems, such as acceptance of studies with flawed designs, improper definitions of control groups, and risk estimates based on the number of doses of vaccine rather than on the number of children vaccinated. She expressed concern about measles vaccine and the possibility that widespread vaccination has increased the case fatality rate for those cases of measles that do occur. She made suggestions for the direction and design of future vaccine safety and efficacy research, including taking into account, in risk-benefit analyses, the changing disease epidemiology that results when vaccines are in widespread use, and the need for properly designed long-term (20-30 years) studies of adverse effects. Robert Moxley, attorney, Cheyenne, Wyoming Mr. Moxley addressed the issue of the effect of vaccination on children with tuberous sclerosis. He criticized the 1991 IOM report (Institute of Medicine, 1991) for not dealing adequately with the issue. He maintained that both DPT and MMR can trigger seizures or worsen an existing seizure disorder in children with tuberous sclerosis and urged the committee to address the issue specifically and to call for more research on the subject if necessary. Eugene Robin, Stanford University School of Medicine, Stanford, California Dr. Robin expressed concern about the balance between the risks and benefits of vaccination and urged that the public be dealt with honestly with respect to such risks and benefits. He noted that, often, randomized controlled clinical trials are not available as evidence about the potential risk of a particular vaccine and that the quality of the available

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality evidence must be considered as part of any discussion of the risks or benefits of vaccination. Arthur Zahalsky, Southern Illinois University, Edwardsville Dr. Zahalsky addressed the need for new and improved vaccines against diphtheria and tetanus. He cited the low purity and undesired side effects of the vaccines and maintained that the bovine components of the vaccines are responsible for adverse events, particularly in the adult population. He made suggestions for the further purification of diphtheria and tetanus toxins in the manufacture of vaccines. ADDITIONAL INDIVIDUALS AND ORGANIZATIONS WHO PROVIDED INFORMATION In addition to the formal presentations, information on adverse events following vaccination was received from the following sources: Bell of Atri, Inc., College Park, Maryland. Material from J. Anthony Morris and Hillary Butler on adverse events after hepatitis B vaccination. Colette Cogliandro, Chesapeake, Virginia. Case report regarding MMR vaccination. Philippe Duclos, Health and Welfare Canada. Information on adverse events following hepatitis B vaccine. Reinhard Fescharek, Behringwerke AG, Marburg, Germany. Published literature on diabetes and measles/mumps vaccine. Bonnie Plumeri Franz, Ogdensburg, New York. Letter regarding concerns about the adequacy and accuracy of research relating to adverse events following receipt of vaccines. Susan Garzonio, Brodhead, Wisconsin. Case report regarding diphtheriatetanus toxoids. Cynthia Goldenberg, Laguna Niguel, California. Information on autism and vaccination. Terry and Kurt Johnson, Mission Viejo, California. Book by Neil Z. Miller, Vaccines: Are They Really Safe and Effective?, New Atlantean Press, Santa Fe, New Mexico, 1992. Gloria Koslofsky, Norwood, New York. Case report regarding DPT and DT. Kathleen Lane, Spring City, Pennsylvania. Case report regarding inactivated poliovirus vaccine. Ruth Macrides, Naples, Florida. Case report regarding hepatitis B vaccine.

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Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality Robert Moxley, Gage and Moxley, Cheyenne, Wyoming. Information on tuberous sclerosis and vaccination. National Vaccine Information Center, Vienna, Virginia. Case reports, newsletters, and informational material. John Pollard, University of Sydney, Sydney, Australia. Case report on Guillain-Barré syndrome following receipt of tetanus toxoid. Dirk Teuwen, SmithKline Beecham, Rixensart, Belgium. Information on a manufacturers' experience with adverse events following vaccination. Burton Waisbren, Waisbren Clinic, Milwaukee, Wisconsin. Case reports and published material relating to demyelinating disorders following receipt of hepatitis B vaccine. Curtis Webb, Webb, Pedersen & Webb, Twin Falls, Idaho. Letter regarding methodology of 1991 IOM report and suggestions for current report. REFERENCES American Academy of Pediatrics, Committee on Infectious Diseases. Report of the Committee on Infectious Diseases: 22nd Edition. Elk Grove, IL: American Academy of Pediatrics; 1991. Centers for Disease Control. Adverse Events Following Immunization: Surveillance Report No. 1, 1979-1982. Atlanta: U.S. Public Health Service, U.S. Department of Health and Human Services; August 1984. Centers for Disease Control. Adverse Events Following Immunization: Surveillance Report No. 2, 1982-1984. Atlanta: U.S. Public Health Service, U.S. Department of Health and Human Services; December 1986. Centers for Disease Control. Adverse Events Following Immunization: Surveillance Report No. 3, 1985-1986. Atlanta: U.S. Public Health Service, U.S. Department of Health and Human Services; February 1989. Dickersin K, Hewitt P, Mutch L, Chalmers I, Chalmers TC. Perusing the literature: comparison of MEDLINE searching with a Perinatal Trials Database. Controlled Clinical Trials 1985;6:306-317. Institute of Medicine. Evaluation of Poliomyelitis Vaccines. Washington, DC: National Academy of Sciences; 1977. Institute of Medicine. New Vaccine Development: Establishing Priorities. Volume I. Diseases of Importance in the United States. Washington, DC: National Academy Press; 1985a. Institute of Medicine. Vaccine Supply and Innovation. Washington, DC: National Academy Press; 1985b. Institute of Medicine. Adverse Effects of Pertussis and Rubella Vaccines. Washington, DC: National Academy Press; 1991. National Library of Medicine. Vaccine-Preventable Diseases of Childhood: Current Bibliographies in Medicine, No. 88-12. Washington, DC: U.S. Department of Health and Human Services; 1988. Office of Technology Assessment. Compensation for Vaccine-Related Injuries: A Technical Memorandum. Washington, DC: U.S. Government Printing Office; 1980. Physicians' Desk Reference, 46th edition. Montvale, NJ: Medical Economics Company Inc.; 1992. Plotkin SA, Mortimer EA, eds. Vaccines. Philadelphia: W.B. Saunders; 1988.