DOCUMENT SU= J reo l .. .,,/ 02512 - [A1852871] June 27, [swine Influenza Program]. HRD-17-102; B-1611031(2). 1977. 11 pp. Report to Rep. Henry A. Waxan; by Elmer B. Staats, Comptroller General. of Issue Area: Consumer and Worker Protection- Regulation Purity, Potency, 4Bological products to Insure their Safety, Diagnosis and and Efficacy (908); Health Programs: Early Disease Control (1201). Contact. Human Resources Div. Health Budget Function: Health: Prevention and Control of Problems (553). and Organizatio Concerned: Department of Health, Education, Welfare. Congressional Relevance: Rep. Henry A. Waxran. U.S.C. 355). Authority: Federal Food, Drug, and Cosmetic Act (21 26?). P.L. Public Health Service Act, as amended (#42 U.S.C. 94-380. 21 C.F.R. 601.25. The swine flu vaccine program was predicated on the(HEW) conclusion by Department of Health, Education, and elfare90% of and officials that the vaccine would protect between 70% those vaccinated against swine flu outbreak. a HEW review Findings/Conclusions: This conclusion was based on of antibody response data gathered during the 1976 swine flu of the effectiveness of previous vaccine trials and observations flu vaccines. Since scientists agree that experimental new virus investigations involving deliberate exposure to a to perform and strain, such as swine virus, are very difficult hazard in the United could pose a potentially serious health effectiveness States, this method was not used to determine the swine flu vaccine's effectiveness of the swine flu vaccine. The trials that measured the was estimated through clinical participants' antibody level before and after receiing the vaccine. HER officials and other flu experts noted that information on possible long-term effects of flu vaccination is needed, but it would be difficult to plan to lockand it would probably knows what for, As part not be feasible because no one of the swine flu immunization program, the Center for Disease Control had responsibility for conducting short-term Center is surveillance on vaccine recipients. In addition, the to supporting two studies 1 women who recieved the vaccine identify unfavorable pregnancy outcomes. JSC) cOMihoTLL.] GENERAL OF THE UNmITD TATI WASHINtWn, D.C .ot to t id a he Gewn eanl JU2 7 \Nda Btr ef .rlo evql Awmmeseeat'lV othe *lXCOtPI thus b ttlo OAl *of Crg oenal latios. _i rCP B-164031(2) The -onorable Benry A. Waxman House of Representatives Dear Mr. Waxman: of February 24 and This is in response to your letters concerning vaccines. March 3, 1977, requesting information office it was agreed that In a subsequent discussion with your swine influenza vaccine. We our response would address only the Food and Drug Admin- die not request formal comments from contents have been discussed istration although the report's with officials of the agency. we raised in your letters,Education, To respond to the issues Department of Health, obtained information from theand Drug Administration, the and Welfare's (HEW's) Food Infectious Diseases of the National Institute for Alliergy and of Health, and the Center for Disease National Institutestalked to members of HEW's Advisory Commit- Control. We also and Drug's Advisory Review tee on Immunization Practices, Food at the Panel on Viral and Rickettsial Vaccines, researchers and others in- New York City, Mount Sinai School of Medi-ine, volved in flu vaccine research. INTRODUCTION affects the respira- Flu is in infectious disease, which weeks. There are to 2 tory system, lasting from a few daysA and B--each of which has a two primary types of flu--types are the different flu organisms number of strains. Strains identified as causing flu infec- which have been isolated and to Flu virus vaccines are biological products designed tion. strains causing the disease, combat the particular strain or and use of flu The first license for the manufacture As of December 31, 1976, virus. vaccine was issued in 1945. manufacture the vaccines six establishments were licensedin toproducing them. Flu vaccine and four were actually engaged to produce an inacti- manufacturers use different processes most striking difference vated or killed virus product. The a "whole" between processes is that two manufacturers produce virus produce a "split" virus vaccie while the other twc virus is split into sub- process .be vaccine. In the latter Recent trials support the units by a chemical treatment. 