Examination of Witnesses (Questions 840
- 859)
THURSDAY 20 JANUARY 2005
PROFESSOR SIR
ALASDAIR BRECKENRIDGE
CBE, PROFESSOR KENT
WOODS AND
DR JUNE
RAINE
Q840 Chairman: Professor Woods, can
I just clarify your answer on "me-toos" because you
appear to be questioning the entire concept of "me-toos"
that has been raised with us on numerous occasions during this
inquiry. Do you accept that there are "me-toos" or are
you saying that there are subtleties between different products
that perhaps we ought to be aware of and that "me-toos"
do not exist and there are distinctions that are important?
Professor Woods: Yes. From practical
experience as a clinical pharmacologist, there are no two drugs
in a class which are identical in terms of their duration of action,
in terms of their handling in the body and how they are eliminated.
For instance, you might have a patient with impaired renal function.
You would select a drug within the class that was not really excreted,
you would choose one that was metabolised. Therefore, if you know
the drugs and you know their individual characteristics, you can
select in a way which maximises efficacy and minimises toxicity.
So, I think the concept of a "me-too" is a rather blanket
description which does conceal some more fundamental facts.
Q841 Chairman: Are you saying that
there are not any "me-toos"?
Professor Woods: There are groups
of drugs which contain an awful lot of agents which have rather
similar actions.
Q842 Chairman: But "me-too"
is not a concept that you would use? I just want to be clear what
your views are.
Professor Woods: One uses it as
a kind of shorthand, but I think we probably have enough beta-blockers;
last time I counted I think there were about 15 and I think that
is enough. The point is that if one took the opposite approach
and said that, in each therapeutic class, there will be one or
two agents, we would actually lose.
Q843 John Austin: I accept your point
that the "me-too" might be efficacious with a particular
patient, but in terms of the overall therapeutic benefit compared
with the cost of the research and all that goes into it, it surely
cannot be the best way to go, can it?
Professor Woods: It comes back
to what I said earlier about the distinction between efficacy,
safety and so forth and utility. The NHS now hasand you
will be hearing later evidence this morning about the work of
the National Institute for Clinical Excellencea mechanism
for providing guidance to practitioners as to which within a class
are the most useful drugs and I think there is a difference there,
a very important difference, between therapeutic utility, which
can actually change over time, and the criteria of safety, efficacy
and quality which allow a drug into the marketplace, and I think
it comes to this question of the intelligent consumer and, by
"the consumer", it might be the NHS as the purchaser,
it might be the prescriber or it might be the patient who is actually
taking the drug. I think that one needs to give those end users
the information to allow them to make judgments about the actual
place of a drug in the treatment of individual patients. It seems
a little extravagant, it seems a waste of scarce R&D resources
to develop a drug which is rather like a drug which is already
there but, on the other hand, it is not something that one should
legislate against because commercially it is not the most attractive
option either.
Q844 John Austin: We have had a great
deal of evidence or argument before us about the importance of
accelerating patients' access to the drugs. I think one of the
witnesses last week said that we were just behind Croatia in terms
of new drugs, but we have also had discussionand we have
had some discussion this morningabout the slowness of the
regulators in responding to safety problems with some drugs on
the markets. One could draw from that a conclusion that, when
it comes to early licensing of medicines, the regulators are willing
to live with a very large amount of uncertainty but, when it comes
to restricting or withdrawing drugs which are on the market, the
regulators are demanding compelling evidence of injury and harm
before taking any decisive action. Would it be fair to say that
you give the benefit of the scientific doubt to the drug manufacturer,
both at the pre-market review stage and the post-market decision
making?
Professor Sir Alasdair Breckenridge:
No, that is not true. The question of early marketing of medicines
is an important one in that one does not want to withhold effective
medicines from getting to patients. On the other hand, one is
very aware that, as we have said already, the amount of safety
evidence which is available for a new medicine once it is licensed,
even under a normal route, is limited. It is going to be even
less if there is going to be early licensing of a drug and what
does happen under the situation is that the company who does ask
for early licensing of the drug is given very strict tasks which
it must fulfil by a certain timeand this is reviewed within
fixed time limitsor the licence will be withdrawn. There
are risks attached to it. It comes back to my theme again of risk
and benefit. If there is overwhelming benefit of the drug, for
example in the treatment of AIDS or a new drug for cancer which
one may be prepared to take, but if it were yet, coming back to
our previous discussion with "me-too" drugs, another
beta-blocker or something like that, it is not an area that one
would want to follow.
Q845 John Austin: What would the
policy of the MHRA be if there was scientific doubt about the
safety of a drug which appeared to offer no significant therapeutic
advantages over other therapies? Would it be left on the market?
Professor Sir Alasdair Breckenridge:
It would depend on what the indication was. As I say, if this
were a drug which had the promise of curing cancer or curing HIV
disease, then the risk to benefit decision would be different
from if it were a drug which was going to treat nasal blockage.
That is the answer.
