Select Committee on Health Fourth Report

8  Influence of the industry on key groups

158. Throughout this inquiry we received much evidence about the influence of the pharmaceutical industry. We were told that it permeates the health service, regulatory and licensing bodies, research institutions, Government and the public perception of medicines. The extent of this influence was pithily expressed by Dr Richard Horton, editor of The Lancet:

The pharmaceutical industry has been enormously successful at inter-digitating itself in the usual process of healthcare in the UK. It provides people; it provides equipment, services, buildings, facilities and, of course, hospitality. At almost every level of NHS care provision the pharmaceutical industry shapes the agenda and the practice of medicine.[102]

159. Here, we examine the claims made by witnesses about the industry's influence on the processes, groups and organisations that determine what medicines patients receive and how they are used. We also look at how those bodies which regulate the industry, and other potential countervailing forces, have responded. The key processes, groups and organisations include:

a)  Research, particularly research priorities and the conduct of medical research;

b)  Prescribers;

c)  Patients and patient organisations/medical charities;

d)  The drug regulatory system; and

e)  Government and associated bodies, including NICE.

Research into pharmaceuticals

Research priorities

160. The pharmaceutical industry determines to a great extent what drug research is carried out. Although expert groups may recommend that research be conducted in certain areas, there is no way of ensuring that companies themselves undertake or fund such research.[103] Approximately 90% of clinical drug trials and 70% of trials reported in major medical journals are conducted or commissioned by the pharmaceutical industry. As it does most of the research, inevitably the industry not only has a major effect on what gets researched, but also how it is researched and how results are interpreted and reported. [104]

161. The ABPI stated that the research conducted by the pharmaceutical industry is well-aligned to the priorities of the NHS. For example, some 43% of new medicines introduced over the past 10 years by the industry support four of the NHS's key health priorities - cancer, coronary heart disease, mental health and illnesses of the elderly.[105] Moreover, the industry explores therapeutic areas that have been overlooked by the medical profession, perhaps due to a feeling that 'lifestyle' problems rather than medical issues are involved. An area such as impotence, for example, was not traditionally investigated or treated to any extent by the medical profession, despite being of great concern to the individuals affected. In large part due to industry promotion and awareness campaigns, the issue is now more likely to be broached by patients with their GPs, and patients are more likely to receive treatment.[106]

162. The Government is fully aware of the pharmaceutical industry's dominance of drug research. An official from the Department of Trade and Industry (appearing alongside officials from the Department of Health) told us:

It is very much a question for the companies themselves what lines of research and development they choose to go down. Obviously, they go down roads where they think there is a real market for their products.[107]

163. The Government stated that it could not support any radically different approach to the present system of medicines development and expressed no concerns about its lack of influence on which drugs are developed by industry and which conditions are prioritised by it:

The Government believes that the current model - whereby medicines are developed by the private sector in response to what they perceive to be the demand of healthcare systems - is more effective and efficient than alternatives that could be considered (such as nationalising the drug industry, or by Government directing the research that the industry should undertake).[108]

164. Others were critical of the Government's approach. They claimed that industry's commitment to provide its shareholders with a good return on investment inhibited development of new and improved treatments in the areas of greatest medical need.[109] It was argued that drug innovation tended to be targeted at diseases of affluence rather than priority health needs, and was primarily directed towards developing products for established and emerging mass markets.[110] Furthermore, it was claimed that, unsurprisingly, there is little commercial interest in non-drug intervention and few clinical trials are carried out in this area.

165. We received evidence about such problems from many quarters. The RCGP noted that more money is now invested in research into the prevention of disease, such as drugs to reduce cholesterol, than into its treatment, which serves to divert investment away from the sick towards the well, away from the old towards the young and away from the poor towards the rich.[111] Similarly, Cancer Research UK was concerned that "there is little incentive for industry to conduct research aimed at small patient populations", and that there is little industry funding for research to determine the subgroups of patients that benefit from particular therapies.[112]

166. However, no one put forward a satisfactory, radically different system. Some witnesses thought that the NHS itself could undertake research on unprofitable areas to counter this problem. Others doubted this, because the NHS lacked robust mechanisms to identify its research priorities and had neither the infrastructure nor funding to undertake this type of clinical research.[113] On the other hand, there were suggestions for a number of relatively minor but useful changes. The Kings Fund argued that new forms of Public-Private Partnership were required in which the public interest would be given greater weight; it added that the Department of Health should use the same criteria for commissioning research on other treatments as on drugs.[114]

167. The RCGP stressed that the health service should encourage drug companies to align their research strategies with the public health aims of the NHS to a greater extent.[115] Lord Warner, Parliamentary Under Secretary of State, had some sympathy with this proposal:

… this is the kind of area you would touch on in a WHO recommended medicines policy. You would start to take a picture of where the areas of less involvement were and where the areas of excess involvement were. It seems to me to fit more easily into that kind of work rather than using the regulatory system to try to block entry.[116]

INNOVATION AND THERAPEUTIC ADVANCE

168. Over the last decade, there has been a drop in the rate of new molecular entities (NMEs) entering the market.[117] At the same time, there has been a high level of 'me-too' drugs - medicines that perform the same or almost the same therapeutic function as one or more products already available. There are no figures for the UK on rates of 'me-toos' that are approved, but evidence from the US, which is likely to be similar, shows this trend clearly. The FDA categorises the NMEs it reviews and approves for marketing into those that deserve priority review and those which receive a standard review. Priority review indicates that the FDA views the NME as offering a potentially significant therapeutic advance whereas standard review implies that the NME is a 'me-too'. Over the last 10 years or so, the proportion of NMEs offering significant therapeutic advance has varied between 23% and 54% (though other sources suggest that these figures overestimate the extent of useful drug innovation[118]). The predominant trend in the absolute number of drug innovations offering significant therapeutic advance is downward. The graph below shows the change in the number and percentage of NMEs granted priority review from 1996 to 2003.

Figure 7

(Source: www.fda.gov/cder/rdmt/NMEapps93-03.htm)

In short, fewer than half of the new drugs approved in the US can be expected to offer significant therapeutic advance and the number of new drugs is falling overall.

