Memorandum by Professor Patrick Vallance
(PI 106)
PERSONAL STATEMENT
I am Professor of Clinical Pharmacology and
Head of Department of Medicine at University College London. The
Department is one of the largest and most research active in the
UK, and has responsibility for teaching medical students. The
research funding income of the Department is in excess of £13
million per annum with about 2% coming from industry. My personal
research group is funded largely by grants from the British Heart
Foundation, Wellcome Trust and MRC. Clinically I am involved in
general medical practice, cardiovascular medicine and clinical
pharmacology. Until recently I was chair of UCLH Trust Use of
Medicines Committee, the body that determines prescribing policy
and the drug list for the Hospital. I have published on evidence-based
medicine and the need for rational policy in relation to drug
use, and was a member of the editorial board of Drug and Therapeutics
Bulletin (Consumers Association) until a few months ago. Earlier
this year I joined the main Research Advisory Board of GSK and
am the only person from the UK on this board. I am an Honorary
Officer (Registrar) of the Academy of Medical Sciences. I was
asked to submit this memorandum in an individual capacity and
I am not representing any of the above institutions.
1. NEW DRUG
TREATMENTS HAVE
RADICALLY IMPROVED
HEALTH CARE
1.1 Despite concerns about the rate and
extent of innovation within the pharmaceutical industry, it is
clear that new drugs have been introduced that have had a major
impact on the health of patients and the organisation and delivery
of health care. Examples include the introduction of streptokinase
and other "clot busters" for the treatment of heart
attack (25% reduction in death rate), ACE inhibitors for heart
failure (the first treatment to produce a major effect on survival),
statins to lower cholesterol (effective in everyone but most useful
in those at highest risk), anti-TNF antibody treatment for rheumatoid
arthritis (altering the outlook in a particular unpleasant disease),
treatments for HIV (that have turned a death sentence disease
into a chronic condition), several new drugs for epilepsy, and
drugs for impotence. Industry also explores therapeutic areas
that are sometimes ignored by the medical profession.
1.2 In each of these examples the introduction
of new effective treatments has also led to changes in the way
clinical services are organised and delivered within the NHS.
For example, the treatment of heart attack used to involve a three
week stay in hospital with little effective intervention and the
administration of toxic ineffective agents (lignocaine), but now
the stay is around five days and the outcome is considerably improved.
Clinical services for impotence were virtually non-existent until
the development of sildenafil (Viagra).
1.3 It is also worth noting that the introduction
of new drugs leads to academically-driven experimentation in new
indications. Examples include current studies exploring the potential
of statins to reduce inflammation and improve outcome in autoimmune
conditions, the use of sildenafil for treating pulmonary hypertension,
or the use of rituximab (a B cell depletion therapy designed for
treatment of leukaemia) for rheumatoid arthritis.
1.4 The contribution of industry to health
care can also been seen in the generation of effective vaccines.
Very recent examples include vaccines against viruses that cause
cervical cancers and progress in developing vaccines for malaria.
Conclusion
Effective interaction between academia and industry
has led to innovation, improvement in health outcomes and development
of health services. Some of the most significant advances in health
care have come from industry funded trials or trials undertaken
in partnership between industry and public funders. Once drugs
are available clinical researchers explore new indications, such
"off-licence" use of drugs has been an important part
of innovation.
Recommendation
Interaction between academic clinicians and
industry should be open, transparent and appropriately recognised
by both sides.
2. SOME NEW
DRUGS DO
NOT OFFER
SIGNIFICANT ADVANCES
OVER EXISTING
TREATMENT
2.1 Alongside these examples of major successes
many drugs have been introduced that offer little advantage or
are simply variants of existing products. These agents are granted
a marketing authorisation on the basis that they are better than
placebo, not because they offer an advantage over existing options.
Industry will try to maximise profits from their developments,
including those that may only offer marginal advances. Marketing
is clearly effective.
2.2 Some high profile "failures"
have been related to innovative products. For example, rofecoxib
(Vioxx) is a member of a new class of drug and an innovative product.
Its effects on cardiovascular events were not predictable prior
to the clinical trials.
2.3 Some disease areas are over-represented
in drug development whereas others are ignored (for example antimicrobials).
Commercial considerations are key determinants of priority areas
for industry.
Conclusion
There is no doubt that commercial interests
determine the priorities of industry. "Me-too" drugs
can make substantial profits and innovative drugs may have unexpected
effects that make them risky to develop. Many doctors do not understand
that the marketing authorisation simply means that the drug is
more active than placebo.
3. CLINICAL TRIALS
IN THE
UK
3.1 Many of the clinical trials that have
identified major clinical benefits and changed practice have been
funded in part or full by the pharmaceutical industry. Examples
include the 4S[1] study showing that statins improve outcome after
heart attack, the ISIS-II[2] study showing that streptokinase
and aspirin reduce death by nearly 50% after heart attack, and
the UKPDS[3] study that demonstrated how diabetes should be managed.