2 HpD-77-10 B-1i4031(2) supposition that whole virus vaccine promotes better antibody responses in younger age groups, but that adverse reactions are more frequent and severe than with split virus vaccine. Flu infection presents a unique problem to practitioners of preventive medicine. Flu viruses usually undergo minor but continuous changes from year to year. With each change, te human body's ability tc neutralize te infection and the value of previously prepared vaccine is lessened. This change i, significant because the protective value of the vaccine is probably related to its similarity with the invading flu virus. C.casionally, perhaps every 10 to 15 years, the type A virus changes significantly, rendering the existing vaccine, as well is the Lody'r defense mechanisms, virtually worthless. Flu differs from polio, smallpox, measles, a other viral dis- eases, becauze the infecting virus for these diseases does not change. There are two principal theories on how flu viruses with epidemic potential occur. One theory claims that flu viruses undergo cyclical changes, and that a virus which caused dis- ease in the rast might reappear in 60 or 70 years. In fact, the 1918 flu pandemic is believed to have been caused by a swine flu virus. The seconad theory postulates that ajor antigenic 1/ changes may result from a genetic recombining of a human virus with one of the many flu strains those natural hosts are animals or birds. Following its appearance, the "new" virus replaces the "old" virus, which disappears completely. Still, much uncertainty exists regarding the origin and pat- tern of flu pandemics. HEW ESTIMATE OF EFFECTIVENESS OF SWINE FLU VACCINE BEW officials concluded that swine flu vaccine would prc- tect between 70 and 90 percent of those vaccinated Against a swine flu outbreak. They based this conclusion on their re- view of antibody response data gathered during the 1976 swine flu vaccine trials and observations o the effectiveness of previous flu vaccines. l/Substance; found on the surface of flu viruses which are believed to dictate human susceptibility to the virus. They also stimulate the production of antibodies. 2 B-164031(2) HEW officials said that scientists agreed that experi- mental investigations involving deliberate exposure to a new virus strain, such as swine virus. are very difficult to per- form and could pose a potentially serious health hazard in the United States. Thus, this method was not used to determine the effectiveness of swine flu vaccine. According to n HEW official, the effectiveness of a vaccine can best be deter- mined if vaccinates are exposed through natural epidemics and the result is compared to a control group whose miembers were also exposed but did not receive the vaccine. He further added that this method was not used because a swine flu epidemic did not occur. The swine flu vaccine's effectiveness was estimated through clinical trials that measured the participants' anti- body level before and after receiving the vaccine. The trials did not demonstrate how well antibody levels protect against a flu attack, but did measure what levels of antibody vaccine recipients should expect to attain. According to REW offi- clals, over the past decade or so there has been a general scientific consensus that antibody studies and not deliberate exposure experiments would be sufficient as the indicator of vaccine effectiveness. These officials said that flu experts generally agree that an antibody level of 40 or more is indi- cative of protection. BEW officials observed that over the last 25 years, type A flu vaccines have provided between 67- and 90-percent protection. Tha- ranje was based on vaccine trials conducted by the Department of Defense and was summarized in the follow- ing table presented March 21, 1977, at the Conference on In.- fluenza Vaccine Activity for 1977-78. 3 B-164031(2) Effectiveness of Flu Virus Vaccines, 1943 to 1969 Year Type Protection rate (percent) 1943 A 72 1947 Al a/9 1950 Al 68 1951 Al 75 1953 Al 88 1957 Al 82 1957 A2 67 1958 A2 86 1960 A2 90 1968 b/PA2 86 1969 B/A2 73 &/A Food and Drug official advised us that the low protec- tion rate for 1947 was due to the fact that a major change in the virus occurred and the wrong vaccine was used. b/Hong Kong flu. The Food and Drug Administration also referred us to a report on an outbreak of type A flu which occurred in a Dade County, Florida. nursing home during January 1977, which snowed a vaccine effectiveness rate of 83 percent. The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) requires that a new drug be approved by the Secretary of HEW for safety and effectiveness before it can be introduced into interstate ommerce. The Secretary has delegated this author- ity to the Food and Drug Administration. The Public ealth Service Act, as amended (42 U.S.C. 262), requires that bio- logical drugs must be shipped interstate from a licensed es- tablishment to insure they are safe, pure, and potent as well as safe and effective under the Federal Food, Drug, and Cos- metic Act. The Food and Liug Administration administers the Food, Drug, and Cosmetic Act and the drug provisions of te Public Health Service Act. The Code of Federal Reagulations (21 CFR 601.25) set up review procedures for determining the effectiveness of flu vaccine and other biological products licensed before July 1, 1972. The Code states that 4 B-164031(2) "Proof of effectiveness shall consist of