169. Several reasons for the high number of 'me-too' drugs and the fall in overall innovation were discussed. One explanation is that investigation into new drug classes or treatments aimed at unexplored illnesses is risky and expensive. AstraZeneca stated:

Pharmaceutical R&D is inherently risky, and tackling the diseases that are hard to cure is always going to be more risky than those we know more about.[119]

The industry argued that truly innovative medicines are often those which are later shown to have difficult side-effects. Industry representatives felt that this meant that they were, "damned if we do and…damned if we do not".[120]

170. Another theory is that 'me-too' drugs may be more profitable. Prof Patrick Vallance agreed that true innovation is risky, but added that greater commercial benefit may also be associated with the development of 'me-too' drugs.[121]

171. It is also alleged that drug companies have turned to 'me-toos' because they are dominated by their marketing force rather than their research teams.[122] Alternatively, several companies may pursue similar lines of research concurrently, and so often release related drugs within a relatively short space of time.[123]

172. Whatever the reason, it was claimed that the existence of too many similar drugs on the market does not benefit patients. Dr Ike Iheanacho, Editor of the DTB, told us:

The advent of new drugs often has very little to do with new cures. If you look at all the drugs that are licensed in a particular year and critically assess whether these actually constitute genuine innovations for patients, you would be surprised, I think, to find that relatively few of them do, and a decreasing number do.[124]

173. Often, however, the first drug in a therapeutic class does not always offer the greatest advance. It may be that the second or third drug of its type to enter the market is more efficacious or has fewer adverse side effects. 'Me-toos' are worthwhile, both because they can produce small therapeutic advantages (e.g. convenience) to patients and prescribers and because unexpected benefits may emerge. For example, Pfizer told us:

Many new medicines produce incremental improvements in patient care, the full impact of which may only be demonstrated after use by the NHS for some years.[125]

GSK concurred, stressing the benefits of small ongoing improvements in drug performance and of creating competition between different medicines to drive improvement. Specifically, the company argued:

Medicines with similar modes of action can have significant differences in terms of their efficacy, metabolism, tolerability and side-effects as well as duration and magnitude of therapeutic effect. The availability of different medicines for the same condition allows physicians to tailor therapies appropriately to meet individual patients' needs.[126]

174. Specific examples of occasions when a new medicine was not truly innovative but offered significant advantages to patients or to the organisation and delivery of healthcare over other drugs in its category were provided by the ABPI (see Table 1).

First to Market (condition)	Follower	Class	Benefit of follower
Accolate (asthma)	Singulair	Leukotriene modifier	More convenient dosing (once a day versus twice a day
Beconase (allergy)	Flixonase	Intranasal steroid	Potency; fewer adverse events
Zovirax (cold sores)	Valtrex	Herpes anti-viral	More convenient dosing
Mevacor (high cholesterol)	Lipitor	Cholesterol-lowering	Potency
Tagamet (heartburn)	Zantac	H2 antagonist	More convenient dosing; fewer drug interactions
Cozaar (high blood pressure)	Diovan	Angiotensin receptor blocker	Potency

Table 1: Benefits of incremental innovation[127]

175. The existence of a number of similar drugs to treat a given condition brings advantages. One drug might be best suited to one group of patients, another to another. However, there are disadvantages when there are a large number of drugs. It is difficult for non-specialists to stay well-informed about more than two or three drugs in any one therapeutic class. Moreover, comparative studies would be needed to assess the relative efficacy and safety of the available drugs, but these are not usually done.

CONDUCT OF MEDICAL RESEARCH

176. There is widespread agreement that a great deal of first-class research is undertaken by the industry, but witnesses made some criticisms of its conduct. These included:

a)  Limited information given to trial participants;

b)  Exposure of participants to unacceptable risks;

c)  Use of ineffective comparator drugs and their inappropriate dosage;

d)  The duplication of research; and

e)  Lack of studies of the effects of drugs given in combination.

Much of the criticism was essentially of the lack of transparency and the difficulties for doctors and others in assessing the research which is undertaken.

177. The conduct of trials that do not yield evidence on which decisions can objectively be made was of particular concern. Five out of six systematic reviews published in the last two years have shown that research that is sponsored by a drug manufacturer is more likely to yield a positive result for the company's product than research that is independently sponsored.[128]

178. Patients eligible for clinical trials are required to sign consent forms to confirm that they are aware of the trial's aims and agree to take part. RECs are obliged to ensure that adequate information is provided to patients about the trials in which they participate, such as whether it is a public sector trial, a contract, a licensing study, whether it is being done through the NHS or in a private capacity where the NHS is not involved.[129] Several witnesses argued that, currently, the information patients receive before they enter a trial fails to adequately disclose the risks they might incur and how the data collected from their participation might be used.[130] The consent forms do not inform patients that the raw data may be maintained by the industry, not made available to the general public or even reviewed by the regulatory authorities. Prof David Healy stated:

The industry takes the data from you, they let you take all the risks, they conceal the data… they take out the good bits of the data, the bits that suit them, and market that back to us and call it science, when clearly it is not.[131]

179. Furthermore, under ICH, even when conducting clinical trials with new drugs intended for chronic use to treat non-life-threatening conditions, patients (and healthy volunteers) may be exposed to such drugs for six months before long-term animal studies are completed to determine whether the drugs cause cancer. The responses we received from the MHRA and industry did not indicate that patients are made aware of this upon entry into trials nor that the MHRA has given serious consideration to whether this is ethically justified.[132]

180. Clinical trials can provide very important data about drugs but they do not always provide the clear information on drug safety and therapeutic effectiveness that is needed. It is claimed that many clinical trials are designed to fit desired outcomes or, worse, primarily for marketing purposes, rather than the advance of health care or scientific understanding. Dr Richard Nicholson, editor of the Bulletin of Medical Ethics, told us:

A clinical trial was proposed to my ethics committee some years ago of Vioxx versus naproxen and we wondered to ourselves why on earth Merck want to compare this with naproxen. They did not give us the details initially and then when we asked and asked, we finally found out that they had already carried out major trials against the two major anti-inflammatory drugs…and found absolutely no advantage of their drug. They were hoping that by comparing it to naproxen, which had just five per cent of the market, they would be able to show an advantage.[133]

181. In order for a drug to be licensed it has to show that it is more effective than a placebo, usually in two controlled trials. However, according to Prof Healy, companies can run 10 or more trials in carefully selected samples using instruments designed to pick up any effect and, even if the results show that the drug failed to beat placebo in the majority of trials, the drug may still be licensed. The trials producing negative results are commonly identified as failed trials rather than drug failures.[134]

182. Whether the experimental drug is compared to placebo or a comparator drug will affect the outcome. Common flaws in trial design include the use of inappropriate comparator drugs, such as those associated with a higher risk of side-effects than others in the therapeutic group. Selection of dosage may also be used to skew results. Administration of a comparator drug in unduly low doses may result in reduced levels of efficacy. Administration of the comparator drug at relatively high dosages might make the test drug appear safer than it really is. These and other methods of trial design may show the new drug in a misleadingly positive light.[135]

183. Also of concern, because it may lead to an over-estimate of the drug benefit, is reliance on surrogate markers of efficacy or disease (in one case, higher numbers of extra abnormal heartbeats were assumed to correlate with increased risk of death[136]). However, such markers may not be directly relevant to treatment outcomes (in this case, drugs used to reduce the number of heartbeats were actually associated with increased mortality). The use of combined clinical outcomes can also be problematic, making it difficult to assess which end point has really changed, while the use of inappropriate safety markers makes extrapolation to safety in clinical practice even harder. Cancer Research UK criticised the industry for not investigating the wider effects of drugs and focusing on specific outcomes.[137]

184. Several witnesses were also concerned about the duplication of research.[138] Some organisations make considerable efforts to avoid this problem: the MRC requires groups seeking financial support to identify existing evidence before applying, to show that the new research builds on previous lines of investigation.[139] On the other hand, others either did not attempt to find out about previous research or could not get access to it.[140] Sir Iain Chalmers argued that a systematic review of existing evidence prior to the planning and reporting of new clinical trials should be mandatory.[141] The following example shows what can happen if such a review is not undertaken:

