Examination of Witnesses (Questions 800
- 819)
THURSDAY 20 JANUARY 2005
PROFESSOR SIR
ALASDAIR BRECKENRIDGE
CBE, PROFESSOR KENT
WOODS AND
DR JUNE
RAINE
Q800 Chairman: So you are saying
that there was a clear qualification?
Professor Sir Alasdair Breckenridge:
There was additional, clear information for the patients and this
was
Q801 Chairman: And you say that was
clear qualification?
Professor Sir Alasdair Breckenridge:
Well, it is a matter of semantics whether that is clear qualification.
I would say with what we are talking about, withdrawal, it is
adding to information which was there already and with respect
to dose, whether that is qualification or adding to the information
which was there already is a matter of debate.
Q802 John Austin: But up until 2003,
both the MHRA and the manufacturers were saying that the incidence
of withdrawal reactions was rare and that has now been revised,
so 10 years after, when all this surveillance has been going on,
that estimate has been raised to 25 to 30%.
Professor Sir Alasdair Breckenridge:
When a drug is licensed and for the first few years until there
is good clinical trial evidence, one cannot say what the incidence
of an adverse reaction is. You cannot tell that from yellow card
reports. Yellow card reports give signals. You have got to rely
either on clinical trials or patient databases. As that evidence
became available, we were able to put a figure on the incidence
of withdrawal which we had never been able to do before. Dr Raine
was involved with this and perhaps she might like to take over
on that, but that is the precise situation about monitoring the
safety of medicines.
Q803 John Austin: With something
like a hundredfold increase in the estimate?
Professor Sir Alasdair Breckenridge:
Well, I do not know whether ever anyone said what the first instance
was. I was not aware that there was.
Q804 John Austin: You said it was
rare.
Professor Sir Alasdair Breckenridge:
Well, you said it was rare.
Q805 John Austin: No, the MHRA said
it was rare and so did GSK when they were before us.
Dr Raine: Clearly quantification
of the incidence was very difficult based on spontaneous reporting
and it was only with gradual better understanding, and I would
say that the patient reports that we had when we set up the expert
group were very valuable in this regard, plus additional data
that we sought that we were able to put a much more real-life
quantification on it. If I may turn to one other point which you
mentioned, Chairman, which was advising on the efficacy of these
medicines. The important step that we took was to ensure that
the advice on risk was accompanied by clear guidance from NICE
at the exact time on the place of these medicines in clinical
use. That in a sense was going beyond the responsibility of the
regulator but clearly the vital part of the jigsaw for those who
are seeking to treat patients with this serious condition.
Q806 John Austin: Could I just go
back to the question of when there was an awareness of the implications
of withdrawal symptoms. I understand that in its original submission
for marketing authorisation, which was submitted in 1990, SmithKline
Beecham did provide an analysis of their clinical trial data which
showed that the experience of adverse effects of withdrawal were
much higher with the drug than the placebo, so in 1990 the company,
when it applied for market authorisation, was aware of the severe
problems of withdrawal and yet the MCA was then still saying that
it was rare.
Professor Sir Alasdair Breckenridge:
Well, I repeat again what we said then, and this was what was
put into the data sheet from the information, and I have read
it out to you already, and the word "rare" does not
occur in that. It said that it can happen. It said, "As with
many psychoactive drugs, it may be advisable to discontinue therapy
gradually as abrupt discontinuation may lead to symptoms",
and it spells out the symptoms very, very clearly. There is no
evidence and the word "rare" does not come into that.
Q807 John Austin: Well, we will leave
that on one side. The company very clearly was continuing to argue
that the incidence was rare when their clinical trial data suggested
that it was not and that information was also in the hands of
the MCA. Now, given your acceptance that there is an issue around
withdrawal and symptoms
Professor Sir Alasdair Breckenridge:
There always has been.
Q808 John Austin:why then,
as the regulator, were you not requiring the expert working group
actually to look for withdrawal problems in their examination?
Although the expert working group has identified severe problems
with withdrawal, their studies were not designed, nor required,
to look actually at that. They discovered it, but it was not part
of the design of the study. Was that a failing?
Professor Sir Alasdair Breckenridge:
Well, we are looking back 15 years now and when the SSRIs were
licensed from 1987 onwards, it was clear that this was an important
group of drugs with many benefits over the previous agents, but
with a different adverse reaction profile. That adverse reaction
profile, as we have discussed already, was known, but the quantification
and the importance of it was not clear.