Q846 John Austin: Dr Taylor may want
to come on to the recording of adverse incidents and whether it
is an effective system at the moment but, in evidence to us earlier,
the Medicines Commission made the point about the amount of research
being carried out into adverse effects of medicines and I think
they said in their evidence that funding for research into adverse
drug reactions was an extremely important aspect of drug therapy
but that it has been impossible to find in the current research
climate the resources and the funding to do that and they went
on to say that the pharmaceutical companies themselves provide
little funding for such research because they do not perceive
it as being in their interests to do so.
Professor Sir Alasdair Breckenridge:
Can I address that by telling you a little about how the Agency
is funded now. The Agency is funded essentially, since 1988, by
the industry, by licensing fees and that was recommended, and
that had the result of accelerating the new drugs which were coming
through, the backlog fell quite dramatically. The second thing
relevant to your question, Mr Austin, is that, in 1991, the decision
was reached that a fee would be charged for every medicine which
had a product licence which was on the market and that annual
fee brings in now 40% of the income of the medicine sector. That
is used for pharmacovigilance studies, for safety studies and
for enforcement studies. So, we are in the position within the
Agency of having a sizeable budget, 40% of our income, which is
used for pharmacovigilance studies and for enforcement. Many other
agencies do not have this.
Q847 John Austin: Is it usual for
you, as regulator, to request companies to carry out further studies
of adverse effects?
Professor Sir Alasdair Breckenridge:
Yes that does happen and the other thing is that we do commission
studies as well. For example, the Agency commissioned a study
in fact from Liverpool, from where I originate, on the whole effect
of adverse reactions on the morbidity and mortality of patients
and this was published in the British Medical Journal last
year, that 6% of patients admitted to hospital suffered from adverse
effects/was due to adverse effects. This had a financial effect
of about £400 million a year. This was the first study which
had been done in the United Kingdom for 15 years to look at the
financial significance of adverse effects and the Agency does
fund studies like that as well.
Q848 Dr Taylor: Can we move on to
drug safety monitoring in more detail and the yellow card system.
You have already mentioned the yellow card system saying that
you are going to put things on to the web. We have also heard
that the yellow card system is going to be widened to allow patients
to fill in yellow cards.
Professor Sir Alasdair Breckenridge:
Yes.
Q849 Dr Taylor: Are you going to
have a method of selection before things go on the web? How are
you going to play this? Do you have any idea of how to make it
more effective, more all-embracing than it is at the moment?
Professor Sir Alasdair Breckenridge:
Dr Raine is in charge of this and she could answer but I would
be very happy to start off. In fact, as of yesterday or two days
ago, the adverse reactions/yellow card reports for every licensed
medicine are available on the web. If you go to the website, yellowcard.gov.uk,
you can call up the adverse reaction profile, all the anonymised
yellow cards for every adverse reaction to every drug which is
licensed in the United Kingdom.
Q850 Dr Taylor: So, you are putting
on any card you get from Mrs Bloggs down the road without vetting
it sort of thing?
Dr Raine: It will be an anonymised
form clearly and the data is aggregated. It is to help patients
who may be about to start a medicine or doctors who are making
prescribing decisions to understand what we have in the way of
data and it is very easy to access. It is there now.
Q851 Dr Taylor: So, whatever it is,
however unlikely it might be, it would go on?
Dr Raine: Yes, but there is very
clear guidance about how the data can be interpreted and how far
it can be interpreted. Clearly, it cannot give any idea of the
incidence of an adverse reaction and, as with many websites, you
have to read all this and say that you have and you understand,
if you like, the health warnings before you go further and look
at the data. We are learning as we go and we have a patient reporting
expert group which is chaired and largely constituted from patients
and those with an expertise in consumer interests and they are
helping us move forward with what are essentially some very important
first steps to truly engage and inform in the way that patients
want.
Q852 Dr Taylor: How can you get the
medical profession to fill in more yellow cards?
Professor Sir Alasdair Breckenridge:
Thank you for asking that question! I hoped you would ask that
question because this has come up several times. Dr Taylor, we
are very clear in the instructions which we give that we want
reports of drugs which have a black triangle and serious adverse
reactions. That is what we want. We are very keen to encourage
yellow card reporting but what we do not want is a lot more reports
of rashes on penicillin and bleeding on warfarin. The yellow card
system is not there to give an incidence of adverse reactions.
It cannot do that. It is there to giveand this is a terribly
important question that you have askeda signal where we
can take that signal and explore it in other ways. So, while we
do want more adverse reaction reports and yellow cards, the main
thing is that we want better ones and the interesting thing, coming
back to what June was saying, is that, when we have patient reporting,
what kind of profile of adverse reactions will this give us? How
will this add to our information on the safety of medicines? That
is a very interesting thing which we are going to explore with
the new way in which we are doing things.
Q853 Dr Taylor: Can you just explain
the black triangle in case people do not know.
Professor Sir Alasdair Breckenridge:
Every new drug and every drug which has, for example, a change
in indication has a black triangle put opposite its name in the
British National Formulary, in advertising and in our publication
Current Problems; every month or two we indicate to people
who read that what a black triangle means. Perhaps we have not
been as successful as we might in informing the health professions
about this. This is what a black triangle means, it means report
any adverse reaction which does occur with this drug.
Dr Taylor: Are there any incentives for
doctors who fill in more of these?