After reviewing the experience of thousands of patients who had participated in controlled trials of new calcium-blocking drugs given to people experiencing a stroke, a Dutch team found no evidence to support the increasing use of these drugs in practice, or for the large numbers of clinical trials that had been performed…Furthermore, when they subsequently prepared a systematic review of the relevant animal studies they found that these had never suggested that the drug would be useful in humans.[142]

185. While in Sydney, we heard from the Australian Federation of AIDS Organisations about the reluctance of the pharmaceutical industry to undertake studies of existing drugs given in combination. Other organisations often lack the funding to undertake this work. Cancer Research UK told us:

Advances in oncology should not only be considered in the context of individual drugs, but also the use of these drugs in combination with other drugs, surgical techniques or radiotherapy. We appreciate that for commercial or legal reasons it is often difficult for the pharmaceutical industry to make drugs available for clinical trials evaluating combinations of novel treatments. Nevertheless, it is essential that the UK finds a way to overcome this barrier for the best patient outcomes from both commercially and publicly funded research.[143]

186. The key to solving many of these problems is greater transparency.[144] Prescribers and particularly those involved in compiling formularies need to understand better how medical research is conducted and results are presented. Witnesses suggested that RECs might have an important role to play in the design of trials, ensuring the use of clinically relevant end points, the meaningful comparison of drugs and other approaches and the proper disclosure of clinical trial results, taking account of both positive and negative findings.[145] A requirement that the applicant should identify existing research would ensure trials were not duplicated.

187. The major impetus for greater transparency with medicines came from a lawsuit brought in August 2004 by the New York State Attorney General against GSK, alleging the company had concealed negative clinical trial results. As part of the settlement, GSK agreed to set up a public register of all clinical trials on all of its drugs.[146] This breached a long-standing convention, vigorously upheld by the regulators, whereby clinical trial results were regarded as company property and commercially confidential. Other companies soon followed suit, and the industry (through national trade associations) made proposals in January 2005 to establish a clinical trials register before the end of 2005.

188. Information on every trial involving patients will be posted at inception, although the full details of the register are not yet clear. Whether the register will include trials carried out in every country and who will be responsible for maintaining the register have not yet been divulged. Witnesses have stated that the results of trials involving drugs that are approved for marketing by the MHRA will be posted on the register and publicly accessible within one year of launch.[147] However, the period immediately after launch is when doctors prescribing the drug for the first time are most in need of such information. Effective drug use depends on awareness of the strengths and weaknesses of evidence on which the manufacturer relies. We are also concerned that the maintenance of the clinical trials register by the pharmaceutical industry itself will not inspire confidence from either the public or healthcare professionals. We make recommendations regarding the clinical trials register in Chapter 9.

189. Priorities for research into medicines inevitably reflect the interests of the pharmaceutical companies and are not necessarily well aligned with the medical needs of all patients. The industry will continue to undertake the bulk of research in this area, but there are improvements which could be made. We welcome Lord Warner's recognition of this and look forward to his proposals to align more closely the drug companies' research strategies with the public health aims of the NHS.

190. However it occurs, the presence of many 'me-too' drugs on the market creates difficulties for prescribers and the NHS. Although this is a considerable problem, we were given no obvious solution. We expect that there will continue to be a large number of me-too drugs. The National Prescribing Centre and others should particularly consider issuing independent advice in areas where many 'me-toos' exist.

191. Much excellent clinical science takes place within the industry and elsewhere, but the current system of clinical testing provides ample opportunities for bias. Too many problems appear to persist unnoticed or unacknowledged by the organisations that are central to the co-ordination, conduct and review of the clinical trials. There is a need for more transparency and we welcome the contribution that the proposed clinical trials register should make to this approach. The regulators must check that research is designed to provide objective evidence of a drug's efficacy and safety at the time of licensing.

Prescribers

192. Medicines information is provided in a variety of ways, many of which are welcomed by prescribers. Drug companies use representatives, advertising, journal articles and supplements, magazines and other media to communicate the benefits of their products.

193. According to the ABPI, "The provision of accurate information through marketing to health professionals is an essential element of a successful pharmaceutical business and is conducted in an ethical, responsible and professional manner." It added:

Our goal - to bring to patients life-enhancing medicines - is not only necessary but noble, and there is no reason why the industry should not use all legitimate means to advance it.[148]

194. On the other hand, some witnesses had serious concerns about how drug companies communicate with doctors. Equally worrying was that some doctors were readily influenced by the promotional activities of the industry.[149] We look below at the use of journals, drug company promotional activities and advertising.

THE USE OF JOURNALS

195. Medical journals, which carry articles relating to clinical trials as well as reviews, opinion pieces, case studies and letters, are an important source of information for healthcare professionals. They are also subject to influence by the pharmaceutical industry. It is alleged that too many articles do not present an objective assessment of the merits of a medicine; for instance, we were told that many are the work of ghost-writers and that there is a bias towards submission of articles that show new drugs in a positive light.

Ghost-writing

196. Approximately 75% of clinical trials published in The Lancet, the New England Journal of Medicine and the Journal of the American Medical Association are industry funded. This is only to be expected since drug companies conduct most drug research, but more surprising was the claim by one witness that over 50% of articles appearing in these journals may also be ghost-written.[150] Ghost-writing is the process by which articles are written by professional medical writers but appear under the name of independent physicians or academics, who are paid as if they had written the article. When the ghost-writer helps a busy doctor write up his research this is an acceptable practice. The key question is whether and to what extent these authors designed and conducted the studies, then independently analysed the original data and critically reviewed the article. It is clear this is often not the case. This is of much concern, since such articles tend to be targeted at prestigious journals; if published, they are cited more often than articles written by authors not linked to the sponsoring drug company.[151]

197. The practice of ghost-writing articles, mainly in the form of reviews and editorials, on the off-label use of licensed medicines[152] was described by Dr Horton, the editor of The Lancet as "standard operating procedure" and he warned of "biased, over-interpreted and misreported research findings." He added:

A very good example, to be very specific, is this whole story surrounding SSRIs. … it is probably the best example where the companies have been very clever at seeding the literature with ghost-written editorials and review papers that promote off-label use of these drugs. You can dress up in an academic argument about "would this drug X be quite useful for this condition; why?" and have an interesting debate about that. What it does in the mind of the prescriber is to think: "Hah, this patient with this condition, perhaps I will try it". It is an off-label use and that is how you had two and a half million scripts a couple of years ago for SSRIs in under-18s with no licensed indication for it.[153]

198. Witnesses from both GSK and AstraZeneca strongly denied that ghost-writing was practiced in their respective companies. Dr Stuart Dollow, from GSK, went as far as to state: "The issue of ghost-writing, as alleged, is not something I recognise at all."[154] However, there may be some confusion about what the term 'ghost-writing' actually means. Dr John Patterson, from AstraZeneca, told us:

The way that it works with professional writers is that they will possibly produce a first draft which will then be reviewed by the author or authors or a committee and who will have significant input into that drafting and how it should then subsequently go forward.[155]

199. Sir Iain Chalmers recommended that the industry adhere to guidelines set out in Good Publication Practice for Pharmaceutical Companies[156] that aim to ensure that publications are produced in a responsible and ethical manner. They include the need to publish results of all clinical trials of marketed products, and to report them in a balanced and objective manner. Authors should all have access to the statistical reports and data supporting each publication. These guidelines are clear on the subject of authorship and the role of professional medical writers:

• The named author/contributors must determine the content of the publication and retain responsibility for it;
• The named author/contributors should be given adequate time to comment on an early draft of the manuscript and approve the final version;
• The medical writer should remain in close and frequent contact with the authors throughout the development of the manuscript; and
• The contribution of the medical writer should be acknowledged.