Q809 John Austin: Would it not have
been sensible to design the study to look at that and not find
it by chance?
Professor Sir Alasdair Breckenridge:
Well, the MCA, as it then was, was not in the business at that
time of designing studies. It was a regulatory body at that time
which did not design studies itself and set up investigations
like that.
Q810 John Austin: Could I ask then
whether any lessons have been learnt from the experience, in particular,
how to improve scrutiny of drug licence applications?
Professor Sir Alasdair Breckenridge:
Yes, there have been many lessons and the main lesson which has
been learnt, as we have touched on already, the first lesson,
is that the safety profile of a medicine, when it is licensed,
is not very well known, the whole profile. Secondly, when yellow
cards become available, they will put up signals, but these are
signals and these signals must be tested in different ways. That
is one of the main lessons that we have learnt.
John Austin: I think we will come on
to yellow cards later.
Q811 Dr Taylor: Can I ask about another
lesson, if perhaps you have learnt and changed it, because we
gather in the past that you worked on company summaries of trial
data rather than the raw data and we have been told that, particularly
with Prozac, you or your preceding bodies chose just to take the
trials or were given just the trials from America and not the
trials from Europe and, therefore, you were relying on the choice
of evidence given to you by the drug firm. Have you changed that?
Are you now looking at raw data or are you making sure you trawl
right across all the availability?
Professor Sir Alasdair Breckenridge:
I think, Dr Taylor, there is a misconception about raw data and
company summaries. Yes, we rely on company summaries. European
medicine regulation says that we should and we do, but a company
summary is for each trial that is done, and there may be 10 or
15 trials for each licence application, and what each company
summary will contain is 80 to 100 pages of dialogue, several hundred
pages of tables, and statistical analysis as well, so the submission
for one agent will be many, many hundreds of volumes. This is
what are commonly called "company summaries". Raw data
are the individual case reports on each individual patient and
we routinely do not look at raw data. We have done on occasion,
but this is not a routine practice. I have noticed on one or two
occasions before in the transcripts that this topic has come up
and I think there is a misconception as to what is meant by a
"company summary". When we get an application coming
in to the MHRA, it is delivered in a pantechnicon there are so
many volumes, and these are the company summaries which, as I
have described, are very full and, if necessary, we go back to
the company or the Agency can go back to the company and ask for
the raw data and it does this on occasion.
Q812 Dr Taylor: And you have a method
of making sure that you are getting all the data, the good data
and the bad data?
Professor Sir Alasdair Breckenridge:
The company signs an affidavit that they are delivering all the
data. There has got to be trust in this. They sign that they are
delivering all the data. When they come to a hearing, they are
asked that and they are asked to give an undertaking. We also
have the ability to send in inspectors to inspect the company
for good clinical practice and pharmacovigilance should there
be any suspicion that they are not producing all the data. I do
not know whether Kent wants to add anything to that.
Professor Woods: No, I think that
is a very clear account of the situation. The ability to inspect
sites for good clinical practice has been recently strengthened
by the provisions of the European Clinical Trials Directive which
has been implemented in the UK with effect from 1 May last year,
so there is at the level of the trial subject the opportunity,
which we take, to carry out random audits to inspect that what
we see in the records is actually representative of the data which
has been gathered, so this adds another layer of security to the
quality of data.
Q813 John Austin: Can I raise a question
which I raised at the last session with AstraZeneca which related
to the promotion, advertising and marketing of one of their products.
I am wondering what the relationship with the MHRA is or what
powers the regulator has. I raised the specific issue of Crestor
and you were saying, Sir Alasdair, earlier that obviously many
drugs with very real benefits do have adverse effects and carry
real risks as well and there does have to be a positive assessment
of those. With Crestor, AstraZeneca launched a very impressive
marketing and PR campaign immediately after the MHRA had identified
certain risks and reformed the advice that goes on the insert
in the packet. Is there any way in which the behaviour of pharmaceutical
companies can be regulated in those circumstances? Would you comment
on that?
Professor Sir Alasdair Breckenridge:
Perhaps Dr Raine could answer that. She is in charge of that part
of the Agency.
Dr Raine: The legal position is
that as long as the company is advertising in line with their
licence the summary of product characteristics, we do not have
powers, say, to make them stay their hands while the new advice
is adopted into clinical care and that is a fact.
