Problems with and Credibility of Clinical Trials

The Problems with & Credibility of Clinical Trials

In order to gain medical acceptance for a non-pharmaceutical treatment the treatment needs NICE approval. NICE demand ‘clinical data from controlled trials', however controlled trials cost many millions of pounds. The industry has these trials so spectacularly complicated and expensive that they are beyond the reach of governments, academia, and most companies, only huge international pharmaceutical corporations can afford to run controlled trials now. By NICE demanding 'clinical data from controlled trials' they are in effect blocking any non-pharmaceutical treatments from becoming a mainstream quickly, regardless of their effectiveness or patient benefits. Critics argue 'It is an organisation that has shown itself to be absurd and irrelevant at best, incompetent and deadly at worst. NICE are the biggest threat to patient health and should be scrapped'.

Any non-pharmaceutical treatments, which help with addiction for alcohol or drugs, are blocked from being used because of the argument they have not been clinically trialed or scientifically proven to delay medical acceptance of the treatment. However those in possession of the facts know this argument is unfounded due to the conflict of interest that exists between the drug companies and the medical profession and the mounting and overwhelming anecdotal evidence that these treatments do work and are proven to work.

Many medical professionals hide behind the 'clinical trials' excuse as a reason not to use a treatment, 'I want to see data from controlled trials', they say this as though clinical data is very easy to obtain and everyone should have it. The reality however is very different as they know, clinical trials are hugely expensive running into the millions of pounds and take years to complete so many critics argue 'demanding trial data for a non-pharmaceutical treatment is clearly inane'. Apart from that, trials also have sever credibility issues and there is also no guarantee that once a treatment has been clinically trialed it would be used anyway. Critics argue 'medical professionals do not, as one would assume say 'that's promising, lets do an observation study and see if the treatment has any merit, they attack and undermine it, rather than exploring and supporting it'.

Trials are only required for drugs to establish 'effectiveness and safety' however once a non-pharmaceutical treatment is used and it becomes established through its use, then its track record proves its effectiveness and safety, if it is unsuccessful, it will not become an established treatment. In addition, clinical trials are not a reliable basis to judge any treatment method as 'outcomes' usually favour whoever is funding the trial, click here for further details.

The argument concerning clinical trials for established non-pharmaceutical treatments is unfounded as 'efficiency and safety' have already been established through its use, in the same way that 80% to 90% of medical procedures have not been clinically trialed either but are still used in common practice, critics argue this double standard is detrimental to patient care. Also there is no guarantee that once a treatment is proven to be efficacious at control trials it would be adopted anyway, so who would fund such a scenario?.

No Commercial Benefit
The only reason for the lack of research or no research in the field of non-pharmaceutical medicine is because there is no incentive to invest in researching treatments or remedies which cannot be exclusively manufactured by a drugs company. You can't patent a herb or homeopathic remedies or a vitamin. The people who actually do the large-scale medical trials are the pharmaceutical companies, but if they can't get a product out of it, why would they bother?

New drugs are often arrived at by extracting active ingredients from plants that have been traditionally used as remedies. So there is now a demand that clinical trials should also be tested against these natural remedy as well as a placebo, as testing against a placebo is merely establishing how much better the drug is, than no treatment at all. In effect drug companies are testing their new drugs against 'doing nothing', which critics argue is not a significant benchmark for testing.

For example: Prozac should have been tested against a placebo and St John's Wort to establish if it better than 'no treatment at all' and a well known 'alternative remedy' used to treat depression.

If a pharmaceutical company is successful in deriving a new drug that is more effective than, say, a tea made from the leaf or flower of the plant, then they can prove that point in the clinical trial. It will also show up natural or traditional remedies that don't work better than placebo, adversely affect the condition being treated, or produce significant side effects. 'Testing against a placebo establishes the lowest possible threshold needed to claim a successful result, the drug companies have managed to convince us all that this method is the best way to test the effectiveness of any new drug, which is ridiculous', claim leading patient groups. Critics also point out, that any health professionals who seek to undermine non-pharmaceutical treatments by stating 'there have been no clinical trials' are either unaware of this fact (but should be aware) or they have other 'undisclosed reasons' for seeking to undermine successful non-pharmaceutical treatments.