200. These guidelines leave no room for ghost-writing, in the form of researchers or academics who put their names to articles but have not seen the raw data to which the article refers.[157] Until good publication practice is put in place for all companies, Sir Iain emphasised:

I think it is a very, very serious situation. In other words, if companies are really genuine about wishing to adopt the sort of publication practices [that do not allow ghost-writing], then they should sign up to that guideline.[158]

201. However, it would be quite wrong to only blame the industry for the excesses of ghost-writing. So-called 'key opinion leaders' agree to lend their name to articles they have not written and may receive a significant fee for doing so. Dr Peter Wilmshurst, a consultant cardiologist told us about the size of fees:

GPs are sceptical about what reps tell them. They are influenced more by opinion leaders, which is why the pharmaceutical industry pays opinion leaders so much. The senior people can get £5,000 plus for one hour's talk to their colleagues in cardiology, and that is obviously because that is how much the pharmaceutical industry rates those people.[159]

Publication bias

202. Several witnesses referred to the fact that studies which reveal a positive result for an experimental treatment are more likely to be published than those showing equivocal or inferior findings.[160] GSK agreed but suggested this might be due to journals' editorial policies:

Unfortunately when the main study hypothesis is not proven, or no difference between treatments in the study is seen, medical journals are often reticent to publish studies, despite the submission of manuscripts. As a result there is an inherent barrier to the distribution of data from "negative" studies.[161]

203. On the other hand, allegations that several studies showing negative or equivalent findings for Seroxat (a GSK drug) were suppressed provide an alternative explanation. We were told that publication bias is more likely to arise from drug companies' reluctance to submit articles showing their products in a less that favourable light.[162] Studies comparing all clinical trials have shown that, overall, pharmaceutically sponsored trials are less likely to be published than trials commissioned by other organisations.[163] As Cancer Research UK emphasised:

This is of concern as a failure to publish can lead to overestimation of treatment effects, which has the potential to lead to inappropriate treatment decisions.[164]

204. There is no current obligation on drug companies to publish all trial findings, although individual companies may do so. AstraZeneca's policy, for example, specifically states that selective publication is not acceptable.[165] According to the industry, the proposed clinical trials register[166] will require that the results of all trials on marketed drugs are made available, but only after marketing approval has been given.

205. The number of articles written about specific treatments also contributes to publication bias. Drug company marketing departments often have a target number of publications on their products to achieve each year. Supplements to medical journals, which contain several articles relating to a single drug, procedure or disease area, are an easy way for the company to attain this goal. Often based on a sponsored symposium at a conference, or company-organised 'workshop' that experts are paid to attend, the articles contained in the supplement might be neither written by the experts themselves nor peer-reviewed by the journal editors. The pharmaceutical companies pay a high price to produce supplements bearing a journal's imprint. Once published, the supplements may be reprinted thousands of times, again at the expense of the sponsoring company. The reprints may be distributed to doctors by visiting company representatives and are usually displayed on the company's stands at related conferences. Sale of reprints represents a major source of income for many journals and an important means of marketing for the pharmaceutical industry. The scientific value of these publications can be limited, however:

In one email that The Lancet has seen about a supplement, the sponsor argued that the more the article was peer reviewed the less value the supplement would be to the company - showing clearly the marketing goals rather than the scientific endeavour that lies behind supplement publishing.[167]

206. In addition, Dr Horton described how journalists working on magazines distributed free (to GPs in particular) may have their travel and hospitality paid in order to attend conferences to report specific research findings. He told us:

They will go with the express purpose of covering the conference but particularly to cover the conference about the products made by the company which is paying for their travel…They will go, they will go to the satellite symposium, they will write up the story and that will then get published in their newspaper. That is what the general practitioner will read. Again, there is no identification that the travel was paid for by the company, no identification that this journalist was there for just 24 hours to go to the sponsored satellite symposium, no indication that the way that study has been reported is misleading. The quality control here is appalling.[168]

207. The "seeding" of this information in literature received by prescribers, and GPs in particular, then "has enormous impact on prescribing habits".[169]

208. These practices, including of ghost-writing and non-publication of negative results, therefore lead to a body of written evidence that may not reflect the true safety and efficacy profile of the drug in question. This may result in potentially dangerous prescribing decisions, as the Royal College of Psychiatrists describes:

If pharmaceutical companies only publish clinical research that is positive and hold back on publishing clinical research which is negative, then patients may well be given treatments which, unknown to either the patient or the doctor, are likely to do more harm than good.[170]

DRUG COMPANY PROMOTIONAL ACTIVITIES

209. Research conducted by Which? has shown that GPs may often not have time to keep themselves abreast of drug developments and may therefore place a high value on their relationships with drug company representatives as a source of information and education.[171] AstraZeneca argued:

Interaction with sales representatives enables healthcare professionals to gain access to the latest information and ensures their continuing professional education…. Representatives educate [healthcare professionals] on the correct use of the Company's medicines through reference to data and licensed indications.[172]

210. According to the ABPI's Code of Practice, visits should not normally exceed three annually but a GP, Dr Des Spence from the group 'No Free Lunch', told us that the cumulative effect was such that drug company representatives' contact with doctors "can almost be on a daily basis".[173] The potential benefits of contact on prescribing habits are not in doubt, however. For example, statistics from IMS Health, an organisation that collects and analyses healthcare data, indicated that the promotion of drugs by representatives increased uptake of NICE guidance:

Representative promotion of NICE approved products can have a supportive effect. The growth of prescriptions in those doctors who received calls from representatives was larger than in those doctors who had not received any calls.[174]

211. The timing of the provision of medicines information and promotion is pertinent. The first few months following drug launch is a crucial period in medicines promotion, during which the industry attempts to establish the market position of a drug; yet this period of explosive marketing occurs at precisely the period in which we know least about the effects of a drug in the community. The MHRA chairman told us that the main lesson learned from investigation into the use of SSRI antidepressants, for example, was that the safety profile of a medicine, when first licensed, "is not very well known".[175]

212. Information is also provided by non-industry sources, such as the National Prescribing Centre, DTB, prescribing advisers and committees. Lord Warner described it as "vast".[176] Based on the evidence we have received, however, the volume of such information pales in comparison to the information received, directly and indirectly, from the pharmaceutical industry. According to Dr Andrew Herxheimer:

The volume [of promotion] is huge. It is not just the mail and the representatives and the meetings, but it penetrates through ghost-written articles and through the consultants who are paid by companies; it creates an enveloping atmosphere that you do not know you are in.[177]

213. Independent information has been described as 'limping along' behind commercially driven information. Not only is it at much lower volumes but it is not so precisely targeted as information from the companies. The imbalance, which is mainly due to the disparity in available funding, is overwhelming.[178] The industry spends £1.65 billion a year on marketing and promotional efforts while the Department of Health spends £4.5 million.[179]

214. In addition to receiving visits from company representatives, doctors are invited to attend sponsored events, meetings, workshops and symposia, which may be little more than "hospitality masquerading as education".[180] In combination with company representative visits, they have a major effect on prescribing practice. When questioned, however, doctors usually deny that drug promotion affects their own prescribing practices (although they do believe that it affects other doctors' prescribing habits).[181]

PROMOTIONAL CAMPAIGNS: TARGETING OF HEALTHCARE PROFESSIONALS

215. Marketing and promotional activity in the pharmaceutical industry has increased in recent years. Since 1995, research staff numbers have fallen by 2% while marketing staff numbers have increased dramatically.[182] Much competition appears to be based on marketing techniques and PR.

