Memorandum by Mr David Thrower - continued
Improving Post-Licensing Clinical Studies
274. There would seem to be an overwhelming
need for improved post-licensing studies to detect relatively
adverse events, particularly as pre-licensing testing appears
to involve relatively small numbers of children (MMR was quoted
as being 10,000 children), and trials seem to have been excessively
short in terms of the post-vaccination period studied (MMR was
quoted as three weeks beyond vaccination).
275. Parents' concern at the need to improve
post-licensing surveillance has also been expressed in the US:
"Several speakers suggested conducting more
focused, powerful, larger and better designed post-licensing clinical
studies to detect serious rare adverse events of vaccines, that
are not possible to detect in a clinical trial" (source:
1997 Institute of Medicine Vaccine Safety Forum proceedings, page
and, from the same source:
"A consumer representative suggested that
there be more government funding for studies designed to detect
long-term adverse effects of vaccines or to identify individuals
at high risk for adverse effects" (page 16).
276. It is interesting to note that US monitoring
officials themselves take the view that a database of adverse
reactions is too small to identify rare events, and that larger
databases are necessary:
"A CDC representative suggested that the
large linked databases are best suited to identifying those at
risk of adverse events following vaccination, once the association
has been established. This individual believed that VAERS does
not have the data necessary for a complete epidemiological study
to assess risk factors." (source: 1997 Vaccine Safety Forum,
277. It is suggested that UK parents investigating
their child's degeneration into autism, or other serious possible
consequences of vaccination, would strongly desire such improved
surveillance in the UK. There would be a cost involved, but there
is already a huge financial cost associated with dealing with
the present problem of autism, including care, education, respite
and lost productivity, not to mention quality of life.
278. It is further suggested that studies
be designed by the MCA in consultation with a wider professional
community, including population statisticians, social service
and education experts, and parents' groups and their representatives.
279. It is further suggested that testing
of vaccines takes specific account of the risks for children that
could be expected, on the basis of available research, to experience
adverse events and outcomes. At present, such children may make
up such a small proportion of the total number of children in
a pre-licensing test that they are in effect excluded in terms
of their influence on the outcome. This concern has been raised
in the US:
" . . . . Although children with genetic
disorders or other chronic conditions represent between 5 and
15 per cent of all children (Warkany, 1971), the effects of vaccination
on these children are not known because they were either excluded
from, or not present in, large enough numbers in the studies that
initially tested the effects of vaccines. (It was) suggested that
researchers assess the risk of adverse events associated with
vaccination in populations with specific genetic makeups"
"Identifying families with several members
who experience similar adverse events (or other associated health/hypersensitivity
problems?) after vaccination . . . could provide a highly enriched
sample of families suitable for studies of genetic factors associated
with adverse events of vaccines" (source: 1997 Vaccine Safety
Forum proceedings, page 33).
280. In the long term, the objective should
be to be able to more closely identify risk factors, including
issues such as:
susceptibilty factors in particular
risks associated with age;
the issue of whether vaccines in
combination are themselves a cause of increased risk.
Requirements for Manufacturers
281. The MCA has stated that there are statutory
requirements on manufacturers:
to provide information on their products
to the MCA;
to report all serious adverse drug
reactions to their products within 15 days of receipt;
to provide comprehensive safety updates
covering all sources of data on safety at six-monthly intervals,
for various intervals following authorisation; and
to provide any information immediately,
if this impacts upon the risks and benefits of their products.
282. However, it is not clear, despite these
provisions, how compliance is checked and independently validated.
This is a source of concern to parents. It also seems extremely
unlikely that parents would report concerns to vaccine manufacturers.
283. The above makes a curious contrast
with the MCA's views on the statutory reporting of adverse events
as practised in France and in Sweden, where it is mandatory for
physicians, unlike the UK yellow card system. In its letter of
21 August 1998, the MCA referred to:
" . . . the difficulty of enforcement as
there is no easy and systematic mechanism for identifying the
reactions that doctors should have reported . . . In contrast,
the statutory obligations placed on companies is based on a requirement
for them to report adverse reactions".