Misconception
The general public assume that if a drug has been clinically trialed it's success rate must be very high, according to a consumer pole an individual would assume a clinically tested drug/product must be around 85% to 100% successful. However this is not the case and can be as low as just 6% as with nicotine patches but most drugs sold are around just 10 to 40 per cent successful. It is well known by the medical profession that the vast majority of drugs - more than 90 per cent - only work in 30 or 50 per cent of the people who take them due their genes which interfere with the medication in some way. Drug companies never refer to a drugs' success rate, they simple rely on the public to assume it must be high and it must work in more than 85 to 100 per cent of the people who take it, which is clearly not the case.

"Just because a drug has been approved in clinically trials, doesn't mean its any good". Anonymous 2007.

Background
In 1976, the writer Ivan Illich warned in a book, Limits to Medicine, that 'the medical establishment has become a major threat to health'. At the time, he was dismissed as a maverick, but a quarter of a century later, even the medical establishment is prepared to admit that he may well be right.

From doctors and patients to drug companies and the media, there are relentless pressures to classify any condition as a disease. Richard Smith, the BMJ 's editor, wrote: 'Doctors, particularly some specialists, may welcome the boost to status, influence and income that comes when new territory is defined as medical. Global pharmaceutical companies have a clear interest in medicalising life's problems. Likewise companies manufacturing mammography equipment. Many journalists and editors still delight in mindless medical formulas, where fear-mongering about the latest killer disease is accompanied by news of the latest wonder drug.'

But drug companies have a vested interest in disease-mongering - because they profit by providing cures. Conditions are hyped as diseases, mild conditions as devastating, rare conditions as common. Whereas shy people used to just rely on a glass of wine, Roche developed the drug Manerix to treat 'social phobia'. It initially claimed that one million Australians suffered this 'soul-destroying' disorder, but then admitted it couldn't even find enough people for clinical trials.

The drugs companies target newspapers with stories designed to create fear about a condition, and then company-sponsored advisory boards supply 'independent experts' for the stories, while consumer groups supply 'victims'. The drug companies argue that there are clear benefits to this system. Their drugs are popular because they improve lives.

Dr Iona Heath, head of ethics at the Royal College of General Practitioners, warns that there could also be clear downsides: 'Alternative approaches - emphasising the self-limiting or relatively benign natural history of a problem, or the importance of personal coping strategies - are played down or ignored. The disease-mongers gnaw away at our self-confidence. Inappropriate medicalisation carries the dangers of unnecessary labelling, poor treatment decisions, economic waste, as well as the costs that result when resources are diverted from treating or preventing more serious disease. At a deeper level, it may help to feed obsessions with health.'

Credibility of Clinical Trials
It is not well known by the general public but it is widely acknowledge and established through a House of Commons Health Committee Report, that clinical trials a fraught with problems and suffer server credibility issues, “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.” Sir Richard Sykes. 'House of Commons Health Committee -The Influence of the Pharmaceutical Industry Fourth Report of Session 2004–05'.

Pharmaceutical companies regularly carry out every aspect of a study on their products, then solicit academics to put their names on the final papers in order to disguise their involvement, according to an essay published in the journal PLoS Medicine. Author Sergio Sismondo calls this practice "ghost management," to distinguish it from mere ghost writing.

"In extreme cases, drug companies pay for trials by contract research organizations (CROs), analyze the data in-house, have professionals write manuscripts, ask academics to serve as authors of those manuscripts, and pay communication companies to shepherd them through publication in the best journals," Sismondo writes. "The resulting articles affect the conclusions found in the medical literature, and are used in promoting drugs to doctors."

PHASE I: Are not designed to see if the drug works, it is to establish how the body deals with it. Often the most dangerous part of the trial process as this is when a new drug comes into human contact for the first time. Only very small doses are give to volunteers. These first studies evaluate how a new drug or therapy should be given (by mouth, injection into the blood or injection into the muscle), how often, and what dose is safe. A phase I trial usually enrolls a small number of patients, sometimes as few as 6 to 10 people.

PHASE II: Are much larger and involve a group of a few hundred people suffering from the disease the drug is designed to treat. A phase II trial usually focuses on one type of illness, continuing to test the safety of treatment and beginning to evaluate how well it works. This is the essential intermediate step that will determine whether the drug will go into bigger and more costly phase III trials.

