oversight

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)

                            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)
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           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