216. We commissioned an analysis by the Institute of Social Marketing (ISM) at the University of Stirling of samples of company information relating to selected promotional campaigns, some of which may already have been considered by the PMCPA for alleged breaches of the ABPI Code of Practice. The analysis revealed the targeting of specific healthcare professionals, such as GPs and practice nurses[183]. The documents obtained were analysed around key themes taken from the Code:

• Servicing the emotional needs of health professionals and the use of branding;
• Creation of 'need' within the medical profession;
• The use of public relations to counteract negative publicity.

217. The documents were also analysed for evidence of targeting patients and the general public. This is discussed in the next section. The companies, the ABPI and PMCPA were given the opportunity to comment on the analysis. We regret that we had to ask for a speedy response in order to publish this report before the election and are grateful for their swift attention to this matter.[184]

Servicing the emotional needs of health professionals

218. A key theme, consistently emerging from the sample documents examined, was the importance attached to identifying the emotional needs of health professionals and designing marketing activity to satisfy such needs. Brands were deliberately associated with attributes that could not be described as 'objective and unambiguous' as required by the Code of Practice, including, "energetic", "passionate", "desirable", "sexy", "romantic", "intimate" and "relaxed". In subsequent evidence, the PMCPA stated that "emotional messages" may be used as long as the material is "factual [and] balanced".[185]

219. The industry also recognised the pressure GPs are under when prescribing and the difficulties they face on a daily basis, such as the risk associated with prescribing the correct medication, perceived difficulties in patient compliance and the risk of criticism from peers. Such worries and concerns were exploited by the industry to promote use of their brands by conveying "trust", "confidence" and "reassurance". Slogans were chosen to tap into insight of hassle of "how difficult the patients will be to treat", "likelihood of compliance", and the emotional "button" of risk.

Creation of need within the medical profession

220. The documents highlighted the tactics employed by pharmaceutical companies to create a need among the medical profession before the launch of specific brands. For example, one company devised a five-stage mail-out to doctors for the launch of a new brand. The first two stages were used to create a need for new treatments and did not include any information about, or branding of, the new product. The remaining three stages were used to introduce the new brand and outline its safety and efficacy and the impression that it was being widely prescribed.

The use of PR to counter negative publicity

221. Public relations is particularly important during times of bad publicity, especially when the safety of brands is called into question. Considerable resources are invested into building long-term, sustainable relationships with stakeholders and 'key opinion leaders' and journalists. These relationships are used to promote the use of certain brands and counter concerns relating to safety. Efforts to undermine critical voices in particular were identified, under terms of "issues management". In later evidence, in response to the ISM's memorandum, Pfizer stated that PR is entirely legitimate and can "help to educate and inform". According to the PMCPA, PR activities may include "placing articles in the lay press, TV documentaries, soap operas etc".[186] The following example of a project worksheet shows the marketing campaign process and the targeting of consumers and the press.

2. Drug company project worksheet

Objectives

• To build advocacy with consumer press to secure greater share of voice
• To increase understanding of the importance of visiting GPs for [disease marker] checks
• To create a positive press environment for BRAND X in 2005
• To generate awareness of the positive risk: benefit of BRAND X
• To secure publication of three articles within the consumer media by end of March 2005

Description

• Identify target publications within the [publishing house]
• Liaison with publishing house to confirm and arrange logistics
• Liaison with design company to develop press materials including take home booklet
• Liaison with key journalists to confirm attendance
• Liaison with XXX to confirm participation
• Identification and recruitment of a practice nurse and GP to conduct [disease marker] tests and provide medical information
• Ongoing liaison with attendees to secure media coverage

Outputs/Deliverables

• Attendance of eight key journalists at the session
• Three articles in consumer press agreed for publication by March 2005 (availability of case studies will support securing coverage)
• 80% key message delivery within coverage

Outcomes

• Positive press environment for BRAND X
• Increased understanding of the need to approach GPs for information on [disease marker] monitoring
• Increased understanding of the centrality of [disease marker] management in reducing the risk of [condition]
• Strengthened relationships with target journalists to ensure BRAND X possesses a greater share of voice in the future

Target Audiences

• Consumer journalists
• Consumers

222. While it is clear that the Code of Practice relates only to literature intended for external use, and many of the documents examined were for internal circulation only, the intention of the companies is clear.

ADVERTISING

223. We were told that advertising to prescribers is conducted on a huge scale; it is targeted and orchestrated to increase prescription of particular drugs in particular groups. According to Dr Herxheimer, the influence of the industry:

…is mediated…by the huge volume of pharmaceutical promotion, direct and indirect …and intense public relations activity. Competition in the industry is based far more on innovative marketing methods and public relations than on the effectiveness and safety of its products.[187]

224. The main concerns are not so much to do with the accuracy of individual advertisements but with the scale of medicines advertising, as Dr Herxheimer indicated, and the process and duration of the complaints procedure, which was frequently referred to during the inquiry.

225. Which? cited the following case to illustrate the inadequacy of the current pre-vetting and complaints system for prescription-only medicines advertising:

In April 2002, Schering Health Care (Schering) launched Yasmin in the UK, claiming, in an advertisement to healthcare professionals, that the medicine was "the pill for well-being" and that "Yasmin is different in many ways. It has been shown repeatedly to have no associated weight gain. In addition, Yasmin has a demonstrable effect on PM (pre-menstrual) symptoms and on skin condition…Women feel well on Yasmin. Make a difference to their lives and prescribe Yasmin."

DTB published a review of Yasmin in August 2002, which concluded that "we believe that the claim that Yasmin 'is the pill for well-being' is unjustified and misleading and should be withdrawn." In response, Schering threatened (on September 9 2002) to sue DTB for defamation.

Prompted by DTB's article, the PMCPA began an investigation into the promotion of Yasmin and concluded (on September 18 2002) that Schering had breached the Authority's Code of Practice on several counts. As a result, the company withdrew its threat to sue DTB. The PMCPA later confirmed its initial findings (after rejecting an appeal by Schering), in concluding (on 22 November 2002) that the company had breached the PMCPA's Code of Practice on 11 separate counts.