PHASE III: These studies test a new drug, a new combination of drugs or a new therapy in comparison to the current standard treatment. A participant will usually be assigned to the standard group or the new group at random (called randomization). Often it involves "double blind" trials, where neither the patient nor doctor knows who is being given the new drug. Phase III trials often enroll large numbers of people and claim to be contolled but many are conducted at many doctors' offices, clinics and centers nationwide. Claiming a success result from clinical trials can be as low as 6% (NRT) but is usually around 10% to 40% for most drugs.

Media Campaign
It is here at stage III trials that 80% of drugs tested fail to establish their effectiveness and so it is becoming ever more popular for drug companies to halt stage III trials once they have 'some' favourable data to publish. They release a story to the press of usually just one person who has responded well to the medication to create public awareness and also demand for the partially tested and unproven drug, Herceptin & Sutent for kidney cancer were recent examples.

Drug trials are over too soon, warn doctors. The benefits of new cancer drugs are being "exaggerated" because trials are stopped too soon, research claims. It says growing numbers of pharmaceutical companies are halting trials, (as around 80% of drugs fail at stage III trials) including those for the breast cancer drugs Herceptin and Lapatinib - shortly after receiving good interim results. And it warns that patients could be at risk if drugs are licensed and rushed into clinics before possible side-effects are identified.

Without such evidence, unsafe and ineffective drugs are being marketed and prescribed, and patients' health could be jeopardised. Acomplia,a weight loss pill was withdrawn from sales 4 months after NICE approval for links to suicide and depression. New data from post-marketing experience and ongoing clinical trials indicated that serious psychiatric disorders may be more common than in the clinical trials.' The EMA said the drug had also proved less effective in 'real life' than in clinical trials, which is the case for most medication.

But three-quarters of the trials were halted after independent monitoring committees said the drugs were so successful, it would be "unethical" to deprive patients of them. Critics claim these committees are not independent and their decisions are hugely influenced by the drug companies.

Another practice is for failed drugs is to repackage for a different condition than the one for which the drugs had been tested in clinical trials, or to expand the market for drugs that don't bring in enough profits when marketed for a particular condition. Strattera and Cymbalta are antidepressants of the selective norepinephrine reuptake inhibitor (SNRI) class. In clinical trials Strattera had failed as an antidepressant, but is now a hot-selling drug euphemistically marketed as a "non-stimulant" treatment for ADHD.

Cymbalta (duloxetine), a potent dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine also failed in its original antidepressant trials. It is now being tested for incontinence at higher doses. The recycling of these failed antidepressants raises concerns because of evidence-from previously concealed clinical trial data and from a large number of case reports--all indicating that the newer generation of antidepressants can trigger serious adverse symptoms that can lead to life-threatening behavior in some patients. These unwanted effects include: movement disorders, withdrawal symptoms, mania, depression, hallucinations, agitation, aggressiveness, anxiety, psychosis, akathisia, and violent or suicidal behavior. The FDA had evidence of these drugs' adverse effects for years but failed to warn prescribing physicians and the public.

As a result, many people question the 'credibility & the findings' of clinical trials & 'scientific data' and consider they should not be regarded as the 'gold standard' as they are fraught with problems, manipulation, engineered for success and in many cases are meaningless. In fact the Government has recommend that a clinical trials register be set up and maintained by an independent body and the results of all clinical trials data, containing full trials information, be put on the register at launch as a condition of the marketing licence, in a hope it will help overcome some of the following common practices:

Manufacturers are known to have suppressed certain trials & suppression of trial results
Haulting trials when favourable data is available to avoid later stage III failure
Repackaging of failed drugs to new markets
Manipulated figures to show better results
PR & hype used to sell products with little benefit
trials not adequately designed
that they could be designed to show the new drug in the best light
sometimes fail to indicate the true effects of a medicine on health outcomes relevant to the patient
selective publication strategies and ghost-writing
suppression of negative clinical trial findings
all the evidence is not published
negative findings are hidden
allegations clinical trials are engineered for victory
company-sponsored information from medical journals
excessive promotion of the drugs to doctors
fragmented and customer un-friendly nature of academic units and clinical services
confusing ethics approval procedures
few adequately trained medical researchers or specialist research facilities
too few individuals who can organise clinical trials or take part in a reviewing or implementation capacity
NHS does not have a coherent approach to industry sponsored clinical trials

Other practical problems exist and are widely acknowledged:

Investigators are often happy amateurs; being a good basic scientists is not enough to make you a good investigator
The investigator is always biased
Bias should be accepted and eliminated through randomisation, controls and, whenever possible, blinding
Clinical trials are expensive
Lack of non-commercial support is a major problem
Drugs go to market without being fully optimized at the clinical trial level
No reason for industry to support trials of drugs which cannot lead to a patented claim
No interest in non pharmaceutical based medicine

No Full Disclosure - No Credibility
The fundamental problem with all clinical trials is only the favourable data is published any adverse data is never published. As the data is 'cherry picked' the value of such trials is therefore meaningless. The standard question about any data published from clinical trials should be, 'what data has not been disclosed?

