Swine Flu: to Vaccinate or not ?
Posted by seumasach on October 17, 2009
Swine Flu: to Vaccinate or not ?
Marc GIRARD, MSc, MD
Consultant in drug monitoring and pharmacoepidemiology
European expert (AEXEA)
76 route de Paris, 78760 Jouars-Pontchartrain – France
(agosgirard@free.fr)
site: http://www.rolandsimion.org
Date of first release: 27 Sept, 2009
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Content
1. Rationale …………………………………………………………………………………………………. 3
2. Which benefit ? ………………………………………………………………………………………… 3
2.1. Vaccines against seasonal flu …………………………………………………………………………………. 3
2.2. Vaccines against swine flu …………………………………………………………………………………….. 5
2.3. Swine flu per se ………………………………………………………………………………………………….. 5
3. Which risk? ……………………………………………………………………………………………… 8
3.1. Risks of drugs in general ………………………………………………………………………………………. 8
3.1.1. Benefit/risk ratio …………………………………………………………………………………………. 8
3.1.2. Past experience with this therapeutic class ……………………………………………………….. 9
3.2. Risk of vaccines ………………………………………………………………………………………………… 10
3.2.1. Duration of action ……………………………………………………………………………………… 10
3.2.2. « The mosaic of autoimmunity » …………………………………………………………………… 11
3.2.3. Associations ……………………………………………………………………………………………… 12
3.3. Risks of vaccines against influenza ………………………………………………………………………… 13
3.4. Additional risk related to the case in point ………………………………………………………………. 14
3.4.1. Prevention and its risks ………………………………………………………………………………. 14
3.4.2. Scale effect ……………………………………………………………………………………………… 14
3.4.3. The “protected species” of pharmaceutical development ……………………………………. 15
3.4.4. Bypassing the regulatory process ………………………………………………………………….. 16
4. Which cost? …………………………………………………………………………………………… 20
5. Conclusion …………………………………………………………………………………………….. 22
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1. Rationale
Projects of forced flu vaccination certainly raise serious issues regarding fundamental
liberties, but more simply, they also raise significant health issues, which require a
factual analysis.
Basically, vaccines are drugs amongst others (and, as will be demonstrated
below, far more complicated agents as compared to most available drugs). From my
professional experience in drug development and pharmacoepidemiology, I have a
simple conceptual frame of relevant issues to be analysed:
1. which benefit?
2. which risk?
3. which cost?
2. Which benefit ?
2.1. Vaccines against seasonal flu
The Cochrane collaboration1 is a non-profit network dedicated to performing
systematic reviews of health care interventions, including a number of drug
treatments. Independent in principle, its reviews are not always above criticism2 – as
is the case with all of us… However, there is general agreement that the “Cochrane
reviews” are amongst the most reliable assessments available in the field of medical
care.
As it happens, the Cochrane collaboration has recently published thorough reviews
on flu vaccines: the significance of these retrospective assessments is even greater
since they have been subjected to quite recent updates.
As opposed to the implacable promotional activism of health authorities (WHO
included), their conclusions are damning.
• In the elderly (65 years and more)3 : “according to reliable evidence the
usefulness of vaccines in the community is modest”.
1
2
Girard M. Meta-analysis on recombinant versus urinary follicle stimulating hormone. Human
Reproduction 2000; 15: 1650-1651
3
Rivetti D, Jefferson T, Thomas RE, Rudin M, Rivetti A, Di Pietrantonj C, Demicheli V. Vaccines for
preventing influenza in the elderly. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.:
CD004876. DOI: 10.1002/14651858.CD004876.pub2.
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• In healthy adults4 : “There is not enough evidence to decide whether routine
vaccination to prevent influenza in healthy adults is effective”
• In healthy children5 : “If immunisation in children is to be recommended as a
public health policy, large-scale studies assessing important outcomes and
directly comparing vaccine types are urgently required.” Not without irony, the
authors add the following comment: “It was surprising to find only one study
of inactivated vaccine in children under two years, given current
recommendations to vaccinate healthy children from six months old in the USA
and Canada.”
• In healthcare workers who work with the elderly6 : “There is no credible
evidence that vaccination of healthy people under the age of 60, who are
HCWs caring for the elderly, affects influenza complications in those cared
for”.
There is no need to be an epidemiologist to grasp the problem raised by this series
of reviews which included all the available relevant studies (randomized controlled
trials, cohort and case-control studies) performed from 1966 to 2006: throughout
40 years, nobody (in particular neither the manufacturers, nor any health
agency) has proved able to produce convincing evidence of a significant
benefit related to vaccines against influenza7!
Incidentally, to be fair, it may be noted that the manufacturers of antiviral treatments
do not seem more demanding than vaccine makers as far as
pharmacoepidemiological evidence is concerned. In a recent letter to the British
Medical Journal, Roche’s medical director did not hesitate to write: “The product
summary for oseltamivir shows that it is effective and well tolerated in children”8 (my
italics). In more than 27 years of professional life devoted to the assessment of
drugs, this is the first time that I have heard of a product summary which could to
“show” any kind of scientific evidence…
4
Demicheli V, Di Pietrantonj C, Jefferson T, Rivetti A, Rivetti D. Vaccines for preventing influenza in
healthy adults. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD001269.
DOI:10.1002/14651858.CD001269.pub3.
5
Jefferson T, Rivetti A, Harnden A, Di Pietrantonj C, Demicheli V. Vaccines for preventing influenza in
healthy children. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD004879. DOI:
10.1002/14651858.CD004879.pub3
6
Thomas RE, Jefferson T, Demicheli V, Rivetti D. Influenza vaccination for healthcare workers who
work with the elderly. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD005187.
DOI: 10.1002/14651858.CD005187.pub2.
