Examination of Witnesses (Questions 440
- 459)
TUESDAY 7 DECEMBER 2004
SIR RICHARD
SYKES, PROFESSOR
PATRICK VALLANCE
AND SIR
IAIN CHALMERS
Q440 Mr Burns: Do you think there
are ever cases where it might be in the interests of the public
to deny access to publication?
Sir Iain Chalmers: I cannot think
of examples, but that is not to say that there may not be some.
Clearly, one of the problems that epidemiologists face is if they
find an association between, let us say, coffee drinking and pancreas
cancer, do they report that association and stop a lot of people
drinking coffee who enjoy it but who might worry they will get
pancreas cancer? There is an issue about not causing unnecessary
alarm, but when it relates to licensed products that have been
given the go-ahead for marketing in our country to our population,
I just do not think it is consistent with 21st century public
values that that information should remain secret.
Professor Vallance: I will go
one stage further. I do not understand how you can use a drug
if you cannot access the information to see if it works.
Sir Richard Sykes: If you really
wanted a system that works more effectively you would have a regulatory
body in terms of approval; then you would have the body that is
determining whether you have efficacy and safety; but NICE can
only make those decisions once the drug has been on the market
for quite some time. Then you can ask those questions. Therefore
the data has to be transparent because there is no way you can
make the decisions. If they say there is no benefit to be gained
from the drug, and the NHS stopped supporting that drug immediately,
that would be a better system at the end of the day, but you can
just imagine the arguments as to whether there was real efficacy.
If you set up NICE correctly, you would be able to do that.
Q441 John Austin: The evidence we
have had both from the United States and Australia has suggested
that only a minority of drug innovations offer any significant
therapeutic advance. Would you say that is also the situation
in the UK; and do you think the industry does concentrate too
much on the so-called "me too" products?
Sir Richard Sykes: If you look
at the whole history of drug development—and really it started
as an industry in this country in the sixties, and the first range
of drugs—if you think about beta-blockers for treating hypertension—obviously
people recognised that there was a mechanism here to attack high
blood pressure, so lots of people get involved in that research
because they see the patterns. Once you are down that track and
you have invested a certain amount of money, you are going to
continue. Again, if you can show safety and efficacy, those drugs
get approved. Let us say there are 15 beta-blockers on the market:
doctors will put patients on the drug that tends to work for them
best, so you are actually doing a genetic analysis on that group
of patients by having 15 drugs available to you. Each one of those
drugs has a benefit to a certain class of patients, worked out
by pure random testing, I suspect. That has been the tradition
going forward, so if you go back to the sixties and seventies,
we have gone through that period where drugs come out and they
are followed by other drugs, because safety and efficacy has been
proven in the market place and therefore you know if you go into
that area you are going to end up with hopefully a safer and more
efficacious drug. This is where I said earlier that the world
is now changing. That model will not work any more, and this is
why we have seen this paradigm shift in the drug industry and
why we read that drugs are not coming out as fast as they used
to, and there are no new molecules, because it is going back to
basics. It is now trying to understand the underlying mechanisms,
and to deal with that right at the fundamental issue, rather than
serendipitously moving along the track and then everybody following
that track. This is the change that is taking place, and my view
is that over the next 20 years we will start to see drugs that
will offer real benefit to patients. You will not get a lot of
"me too-isms" I suspect.
Q442 John Austin: You said earlier
that the industry manufactures the drugs and the doctors prescribe
them. You have gone through a period of asking why doctors prescribe
a particular drug. Professor Vallance, in his evidence, has pointed
out that in order to gain a licence a drug does not have to prove
it is more effective than existing treatment; it just has to prove
that it is more effective than the placebo. Professor Vallance
says that not a lot of doctors know that.
Sir Richard Sykes: It is not true
in the United States of course. The FDA will tend to eject drugs
that do not show benefit over existing drugs.
Q443 John Austin: That is not the
case in the UK.