A senior executive with Britain's biggest drugs company has admitted that most prescription medicines do not work on most people who take them. Allen Roses, worldwide vice-president of genetics at GlaxoSmithKline (GSK), said fewer than half of the patients prescribed some of the most expensive drugs actually derived any benefit from them. "The vast majority of drugs - more than 90 per cent - only work in 30 or 50 per cent of the people," Dr Roses said. "I wouldn't say that most drugs don't work. I would say that most drugs work in 30 to 50 per cent of people. Drugs out there on the market work, but they don't work in everybody." This goes against a marketing culture within the industry that has relied on selling as many drugs as possible to the widest number of patients.

GlaxoSmithKline were also criticised, but not prosecuted, over claims that it withheld information about the increased risk of suicide for children taking Seroxat, the bestselling antidepressant drug. Ministers have promised to tighten laws that require pharmaceutical companies to disclose data from clinical trials after a report suggested that GlaxoSmithKline (GSK) knew about safety risks but failed to report them to the medicines safety watchdog for five years.

In the legal system, witness evidence (anecdotal) is considered the best form of evidence, now imagine a document that everyone knew had been specially doctored with only the favourable points and any unfavourable evidence had been deleted, how much weight would the Court allow this document? None as it is meaningless. In the scientific community this is how 'clinical evidence' is prepared, in the legal system it would not even be allowed as ‘evidence'.

'Cherry Picked' Clinical Data Vs Client Comments
If pharmacology history teaches any lesson it is that clinical studies have no credibility and are engineered for victory, and unless real-world users can find a way to duplicate study engineering they should expect to experience dramatically lower success rates. Many people actually consider what happens in the 'real world' (anecdotal evidence) to be far more important than in the engineered laboratory under clinical conditions, as this is a true reflection of the drug or treatment, however anecdotal evidence about successful non-pharmaceutical treatments are ignored by the industry. As one scholar said, 'clinical data is easily manipulated, true anecdotal evidence is not'.

Media Hype
Clinical trials are cut short or stopped as soon as there is sufficient evidence to support a favourable outcome with a success story released to the press of usually just 1 patient who has responded well to the treatment. One good result is often all it takes to launch a media campaign to raise public awareness and demand for the latest 'wonder drug' however numerous successful cases for a particular complementary therapy are ignored by medical professionals who demand clinical trials to validate their claims. One very clear example of this practice involves cancer treatment, Sutent for kidney cancer was the subject of much media attention although it was only 20 to 40% effective in limited trials whereas the news from U.S government scientists that vitamin C injections stop cancer cells was greeted by the medical profession and Cancer Research with scorn both stating 'there is currently no evidence from clinical trials in humans that injecting vitamin C is an effective way to treat cancer'. The simple reason for this is because no trials have been done but more concerning is the fact Cancer Research who have an annual income of £468 million and spend £315 million on 'research' have no plans to conduct such trials in the future.

Monopoly
It costs £500m to bring a drug to market. Much of that is spent on randomised trials. The industry has these trials so spectacularly complicated and expensive that they are beyond the reach of governments, academia, and even small companies: only huge international pharmaceutical corporations can afford to run drugs trials now, and so corporations are in complete control of the information. This is bad, as the problems with Vioxx, SSRI's, and other 'killer' drugs have shown.

Often clinical 'results' often have little value, as it all depends on: who is doing the counting, how they are counting, what they are counting or measuring and what they have excluded. Click here for further details.

Even blockbuster drugs are not efficacious all the time and adverse drug reactions (ADRs) cause many untimely deaths. "Right now, even the best of medicines work in only 50% to 70% of the patients who get them," reported The Wall Street Journal in its April 16, 1999 issue. In addition, adverse drug reactions in U.S. hospitals may be responsible for more than 100,000 deaths nationwide each year, making it one of the leading causes of death, according to an article in the April 14, 1998 issue of The Journal of American Medical Association .