7
Even more paradoxical since, as everybody knows, available studies are rather skewed towards an
overestimation of benefits, because of the publication bias. To say the same in more mathematical
way: if an overestimation of benefits proves to be near zero, at which level may be the real
benefits?…
8
Rashford M. BMJ 2009; 339: 650
5
To sum up:
• throughout 40 years, the manufacturers have never made any effort to get
any scientific evidence of the efficacy of their flu vaccines;
• within the same period, the health agencies have never requested any
scientific evidence of efficacy for the flu vaccines for whose registration (or
not) they were responsible;
• in spite of this depressing state of affairs, these vaccines are increasingly
promoted (and, quite often, reimbursed) with the active participation of
regulatory bodies: as rightly pointed out by the leading authors of these
Cochrane reviews9, their activism in promoting flu vaccines places health
agencies as well as their “experts » in an objective conflict of interest10.
2.2. Vaccines against swine flu
For health agencies as well as their experts, it is a leitmotiv that a longstanding past
experience with vaccines against seasonal flu is clearly relevant for the development
of new vaccines against swine flu and justifies the frightening swiftness of their
current development. But as demonstrated in the previous section, a thorough
assessment of this past experience is now available – and it is disastrous.
Worse, the manufacturers and health agencies are not content with using this
disastrous precedent as a shield: they seek to take advantage of a supposed
pandemic emergency to get rid of time-consuming regulatory prerequisites regarding
major pharmaceutical innovations such as new adjuvants or new processes of viral
cultures (each of them likely to require years of research).
If, in some 40 years of anti-flu routine, those responsible have not proved to be
capable of producing any sound evidence of efficacy for their vaccines, who is ready
to believe that they will do better under the pressure of emergency ?…
2.3. Swine flu per se
The intrinsic efficacy of a drug against a disease is not the last word of the benefit
assessment: it remains to be demonstrated whether the risks of this disease are
9
Jefferson T, Demicheli V. Influenza vaccination for elderly people and their care workers. Lancet
2007; 369:1857-8.
10
This may be the place to pick out that, in April 2007, US Representatives Dave Weldon and Carolyn
Maloney have introduced a new bill that aims to allocate responsibility for vaccine safety in the US to
an independent agency within the Department of Health and Human Services. The Vaccine Safety and
Public Confidence Assurance Act of 2007 will remove most of the vaccine safety research from the
Centers for Disease Control (CDC), which currently has responsibility for both vaccine promotion and
safety, posing a conflict of interest that has been receiving public criticism (Reactions Database, AN:
809074716). Such a move largely confirms the criticism of Jefferson and Demicheli regarding the
credibility of health agencies “experts” in assessing retrospectively the benefit/risk ratio of vaccines.
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significant enough to require any treatment. To be specific, the question is whether,
on the basis of objective available data, swine flu appears threatening enough to
require an extraordinary wealth of preventive measures.
The answer is obviously NO.
• Even the most alarmist (professional or not) medias agree that, for the time
being, the new virus seems rather less virulent than its seasonal predecessors.
• Modest though it appears now, the severity of swine flu as currently assessed
is markedly biased towards an overvaluation.
o Obviously, the death toll has been exaggerated: at the end of April,
within a single day, the number of Mexican deaths ascribed to swine flu
dropped from some 200 to 7 only ; similar examples could be
multiplied.
o World areas where the rate of presumed deaths was highest were also
those with the least performing health systems, so that one may
wonder about: 1/ the baseline health status of patients with a fatal
outcome; 2/ the adequacy of medical care in case of respiratory
complications; 3/ the reliability of aetiological diagnosis (it is perfectly
possible to suffer from a mild flu and to die from an infarction – or an
assassination for unrelated reasons…).
o In contrast with their hysterical mediatisation of most deaths,
newpapers usually remained discrete on the question of underlying
diseases and medical history: yet, a trivial cold – not even influenza –
may be sufficient to kill a patient suffering from immunodepression…
That is not a scoop.
o Objectively low though it was, the number of fatal cases was
exaggerated by an underestimation of the total number of cases, as the
symptoms were so mild in many of them that they did not feel the need
to visit a doctor: if, amongst 10,000 recorded cases, death occurred in
10 cases, the apparent mortality is 1/1,000; however, if in addition,
90,000 patients did not display significant symptoms, the real mortality
will drop to 1/10,000, that is ten times less.
Once established that swine influenza currently corresponds to a fairly mild form of
influenza, health agencies retort that their concern is not the virus as it is now, but
as it could become in near future after a mutation. However:
• propensity to mutate is a strong characteristic of any virus in general, and of
influenza viruses in particular: there is nothing new in that;
• if this swine virus is supposed to mutate in the future:
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o this could be in the direction of an even lower virulence ;
o as the vaccine is currently prepared against the current strain of the
virus, it could be ineffective against a mutated strain (this
unexpectedness of a mutation is the classical excuse of the
manufacturers each time the efficacy of the vaccines against seasonal
flu proves to be obviously poor).
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3. Which risk?
3.1. Risks of drugs in general
3.1.1. Benefit/risk ratio
Any drug, even targeting trivial symptoms, carries a potential of hazards, some of
which may be severe: just think of the precedent of thalidomide, a product normally
used to relieve pregnant women from their nausea… As drugs amongst others,
vaccines against swine flu will therefore induce hazards whose frequency and
severity will be difficult to anticipate, as is usually the case when drug exposure has
not been wide enough.
The natural correlate of the inherent drug-induced toxicity is the benefit/risk ratio,
which, in the case in point, may be considered from two complementary standpoints.
• Having regard to the average mildness of swine flu, it could happen that , by
their frequency or their severity, the unwanted effects of a vaccine could
overtake the risk inherent to the disease that it is supposed to prevent.