3.2 It is also clear that some studies funded
by industry have been more helpful to marketing than to advancing
clinical care. Common flaws include the use of inappropriate comparator
drugs (sometimes used in doses lower than appropriate), assessment
of surrogate markers of disease that do not relate well to clinically
relevant end points, the use of composite end points that make
it difficult to assess which end point has really been changed,
the use of inappropriate safety markers or drug-specific quality
of life assessment tools.
3.3 It is important to note that design
flaws are not confined to trials conducted by industry, although
there is a concern that some of the design flaws in commercial
studies may be conceived to exaggerate benefit or obscure access
to the clinically important result.
The pharmaceutical industry will pursue drugs
that provide profit and will want to design studies that maximise
the chance of doing so. Does this objective distort the general
research agenda and reduce capacity for other research?
3.4 First it is important to consider funding.
The majority of funding for clinical trials comes from industry.
It has been my experience that other funding agencies may contribute
to joint funding with industry, but are often unwilling to fund
in full the cost of large scale clinical trials. This means that
it is easier to fund a trial of a new medicine than it is to ask
questions about the efficacy or safety of existing therapeutic
options, or to fund therapeutic trials of non-drug interventions.
The underlying reasons include the logistic difficulty in mounting
a large clinical trial, the huge costs involved, and the priorities
of funding agencies and their advisory committees which may (often
rightly) favour spending money on more basic discovery research
rather than applied clinical trial research.
3.5 Second there is a perception that the
funding of commercial studies uses up capacity and thereby reduces
the opportunity for undertaking other research. There is little
evidence to support this view. In the UK a very low percentage
of patients are enrolled in clinical trials and the experience
of the cancer trials networks shows that recruitment can be increased
substantially provided infrastructure is in place. There is a
shortage of appropriately trained clinical investigators in the
UK, and this reflects lack of investment in clinical research
and problems with clinical training pathways (outlined in a recent
report from the Academy of Medical Sciences "Strengthening
Clinical Research"). This deficiency affects both commercial
and non-commercial studies.
3.6 Third there is the issue of duplicate
research. In many instances the evidence base is not reviewed
in a systematic way prior to starting a clinical trial. Many small
studies are funded that apparently show promise for a new drug
or intervention but each individual study is too small to be persuasive
or definitive. There must come a point at which another small
study designed to investigate a therapeutic effect is either redundant
because the answer is already available, or unnecessary because
it will not produce the definitive answer that is required. In
my opinion these are matters that funding agencies and ethics
committees should consider very carefully before approving a study.
At the very least, the patient information sheet should indicate
clearly the realistic likely impact of the study.
Conclusion
Industry supports and develops areas of interest
to itself but it is wrong to assume that industry is solely to
blame for the lack of research in certain unprofitable/unfashionable
areas or that industrial trials exhaust capacity for research.
Rather, there is a lack of infrastructure to undertake research
within the NHS, a failure to develop robust mechanisms to identify
research priorities for the NHS and inadequate funding for this
type of clinical research. The NHS should be a knowledge-based
organisation and requires substantial investment in RandD.
Recommendations
The NHS infrastructure for clinical trials needs
to be improved. The example of cancer networks suggests that it
should be possible to increase substantially the clinical trials
capacity and number of patients involved in studies. This will
need investment in clinical trials networks, development of trained
clinical investigators, simplification of the regulatory burden
placed upon clinical investigators, and a change in culture within
the NHS. These needs have been anticipated in the establishment
of the UK Clinical Research Collaboration (UKCRC) earlier this
year. NHS Trusts need to have a reward mechanism for engaging
in clinical research that addresses NHS priorities.
UKCRC and its disease specific networks will
need to scope in a systematic way their specific areas to identify
where research gaps lie and which are the key questions of importance
to patients, practitioners and the NHS. Where answers are known
and no further studies are required, this should be identified
and clearly stated.
4. PRESCRIBING
DRUGS
4.1 There is confusion amongst prescribers
about the significance of a marketing authorisation (product licence).
It is my experience that many prescribers view the issuing of
a marketing authorisation as evidence that the drug has a place
in practice and should be available for them to prescribe.
4.2 Once a drug is available its use will
increase and it will be used for indications outside the initial
licence. This extension of use is an important part of innovation,
but only if properly evaluated.
4.3 The existence of Drug and Therapeutics
committees, formularies and more recently NICE, adds an additional
layer to try to explore and regulate the place of new treatments
against current alternatives. However the working of these bodies
is complicated by patient pressure groups, clinician pressure
and, increasingly, by the need for some NHS Trusts to be seen
as offering a "cutting edge" service, which may mean
a service that anticipates the arrival of a supporting evidence
base.