284. It is unclear to parents as to why
the MCA sees enforcement for a GP (an NHS employee) to report
an adverse reaction as a problem, yet sees enforcement for free-standing
manufacturers to report adverse reactions as not being a problem!
285. Also, it was stated by the Department
"When a new component is added to established
vaccines, manufacturers have to demonstrate that . . . there are
no new acute adverse reactions, and that any recognised adverse
reactions are not increased in frequency or severity" (source:
letter from Immunisation and Communicable Disease Branch, 19 March
286. However, the Department does not explain
how this reporting mechanism is being independently verified,
nor what would occur (or not occur) if the adverse reactions were
unrecognised, rather than recognised. The latter could include
gradual degeneration into autism over a period of weeks/months
287. The MCA could also enable parents to
make greater sense of adverse event statistics if these could
be related to a standard batch size. At present, vaccine manufacturers
do not have to conform to any particular standard batch size.
Sizes of batches have been quoted as "5,000", "constantly
variable", and "140,000".
288. These variations help to obscure an
assessment by parents of risks, and as such, are an advantage
to the manufacturers. There seems no reason why this advantage
should continue to lie with the manufacturers, rather than the
patients. It is therefore urged that vaccine batch sizes are standardised,
say at 5,000 shots. There would seem no technical impediment to
this, though no doubt there will be industry resistance to it.
However, as it is the State that places the orders and makes the
rules, the issue should be resolved by making it a condition,
of tendering to supply vaccines to the NHS, that batch sizes are
MCA Position as at March 1999
289. A letter of 29 March 1999 confirmed
that, on the autism/MMR issue:
"the matter is still under review";
"the MCA has sponsored a cohort
study to determine the prevalence of autism before and after MMR
vaccine availability". (Note: as my son initially degenerated
following pre-MMR monovalent measles vaccination, the outcome
of this study may need to be treated with circumspection);
"the MCA has formed a working
group of independent experts (the Agency does not explain how
use of this term is precisely justified) which is conducting a
detailed evaluation of reported cases of autism and closely related
disorders and inflammatory bowel disease. This work is ongoing
and information resulting from this will be made availabe in due
course." (This was in response to a query as to the outcome
over about 530 yellow card questionnaires that were filled out
by parents with cases with Hodge Jones Allen, solicitors, and
forwarded by the solicitors to the MCA to assist their investigations).
290. Given the crucial role of the MCA and
its reporting mechanism, and the obvious close relationship it
has with the Department of Health, whose own independence in the
autism/vaccination issue has already been questioned, it would
seem highly advisable that the MCA's statistical techniques and
surveillance should be subject to audit through a wholly independent
(of the Department and Agency) advisory group of academic personnel
with a professional background in analysing population statistics
and investigating patterns of reporting, including anecdotal reports.
291. Key conclusions: the MCA relies on
surveillance systems which it has expressed satisfaction with,
but which it has acknowledged there may be shortcomings in relation
to the reporting of serious but relatively rare adverse events.
Under-reporting is an acknowledged problem, but some of the measures
being put forward to overcome under-reporting do not seem to address
the autism/MMR under-reporting concerns. The MCA is now actively
investigating the cases of some 530 of the children that are now
with solicitors, and further developments are awaited. The Agency
is committed to making the outcome of the review of cases public
in due course, but any prolonged delay in this will be unacceptable
to parents of the children affected. The MCA could also play a
pivotal role in sorting out other problems, for example the constant
variations in batch sizes.