• The significance of this warning (relevant to any drug) is increased inasmuch
as the target of a vaccine is preventive – and that a majority of the vaccinated
subjects are not supposed to contract influenza. Thus, however “collective”
the benefit might be, who would be stupid enough to take even a small risk of
adverse effect from a drug which carries no personal benefit? In other terms:
inasmuch as the expected personal benefit decreases, the potential risk must
decrease in parallel. Finally, for a drug whose personal benefit is
negligible, the sole acceptable level of iatrogenic risk must be zero or
something quite close.
On the basis of available data, is it possible to contend that the level of risk related to
the new vaccines against swine flu is near zero? Clearly NO, and this will be
demonstrated below.
But beforehand, I would add a word on the hypocrisy of the argument about the
collective benefit of flu vaccination. As already stated, there is general agreement
about the average mildness of this new flu: therefore, this could be the right time to
facilitate the dissemination of the virus in order to allow a “natural” vaccination of
populations (a strategy whose financial benefit could be far more advantageous than
a mass vaccination with products sold at indecent prices…) No doubt that there will
be some kind souls to retort that such an ecological vaccine policy would have a cost
in terms of individual complications occurring mainly in fragile subjects: that is clear,
but why, in that case, should the priority of “collective” benefit become irrelevant?11
11
Taking into consideration the additional fact that, because of the current mildness of swine flu, the
overall cost (mortality, morbidity and resulting financial cost) of such an epidemics would be probably
less than the cost normally accepted every year with seasonal flu.
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3.1.2. Past experience with this therapeutic class
One major argument of health authority to justify the urgent development of a new
vaccine in the setting of a regulatory anarchy is that in their pharmacological
principle, vaccines against A/H1N1 have nothing new: their development may benefit
from the acquired 40-year experience with seasonal flu.
Apart from the intrinsic contradiction of a virus new enough to justify a panic but
classical enough to require only experience acquired with the traditional virus (!), let
us summarize our past experience with vaccines against seasonal flu.
In short, it suffices to go back to the previous Cochrane reviews (see 2.1): according
to the authors, there is a lack of evidence regarding the safety of flu vaccines,
especially in children. Therefore, past experience with vaccines against
seasonal flu can, in no way, be used as a reassurance regarding the safety
of the new vaccines.
From this statement of fact, it is also possible to raise a question parallel to that
made about the efficacy parameter: if, within some 40 years, the manufacturers or
regulatory bodies have not been able to gather any convincing evidence about flu
vaccines, who can believe they are able to assess the safety of new vaccines in a
climate of methodological hurry and regulatory anarchy?
An additional remark may be of significance. As everybody knows, the marked
involvement of the biggest pharmaceutical firms in vaccine sectors is fairly recent.
Thus, if one refers to documents published before this self-seeking involvement (with
its impact on the integrity of medical publications…), it is easy to record that, the
adverse effects of flu vaccines were then acknowledged as an obvious fact. To take
just one example, the 30th edition of the reference book Martindale12, in 1993, reads
that adverse effects were “as for vaccine in general” (including anaphylaxis and
effects on the nervous system), with an additional mention of pericarditis, Henoch-
Schönlein purpura and acute polyarteritis. Finally: “An epidemiologic and clinical
evaluation of these cases suggested a definite link between vaccination and the
onset of the syndrome [of Guillain-Barré] with extensive paralysis (…) Influenza virus
which lack a swine influenza virus component seem not to raise the risk of paralysis
above background levels”.
Five years before, the 11th edition of Meyler’s Side Effects of Drugs, another
reference book13, listed amongst the adverse reactions reported with influenza
vaccine: “neurological reactions [ranging] form polyneuropathy to
meningoencephalitis and Guillain-Barré syndrome”, optic neuritis, myocardial
infarction and pericarditis, interstitial lung disease, as well as drug interactions…
12
Martindale . The Extra Pharmacopoeia, 30th edition. London, The Pharmaceutical Press, 1993.
13
Dukes MNG (ed). Meyler’s Side Effects of Drugs. An Encyclopaedia of Adverse Reactions and
Interactions, 11th edition. Amsterdam, Elsevier, 1988
10
This acknowledged evidence from the past of a significant toxicity of flu vaccines
downgrades to lies or ignorance the contrary statements of most “experts” now.
3.2. Risk of vaccines
3.2.1. Duration of action
Usually, when a drug is administered, it has a limited duration of action; within the
fluctuations of its elimination (which may take some weeks with some drugs), the
duration of its pharmacological action is more or less restricted to the time of
administration.
In contrast, vaccines have a quite unusual particularity: for only one administration
(sometimes followed by a few boosters), the expected effects are supposed to last
for years, decades or even the whole life span.
Yet, strangely enough and still in contrast with usual drugs, the safety trials
performed with most vaccines are extremely short: from the Physician Desk
Reference, for example, one may learn that those carried out during the
development of the hepatitis B vaccine Engerix did not last more than 4 days…
Accepted though it is by regulatory authorities, this design is obviously defective –
especially to assess delayed adverse effects… But in addition and as exemplified by
the abovementioned Cochrane review or by experience, these trials are, in practice,
quite often carried out in a fairly lax manner, to be euphemistic. It seems to be taken
for granted that, compared with other drugs, vaccines cannot induce significant risks,
so that monitoring their safety requires neither effort nor rigour.
The Engerix case once again gives an eloquent illustration of this paradox. It appears
from the summary of product characteristics that some 8 years were necessary to
see the mention of a risk of “anaphylaxis”14. Thus, it took no less than 8 years for the
manufacturer or the health agencies to record the most immediate drug-induced
reaction that could be imagined. One can hardly rely on the same “experts” to assess
properly:
• delayed adverse effects such as auto-immune diseases, multiple sclerosis or
lateral amyotrophic sclerosis;
• the safety profile of the new influenza vaccines which, in contrast with Engerix
(whose development took several years), will have been developed within a
maximum of a few weeks.