Sir Richard Sykes: It is up to
the regulatory agency to make that decision. They have the right
to make that decision. Of course, we then have the body called
NICE, which is another regulatory agency. Even if the MHRA has
approved a drug, NICE could say "this adds no real benefit
to what is already there and therefore we will not support it."
You have to remember that with the exception of the infectious
diseases, we do not cure disease but we treat the symptoms. Hypertension
and high lipid levels are not diseases at all. We are treating
something that is a symptom or hopefully it will prevent something
by treating that symptom. We are moving into an area that will
change quite significantly. Most of the drugs are palliatives.
Q444 Dr Naysmith: You have used the
phrase, Sir Richard, quite a lot, "safety and efficacy"
and "approved by the market place". How long would you
give for the market place to bring something both safe and efficacious
if you were still in charge of a company?
Sir Richard Sykes: I do not think
it is a time issue; it is a quantitative issue. You could put
a drug on the market like a Cox-2 inhibitor, and in one year you
have millions of patients on that drug. If you were treating small-cell
lung cancer, you would only have perhaps a few thousand. You have
to somehow contain that period on numbers of people treated.
Q445 John Austin: Lots of people
take RSAs, and some of the predecessors have been pretty toxic
and have been marketed very heavily and sold in their millions.
When are we going to recognise that?
Sir Richard Sykes: If you started
from square one now and did that, I would say now within a period
of three years you would have a pretty good idea of whether those
drugs are safe and efficacious. Remember, it is always a risk/benefit
ratio. There has to be a risk. There is a risk with every possible
drug.
Q446 Dr Naysmith: I think what the
industry is play down the risk and play up the benefits.
Sir Richard Sykes: Yes.
Q447 Dr Naysmith: You said there
were 15 beta-blockers.
Sir Richard Sykes: I used an example,
but there are probably more.
Q448 Dr Naysmith: It will take a
very long time until a doctor finds the right one for the right
patient, if he is having three months at a time.
Sir Richard Sykes: Until you get
the genome sequence for every individual patient and you can use
that information to the best advantage to determine which drug—
Q449 Dr Naysmith: That is not there
yet, is it?
Sir Richard Sykes: We are not
there yet.
Dr Taylor: For clarification, a doctor
does not use all 15.
Dr Naysmith: No, but he was talking about
finding the right one for a patient.
Q450 Dr Taylor: I wanted to go back
to Sir Iain. You have touched on the final recommendation in your
paper. The recommendation was that selected promising but inadequately
evaluated drugs should be used in the NHS only in the context
of controlled evaluative studies until enough is known to judge
their cost-effectiveness. Cox-2 inhibitors probably had some real
benefits. If Vioxx for example had only been released on a controlled
trial basis to start with, would that have allowed it to be restricted
in its prescribing, and then when it was eventually released would
that have just delayed the discovery of the side effects? Can
you comment on that?
Sir Iain Chalmers: I would like
to comment on two issues. People embarking on new studies and
reporting new studies do not do a systematic review of what is
already available in terms of evidence, and when they have new
data set the new data in the context of an updated systematic
review. We know now, from evidence published in the Lancet
a couple of weeks ago , that had such a process been in operation
for Vioxx, then the adverse effects might have been identified
as long as four years ago. The first thing to do is to take notice
of all the current evidence. At the moment, that is impossible
because of this problem of publication bias and because of the
fact that academia does not value the process of finding out what
is known already, using scientifically defensible methods. That
is academia's problem; it really is. It is their fault. In terms
of allowing a drug a provisional licence, there may be some drugs
that have been given a licence on the basis that they seem to
have an encouraging effect with an outcome patients that patients
may not value, but which is seen as relevant . In those circumstances,
if you want to find out whether it holds value for the patients,
the drug should be released in the context of a further evaluation.