controlled clinical investigations * * *. [This requirement can be] waived on the basis of a showing that * * * an alternative method of investigation is adequate to substantiate effectiveness. Alternate methods, such as serological response evaluation in clinical studies, and appropriate animal and other laboratory assay evaluations may be adequate to substantiate effectiveness where a previously accepted correlation between data generated in this way and clinical effectiveness alead exists * * *. (Underscoring aded.) Food and Drug's Advisory Review Panel on Viral and Rickettsial Vaccines reviewed the safety, effectiveness, and labeling of flu and oher vaccines. The Panel's January 1977 draft report concluded that "Influenza vaccine is relatively (70-80 percent) effective against disease caused by the homo- logous [vaccine properly matching the infecting virus strain] virus * * *." The Panel added that duration of the protection is limited by continuous changes in the virus. In its review of data from the four current flu vaccine manufacturers, the Panel concluded that each product was safe and effective. Bowever, it noted that while there is sub- stantial evidence for the safety and effectiveness of wholt vi'us vaccines produced by two manufacturers, 'Further effi- cacy trials must be designed and implemented by the * * * [two manufacturers of split prodruct vaccine]." The draft report adds that the protective efficacy of split flu virus vaccines "is not clearly demonstrated" although evidence "favors the view that protection of vaccineJ is correlated [to the antibody levels produced] * * * without regard to [whether a vaccine is the split or whole type]." The Panel also noted that because of the frequent changes in flu vaccines, evidence of effectiveness is difficult or im- possible to obtain before the vaccine must be released for use. The Panel further said: "Changes in component virus strains [such as was needed to produce swine flu vaccine], dictated by * * * [FDA], do not require efficacy tests for protective effect of each vaccine in human sub- jects. * * *' 5 B-164031(2) EVALUATION OF LONG-RANGE EFFECTS OF FLU VACCINE HEW officials and other flu experts noted that informa- tion on possible long-term effects of flu vaccination is needed, but it would be difficult to plan and it would prob- ably not be feasible because no one knows what to look for. They pointed out that serious long-term effects of flu vac- cines "would certainly have become manifest by this time." It was felt that this was a reasonable conclusion because of the many ears of experience with flu vaccines and the mil- lions of persons who have been vaccinated without detection of serious complications. HEW officials informed us that "Influenza accines have been in general use for more than 20 years, and their safety and effectiveness have been studied throughout this period." They were only aware of one study which examined mortality associated with adjuvant 1/ flu vaccine. This Department of Defense-sponsored study was published in 1972 and eamined mortality among Army recruits who received adjuvar.t flu vac- cine from 1951 through 1953. The study found no evidence that the risk of death was enhanced among recipients of ad- juvant flu vaccine. Also, its findings were essentially negative with respect to malignant growths and allergic dis- eases. The principal researcher involved said that the study was specifically designed to determine the effects of the ad- juvant vaccine and not the effects of standard flu vaccine. He added, however, that the findings are somewhat applicable to flu vaccine in general, to the extent that adjuvant and standard nonadjuvant) vaccines are the same. This researcher was not aware of any other studies of long-term effects of flu vaccine. A Food and Drug official said he believes that findings pertaining to adjuvant vaccine would be completely applicable rather than somewhat applicable, because if two things cannot cause tumors together, it is hard to imagine how one can. The National Institute for Allergy and Infectious Diseases is beginning a 3-year study of possible adverse reactions to flu immunizations. This study will focus on individuals who were vaccinated during the national swine immunization clinical 1/A substance that, when mixed with an antigen, enhances anti- genicity (the promotion of antibodies) and gives a superior immune response. 