14
That is a shock (possibly severe or even fatal) of immunological determinism within the seconds or
minutes following injection.
11
Here is the appalling illogicality of vaccine development: whereas these drugs are
supposed to exert their beneficial immunological effects on a very long term, they
are never conscientiously suspected (and, in any case, never conscientiously
assessed) regarding their potential to exert adverse immunological effects within the
same long term.
This blatant illogicality justifies a re-appraisal of the ferocious antagonism between
supporters of vaccines and antivaccinationists. Unlike any other domain in
therapeutics15, vaccination cannot be a matter of academic controversy: either you
have no doubt about the obvious benefits of every vaccine and you are on the side
of “Reality”; or you are inevitably on the side of “myth”, “misinformation”,
“misconception”, “falsehood”, “archaism”, etc.16 Actually, evidence is more balanced.
To be frank, it is clear that antivaccinationism is on the agenda of a number of sects
– to say nothing about the paranoid. No doubt either that most antivaccinationist
groups have vested interests in the marketing of “alternative” medicines as opposed
to “allopathic” products, with papers, journals or sites closer to sales promotion than
to scientific communication. For a professional in pharmaceutical development,
however, it is no less true that vaccine promotion – even performed in the most
prestigious journals (like NEJM, The Lancet or BMJ) – is distinguished by a distressing
amateurism – to say nothing about latent conflicts of interests. Marked in particular
by gross inconsistencies and a rare illogicality, this pro-vaccine amateurism feeds
anti-vaccine movements, making every person endowed with a minimum of cultural
background and elementary logic able to point out its most blatant failures17.
In my papers devoted to the vaccines against hepatitis B, I have given a number of
amazing examples of this amateurism of pharmaceutical firms, experts or health
agencies where vaccination is concerned18. Additional evidence will be given at the
end of this paper.
3.2.2. « The mosaic of autoimmunity »19
A vaccination corresponds to the introduction into a human organism of antigenic
material which has been subjected to more or less precise identification20 and which
15
L. Lasagna (ed). Controversies in Therapeutics. Philadelphia, Saunders, 1980.
16
Kimmel SR. Vaccine adverse events. Separating myth from reality. Am Fam Physician 2002; 66:
2113-20
MacIntyre CR, Leask J. Immunisation myths and realities: responding to arguments against
immunization. J Paediatr Child Health 2003; 39: 487-91
Wolfe RM, Sharp LK. Anti-vaccinationists past and present. BMJ 2002; 325: 430-3
Begg N, Nicoll A. Myths in medicine – Immunisation. BMJ 1994 ; 309 : 1073-5
17
Girard M. Being or not being an “activist”, that is the question. Medical Veritas 2006; 3: 1214-5
18
Girard M. When evidence-based medicine (EBM) fuels confusion: multiple sclerosis after hepatitis B
vaccine as a case in point. Medical Veritas 2007; 4:1436-51
19
Shoenfeld Y, Aharon-Maor A, Sherer Y. Vaccination as an additional player in the mosaic of
autoimmunity. Clin Exp Rheumatol 2000; 18:181-4.
12
carries per se a potential for inducing reactions of autoimmunity, for example by a
mechanism of molecular mimicry (if there is a similarity between this antigenic
material and any physiological structure of the self21).
In addition and as with every drug, even a minute contamination22 or impurity during
the manufacturing process is likely to trigger an unwanted immune reaction and, in
particular, an autoimmune one. Overall, there is a strong record of the potential of
vaccines to produce autoimmune diseases (such as rheumatic disorders)23.
Already significant – if not frequent – from an epidemiological standpoint, this
autoimmune risk is obviously magnified by the use of adjuvants.
Acceptable though it may be in some preventive indications precisely targeted
against significant infectious risks (which, I repeat, are not uniformly distributed all
over the world…), this risk of autoimmune hazard is statistically correlated to the
number of vaccines administrated. Thus, it is not exaggerated to assert that the
continuous reinforcement of the immunization schedule, with its mathematical
increase in the autoimmune risk, is certainly not offset by a parallel effort to extend
or deepen the epidemiological assessment of these new recommendations. To take
just one example, since the time of my medical training, the targeted population for
the immunization against seasonal influenza has shifted from fairly small “at risk”
groups to everybody every year, which means on average an additional burden of
some 80 new immunisations in each person over his/her life span: to the best of
my knowledge (and as confirmed by the recent Cochrane reviews), progress in the
safety assessment of these vaccines is not in keeping with this dazzling increase.
3.2.3. Associations
As illustrated by the Physician Desk Reference or any equivalent book, the issue of
drug interactions is a crucial one with any pharmaceutical product. Compared with
this norm, concerns about interactions seem quite diluted as soon as the product in
question is a vaccine.
20
If the linear structure of antigenic molecules may be identified, it is far more difficult to anticipate
their spatial disposition : yet, it is precisely this spatial disposition which will determine the main part
of immune reactions in the host.
21
Selmi C, Battezzati PM, Tishler M, Shoenfeld Y, Gershwin ME. Vaccines in the 21st century: the
genetic response and the innocent bystander. Autoimmun Rev 2005; 4(2):79-81.
22
Faure E. Multiple sclerosis and hepatitis B vaccination: Could minute contamination of the vaccine
by partial Hepatitis B virus polymerase play a role through molecular mimicry? Med Hypotheses 2005;
65:509-20
23
Shoenfeld Y, Aharon-Maor A, Sherer Y. Vaccination as an additional player in the mosaic of
autoimmunity. Clin Exp Rheumatol 2000; 18:181-4.