Exploiting GP Ignorance
Drugs need to be tested to qualify their claims and establish any harmful side-effects especially as many GP's know next to nothing about the powerful drugs they prescribe, leading medical experts admit, doctors know so little about the drugs that they are prescribing that their ignorance is harming – and sometimes killing – their patients, leading pharmacologists have said. GP's rely on what they are told about the drug by the pharmaceutical companies, which highlight the benefit and play down the risks.

Improper Use of Clinical Trials
Due to the public perception that clinical trials are in some way ‘beyond reproach' this trust has been abused in many cases as critics point out that clinical trials are often used to validate poor results in an attempt to market drugs which have little or no merit.

Many drugs have little to no benefit but are hyped or sold as an effective treatment. Anti-depressant tablets taken by millions of Britons may be a waste of time and money, research shows. An analysis of dozens of studies involving thousands of patients revealed that some of the most widely-prescribed anti-depressants work little better than dummy pills. The drugs studied - including Prozac, Seroxat and Efexor - were little more effective than placebos in improving the mental health in the majority of cases, the University of Hull research showed. Only in the most extreme depression did the tablets, which are taken by around two million Britons and have been linked to a host of side-effects including suicide, prove substantially superior in improving mental health.

Dr Tim Kendall, of the Royal College of Psychiatrists, described the results as "fantastically important". He added that one of the study's strengths lay in the inclusion of data which drug companies had chosen not to publicise - perhaps because it was less favourable than they would like. The study, published in the respected journal PLoS Medicine, suggests hundreds of thousands of Britons are needlessly taking powerful - and potentially dangerous - drugs.

Drug companies have to submit all their clinical evidence to drugs watchdogs in order to gain a licence but they do not have to publish negative results to the wider medical community. Researchers at the University of Hull used the Freedom of Information Act to obtain all clinical trial results submitted to the Food and Drug Administration including trials that had not been published.

Seroxat is the most frequently prescribed antidepressant in Britain and among the selective serotonin reuptake inhibitors ( SSRI ) group of drugs that account for 16 million prescriptions a year. It was subsequently banned for use in under18s.

Another well established unethical practice is the use of NRT. 'Manufacturers say NRT is 'clinically proven' to double a smoker's chances of giving up. - But critics point out that this is still only an improvement from 3% with no assistance at all, to 6% with NRT'. The use of the words 'clinically proven' is to imply that NRT actual works.

Critics also point to Champix tablets another aid to smoking cessation as an example of misleading data used to sell a product which during trials had to be supported by counselling sessions and the use of NRT to achieve an average 22% success rate over 12 weeks. The use of counselling and NRT was not disclosed to the public. In addition it was claimed during NICE approval that the drug was effective after a 12-week course, with 44 per cent of smokers managing to stop, which was clearly not the case.

Evidence Based Medicine - An Averaged Result
Evidence based medicine is the new buzz word for the medical community, however the quality of the 'evidence' can be highly questionable. Treatment effectiveness reported from clinical studies may be higher than that achieved in later routine clinical practice due to the closer patient monitoring during trials that leads to much higher compliance rates and so what happens in the 'real world' proves in many cases to be far more significant than under clinical conditions. The most common criticism is that EBM applies to populations, not to individuals and is based on an average percentage result, which is often quiet low. EBM is a generalised result and therefore not a 'gold standard'. Click here to read more about EBM.

Blocking Non- Pharmaceutical Addiction Treatments
Clinical trials are merely used as a smoke screen to block any non-pharmaceutical addiction treatments from being widely available even though trials are fraught with problems and manipulation and can not always be relied on as 'credible'. And hiding behind the excuse 'that no system is perfect' is simply not good enough, especially when these treatments are blocked from being widely used by using the argument, 'but it has not been clinically trialed'.

Detractors are very quick to point out there is ‘no scientific basis' for alternative addiction treatments and they are usually right as independent practitioners can not afford to carry out scientific research, a simple fact which continually escapes the vision of any detractor, in addition no journal wants to run their studies, dominated as they are by Big Pharma, and that most of their patients have already tried conventional allopathic medicine, with no improvement in their condition.

