Examination of Witnesses (Questions 260
- 279)
THURSDAY 11 NOVEMBER 2004
DR IONA
HEATH, DR
TIM KENDALL,
MR MATT
GRIFFITHS, MR
JOHN D'ARCY,
MR ROB
DARRACOTT AND
DR RICHARD
NICHOLSON
Q260 Mr Jones: Another way of potentially
addressing this issue of the effectiveness of me-too drugs might
be, rather than specifying what sort of trial should be required,
that the Department of Health should agree prices for drugs, dependent
upon the evidence of its therapeutic value. Where a drug has not
been able to demonstrate its effective therapeutic value, as compared
to a well-known market leader, the Department of Health would
agree only to pay a much more modest price for this drug.
Dr Nicholson: Whether the drug
companies would be willing to sell at a much lower price is something
the Department of Health could explore.
Q261 Mr Jones: I ask the question,
because something similar apparently applies in Australia.
Dr Nicholson: I do not know the
Australian scene, but it is certainly something that would be
well worth exploring and if countries around the world could adopt
such a policy, then the emphasis on pharmaceutical companies trying
to produce me-too drugs rather than looking for really innovative
drugs would be much reduced. It is worth remembering that the
proportion of new drugs which have been licensed over the last
two or three years which really are a new principle rather than
just a me-too drug is well under 10%
Q262 Dr Naysmith: Moving to the question
of the protection of patients who are involved in clinical trials
and we actually just touched on it a moment ago, are you satisfied
that the ethics committee system is working well in terms of protecting
patients? I know you have had a look at the evidence that we got
from the Department of Health about ethical audit a couple of
weeks ago.
Dr Nicholson: I think the Department
of Health was extremely optimistic in the picture that it painted
in the evidence it sent to you. The ethics committees have had
two overriding needs for well over 20 years: firstly, support
for their administration; secondly, support for training of the
members. The need for support for administration is shown in that
even in the last three years I have come across committees where
there is a lay chairman and the only support that he has is 10
hours of a temp per month. That is absolutely no way to run a
serious committee. These committees are made up volunteers who
put in on average 150 hours of completely unpaid time and unsupported
time and they are not even sent a publication on a regular basis.
They do need some support. Likewise, if they are to work together
effectively and come to reasonably common decisions—there
is no reason why they should always come to the same conclusion
because very often protocols are so riddled with ethical problems
that one committee will pick up one set of ethical problems, another
committee will pick up a different set, so there is no absolute
reason why they should all come to the same decision—were
they to have much more training, then you probably would get better
uniformity.
Q263 Dr Naysmith: So you are suggesting
more training, more resources. Any other recommendations?
Dr Nicholson: The resources have
gone into the Central Office for Research Ethics Committees (COREC),
but they have not come out the other side. It has decided to build
itself an empire and COREC is now made up of nearly 40 staff.
In 1997 the Department of Health thought that 250 ethics committees
could be supervised by half the time of a higher executive officer.
Now, when there are only about 180 committees, we have an office
of about 40 staff. Interestingly, the American equivalent, the
Office for Human Research Protections in Washington, also has
about 40 staff, but it has oversight of 10,000 research ethics
committees and is a great deal more effective. So the real problem
is that there is a variety of ways in which the work of COREC
completely lacks coherence. For instance, at the moment, we have
the clinical trials regulations which were approved in April this
year, and came into force on 1 May, which have one approach to
getting consent to the involvement of an adult who lacks capacity
who is to be in a clinical trial in that sort of research. The
latest version of the Human Tissue Bill which has come out of
the House of Lords has another version of how consent is to be
obtained from adults who lack capacity, if their tissue is to
be involved in research. The mental capacity bill which is going
to be before parliament next session has a third set of regulations
proposed for how to obtain consent when you are dealing with an
adult who lacks capacity.
Q264 Dr Naysmith: We are struggling
with that at the moment.
Dr Nicholson: Already we are likely,
with the Human Tissue Bill—it is likely to go through, is
it not?—to have some proposals and what it has to say about
consent is contrary to what the clinical trials regulations say.
Many clinical trials involve human tissue nowadays because people
take blood samples to do DNA analysis at a later stage and so
that research comes under the Human Tissue Bill. We are having
real problems with coherence and the other problem with coherence
is that, unlike America where one has institutions trying to develop
a proper system throughout the institution for protecting the
subjects of research which involves the researchers having to
have training in research ethics, it involves those who assess
the science as well as those how assess the ethics working together,
we do not have that here. The R&D departments have to approve
research before it goes ahead and they are working totally differently
to the ethics committees and sometimes on totally different timescales.