Le lecteur intéressé pourra trouver bien d’autres références sous la plume de Y. Shoenfeld et de ses
collaborateurs.
13
Yet, as exemplified by note 13, there is no convincing reason to believe that vaccines
do not expose immunized subjects to significant problems regarding interactions with
other drugs.
In addition, there is no reliable evidence that the risk of multiple immunizations has
been seriously considered: to take just one example, it does not seem that the
frightening issue of sudden infant death syndrome (SIDS) – which cannot be ignored
on the basis of anecdotal evidence (as reflected by experience or by the VAERS,
amongst other data) – has received the epidemiological attention it deserves24.
This poverty of clinical or epidemiological research on drug interactions induced by
vaccines is all the more paradoxical since, as stressed above, the duration of action is
normally far more prolonged with vaccines as compared with any other drug
subjected to a far more rigorous screening in this regard.
3.3. Risks of vaccines against influenza
As compared to vaccines in general, those targeted against influenza have two
additional drawbacks.
• As already said (cf. 3.2.2), these vaccines require an additional immunization
every year: it must be born in mind that these yearly injections are not
booster doses, but correspond each time to a new active principle. If the
current recommendations of health authorities were to be followed, it is clear
that over a life span, flu vaccines would be major contributors to the mosaic
of autoimmunity. From a simple Hippocratic standpoint, the imprudence of
such recommendations is vertiginous.
• Each year, depending on the characteristics of the virus isolated as responsible
for the epidemics, the new influenza vaccines are prepared in an incredible
rush, which has no equivalent elsewhere in pharmaceutical development (I will
come back to this important point: see 3.4.4.2). Here is most probably the
genuine cause of the disastrous results of the Cochrane review: it is simply
not possible to develop drugs within 2-3 months. And arguing the
contrary is both irresponsible and deceitful.
24
When the vaccine Hexavac was registered, the summary assessment posted on the site of the
European Agency (EMEA) showed that, simply during the development, the rate of SIDS (7 amongst
some 3905 infants exposed) was 35 times higher in those exposed to the vaccine than normally
expected: the Agency contended itself with claiming placidly that these deaths were unrelated to the
vaccine. Later, the Agency never undertook the slightest epidemiological assessment and completely
ignored unusually alarming signals of postmarketing experience such as that by Zinka B. et al
(Unexplained cases of sudden infant death shortly after hexavalent vaccination. Vaccine 2005 May
18).
14
3.4. Additional risk related to the case in point
3.4.1. Prevention and its risks
In evolution, immunity is not a stock given once and for all to individuals: it is a
dynamic system which requires periodic reactivations, especially as far as “non
specific immunity” is concerned.
It may be difficult to find reliable epidemiological evidence on this point, but there
are a number of good reasons to take as a serious hypothesis that trivial viral
infections such as cold or flu have the adaptive function of maintaining the reactivity
of our non specific immunity. In other words, even if these infections carry an
undisputed burden in terms of individual casualties, they are probably beneficial on
the scale of the general population.
It is striking that a number of scholars who are certainly not antivaccinationists
recognize that natural infections could have, overall, a protective role against
autoimmune diseases and that anti-infectious prevention (with vaccines or, in some
cases, with antibiotics) may have a harmful impact on the risk of diseases such as
asthma25 or diabetes. This should be taken into consideration when assessing the
benefit/risk of immunisations.
3.4.2. Scale effect
There is wide agreement that, even when clinical trials are properly carried out
(which is certainly not the case with the new influenza vaccines), the probability of
recognizing a hazard is near zero if it occurs at a frequency of 1 in 1,000 exposed
patients26. Incidentally, let me remind readers that this lack of statistical power
inherent in clinical development is the classical plea of the manufacturers once the
toxicity of their products can no longer be denied, as was the case in the Vioxx affair.
For the time being, a number of experts claim that swine flu could hit one third of
the population with a mortality of 0.1% (which, in my opinion, is probably an
overestimation). Applied to the USA population, these estimates correspond to
100 millions of affected persons, with a maximum death toll of 100,000 persons,
mainly in the elderly or in patients made vulnerable by severe underlying diseases:
overall, this mortality would not have much impact on the average life expectancy
there.
Inasmuch as most of the alarmism regarding swine flu is based on “the worst case
hypothesis”, let me temporarily adopt the same rhetoric: so, let us suppose that the
“clinical trials” on the new influenza vaccines will miss 1 adverse reaction in
1,000 exposed patients, and that this reaction will be fatal (a pessimistic hypothesis,
of course, but not extravagant from a statistical standpoint: there are precedents…).
25
J Allergy Clin Immunol 2008 ; 121 : 626-31
26
Schneiweiss F, Uthoff VA. Sample size and postmarketing surveillance. Drug Information Journal
1985 ; 19 : 13-6.
15
Thus, if obliged, or panic-stricken, the whole of the US population was vaccinated,
there would be 300,000 deaths: three times the death toll due to influenza and, this
time, in babies, children, young adults, all of them in perfect health – with a major
impact on average life expectancy.
Not to speak of the other adverse reactions of these new vaccines (e.g. Guillain-
Barré syndromes), as it never happens that a drug carries the risk of one hazard
only…
3.4.3. The “protected species” of pharmaceutical development
Pharmaceutical development has always considered as “protected species” four
categories of persons: the elderly, pregnant women, children and patients with
underlying diseases (cancer, autoimmune disease, diabetes…). As a matter of policy
and allowing for exceptions (e.g. to develop a treatment against Alzheimer’s disease
or metastatic cancer), study protocols exclude these subjects: as a consequence easy
to verify, the summary of product characteristics of new drugs usually includes
severe warnings about prescription in pregnant women or below a certain age.