Double Standards
When a therapy is widely accepted by the medical profession, no scientific proof of effectiveness is required, and anecdotal evidence is accepted as valid. If an alternative therapy is contested by those physicians, however, they attack by demanding that the therapy in question be subjected to very expensive and time-consuming double-blind, placebo controlled trials. Medicare regulations also exclude the need for scientific proof for treatments that are utilized by a majority of physicians.

The most frequent criticism leveled by critics of non-traditional and alternative medical therapies is that new treatments are "unproven" because randomized, double-blind, controlled studies have not yet been done to prove effectiveness. Those criticisms ignore the fact that most medical procedures routinely performed in the practice of medicine are also unproven using those same criteria.

The Office of Technology Assessment, a branch of the United States Congress, with the help of an advisory board of eminent university faculty, has published a report with the conclusion that, " . . . only 10 to 20 percent of all procedures currently used in medical practice have been shown to be efficacious by controlled trial." Therefore, 80% to 90% of medical procedures routinely performed are unproven. That report further points out that the research which purports to prove effectiveness of the remaining 10% to 20% of medical procedures is largely flawed, and "many of the other procedures may not be efficacious."

But despite the lack of any scientific evidence whatsoever, millions of people around the world continue to use alternative medicine therefore the evidence must be of a personal nature and by recommendation to others. If people did not get a result from such treatments they would not use them or recommend them. But a leaked memo reveals that there is 'a co-ordinated campaign' to derail alternative therapies on the NHS and more recently funding is been withdrawal from NHS homeopathic hospitals.

The standard technique used to block any non-pharmaceutical addiction treatment from being tried (let alone widely used) is 'clinical trials' as to most the proposition seems insurmountable, however those in possession of that facts know firstly, that clinical trials are not all they claim to be, secondly there are enormous costs involved and thirdly the lack of a coherent infrastructure to conduct such trials makes the statement and argument almost inane.

Those who immediately state 'there is no scientific proof' do not understanding the complexities of obtaining scientific proof and their ignorance is often detrimental to the advancement of patient care. However there is a mountain of evidence for those who can be bothered to look. The newly published encyclopedia gathers a lot evidence on complementary medicine based on double-blind, placebo-controlled studies, regarded as the best assessment of whether a treatment is effective.

Public Interest
Clinical trials are only required for a new drugs to establish their effectiveness and safety however once a treatment is used and it becomes established through its use, then its track record proves its effectiveness and safety, if it was unsuccessful, it would not become an established treatment. Bio-Reduction Therapy for addiction should become a mainstream treatment as it is in the public interest and established by independent monitoring committees that it would be "unethical" to deprive patients of successful treatment.

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Source: House of Commons Health Committee -The Influence of the Pharmaceutical Industry Fourth Report of Session 2004–05.

About 650 million prescriptions are written each year by GPs alone. Medicines cost the NHS in England over £7 billion every year, 80%
of which is spent on branded (patented) products. However, there are disadvantages in the increasing use of and reliance on medicines. The
inappropriate or excessive use of medicines can cause distress, ill-health, hospitalisation and even death. Adverse drug reactions are responsible for about 5% of all admissions to hospitals in the UK.

Professor Pirohamed from the University of Liverpool, England, conducted a study into ADRs at the Liverpool Royal and Arrowe Park hospitals in 2001 - 02 and found that they cause 18,000 deaths and 600,000 hospital admissions in the UK every year, costing the NHS £466m per year. (British Medical Journal 3.7.04)

Allegations that clinical trials were not adequately designed – that they could be designed to show the new drug in the best light – and sometimes fail to indicate the true effects of a medicine on health outcomes relevant to the patient. We were informed of several high-profile cases of suppression of trial results.

We also heard of selective publication strategies and ghost-writing. The suppression of negative clinical trial findings leads to a body of evidence that does not reflect the true risk:benefit profile of the medicine in question. Guidance produced by NICE and others relies on the published evidence. If all the evidence is not published, or if negative findings are hidden, accurate guidance cannot be issued and prescribers cannot make truly evidence-based decisions.

As medicine progresses ‘from bench to bedside' over a period of many years — from initial development in the laboratory, through clinical testing, licensing, promotion to doctor and patient, and final prescription. The rationale for the very existence of major pharmaceutical companies is their ability to bring new and useful drugs to market. According to the ABPI, it takes an average of 12 years and over £500 million investment to
bring one new drug to patients.