Recently, a clinical trial was proposed in East Anglia to be done
at four centres. All four research ethics committees approved
it within a month, three out of the four R&D departments approved
it within the month, the fourth R&D department took five months
to approve it, by which time the trial had been up and running
in Poland for three months because this is a competitive field
and if you do not get on and do things quickly, the research will
go elsewhere.
Q265 Dr Naysmith: What you have just
said brings me on to the second major question I wanted to ask.
What evidence do you have that patients are well enough informed
before consenting to take part in drug trials? I am going to bring
in Dr Kendall in a moment as he has been sitting there very quietly
for the last half an hour not saying very much but I am sure this
is an area that you will have views on also.
Dr Nicholson: Essentially very
little evidence because the empirical studies on informed consent
show that, as with any form of education, patients are best informed
if you give them the information in a variety of different ways
on a variety of different occasions. The problem is that we are
stuck in a routine of giving an information sheet and having one
conversation with a researcher and that is really inadequate.
Q266 Dr Naysmith: Bearing in mind
that we are looking at the pharmaceutical industry and its effect
on the National Health Service.
Dr Nicholson: The pharmaceutical
industry is as bad as any because the patient information sheets
which they submit have on average a reading age of about 19 years,
when they should be aiming at a reading age of about 11 years.
They do not include on average about 20 of the items which the
various international regulations say should be in a patient information
sheet. Normally they are called Version 1 and they have been written
a few days before the application to the ethics committee. Absolutely
no effort has been put into providing information in a way that
patients are likely to understand. That means that every time
their research proposal is delayed for a month because the ethics
committee rejects it and says "Go away and rewrite this patient
information sheet" they have wasted a month. Yet this happens
on 90% of the information sheets sent to us.
Q267 Dr Naysmith: What about the
relationship with the pharmaceutical industry? Do they have influences
on patients and patient selection and that sort of thing?
Dr Nicholson: Not directly, because
of course it is going to be the researcher who should be approaching
the patient and we would regard it as highly unethical for there
to be any direct approach from the pharmaceutical company sponsoring
the trial to the patients. Normally it is the researcher who makes
the approaches. In some situations, if the researcher has written
one of these patient information sheets, one has to wonder what
language he would use when he talks to the patient and whether
he is capable of communicating.
Q268 Dr Naysmith: Dr Kendall, what
do you think about all this area of conducting clinical trials
and making sure that the patients understand what they are doing
it for and that kind of thing?
Dr Kendall: Unfortunately an awful
lot of the clinical trials done by drug companies are done probably
not to find out whether or not the drug is efficacious or safe
or whatever, although those are concerns. They are largely done
to support advertising campaigns so that the results which come
out of trials are very selectively used for that. There are also
problems with things like recruitment. For a lot of the trials
which drug companies recruit to, they recruit from populations
which are completely inappropriate. For example, in some of the
work on treatment of depressed children, some of the trials have
recruited depressed children by advert. They are not people who
in this country would have been treated with any anti-depressant,
but it is on the basis of those studies.
Q269 Dr Naysmith: We will be talking
about that a little later on, but at the moment we are just talking
about clinical trials. You are saying that the real reason for
some of the clinical trials being carried out is to back up advertising.
Dr Kendall: Yes, it does seem
to be and certainly that is reflected in the publication bias
I suppose. What appear in print are generally only things which
are favourable to the drug.
Q270 Mrs Calton: Dr Heath, can we
turn to post-marketing research? You say in your submission that
post-marketing research should be independent of the pharmaceutical
industry. Who do you think should conduct such research? Should
this independent body, if there is one, have legal rights of access
to all company data in order to compare post-market data with
pre-market results?
Dr Heath: I am absolutely certain
that any data should be publicly available for any product which
is going to be used by the National Health Service. Selective
publication is dreadful, because half the information is missing
and everybody at every level is making decisions on the basis
of half the data and therefore is being misled. The huge problem
of unravelling post-marketing research from marketing is something
which is crying out to be solved in some way; the fact that a
large number of campaigns which involve financial inducements
seem really designed just to get the product prescribed and somebody
into the habit of prescribing it rather than to do a serious evaluation.
It has to be some sort of arm's-length . . . On the problem of
who should fund it, it is not for us to say, but if it continues
to be funded by the pharmaceutical industry it has to be in some
way at arm's-length so that the actual regulation of the research
and the publication of the research is not in any way controlled
by the industry. I also think that patients need to be very much
more fully informed about what exactly they are involved in. Our
College definitely has debated this issue and made a statement
about full information being available to patients involved and
this thing about inducements offered to the prescribing doctor,
for example.