292. Issues For Discussion:
is the experiencing of severe delays
in response a general one for parents?
to what extent is the MCA not confronting
the inadequacy of its surveillance?
how can the statutory obligations
upon pharmaceutical manufacturers to report problems be independently
how do the various mechanisms for
identifying adverse reactions to vaccines relate to slow degeneration
into autism, a condition which may take weeks/months to take effect,
may take a further time to be fully identified, and which may
take months/years to be properly diagnosed?
how can additional statistical expertise
be added to the MCA's primarily medically-based advice sources?
should the statistically methodology
of the MCA's reporting systems be subject to independent validation
and regular audit?
should degeneration into autism be
made a recognised ADR in case it is connected with vaccination?
what other mechanisms should be introduced
to link the MCA database with autism detection?
should the yellow card system be
given statutory force?
should the "polarity" of
the yellow card system be reversed, in other words to positively
require each case to be signed-off by the GP concerned three months
afterwards as having had no adverse consequences?
what recent improvements has the
MCA made to yellow card that could be expected to pick up the
autism degeneration issue?
should the MCA be encouraged to actively
seek out every single case of potential degeneration, to enlarge
should the MCA develop LLDBs (large
databases) to improve all health surveillance?
293. Suggested Recommendations for Action:
the response times of the MCA to
parents require monitoring, and the results regularly publishing,
as per Department of Health responses;
the statutory obligations upon manufacturers
need independent audit, preferably by an independent Health Regulator;
the effectiveness of the MCA's surveillance
methods also require audit, and it is essential that this is a
wholly independent regulatory function. The MCA must not be judge
of its own effectiveness. This should be part of a new independent
greater independent statistical expertise
needs to be brought to bear as part of the above;
when there is a pattern of parents'
reports alleging an adverse reaction, such as degeneration into
autism, the alleged syndrome needs to be added to the MCA's recognised
ADRs at the earliest opportunity, and advice circulated according,
so that parental allegations can be actively investigated in the
context of a more meaningful statistical base;
the databases that are linked into
the MCA yellow card database need widening. With computerisation,
there seems no reason not to have an all-child database that the
MCA can regularly review for suspected ADRs;
the yellow card reporting system
needs to be reversed, and replaced by a "green card"
system where every child is positively cleared six months after
vaccination, replacing the present "no news is good news"
system. An early-ADR system would need to be retained for chronic
urgent reactions; and
degeneration into autism and other
conditions needs to be built into any future reporting mechanism.
294. The Department of Health repeatedly
seeks to attempt to reassure parents of children that have suffered
an adverse consequence of vaccination that there are several bodies,
such as the Joint Committee on Vaccination and Immunisation, and
the Committee on Safety of Medicines, which, if there was any
problem, would have identified it and acted upon it.
295. However, to parents, the Joint Committee
on Vaccination and Immunisation in particular is a body that is
secretive and lacks proper accountability. Its decisions lack
transparency. The "accountability chain" between its
members and the patient is extremely long, and potentially seriously
296. No effort seems to be made by the Department
of Health to verifiably demonstrate to the public that committees
such as the JCVI really are independent.
To demonstrate this properly requires transparency.
Generalised Departmental assurances are wholly insufficient.
297. It is understood that membership of
the Joint Committee on Vaccination and Immunisation, and the Committee
on Safety of Medicines, is subject to strict rules of secrecy.
The proceedings and decisions of both bodies are confidential,
and cannot be scrutinised by parents or agents acting on their
298. It is also understood that, in the
event of any breach of confidentiality, an individual member of
either Committee can be sued by pharmaceutical manufacturers or
subject to other sanctions, and that there is no defence of public
interest immunity to defend any individual member against litigation
299. This appears to place excessively great
reliance on the infallibility and quality of decisions of these
bodies. It also appears to give greater weight to the professional
interests of the private sector and of the Department of Health
and its agencies, compared with the interests of protecting vulnerable
subsets of children. Also, the permitting of the destruction of
vaccine records after just six years, far less than the timeframe
of the Consumer Protection Act and the 21-year rule for child
health records, is testimony to the lightness of regulation operated
by these bodies.
300. There is also concern at how independent
these two "independent" bodies are, given their critical
role in relation to influencing Government and the public as to
vaccine safety and possible links between vaccination and autism.