Once an additional postmarketing experience is available, it becomes possible to
envisage a progressive extension of the drug indications, but always at the price of a
new development with appropriate clinical trials leading to a new drug application.
Experience shows that the regulatory authorities are often overcautious regarding
such extensions and that the probability of the application being rejected is far from
negligible.
Yet, in the case in point and according to health agencies, who will be the
subpopulations to be first and foremost exposed to these flu vaccines developed in
an incredible technical and regulatory anarchy? As it happens: the elderly, pregnant
women, children and patients with underlying diseases – and even the newborn
babies according to some experts.
It must be said without any political correctness: this is criminal nonsense.
As a single counter-example, let me remind readers that no less than 20 years – and
a fantastic exposure – were necessary before the neonatal hazards of serotoninergic
antidepressants (such as Prozac) were identified27, whereas these products – unlike
the new influenza vaccines – were developed in the standard way, including very
long studies in animals and over an incommensurable duration comparatively
speaking: it took some 15 years or more to put Prozac28 on the market. Yet, in its
principle, this drug is far simpler than products which may contain several antigenic
27
Spencer MJ. Fluoxetine hydrochloride (Prozac) toxicity in a neonate. Pediatrics 1993; 92: 721–2
28
Early development started at the very begining of the 1970s (Wong D et coll. “A selective inhibitor
of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine”. Life
Sci 1974 ; 15 (3): 471–9). The first registration was given in Belgium in 1986 ; in the US, i twas not
given before 1988.
16
parts added to adjuvants… It is worth noting to that the risk of foetal toxicity is still
debated with these antidepressants29.
3.4.4. Bypassing the regulatory process
Although quite restrictive legally and highly significant as far as public health is
concerned, the process of a new drug application (NDA) and its registration is widely
ignored by most people, including most health professionals. Hence the following
brief account.
3.4.4.1. Usual duration of drug development
As opposed to the public declarations of some “experts” clearly unfamiliar with drug
making, the development of a new drug is not confined to clinical studies only.
Besides the mass of administrative data, it includes three main parts30.
• Chemical, pharmaceutical and biological documentation: composition of the
drug, method of preparation, control of starting material, control tests on
intermediate materials, control tests on the finished product, stability testing,
bioavailability/bioequivalence, data related to the environment risk assessment
for products containing genetically modified organisms…
• Pharmacotoxicological documentation: toxicity, reproductive function, embryo-
fetal and perinatal toxicity, mutagenic potential, pharmacodynamics,
pharmacokinetics, local tolerance, environment risk assessment…
• Clinical documentation: clinical pharmacology, clinical experience…
Without entering into more details, it is clear already why it is simply not possible to
develop a new drug within one, two or three months. According to the author
referred to in note 30: “Prior to the introduction of high-density computer storage
media (e.g. CD-ROMs), the physical size of a marketing authorisation application
could be daunting”.
It is my guess that the physical size of the applications regarding the new vaccines
authorised against swine flu is, by no means, “daunting”…
Just to evoke briefly what a drug development should be like, let me sketch the usual
timing of a customary clinical trial (to say nothing about the pharmacotoxicological
prerequisites prior any introduction for man).
• Protocol redaction: this normally takes several months.
29
http://www.medicinescomplete.com/mc/martindale/current/12763-
x.htm?q=%22prozac%22#r12763-a5-7-d-8 (consulté le 25/08/09)
30
The brief summary is mainly inspired from RJ Harman, Development and Control of Medicines and
Medical Devices, London, Pharmaceutical Press, 2004.
17
• Choosing the investigators, having their feedback on the protocol and
integrating their suggestions if any: this may take some time, especially if the
centres are distributed all over the world, as is often the case as soon as a
certain sample size is required. Before, of course, you took the time to write
the “investigator brochure” which summarizes available data on the new drug
(esp. animal prerequisites) as well as on the therapeutic class (i.e. 40-year
experience with flu vaccines…)
• Submitting the protocol to an ethical committee as well as to the regulatory
agencies (several of them if the study is international): you can count on a
minimum of several months (and more if these guys criticize your protocol and
request modifications).
• Sooner or later, you have to manufacture a placebo or a comparator in exactly
the same form as your drug under investigation: you may have some technical
problems – as pharmacy is tricky cookery…
• In some countries like mine, you have to get the agreement of the medical
association on the contract between any investigator and the sponsor: usually,
this is not a matter of a few days.
• Then, you have to recruit the patients, which may be a long process –
especially with a new vaccine people are often afraid of (remember that you
have to get their informed consent…)
• You will have to follow the patients over the treatment duration specified by
the protocol: if it is 2 months and if the last patient is recruited some
2 months after the first (which is unusually quick), the overall duration of the
treatment phase cannot be less than 4 months.
• Once the last dose has been administered, a minimum follow-up of one month
is normally required – for each patient.
• Then, you will have to carefully check that the data entry in your base has
been strictly consistent with the patients case report form. You will also have
to check that, for each patient, every prescription of the protocol was
respected. For every detected mistake (spelling of a name, error on a date or
on a dose, etc.) you have to get it corrected by the investigator who usually
has other concerns than your study in his professional life (hospital activity,
other clinical trials with other manufacturers, continuous medical education,
litigations with past patients…)
• This will be the time of the statistical analysis: you can count some months, if
your statisticians are diligent – and if you do not detect retrospectively
problems in the protocol conception or in the way data were entered.