Q271 Mrs Calton: We have heard in
previous evidence that actually not that much post-marketing research
goes on, but most of the research is pre-marketing. The very little
which goes on is not in the hands of independent people. Do you
believe that it is possible for an independent body to be set
up which could look at post-marketing research?
Dr Heath: I am wondering whether
the same organisation that looks at the adverse drug reactions
in that first crucial interval with a new drug, when adverse drug
reaction surveillance is so much more important than in any other
stage in the life of the drug, could in some way be tied into
post-marketing research.
Q272 Mrs Calton: In some senses the
fact that people are being prescribed a drug is a whole new, big
trial, is it not?
Dr Heath: Exactly and there is
an opportunity there to put a research framework round it and
to get real prospective data which is lost at the moment.
Q273 Mrs Calton: Do you think it
could be linked to the yellow card system?
Dr Heath: I do and also systematically
getting feedback from patients who take new drugs, rather than
waiting for the patient to come to tell their doctor or their
pharmacist who then may or may not do a yellow card depending
on what sort of morning they have had.
Q274 Mrs Calton: How much do you
think it would cost to do that?
Mr Griffiths: I do not have the
first idea.
Q275 Mrs Calton: May I turn now to
Dr Nicholson? In our last evidence session, Dr Andrew Herxheimer
suggested that ethics committees might have a key role to play
in relation to disclosure of clinical trial results by insisting
that trials be registered at inception on an appropriate registry
before people are recruited to it. Do you see merit in this proposal?
Dr Nicholson: Certainly I see
merit in that proposal. However, as I explained earlier, we are
stymied by the Department of Health saying that clinical trials
are to be conducted according to out-of-date ethical guidelines,
so we do not have any way of enforcing such a requirement. Personally
I have been arguing that all research should be registered for
over 20 years now. I am absolutely in favour of giving ethics
committees the power to insist on registration of any trial they
approve.
Q276 Mrs Calton: And the parts of
the trial, so that all the different parts of the research are
all fully reported at a later date.
Dr Nicholson: Yes; not necessarily
published, because one cannot insist on journals taking material,
but they must be publicly available and put on the website. Indeed
the most recent version of the Declaration of Helsinki says that
the design of all the studies should be publicly available. I
see absolutely no reason why the protocols of these trials should
not be required to be put on the internet or made publicly available
in some way before you even start the trial. The drug companies
will shout and scream about commercial confidentiality, but if
their competitors have not already done their industrial espionage
at least five years earlier I would be amazed. Their competitors
will know very well what is going on by the time something gets
to clinical trials. The idea of commercial confidentiality is
meaningless in that situation.
Q277 Mrs Calton: Thank you; that
is helpful. You think the main way of doing this would be to insist
on publication on the website rather than depending on the journals
such as The Lancet requiring that sort of publication.
Dr Nicholson: Obviously you have
to leave the journals to choose what they are going to publish;
they are independent bodies in that sense. I do think that there
are ways in which one could ensure that the material is publicly
available via the internet. May I just make one point about the
post-marketing studies? It should be remembered that every study
of the yellow card system has shown that something between one
fifth and one quarter of adverse events are actually reported,
that one does need to have some active surveillance to pick up
the true level of side effects and adverse events. So, if one
were doing post-marketing, one would have to insist that there
was some sort of active system, rather than relying on some further
use just of yellow cards.
Q278 Mrs Calton: Dr Heath mentioned
earlier that there should be much more patient reporting. Do you
think that would make up the gap between what we are seeing at
the moment with the yellow card system and what there could be?
Dr Heath: It is hard to predict
the future, but it would be well worth a pilot to see the quality
of the information which was coming back and how it compared with
the yellow card system. I should be surprised if it was not more
useful.
Q279 Mrs Calton: You, Dr Nicholson,
are thinking more in terms of a compulsory system rather than
the voluntary system.
Dr Nicholson: We have had a lot
of examples of drugs being thought to be the latest wonder drug
and then turning out to have some fairly nasty side effects a
year or two down the road which end up with the drug being withdrawn.
We do need some sort of active surveillance system in order to
pick up those instances earlier. However, it may well be that
in most of those cases, had we had access to the results of all
the clinical trials which have been carried out and had there
not been in some a disclosure failure by the pharmaceutical industry,
we might have got to the point of not licensing those drugs to
begin with.
Mr Griffiths: I believe yellow
card reporting is actually open to the general public now. It
was made available about a year ago, at the same time as they
opened it up to the nursing profession, to members of the general
public to yellow card report via NHS Direct. I do think it does
need publicising.
Mrs Calton: Are you aware whether that
has made a difference?
Chairman: That is news to us.
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