For a key public body to be independent, it is suggested that:
it should not be the case that individual
members of these bodies, or any other relevant bodies, should
have a direct financial interest in the manufacturers of products
that are under the srutiny of these organisations, for example
through personal or close-family shareholdings;
there should not be frequent and
direct transfer of employment of individuals between "the
regulators" and "the regulated", particularly in
the case of individuals moving from regulatory functions into
private-sector organisations within the regulated sector. (This
exchange of employment is sometimes referred to as "the revolving
door", and could compromise the degree to which an individual
acted against the financial interests of a private-sector provider,
or in favour of greater openness or transparency to the benefit
decisions, and minutes of meetings
(barring the most limited-possible definition of commercially
confidential material) should be published;
registers of members' interests,
including shareholdings and other obvious potential conflicts
of interest, should be published on the Internet.
301. It is not clear that these principles
are being upheld in practice, and press reports in April 1999
actually indicated that in the case of the first-mentioned, the
exact reverse was the case (Insight Sunday Times, 4 April
1999). Parents investigating adverse outcomes to medical treatment
should be able to expect a watertight partition between "the
regulators" and "the regulated", and believe that
this is not occurring at present. The Sunday Times confirmed that:
a senior pharmacist on the CSM held
shareholdings in Glaxo, SmithKline Beecham and other companies;
the Chairman of the Standing Medical
Advisory Committee (SMAC) held £130,000 shares in Glaxo and
another member of SMAC had neglected
to declare £15,000 of shares in drug companies.
302. Issues for Discussion:
how can the accountability of the
JCVI and CSM be very significantly improved?
how can this accountability be made
to work in a practical way for individual members of the public?
Should all minutes and decisions be published, subject to exemption
for the most limited number of specific issues?
should public interest immunity be
provided for JCVI and CSM members and their staffs?
how can the present overriding concern
of the JCVI/CSM for public confidence in vaccines be more properly
balanced against the legitimate concerns of individual members
of the public that their child may have been damaged?
should all members of the JCVI/CSM
and their support staffs, and employees of the MCA and relevant
parts of the Department of Health, be debarred from holding shares
in pharmaceuticals manufacturers?
should members of the JCVI and CSM
be debarred from future membership if they return to the pharmaceuticals
industry in the meantime?
how should issues such as offers
from manufactuers for research funding be managed in order to
avoid potentially compromising the actions of regulatory/Government
personnel and committees?
303. Suggested Recommendations for Action:
the decisions and minutes of the
JCVI and the CSM should be open to public scutiny, subject to
limited commercial-consideration protection only insofar as absolutely
necessary. The minutes and decisions should be published on the
Internet, and available upon request from members of the public;
public interest immunity should be
provided for members of the JCVI and CSM. Both bodies should include
observer members from a new Office of the Health Regulator;
members of the public with legitimate
concerns regarding their children should be taken proper account
of by the JCVI and the CSM. The law regarding the activities of
these organisations and their need to properly balance the rights
of individual children against the health needs of the community
should be clarified and enforced through independent regulation;
such regulation should not permit
"wider health interests of the community" to be used
as an unquantified blanket argument for disregarding cases of
suspected damage. The benefits of community immunisation and the
risks of identifiable individual damage should be properly weighed-up,
and independently validated;
all JCVI, CSM, Department of Health
and other appropriate personnel and appointees should be debarred
from themselves or their families holding shares in, or receipt
of other benefits from, pharmaceutical manufacturers;
a formal Code should be drawn up
to discourage the "revolving door" whereby personnel
freely and regularly move between "the regulators" and
"the regulated", and this should become a condition
of employment within the JCVI, CSM, etc; and
a review should be undertaken of
other financial support, and support in kind, from the pharmaceutical
manufacturers to central government and the NHS, including academic
research at hospitals and universities, to ensure that regulating
functions are not compromised by financial-support considerations.
304. The Medical Research Council is an
independent body which receives its grant aid from the Office
of Science and Technology, which is part of the Department of
Trade and Industry.
305. The Medical Research Council has been
extremely helpful in answering inquiries from myself as a parent
investigating their child's adverse outcome to medical treatment.
It is understood to have formed a sub-group on research into inflammatory
bowel disorders and autism.