The Yasmin advertisement had originally been vetted by the MCA (now the MHRA) in late Spring 2002. The MCA told Schering (in a letter dated 13 June 2002) that its promotional claims for Yasmin were acceptable. The findings of DTB (subsequently echoed in the PMCPA investigation) suggest a serious failure in the MCA's original vetting of the advertisement.

Although the PMCPA first ruled against the Yasmin advertisement in September 2002, the delayed action by the MCA allowed the company to continue the misleading promotion unchecked for around two months after DTB first highlighted the misleading advertisement (and in total, for around six months from the product's launch).[188]

226. The MCA did not know that the PMCPA was investigating DTB's concerns until alerted by DTB itself, indicating a lack of coordination or communication between the two. Following DTB's article in August 2002, the MCA undertook a second assessment of Schering's claims for Yasmin, the results of which were released in a letter to DTB on 6 December 2002. This time, the MCA found Schering's claims unacceptable and asked the company to withdraw the advertising and to publish a corrective statement in the journals that had carried the original advertisement. The correction appeared in February 2003, which was around 10 months after the launch of Yasmin.

227. The ABPI stated that, "like the House of Commons, the pharmaceutical industry works well within self-regulation,"[189] but the examples cited to us of breaches of advertising regulations, cover-up of negative medicines information and provision of misleading information to prescribers suggest that self-regulation is not working satisfactorily.

228. The delay in investigation and issue of corrective statements, which are not always mandatory, is clearly unacceptable. Where such statements are issued, their effect on the original impact of the campaign is usually limited. Patients may be already taking the new medicine and are therefore unlikely to be switched back to their original treatment. Mr Mike Paling, the director of a large advertising company, stated:

I would have thought they would be able to adjudicate much more quickly than that. As I said, there is not a vast amount of complaints so there are not a thousand complaints sitting waiting. …I think if there is a complaint, particularly if it is going to be upheld, it should be adjudicated and sorted out very quickly.[190]

229. Small alterations to advertising slogans may also be requested - from, for example "Protection for hearts" to "Help protect your heart". This case, involving Zocor Heart-Pro, was one on which the MHRA took a "very serious view".[191] We do not consider this a very serious sanction.

230. Promotional activity takes place on a huge scale. Nevertheless, it is impossible to solely blame the industry because some doctors do not take enough care when prescribing. Although doctors are taught clinical pharmacology at medical school, the quality of teaching on evaluation of clinical trial data and drug marketing techniques seems to be highly variable and prescribers often lack the time or skills to distinguish between weak and strong clinical studies and to evaluate critically the claims made. The 'How to use a drug' lectures that form part of the Clinical Pharmacology course at UCL Medical School include essential information about the processes needed to evaluate data on new medicines fairly and effectively. Areas covered include the power of the trial and size of treatment effect as well as factors such as conflicts of interest, the use of 'rentaquote' doctors and how new treatments are reported in the lay press.[192] However, it would not be safe to assume that all doctors receive such training.

231. The volume of information received by prescribers and the accuracy (data interpretation, completeness, comparison with existing treatments) of the information provided were questioned by many witnesses.[193]. However, some doctors' failure to recognise that promotional techniques used by the pharmaceutical industry have any effect on their decision-making suggests a dangerous complacency that needs to be addressed. The enormous variation in prescribing of some medicines illustrates this point.

232. The aggressive promotion of medicines shortly after launch, the sheer volume of information that is received in its many forms by prescribers and the "promotional hospitality masquerading as education", in the absence of effective countervailing forces, all contribute to the inappropriate prescription of medicines.

233. Ghost-writing, in conjunction with suppression of negative trial results, is harmful. If prescribers do not have access to fair and accurate accounts of clinical trials they cannot be expected to make informed prescribing decisions. Guidelines on the subject of authorship and the role of professional medical writers (quoted in Paragraph 199) must be followed.

234. At the same time, the blame for inadequate or misinformed prescribing decisions does not only lie with the pharmaceutical industry, but with doctors and other prescribers who do not keep abreast of medicines information and are sometimes too willing to accept hospitality from the industry and act uncritically on the information supplied by the drug companies.

3. Over-promotion and over-prescription of benzodiazepines: legacy of a bad campaign

Although much has changed in drug regulation and prescribing practice in the last decade, the over-prescription and subsequent widespread adverse events and 'therapeutic' dependence on benzodiazepines is perhaps a good illustration of the dangers of drug promotion by the pharmaceutical industry and under-regulation or over-reliance on industry self-regulation.

Benzodiazepines, which include Valium, Librium, Mogadon and Ativan, were introduced as a replacement for barbiturates, which were found to cause dependence, were associated with severe withdrawal symptoms (such as seizures and hallucinations) and lethal in overdose. Benzodiazepines were first marketed in the early 1960s and were widely prescribed until the 1980s for a variety of conditions, including anxiety and panic disorders and insomnia.

Despite anecdotal evidence and some clinical trial data to the contrary, most large-scale (industry-sponsored) trials led people to believe that benzodiazepines did not cause dependence and that they were much safer overall, particularly in overdose, than barbiturates. More and more anxious or sleepless patients were therefore prescribed them as a treatment. In 1979, 30 million prescriptions for benzodiazepines were written in the UK.[194]

A report in 1980 by the Committee on the Review of Medicines (a body since abolished) stated that benzodiazepines tended to lose their sleep-promoting properties after approximately two weeks of continuous treatment and to lose their anti-anxiety properties after approximately four months' treatment. However, the results of short-term trials were extrapolated and many patients continued being prescribed them for years on end. There is also evidence that the dosages used were far above those necessary to treat the conditions intended.

The side-effects of benzodiazepine treatment are now known to include excessive sedation, decreased attention, amnesia and sometimes intractable dependence. Abrupt cessation can lead to severe withdrawal symptoms, including convulsions in some patients. Short-term treatment and a long tapering period is now recommended to limit these risks.

It has been estimated that around 500,000 people in the UK were dependent on benzodiazepines in the mid-80s. High current levels of addiction (up to 1.5 million) have also been suggested. According to Mr Barry Haslam, who was addicted to benzodiazepines for 10 years:

I could take members of the Committee to Oldham people who have been benzo addicts for 20-40 years…so much for efficacy! The only reason they are still taking their drugs is to keep withdrawal symptoms to a minimum.[195]

A large-scale legal action was brought against the manufacturers of Ativan (John Wyeth) and of Valium, Mogadon and Librium (Roche) in 1986. By 1992, over 12,000 claimants were involved in this litigation. However, most claimants were funded under the Legal Aid scheme and the Board withdrew this funding in 1996. To date, no redress against the companies involved has been made, and the legacy of an influential promotional campaign in the 1960s continues.

There is a lack of support and rehabilitation services available for people still addicted to benzodiazepine drugs, many of whom may have been first prescribed them in the 1970s or 1980s. Not a single NHS benzodiazepine rehabilitation clinic exists in the UK to this day.

Patients

235. There is much contact between the pharmaceutical industry and the general public and the extent is increasing. The industry is obliged by law to provide information to the public in the form of the patient information leaflet (PIL) supplied with all medicines. OTC drugs may be advertised directly to the public; prescription-only medicines may not. However, we were informed that promotional campaigns for prescription-only medicines were also targeted to patients.