6 B-164031(2) trials but who had not been previously exposed to the parti- cular flu vaccine or virus. This followup study was con- sidered particularly important for children because of the scarcity of information on possible long-term reactions in children. As part of the swine flu immunization program, the Center for Disease Control had responsibility for conducting short- term surveillance on vaccine recipients. It was this surveil- lance effort that identified the occurrence of the Guillain- Barre syndrome among vaccinated individuals. A Food and Drug official said the Guillain-Barre syndrome would not have been discovered without the intensive surveillance which was car- ried out during the swine flu program. In addition, the Center is supporting two studies on women who received the swine flu vaccine to identify unfavor- able pregnancy outcomes, such as spontaneous abortions, still- births, and congenital malformations. These sudies will follow reactions in children up to 6-weeks beyond birth, born of women in the studies. CONSIDERATION OF ADVERSE EFFECTS IN BENEFIT-RIS ANALYSIS FOR SWINE IMMUNIZATiON PROGRAM HEW and its Advisory Comnittee on Immunization Practices, which annually develops recommendations for the use of flu vaccine, considered the benefits and risks of swine flu acci- nation. At a June 22, 1976, advisory committee meeting that was open to the public, Center officials presented information on adverse effects of flu vaccines. The meeting was held to dis- cuss recommendations for vaccine usage. The reactions dis- cussed were acute allergic reactions; fever, chills, and my- algia; and neurological or nervous system reactions. These were expected to occur within days following vaccination. In summarizing these reactions, a Center official pointed out that fatal allergic and nervous system reactions were reported before 1963 but no such incidents were reported in recent years. e said that reactions manifested by conditions such as fever, chills, and myalgia were reported from 0 to 51 per- cent of vaccine recipients covered by studies since 1968. The conclusion presented was that the absence of reported fatal reactions in the past 13 years and the low frequency of re- ports of other nervous system disorders suggests that these complications are extremely rare. 7 B-164031(2) HEW officials and the advisory committee also discussed vaccination risks in special groips, such as children under 3 and pregnant women, before vaccine recommendations were made. However, the National Commission for the Prot-tion of Human Subjects of Biomedical and Behavorial Research 1/ expressed concern that the advisory committees' conclusions regarding pregnant women were based on general observations and not on conclusive studies showing relative benefits and risks. In some instances, adverse reactions are discovered only after widespread use of the product and surveillance of many vaccines; this was the case with the Guillain-Barre syndrome. As a method of obtaining information on hazards after a product is in use, the Food and Drug Administration maintains an adverse reaction data system. Food and Drug officials ad- vised us that they did not prepare a formal summation of ad- verse reactions from flu vaccine base! on data from their system. They said that adverse reactions are monitored as they are reported and that Food and Drug officials and others are well aware of what reactions are in this system. Accord- ing to these officials, most reports are about mild, rela- tively common reactions, such as fever and myalgia. According to Food and Drug officials, when evidence of an unusual or significant reaction is found, workshops with flu eperts and manufacturers are organized to discuss the problem. They said that workshops were organized on two separate occasions to discuss adverse reactions detected through the Food and Drug system. They said that in one in-- stance convulsions were detected in children and a warning was put in vaccine circulars. In another instance a large number of persons at a Boston utility company became ill after being vaccinated, but the actual cause of the illness could not be determined. The National Institute for Allergy and Infectious Dis- eases is doing a 3-year study (see p. 6) which ill examine the possibility that flu vaccination may potentiate flu ill- ness (make vaccinates more susceptible to severe natural 1/Public Law 94-380, which authorized the National Swine Flu Immunization Program of 1976, required HEW to consult with this commission on the content of the program's informed consent form. The law did not require HEW to obtain ap- proval from the commission. 8 B-164031(2) infection than unvaccinated individuals). This consideration was discussed by several EW officials and flu experts. Food and Drug's Advisory Review Panel on Viral and Rickettsial Vaccines and the Food and Drug Administration are required to consider the benefit-risk ratio in determining the safety and effectiveness of flu vaccines. In its January 1977 draft report (see p. 5.), the advisory panel stated that "the ultimate approval of a vaccine hinges heavily on the benefit-risk ratio. This term implies a quantitative formula which, unfortunately, is not attainable with exactitude." In its assessment of the benefit-risk ratio for flu vac- cine, the advisery panel concluded that "Epidemic influenza is associated with a consider- able morbidity [disease] and, in certain groups, an