Following initial drug discovery, NMEs undergo several phases of development involving all levels of research from molecules, cells and tissues, animal models, whole organs and systems to individuals and populations, as shown below:

Candidate/target selection – selection of a promising compound for development
Pre-clinical and non-clinical – necessary animal and bench testing before administration to humans plus start of tests which run concurrently with exposure to humans
Phase I – First Time In Man (FTIM); the first study of a new compound in humans, usually healthy volunteers
Phase II – Proof of concept (PoC); evidence of efficacy and safety in patients
Phase III – studies in a large population to generate safety and efficacy data for licence application
Licence Application (in UK) – filing all data to regulatory bodies (known as Marketing
Authorisation Application in Europe, New Drug Application – NDA – in US)
Phase IV – post-marketing studies.

Once licensed, medicines are intensely promoted to prescribers. The very high costs of developing a new drug make it vital that a company recoups its costs as quickly as possibly after licensing. Coupled with company-sponsored information from medical journals and supplements, ‘medical education’ materials, advertisements and sponsorship to attend conferences, workshops and other events, it is little wonder that prescribing practices are affected.

GPs are particular targets; they have more prescribing freedom than hospital specialists and their prescribing practices are not limited to hospital formularies. Promotion of medicines to patients and links between drug companies and patient organisations may add to this problem, leading patients to demand new drugs from their doctors. The problem is far less to do with any particular activity; rather the volume may distort prescribing practice. At the heart of the problem may be the trend for the industry to become ever more driven by its marketing force.

The most immediately worrying consequence of the problems described above is the unsafe use of drugs. Over-prescription of the COX-2 inhibitors, Vioxx and Celebrex, has been linked to thousands of deaths and many more cases of heart failure. These case illustrate a series of failures. Manufacturers are known to have suppressed certain trials for these drugs in the US and may have done the same in the UK. In addition, there were inadequacies in the licensing and post-marketing surveillance procedures and excessive promotion of the drugs to doctors.

What has been described as the ‘medicalisation’ of society – the belief that every problem requires medical treatment – may also be attributed in part to the activities of the pharmaceutical industry. While the pharmaceutical industry cannot be blamed for creating unhealthy reliance on, and over-use of, medicines, it has certainly exacerbated it. There has been a trend towards categorising more and more individuals as ‘abnormal’ or in need of drug treatment.

Government has rightly sought to assist industry, but it needs to do more to help pharmaceutical companies conduct research. They have to cope with confusing ethics approval procedures as well as relatively few adequately trained medical researchers or specialist research facilities.

The “fragmented and customer un-friendly nature of academic units and clinical services” was highlighted by the Royal College of General Practitioners (RCGP). The College also mentioned the “multiple layers of Research Ethics approval” that may be required and a “disparate, and sometimes competing, collection of clinical and academic teams” that may need to be brought together to achieve sufficient mass for large-scale
research.

Many large-scale Phase II and III trials are currently being carried out in Eastern Europe and elsewhere as a result of high costs imposed here.36 Dr Malcolm Boyce, who runs a London-based Contract Research Organisation (CRO), stressed: A strong pound sterling makes matters worse for overseas companies. For those reasons, companies are increasingly placing their Phase II and III trials outside the UK, in low cost areas such as Eastern Europe, Russia and India.

There are not enough trained medical researchers in the UK. This means there are too few individuals who can organise clinical trials or take part in a reviewing or implementation capacity. Prof Patrick Vallance, from University College London (UCL), told us "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".

Specialist facilities are also lacking. There are very few centres in which paediatric clinical trials may be effectively conducted, for example. This will become more relevant following the introduction of a new European Regulation on Paediatric Medicines in 2006, which will require more medicines to be licensed for use in children.

Witnesses pointed out that the NHS does not have a coherent approach to industry sponsored clinical trials and lacks the staff and specialist facilities in which to conduct them. This partly explains why a very low percentage of patients are enrolled in clinical trials in the UK; experience shows that recruitment can be increased substantially provided suitable policies and other measures are in place. For example, the National Cancer Research Network (NCRN) provides the NHS with the ‘infrastructure’ to support cancer clinical trials in England. It was established by the Department of Health in April 2001.

Since that date the number of patients taking part in cancer clinical trials in the UK has doubled. All results from NCRN trials are scrutinised by an Independent Data Monitoring Committee, which is the only body to see unblinded data. All results emerging from trials approved by the Clinical Trials Awards and Advisory Committee are published.