236. In this section we examine the information that is received by patients, in the form of the PIL, through direct-to-consumer advertising (DTCA), disease awareness campaigns and other promotional campaigns. We also look at the relationship between industry and patient organisations and charities.

INFORMATION TO PATIENTS: THE INTERNET AND PILS

237. Patients (and their carers) clearly wish to be informed about their condition but find it difficult to obtain independent specialist information. The wealth of information available on the Internet reflects this demand. The mental health charity Mind summed up the situation:

Research with users of medication consistently shows a demand for information, which is often not met by the prescriber. For example, 61 per cent of respondents to Mind's Yellow Card survey about drug side effects (Cobb, 2001) said they did not receive enough information when they were prescribed medication.[196]

238. Many companies stressed frustration at their inability to provide information directly to patients through their information service when much unofficial and unchecked information is on the Internet and elsewhere. According to AstraZeneca:

The majority of enquiries about their medicines that comes directly from patients and their carers cannot be fully answered because this would be construed as an illegal promotion of a prescription-only medicine to the public. At present patients can find out more information about the safe use of tamoxifen (to treat breast cancer) from the Internet than they can from the company who discovered it.[197]

239. PILs should be the most straightforward way for the industry to provide patients with the information they require. Unfortunately, they are rarely in a comprehensible form. Dr Iona Heath, from the RCGP, commented:

A definite problem is that people are frightened by these things and the fact is that [a] huge list of potential side effects is written to defend the company legally with no indication of prevalence. … They are not contextualised in any sort of way about how likely that is to happen to you and that information is available. In the actual way it is presented, nothing is done to mitigate the fear which comes with information.[198]

240. The problem is widely recognised and the MHRA has set up a Patient Information Working Group to address the matter. There are concerns that too few lay people are involved in this group, however. There may need to be a change in the legal requirements for PILs. A design firm provided the Committee with an impressive example of a PIL which was clear and patient-friendly but, as the designers admitted, it did not meet the existing legal framework.[199]

Direct-to-consumer advertising

241. Direct-to-consumer advertising of prescription-only medicines is currently only permitted in the US and New Zealand. Advertising medicines in this way is clearly effective in increasing sales of medicines. A US study published in August 2002 by PharmTrends, a marketing service for the industry that monitors purchasing of prescription-only and OTC drugs, reported that one in five of 25,000 respondents said DTCA prompted them to visit their family doctor to discuss a drug they had seen advertised. In total, 22% said DTCA had made them aware that there were drug options to treat their condition and 12% had been prompted to ask their doctor about an advertised drug.[200]

242. The increase in the number of drugs reclassified from prescription-only to OTC status has implications for advertising. Zocor, for example, is now widely advertised on television and in publications such as the Radio Times and national newspapers. The Daily Mail's medical correspondent reported that the newspaper now carries full-page advertisements for this drug.[201]

243. While increased awareness of the availability of treatment options is desirable, sharp increases in annual spending on medicines have been observed in the US and New Zealand following successful advertising campaigns. Overall, the proportion of expenditure on advertised drugs, and number of prescriptions written, is significantly higher than for non-advertised drugs (see Figure 8).

Figure 8: Change in sales and number of prescriptions 1999-2000 (US).Data from US NIHCM Report 2001

244. Studies of this kind have led to concern that DTCA encourages the unnecessary and inappropriate use of medication. Distorted prescribing behaviour, due to doctors and other prescribers being 'talked into' prescribing the drug of the patients' choice, has also been reported. Healthcare professionals are more likely to prescribe a brand-name drug when a patient asks directly for it rather than another, possibly generic, version of the same medicine.[202]

245. In the UK (and Europe) the industry has emphasised that it is not intent on introducing DTCA of the kind seen in the US, which now attracts expenditure about $4 billion/year.[203] We were told by Ms Margot James, European President, Ogilvy Healthworld:

The pharmaceutical industry in the most part is actually now against bringing in this form of advertising into the UK. They might have had a more open mind about it a few years ago. …There is no appetite among pharmaceutical companies for bringing that kind of advertising to the UK.[204]

246. However, the industry is determined to communicate directly with patients; the ABPI argues that, "no one knows more about a medicine than the people who discovered, developed and made it available". The ABPI's Informed Patient Initiative Task Force (whose remit is to work with the ABPI to make recommendations to the MHRA on patient information) believes that pharmaceutical companies could "help patients be better informed if current restrictions on industry providing scientifically reliable information on healthcare, medicines and treatments directly to patients were relaxed."[205] It seems anomalous that others can provide information about drugs on the Internet but pharmaceutical companies cannot do so officially. However, there are concerns about relaxing the rules, not least because a suitable format for PILs has not been established.

DISEASE AWARENESS CAMPAIGNS

247. Disease awareness campaigns encourage individuals to seek advice or treatment from their doctor for previously undiagnosed conditions. We received allegations that disease awareness campaigns can act as advertisements for prescription-only drugs, particularly where there is a particularly well-known brand of treatment.[206] Such campaigns, which may be established by a drug company with or without the endorsement of a patient group or charity, often take place at the same time as the drug's launch and may involve aggressive promotion of a particular medicine to prescribers. Mr Graham Vidler, from Which? told us:

What those awareness campaigns will do is encourage the public to go and see their GP, often in quite strong terms, saying, "Go and see your GP. Be forceful. There is something that can be done." Simultaneously, the companies will be advertising specific drugs to those GPs, and … quite often it [is] easiest for them to take the path of least resistance.[207]

248. Witnesses argued that the use of disease awareness campaigns, which in the past have involved conditions including depression, anxiety and obesity, play a major part in the "medicalisation" of our society; in short:, "where disease awareness campaigns end and disease mongering begin is a very indistinct line".[208] Dr Des Spence, representing the group 'No Free Lunch', asserted that the bombardment of the general public and patients served, "to undermine our collective sense of well being".[209] Dr Spence was especially concerned about the 'Defeat Depression Campaign' and its effect on prescribing patterns and the public's perception of depression:

[That campaign] led to us being told that a third of people were depressed, that we should screen for it, that we should start using antidepressants early, and we did. If I think back five or ten years ago, we were diagnosing large numbers of people with depression, and we were prescribing many antidepressants. As time has gone on, I have certainly begun to realise that in some ways yes, there are many people who do have depression, but lots of people are just unhappy and that is a part of life. So there is a whole generation of people coming up who almost feel that being unhappy is an abnormal state, which, of course, it is not.[210]

249. The 'Defeat Depression Campaign' (1992-1997), which was run through the RCGP and the Royal College of Psychiatrists, and sponsored by the manufacturers of antidepressants (who provided approximately one-third of the funding) targeted doctors as well as patients, in particular to emphasise that these drugs did not cause addiction or dependence. These claims have since been disputed and a warning about withdrawal symptoms is now included in the SPC. The Royal College of Psychiatrists provided supplementary evidence emphasising that the Defeat Depression Campaign had been intended to make it clear "that antidepressant treatment was not appropriate for mild to moderate depression, but effective only for severe or clinical depression".[211] This important message evidently got lost; indeed there remains much confusion on this point today.[212] The Royal College also told us it had recently reviewed its policies on accepting commercial sponsorship, and now aims to keep total income from these sources at around 5% of the College's annual turnover. Commercial sponsorship accounted for under £500,000 (5.5% on turnover of £9m) in 2003.