• Once the statistical results are available, it is time to write the study report: if
you go on internet to get available templates (e.g. those of the International
18
Conference on Harmonisation), you can easily understand the inherent
burden…
• Once the report has been completely written, then you have to enter into the
process of internal approval – actually a nightmare (the moment where those
who did nothing thus far take the opportunity to show that: 1/ they exist,
2/ they have some degree of power in one way or another). Regarding the
last report I was commissioned to write (in a major firm, on a project labelled
as “very urgent”), the medical director alone asked for a 2-month time limit
for his approval: challenged on that duration in view of the urgency, he
answered that this was “incompressible” – and everybody in the firm seemed
to agree…
That was just an average sketch. But I am sure that everybody understands that, for
any clinical trial, the natural units to measure the duration of the process are years
and not months, and certainly not weeks or days… In addition, one single study is
not sufficient for a drug development. Finally, when you have performed all the
required studies, you have to assess them on the whole in an “expert report” – once
again a quite complicated document normally structured by pernickety guidelines and
templates: of course, such an expert report has to be done for each part of the
dossier (pharmaceutical quality/ pharmacotoxicological data/ clinical data). I say
nothing of the physical making of the application, which includes amongst other a
scanning of all individual data (that of the patients, but also of the animals included
in the toxicological studies).
It is now up to the vaccine manufacturers and governmental agencies to explain how
such an enormous task may be compressed into a few weeks…
3.4.4.2. Which registration?
Normally, the introduction of a new drug on the market is conditioned by a
registration process, which corresponds to the scientific assessment performed by
regulatory authorities of a marketing authorisation application (or: a new drug
application): this application includes all the investigations carried out by the
manufacturer during the drug development to comply with quality, safety and
efficacy criteria required by pharmaceutical regulations.
Yet, it is not difficult to document from media that quite early in the summer months,
the governments of developed countries such as the US, the UK, Germany or France
(which are not supposed to lack legislation or regulatory bodies) have prided
themselves on having ordered (and even paid for) huge amounts of vaccines against
swine flu and on being ready to trigger (or even: to force) massive campaigns of
immunization.
It is not difficult either to document that for the time being (end of Sept, 2009),
these vaccines are still in their phase of development – which, in the process
described by the current legislations, normally corresponds to a step preceding the
19
making-up of a new drug application (which precedes itself the process of
registration involving a careful assessment of this application).
From which one may raise an interesting question (to my knowledge, never brought
up before): how is it possible to buy, pay for and administer a drug before the health
authorities have complied with their duty of protecting consumers by carefully
assessing the quality, safety and efficacy of this new agent?
In a country like mine where I pride myself on having introduced this regulatory
issue into public debate, the government, obviously shaken by this unexpected
objection, tries to justifies itself by making up now a retro-planning tending to
demonstrate that – of course – the marketing authorisation will be available before
any significant campaign of immunization.
With such fancy claims, however, the government is getting itself in deeper and
deeper water: if, depending on local regulations, the timing of the registration
process may be scheduled (with a deadline for the final decision, in particular), the
authorisation cannot be subjected to any a priori schedule.
A useful metaphor for the registration process is that of a school examination: you
can succeed if you are good, be subjected to an additional examination if you are
borderline, but also… be flunked if you aren’t up to standard. In the process of a
drug application, the drug maker is like a student: his new drug may be approved, he
can get blocking questions (“measure of investigation”) which may require
clarifications, additional checks or even new investigations, and of course the
application may be rejected by the regulatory authority.
Therefore: how is it possible to have a pre-specified schedule of approval in a
process where the approval may be delayed or even rejected? And how is it possible
for governments to spend public funds by paying in advance products whose
introduction on the market may never be granted? The answer is clear: our health
authorities have never been seriously thinking of genuinely assessing the
new influenza vaccines.
And while giving by their orders a strong signal to the manufacturers that they were
ready to co-operate in transforming into a blockbuster any dirty kind of vaccine
mixture, our governments put the finishing touches by making sure that no judicial
litigation could hit the manufacturers.
This is a scandal and a tragedy.
20
4. Which cost?
On the question of financial cost, I will be briefer as I have no special competence in
pharmaco-economy. But, however brief, the following remarks may be of relevance.
Vaccine prices – The leitmotiv of the manufacturers to justify the exorbitant price
of their drugs has always been the time spent in their development31: years, and
sometimes more than a decade. Thus, if you follow the same line, you should expect
that the cost of vaccines developed within a few weeks only should be lowered
accordingly: this does not seem to be the case…
Number to treat – Having regard to the enormous population targeted by an
immunisation, as compared to the current mildness of swine flu, the relevant
parameter to assess the cost/benefit of the vaccination should be the number to
treat: how many people should be vaccinated to avoid one fatal case of influenza?
And with the prospect of a massive campaign: how many persons will be vaccinated
to avoid one fatal case of influenza?
Indirect costs – To the direct cost of the vaccines (and of the remuneration of the
health professionals who would perform the injections), indirect costs should be
added. That of the anarchy inherent in the extravagant preventive measures taken
by the governments, and of course that of the side-effects of the vaccines: according
to some medical sources, up to 30% of adults developing a Guillain-Barré syndrome
may have neurological sequels, and the proportion could be higher in children (and
of course, Guillain-Barré syndrome is not the only hazard one can expect with
vaccines developed in an unprecedented rush – some by firms which already have a
previous history of malpractices…)
Resource allocation – From a scientific point of view, this is a safe bet to claim
that the swine virus can mutate and become exceedingly naughty, as no serious
professional can deny such a possibility: but the relevant question is rather the
probability of such a mutation. In a world where money is limited, once you focus on
one issue, you take resources which will not be devoted to other issues. Therefore,
our responsibility as experts is not to cry wolf under any pretext: it is rather to rank
priorities in health problems on the basis of available data in order to enlighten the
politicians about resource allocation. Until the contrary is proven, I maintain that thus
far, available data do not make swine flu as a health priority: neither at the scale any
country considered individually, neither at an international scale.