For example, the Class 1 anti-arrhythmic drugs were given to people
who had heart attacks to try to prevent arrhythmias because arrhythmias
were a risk marker for subsequent premature death. These drugs
were very good at suppressing arrhythmias , but they were also
pretty good at suppressing life; they killed people. They were
licensed on the basis of a surrogate outcome, which patients would
not have been worried about, and they came into widespread use.
An estimate has been made that during every year in the United
States at the peak of their use in the late 1980s they were killing
more people than all the Americans who had been killed in the
whole of the Vietnam war. That shows an example of the kind of
circumstance where it would be important to release a drug or
a device or a surgical operation—only in the context of
a randomised trial, until we knew more about its worth to the
NHS and the patients who use the NHS.
Q451 Dr Taylor: In the case of Vioxx,
if everything has been available beforehand we would not have
got into this problem.
Sir Iain Chalmers: That is the
evidence that was published in the Lancet about three weeks
ago, that four years ago ,we could have known there was a real
problem.
Q452 Dr Taylor: Can I go on to picking
up side effects after marketing, when there is not that bank of
information before. The yellow card system, as we have heard so
many times, is not really working effectively. It was Professor
Vallance who talked about the GP database. How will that help?
Professor Vallance: That, and
increasing numbers of databases, as the NHS becomes computerised,
will allow you to collect data from everyday practice, for dealing
with the issue that Sir Richard raised—the variability once
a drug is out there in the real world away from the rather tight
setting of a clinical trial.
Q453 Dr Taylor: So one will be able
to tie up side effects with drugs.
Professor Vallance: Yes. You can
on that system already. You can interrogate it. Of course, it
is not randomised and not very good at estamlishing efficacy,
but it is quite good for picking up safety signals, and once a
drug is out there in practice it is very difficult to get efficacy
data unless you have randomised controlled trials; it is much
easier to pick up safety signals.
Q454 Mr Bradley: Do you think the
Department of Health is the right sponsoring Government department
for the pharmaceutical industry as opposed to the DTI?
Sir Richard Sykes: My view has
always been that it should be the DTI. The pharmaceutical industry
in this country is a global business, not a national business.
The DTI is a global business, but the DoH is not global. Therefore,
the DTI should be the sponsor. The only reason that the DoH is
the sponsor of the pharmaceutical industry is so that the fox
would not eat the chickens!
Professor Vallance: Sir Richard
knows far more about this than I do, and I think there is some
sense in that, but it is not an area I know about.
Sir Iain Chalmers: I was only
introduced to this possibility quite recently, and it does seem
very sensible. Clearly, the pharmaceutical industry in this country
is a very important part of our manufacturing economy, but I do
not see that we should subsidise that industry by buying useless
treatments for the NHS, just because they are being manufactured
in this country. There is a tussle, and I can see that there is
a real debate to be had there, presumably at Treasury level, but
the NHS ought to be giving the best possible treatment to patients
who use it.
Professor Vallance: Sir Richard
will comment on it more, but the percentage of the market involved—
Sir Richard Sykes: It is 4% of
the world market.
Q455 Dr Taylor: By pure chance we
started this inquiry at the stage when Vioxx and SRI's problems
were coming out, so the inquiry was greeted by the press with
a huge welcome; but here we are, we are going to expose all the
iniquities of this desperate industry. Is this just prejudice,
and would you make a comment on this, because we have this terribly
difficult problem of writing this report and getting it right
and not blaming an industry, if it is not iniquitous, and blaming
it if it is? Do you have any comments?
Sir Richard Sykes: It is not an
iniquitous industry. I think it adds great value, first of all
to the UK, the industry in this country. It has been one of the
great success stories. It has spun off a lot of bioscience activity
in this country, which is still some of the best in the world,
and that has been very important because it has been a base for
many pharmaceutical companies' research and development, which
is critically important for the economy. Like all businesses,
they are private businesses and they have shareholders. They have
to provide returns. The industry itself has always been highly
regarded, particularly in times of recession. Everybody is sick
and the industry has always been a good place in terms of investment.
