Select Committee on Health Minutes of Evidence

Memorandum by Professor Patrick Vallance (PI 106)


  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.


  1.1  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.


  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.


  Interaction between academic clinicians and industry should be open, transparent and appropriately recognised by both sides.


  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.


  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.


  3.1  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.


  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.


  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.


  4.1  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.


  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.


  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 treat—NTN" 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).


  5.1  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.


  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.


  [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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Prepared 26 April 2005