Profitability – At the end of the 1990s, it was not a secret that drug makers were
becoming nervous about the persistence of the indecent profitability of their business
because of blockbusters coming out of patent and, more seriously, their lack of
innovation. Since then, it suffices to skim through the economic press to note that
vaccines have become the providential sector for maintaining this profitability. In
31
Angell M. The Truth about the Drug Companies. How they deceive us and what to do about it. New
York: Random House, Inc, 2004.
21
spite of their depressing lack of imagination for the creation of valuable new chemical
entities, it did not take drug manufacturers long to understand that from the point of
view of pure profitability, vaccines offer two major advantages: 1/ with adequate
lobbying (thanks to the WHO experts32 and to those of governmental agencies with
their vested interests), it is not difficult to widen the target population to
everybody33; 2/ with their slapdash development, vaccines are not expensive to
make. It should have been an eminent priority for health agencies to protect citizens
against such prospects: for the time being, they have preferred to serve the
manufacturers interest, giving credibility to the tales of pharmaceutical promotion by
their outrageous alarmism and supporting the amateurism of vaccine makers by
ignoring the regulations they should have the duty to enforce.
32
Girard M. World Health Organization Vaccine Recommendations: Scientific Flaws, or Criminal
Misconduct. American Journal of Physicians and Surgeons 2005; 11:22-3
33
Just consider the current tragicomic fuss made by the manufacturer and its experts to justify the
administration of Gardasil (normally aimed at preventing cancer of the uterus) to men, under the
pretext of dirty sexual practices that any moral person should reprove… Even the inescapable
determinants of gender anatomy are not serious obstacles for the « experts » of drug makers !
22
5. Conclusion
As mentioned above, a positive consequence of the swine flu story could be a radical
reappraisal of the ferocious antagonism between vaccine promoters and
antivaccinationists. This time, by dint of ignoring the basics of drug development,
things have gone too far – and everybody may take notice. It is time now to go back,
to understand that vaccines are drugs amongst others, with their potential of
hazards and the inherent requirement of a cautious assessment regarding their
benefit/risk ratio. It is time now to stop considering that vaccines must be beneficial
and that they cannot be risky. It is time to require that the elementary principles of
drug development be not ignored as grossly as they are nowadays with vaccines. It
is time to recognize that the human body is not a bin for the dangerous gadgets that,
through lack of professionalism, Big Pharma develops instead of useful drugs.
In April 2007, on the site of the French Association des médecins de l’industrie
pharmaceutique, an association of professionals working for pharmaceutical firms,
one of the major vaccine makers posted a job advertisement in English (attached).
This was for the appointment of “clinical team leaders, global clinical development,
vaccines” – typically the kind of guys that may now be in charge of the development
of influenza vaccines. After emphasizing an “excellent salary, bonus and benefits
package (including 53 days annual leave)”, the ad turned to the candidate profile:
“An understanding of the clinical aspects of infectious diseases – virology,
immunology or microbiology would be very useful but is not essential. You need to
demonstrate the core interpersonal skills, including international outlook, excellent
presentation and communication skills, team leadership, impact and influence (…)”
(my italics). The ad was strictly silent on any requirement of past experience in drug
development…
This should be a serious concern for any health professional – and for any citizen –
that, in the vaccine sector, things have gone so far that manufacturers are not
ashamed of publicly advertising that, to develop new vaccines, even a simple
“comprehension” (not an expertise!) of infectious disease “is not essential” as
compared to smartness (“excellent presentation”), a personal gift for chatter
(“communication skills”) and good manners with people (“impact and influence”:
preferably with opinion leaders and experts of the governmental agencies?).
No wonder that on the basis of such amateurism, vaccine makers are just able to
develop defective products. But, as is perfectly illustrated by the current story of
swine flu, the problem is that they are actively encouraged by health authorities to
introduce and maintain their defective products, in blatant contradiction with the laws
in force34.
What is the explanation of this contradiction between the law on the one hand, and
regulatory practice on the other? In its Directive 65/65/EEC (26/01/65), the Council
of the European Economic Community did not hesitate to write:
34
For example in Europe, the Directive 85/374/EEC (25/07/1985)
23
Whereas the primary purpose of any rules concerning the production
and distribution of medicinal products must be to safeguard public
health;
Whereas, however, this objective must be attained by means which will
not hinder the development of the pharmaceutical industry or trade in
medicinal products within the Community
At least in Europe, this was probably the first time in the whole history of pharmacy
that a mercantile target was put exactly at the same level as the primacy of public
health: when laws are so hypocritically ambivalent in their inspiration, no wonder
their enforcement is schizophrenic in practice35…
By contrast, let us compare the Royal Charter granted by King James I of England to
the Society of Apothecaries, in 1614:
(…) very many Empiricks and unskilful and ignorant men do abide in
the City of London, which are not well instructed in the Art or Mystery
of Apothecaries, but do make and compound many unwholesome,
hurtful, dangerous and corrupt medicine and the same do sell (…) to
the great peril and daily hazards of the lives of the King’s subjects36
“Unskilful and ignorant” drug makers, “unwholesome, hurtful, dangerous and corrupt
medicines”, “great peril and daily hazard” for citizens: which of the royal concerns is
not sadly exemplified by the story of swine flu?
Conflicts of interests: Dr Girard works as a consultant for pharmaceutical firms,
including manufacturers likely to have an interest in the influenza pandemic and (at
least until recently…) a number of vaccine makers.
Acknowledgements: Many thanks to Tony James for his kind help in improving the
English manuscript.
35
I suppose that similar ambivalence may be found in American regulations.
36
Quoted in Dukes G, The Law and Ethics of the Pharmaceutical Industry, Amsterdam, Elsevier, 2006,
p. 87
In These New Times 
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