Obviously, like anything else in the world today, it becomes very
competitive and once people become highly competitive they are
driven to do strange things, so I think that today the industry
has got a very bad name. That is very unfortunate for an industry
that we should look up to and believe in, and that we should be
supporting. I think there have to be some big changes. The industry
has got to get back on track and get rid of its bad image by being
much more transparent in some of the things we have been talking
about, by working closer with other bodies, and being much more
interactive with the public. We need this industry; it is critically
important. We need it to work with other people, with academia
and with industry. I think we have a great opportunity in this
country to continue to be leaders in this area of research.
Q456 Dr Taylor: You are almost in
a unique position to comment from both sides of the argument,
so it is very valuable.
Professor Vallance: My experience
of research from the industry is that they want to make innovative
drugs and often in areas where there is a need, which is sometimes
not recognised by doctors but by patients, such as incontinence
and other areas. I think within the research side that is what
they want to do. From the marketing side they have a different
job, which is to sell whatever they have. It seems to me that
part of the response to that is to be much more robust about what
we are prepared to buy and pay for, and have our own criteria
for what works and is an advantage.
Q457 Jim Dowd: You say industry wants
to make innovative drugs. We received evidence, certainly when
we were in Australia and elsewhere, that the vast majority of
intellectual effort in drug companies is now going into maximising
patents, not in developing new drugs..
Professor Vallance: I think the
research side of industry wants to create new drugs. If you ask
anyone in research, that is what their aim is. The marketing and
other side of industry may have other objectives which are about
patent extension. Within industry there is exactly that tension
that you are exploring here. Most people want to make innovative
medicines.
Q458 Jim Dowd: Clinical practitioners
are all clear-eyed optimists—
Professor Vallance: No. The basic
scientists in industry are striving very hard. They recognise
that the real money comes from the innovative blockbuster that
beats everything else. That is what their focus and energy is
on in terms of drug discovery. Another end of industry is all
about making the most money you can from what you already have,
and that is where patent extension comes in. That is why we need
to be much more robust about what we need and what we do not need,
and why we need it.
Sir Iain Chalmers: I would like
to separate these two things. One is the influence of industry
on the scientific record, which at the moment is indefensible,
and sly we are agreed on that. There needs to be a great deal
more transparency. The other is the influence of industry on the
way that drugs are used. Basically, you are in a market place
then, and it is up to organisations like NICE to make sure that
the NHS gets good value for money. All sorts of tricks will be
used, as marketeers will always use to get people to use their
products. There is however such a distortion now in that the things
that do get studied, because of the economic power of industry
and its influence not just on individual academics, but the whole
academic institutions, that some important questions are not being
addressed. That is a great shame. If one takes of some of the
recent innovations that have come not from industry but from looking
at old drugs like aspirin and magnesium sulphate—Epsom salts
for the treatment of convulsions of women during pregnancy and
devices to help people who are having subarachnoid haemorrhage,
which are nothing to do with the drug industry—there are
all sorts of important questions like those that are very relevant
to patients using the NHS and which are in some instances getting
squeezed out because of this increasingly close partnership between
industry and academia. I do not think that is a good trend.
Q459 Mrs Calton: What do you advise
your colleagues and students about the influence of the pharmaceutical
industry on prescribing patterns?
Professor Vallance: We have a
pretty robust course for students, which illustrates very clearly
the influences on prescribing. We have a system which we introduced
for the students which I was explaining to Iain beforehand, which
was rather unpopular when I first introduced it, which is a simple
evaluation sheet that they carry around on their ward rounds,
and when they see anything being prescribed they go away and ask
whether it was a reasonable or unreasonable decision, and what
was behind it. That was unpopular. The idea of students challenging
consultants about the evidence generated a very interesting culture
amongst students.
| 