Chairman: What do you have in mind?
Q854 Dr Taylor: I have to remember
that I probably did not fill in more than a fraction of the number
of yellow cards that I should have done and it is so important
that I am just trying to explore . . .
Professor Sir Alasdair Breckenridge:
There is an apocryphal story that one of our fellow countries
which is slightly to the west of us decided several years ago
that they would give incentives to doctors to fill in yellow cards
and the apocryphal story is that the number of yellow card reports
went up a hundred fold by doing that but the therapeutic value
of it did not rise commensurately.
Q855 Dr Taylor: What other major
sources of information on adverse reactions are there?
Dr Raine: A broad range. We look
at the published literature and we have studies that are commissioned
post-authorisation and a very, very broad range. Internally, we
have the General Practice Research Database (GPRD) which has information
on 35 million years of patient data in primary care and we are
trying to develop tools to use the data there to help detect signals.
So, it is a very broad range. Probably about 40% of our new signals
come from the yellow card scheme and others come from the published
literature and so forth.
Q856 Dr Taylor: We get very worried
when prescription drugs that have been licensed and released are
withdrawn relatively soon after they have been marketed. How could
we better prevent that? When we put that to the drug firms, they
feel that the only way you are going to pick up side effects relatively
quickly is if drugs are marketed on a big bang sort of approach.
I would like to have thought that drugs that offer a very real
advantageand I do not just mean one of the minor developments
that have been called "me-toos"should be released
more on a limited basis, perhaps consultant-only prescribing which
inevitably goes for the things with high risk like the anti-TNFs
and the anti-cancer drugs. If the COX-2s had been liberated on
a more limited fashion because they did potentially have a real
advantage, would that have just delayed the declaration of all
these side effects or would it have been beneficial in the long
run?
Professor Sir Alasdair Breckenridge:
That is a debate which is very active at the present time. As
you are aware, when the COX-2 inhibitors were launched in the
late 1990s, because of a knowledge of the pharmacology, it was
predicted that these drugs would firstly have a beneficial effect
on gastrointestinal bleeding, but secondly they would not prevent
cardiovascular disease as the old non-steroidals did. My understanding
isand I have probably read the same literature as you havethat
the company that marketed the first of these did in fact set up
studies at that time, at that very time, to explore the possibility
that there might be adverse cardiovascular effects and it is these
studies now which are coming through, which have shown that there
was this increased incidence of cardiovascular disease. So, I
think there are some adverse effects which are immediately apparent,
there are some other adverse effects which take a long time to
become apparent and of course, coming back to our discussions
about yellow cards with respect to problems like cardiovascular
disease, the yellow card is a very poor system of picking up adverse
reactions which mimic a disease which is common in the population.
So, as June was saying, you have to rely on either patient databases
or clinical trials like I am describing to you with respect to
the COX-2s.
Dr Raine: I do think that our
new legislation which is coming through in October which gives
us the powers to demand risk management plans at the time of authorisation,
so studies will begin in a very proactive way to test these questions,
will actually prevent the shock of a medicine being withdrawn
in quite the way that happened with so many people exposed to
risk. It will never prevent a medicine ever being withdrawn again,
but it gives us a much better tool to be on top of the safety
as it unfolds.
Dr Taylor: That is encouraging.
Q857 Chairman: Before we move on
from adverse reactions, obviously you have talked about our system
and you will be aware of different approaches in different parts
of the world and we have looked at one or two. Do you have any
thoughts of other systems that might have any merits to recommend
them to this country or do you feel that, with the qualification
you have just mentioned and the changes you have described, we
are broadly in the right direction?
Dr Raine: I think we are moving
in the right direction and I think that the world is moving in
that direction too. We have to use better sources, more robust
sources of evidence that are at our disposal. I think we actually
do have to make a very active attempt to include the patient perspective.
There are areas of our so-called "Excellence" strategy
such as decision analysis that need careful testing as to whether
they are applicable. They are applicable in other fields but are
they applicable here? I am not aware of another regulatory system
that is really delivering a better and more prompt identification
and action on risk than we are at the moment. We must keep returning
to transparency. Once the evidence for risk decisions is made
public as a matter of course, then I think the whole discipline
will move forward worldwide.
Q858 Mr Bradley: You mentioned the
clinical trials register earlier and you said that you were in
discussions about it. What form do you think such a register should
take?
Professor Sir Alasdair Breckenridge:
There are several proposals around just now. Let me start from
where we are just now. With respect to the European Clinical Trials
Directive, every trial which is started within Europe must be
registered with the Agency in the country where the trial is being
done and this will be collected on a European-wide basis and that
information will be available to regulators. Broadening it from
there, if the studies are being done in different environments
to that, I think it very much depends on the willingness of the
companies, because they are the people who do most of the studies,
to conform to a single system and the companies are having these
debates just now. Whether or not that will be sufficient or against
some other discussions which are taking place just now that this
should be made compulsory is, I think, an interesting decision.
Q859 Mr Bradley: Do you have a view
on that yourself?
Professor Sir Alasdair Breckenridge:
I would hope that, in the current climate, a voluntary system
will be able to work combined with the European
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