Q814 Chairman: Do you think you should
have those powers?
Dr Raine: I think it is something
that we should consider. We are currently, having overhauled our
advertising processes since 2003, consulting on how we interpret
some of this guidance. Our guideline is out to consultation and
clearly it puts into the current climate the capability to look
to see how we would wish best to interpret these things nowadays
and it is not just how actively and aggressively products are
promoted, but matters such as inducements and hospitality.
Q815 Dr Taylor: I must just ask something
about the Panorama programme because I think many of us
who are doctors were desperately embarrassed and sorry for you
with the way you were forced to come out. Now, you have made a
much more robust defence of the situation to us today. Is that
because some of your comments were edited out?
Professor Sir Alasdair Breckenridge:
I was interviewed for 2½ hours without a break for Panorama
and I was shown on the programme with 7½ minutes of what
I said. The bits of my robust defence of the position of the Agency
were not shown and I cringed from behind the sofa when I saw the
bits which they did show of what I had said. It was very embarrassing.
Q816 Chairman: We have been through
that process, don't worry!
Professor Sir Alasdair Breckenridge:
Well, I am reassured by that.
Q817 Dr Taylor: We certainly have.
We have been told that there are recent changes in the safety
standards in the International Conference on Harmonisation which
perhaps could put patients at greater risks from new drugs. Any
comments on that?
Dr Raine: I would be interested
to know how Dr Taylor has, if you like, been alerted to this.
Our take on the International Conference on Harmonisation is that
it is a vehicle actually to raise standards, and our own strategy
to improve standards of pharmacovigilance and to turn drug safety
monitoring from a reactive to a proactive process has used ICH.
We have recently adopted the guideline on pharmacovigilance planning
and worked with the European legislature to achieve an amendment
to the law this October 2005 to ensure that when a new medicine
comes on to the market, we have a proactive plan to gather the
safety data and to look for new risks rather than to wait until
they come and hit us, so my take on ICH is that it is a tool for
improvement rather than a danger to us.
Q818 Dr Taylor: If I may just quote
from our brief because I am not an expert on this, our brief tells
us that there appears to have been a certain amount of downgrading
in standards relative to the higher standards practised at the
time within ICH, that, most importantly for drugs for non-life-threatening
illnesses, the requirement for expedited reporting of known serious
adverse drug reactions has been dropped, and that periodic safety
update reports from companies to regulators during the first three
years post-launch have been reduced in frequency, those sort of
concerns.
Dr Raine: These are actually not
the true position at all. We have ratcheted up the frequency of
periodic safety update reports. It is obviously six-monthly in
the early stages, but they will now be coming in three-yearly
rather than five-yearly and we are working with our colleagues
in Europe to ensure that whilst every Member States has many thousands
of these to look at, we can focus with different Member States
taking the lead in different established products, so I would
like to reassure you that this is not the case and we are pushing
ahead with ICH.
Q819 Mr Bradley: Can we explore a
bit further information and promotion. One of your stated objectives
is to "provide authoritative and accessible information".
How successful do you think you are in achieving that and how
would you say you compare with the information that is supplied
by the industry itself?
Professor Sir Alasdair Breckenridge:
Well, thank you for that question. There are several ways in which
we do inform patients. The obvious ones are, firstly, the summary
of product characteristics and the patient information leaflets
which we have approved, and that is a very important bit of getting
information about the medicine through to patients perhaps taking
a specific drug. The second broad areas that we are involved in
is disease awareness campaigns, the Ask About Medicines Week,
the Medicines Information Project, and these are broader ways
in which we inform patients as well. The other way in which we
inform patients is when there is a safety issue. When a safety
issue does come back and we are acting reactively, we have quite
a good mechanism now for informing healthcare professionals and
the media about the safety issue and this is picked up and usually
well reported by the press, so the public do get to hear about
safety issues as well. It comes back to something, Mr Bradley,
that I was saying earlier on, that we believe it is important
that we do more than that, that we have got to be far more on
the front foot rather than on the back foot and the change which
you will see in the Agency in the future is better communication
about the issue of risk:benefit which I believe is terribly important
and working with the press, with the media, putting our heads
above the parapet and letting people know that there is no such
thing as a drug which is a silver bullet, that there are risks
and benefits everywhere that you look, and that is a change which
you will see coming from the Agency in the future.
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