excess mortality [death]. Prevention of such disease and death is highly desirable. The isk associated with present vaccines is small, even including the risk of * * * [Guillain-Barre syndrome].' The panel also noted that there is a need to study effective- ness in high-risk populations so that the true benefit-risk ratio in those groups can be more precisely assessed. RESEARCH STUDIES ON PANDEMIC POTENTIAL O SFWINE VIRUS On October 7, 1976, researchers from the Mount Sinai School of Medicine, New York City, published a study on the swine flu virus isolated from recruits at Fort Dix, New Jersey. As previously noted, one theory on why a flu virus has epidemic potential is that the virus represents a genetic re- combination of a human virus with one whose natural hosts are animals or birds. Although the study recognized possible limitations to making a definitive analysis of the composition of the Fort Dix swine virus, it suggested that this virus was closely related to otbh swine viruses which have always been evident in swine, an4 t likely it was not derived by re- combination with a pr, .ert uman virus. The study concluded that, i recombination of human and animal strains is generally required for the emergence of new strains virulent for man, the Fort Dix swine virus is an "unlikely candidate for the next influenza pandemic." 9 B-164031(2) Dr. Edwin D. Kilbourne 1/ told s that the study findings were "very provocative" but hat he and his staff did not believe it should have altered the continuance of the immuni- zation program. e said that he and his staff decided that since the study involved application of a new technique, it should undergo additional peer review before it was formally presented. Consequently, they did not present the study's findings at the HEW-sponsored June 21, 1976, public meeting on the swine flu vaccine program. Dr. Kilbourne said that on the weekend before the June 21 meeting, HEW officials, clini- cal trial investigators, and others met to prepare for the public meeting and he mentioned the study to several of those in attendance, which included Food and Drug, National Insti- tute for Allergy and Infectious Diseases, and Center for Dis- ease Control officials. Dr. Xilbourne also said that the study was never discussed by he Advisory Committee on Im- muDization Practices as an agenda item HEW officials said the study was not considered entirely pertinent to the question of vaccination because (1) the re- searchers' results suggest that the Fort Dix swine vus did not arise through recombination of a swine virus with a recent human virus, but did not prove that recombination could not have occurred with human viruses prevalent several years ago, and (2) the researchers did not consider other known methods of adopting a virus to a new species. British researchers reached a similar conclusion in a study published July 3, 1976. These researchers exposed six volunteers to the swine flu virus. Volunteers showed mild or moderate reactions, suggesting that the swine virus was less virulent than other recent forms of human flu virus. They noted that the virus was not likely to spread among people and that the outbreak possibly "was an isolated event and that the virus will not become established in man." HEW officials advised us that this study was discussed in several public meetings and its results were well-publicized. Food and Drug officials questioned the validity of the con- clusions reached, stating that the virulence can be affected by transmission in humans or by laboratory conditionp. 1/Dr. Kilbourne served as a member of the Advisory fommittee on Immunization Practices and as a consultant fo. che Food and Drug Administration's Advisory eview Panel n Viral and Rickettsial Vaccines. He is Chairman of the Department of Microbiology, Mt. Sinai Hospital, where the research was performed. 10 B-164031(2j We discussed this study in a telephone conversation wit, a Center official, who also served on the advisory committee. Be said that the conclusion of the British study was not prising because there was no evidence that swine flu virussur- was extremely virulent. Be said that the major concern was that tnt virus was different from ither flu viruses to which persons hd been exposed and had protection. As a result, the swine virus was capable of causing widespread illness and subsequent death. We are preparing a report to the Congress on the swine flu immunization program which will also address certain questions posed in your letter. A copy of that report will be furnished to you when issued. We will be in touch with your office in the near future to arrange fr release of this report to the Food and Drug Administration. Sincerely yours, Comptroller General of the United States 1
Swine Influenza Program
Published by the Government Accountability Office on 1977-06-27.
Below is a raw (and likely hideous) rendition of the original report. (PDF)