4.4 Expert clinical opinion or "opinion
leaders" in specific disease areas are influential forces
on prescribing. Sometimes this is appropriate and makes an important
contribution to disseminating best practice. However this is not
always the case, and sometimes opinion leaders in specific disease
areas benefit directly or indirectly from activities that amount
to endorsement of specific products. This can distort prescribing
practice.
4.5 Skills for evaluation of therapeutic
claims are generally not well developed amongst doctors. It is
time consuming to evaluate claims and for busy doctors the time
is often not available. Much postgraduate education comes from
industry-sponsored meetings.
4.6 Patient groups can exert very significant
pressures to make new therapies available within the NHS. This
is especially true for diseases in which existing treatments do
not exist or are widely considered ineffective. Examples include
the patient lobby for the use of interferons for multiple sclerosis,
drugs for Alzheimers disease, and some cancer treatments.
4.7 Clinicians wanting the best for their
patients are sometimes overly optimistic in their interpretation
of phase II studies not designed to prove efficacy. Drugs are
made available to patients before there is clear evidence for
efficacy in clinically relevant outcomes.
4.8 Once a benefit has been described in
the literature, it is very difficult to deny access to the drug.
However the nature of the benefit is often not clear. For example,
for a cancer drug, "benefit" may be expressed in terms
of cure, quality of life, time until death, time until disease
progression, reduction in tumour size, or change in rate of change
of tumour bulk. The size of the benefit may vary from clinically
important to potentially irrelevant. Similarly, the number of
patients that need to receive a given treatment for one of them
to benefit may vary from hundreds to only one or two.
Conclusion
There are pressures from industry, doctors and
patient groups that mean that drugs are sometimes introduced into
routine clinical practice in the NHS in advance of strong evidence
of benefit in the target patient population. There is a tendency
to give a new drug "the benefit of the doubt" in favour
of it being an advance. Once a drug is being used in routine practice
it becomes very difficult to gather any meaningful data on effectiveness.
Recommendations
NICE should explore whether defined targets
for new treatments could be set in a limited number of disease
areas. For example, in the treatment of heart failure NICE might
prospectively define the type and size of benefit that would be
considered an advance likely to merit inclusion in an NHS formulary.
This would have the advantage of helping to define general trial
objectives, avoid having to respond to every "advantage"
of a new product however small or clinically irrelevant, and would
bring academics, clinicians, patient groups and industry into
the target setting process before a specific product is considered
or even developed. This approach could help guide industry to
trials of most benefit to the NHS.
Money currently spent on some new drugs could
be better spent on ensuring that where the evidence base is insecure
but the potential need is great, the drug is introduced into the
NHS only as part of a clinical trial. This will require an improved
NHS infrastructure and clinical academic workforce as envisaged
by UKCRC. The drug costs could be met from the drugs budget since
no more patients would receive the drug than at present, they
will simply be evaluated. Designating a small percentage of the
NHS drug budget for "Research and Evaluation" would
facilitate this process. A similar budget would need to be identified
for trials of non-drug interventions.
The public should be informed about areas of
"uncertainty" in medical practice and clinical trials
to address uncertainty should be commonplace within the NHS. Trial
design and results should be in the public domain.
Use of the concept of "Numbers needed to
treatNTN" and "Numbers needed to harm" for
given intervention would improve information for prescribers and
the public and aid informed decision making.
Medical students need to be trained in evaluation
of evidence and this should form a major part of continuing medical
education.
More funds should be available for independent
postgraduate educational meetings.
Advice given to prescribers, and presentations
or publications discussing therapeutic agents should always come
with a clear statement about financial relationships and real
or perceived conflicts of interest. This is common practice in
the best medical journals but needs to be extended to meetings
and all activities credited for CPD (continuing professional development).
5. DATA BASES
FOR DRUG
SAFETY
5.1 Drug safety is evaluated before launch
of a product but many effects of drugs only become clear after
the drugs have been used by many thousands of patients over several
years.
5.2 The NHS data sets collected as part
of computerised records provide a unique resource for evaluating
drug safety.
Recommendation
Computerised databases of information collected
as part of routine clinical care should be used to evaluate drug
effects. The UK should develop increased research capacity in
this area.
REFERENCES:
[1] Randomised trial of cholesterol
lowering in 444 patients with coronary heart disease: the Scandinavian
Simvastation Survival Study (4S). Lancet 1994; 344: 1383-89.
[2] Randomised trial of intravenous
stretokinase, oral aspirin, both, or neither among 17,187 cases
of suspected acute myocardial infarction (ISIS-2). Lancet 1988;
ii: 349-360.
[3] UKPDS. BMJ 1995; 310:
83-88.
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