250. According to the Royal Pharmaceutical Society of Great Britain (RPSGB), disease awareness campaigns may hide potentially adverse consequences. Those seeking screening, diagnosis or treatment might, for instance, receive a false-positive result that leads to the individual undergoing an unnecessary procedure. Witnesses said that the guidelines, which were drawn up between the MHRA and the ABPI, are inadequate.[213] The guidelines state that the risks associated with treatment and the fact that treatments are not always suitable or effective for every individual should be made clear[214] but, we are told, the industry does not always adhere to these recommendations.

251. No witness suggested that all disease awareness campaigns were cynical attempts to increase drug sales, but many doubted that they were simply aimed at improving the lives of those with unmet medical needs. It is not acceptable for such campaigns to be veiled advertising for branded prescription-only medicines.

PROMOTIONAL CAMPAIGNS: TARGETING PATIENTS AND THE GENERAL PUBLIC

252. Documents requested from drug companies were analysed to determine whether promotional campaigns also targeted non-professionals[215]. The pharmaceutical industry is prohibited by law and by the ABPI Code of Practice from not only targeting but from aiming to target patients and the general public with marketing and promotional activity relating to prescription-only drugs. In many of the documents, however, patients and the general public emerged as key targets in internal literature (which is not covered by the Code of Practice). Detailed and continuous market research, for example, is conducted with these groups to uncover their emotional drivers and motivations, which are then exploited to encourage presentation to medical services with the overall aim of benefiting the pharmaceutical company in question. PR activity is also used to encourage media coverage with the clear intention of targeting patients, patient groups and the general public. As Ms Jenny Hope, medical correspondent with the Daily Mail, told us:

I do not feel that I am being used but I feel I am a target for promotional and marketing activity.[216]

253. There is clear evidence that the industry is concerned with identifying populations who are not currently presenting for diagnosis. In one document relating to the "strategic planning process," these patients, who, "do not currently present to their GP or take prescription medications," are referred to as "the missing millions" and are estimated to comprise almost 2 million people in the UK. This population is viewed as providing a "significant opportunity" for the company.[217]

254. Research is then conducted on behalf of the company that aims to understand what barriers exist to prevent these people from presenting and to identify factors, both rational and emotional, that will overcome these barriers and encourage patients to seek professional advice. The following example comes from the company's brief for a PR firm:

Overall aim

• To understand how to target these patients and overcome their barriers to presentation

Specific aims

• To understand the segments of patients that do not currently present to GPs with [the condition]
• Explore their rationale/belief systems that inhibit them from presenting
• Identify hooks and drivers to encourage them to seek advice both emotional and rational.

255. The documents make it clear that the companies are concerned with using the results of such research to design strategies that are able to "target these customers" and go as far as identifying which of these customers will be most "receptive" to their communications. Research is also conducted with the general public to "evaluate and communicate channels that could be used to target customers" and highlights more general communication principles that need to be considered when targeting such groups. The outcomes of the research suggest that the perceived source of the message is vital to the target audience's receptiveness to the communication:

Strong perception exists amongst missing millions that any communication or information provided needs to be from credible source, eg. GP, 'medical organisation',…patient group - NOT outwardly a drug company - stigma attached to pharmaceutical companies that they'd 'just be doing it to sell drugs', not seen to be patient focussed.

256. Similarly, other more "credible" channels of communication are outlined:

Patient leaflets left on the counter in pharmacies / GPs surgeries — perceived to be more 'credible' source than, eg. at end of supermarket aisle.

257. These company documents suggest that the pharmaceutical industry intends to manipulate marketing principles, such as the perceived source of communications and distribution outlets, in order to make the general public more receptive to its marketing activity.

Examples of PR activity targeting patients and general public:

258. A considerable number of documents described PR activity targeting patients and the consumer press. It is clear that PR activity is vital and part of a coherent strategy, both reactive and proactive, for many pharmaceutical companies. Specifically, this activity is consistently designed to tap into and exploit the target audience's emotions and deliberate efforts are made to build emotional elements into campaigns. One document mentions the specific targeting of consumers, while another mentions the use of "patient case studies for use in articles/press and media interviews", with a view to targeting patients and patient groups.

259. The use of 'key opinion leaders' for such purposes was recognised by two witnesses from the press, though both were somewhat sceptical about their effectiveness. Ms Hope told us:

The PR industry sets great store by opinion leaders which slightly mystifies me…I fear that the influence of these opinion leaders is really rather something that has been got up, to be honest with you, by the PR industry.

Ms Lois Rogers, medical editor at the Sunday Times, added:

Even the expression "opinion leader" to me is a deterrent [it] would immediately tell me that that person is in the pocket of that drug company.[218]

4. Medicalisation: future risks of genetic testing

The introduction of gene-based therapy, which targets pre-disposition to disease rather than disease itself, is a recent development in medical research. Gene sequences can be patented and genetic tests developed on the basis of these groups of genes. There is currently no regulatory assessment of clinical data relating to genetic testing in the EU, although the UK Genetic Testing Network has developed procedures and criteria for evaluation of genetic tests for use within the NHS.[219]

There has been a surge in recent years in the use of genetic tests in medicine. Genetic testing has, for example, led to increased numbers of women with a strong family history of pre-menopausal breast cancer undergoing genetic screening for mutations in the BRCA1 and BRCA2 genes. Testing is only suitable for a small number of women who are particularly at risk. Options to reduce this risk include elective mastectomy. Inherited, or familial, forms of breast and other types of cancer represent approximately 5-10% of all cancers. In addition to genetic testing for several inherited types of cancer, testing for other conditions is increasingly common. Examples of predictive diagnostics include genetic tests for Tay-Sachs disease and cystic fibrosis.

The WHO recently announced the approval of the first international standard for a human genetic test, for a genetic mutation known as Factor V Leiden. This mutant gene induces a defect in the blood clotting system and is a major risk factor for venous thrombosis, and also increases risk of miscarriage and pre-eclampsia.

A further positive aspect of genetic research is the determination of those patients likely to respond to treatment on the basis of their genetic make-up. So-called pharmacogenetics are being increasingly used by industry and drug companies have been keen to point out the benefits of individualised treatment based on this type of research.

The concept of 'genetic predisposition to disease' is therefore one that has gained widespread acceptance in recent years. However, being genetically predisposed to a disease does not mean that it will actually develop - there is an environmental component that interacts with other biological factors, such as the presence of particular disease antibodies. According to GeneWatch:

Increasingly, medication is now prescribed to reduce risk of future illness. Selling medication to treat risk factors rather than diseases is immensely profitable for the pharmaceutical industry: for example, statins (to lower cholesterol levels) are now the biggest selling prescription drugs in the world [and are also now available over the counter][220]

We were told that it is in the pharmaceutical industry's interest to classify as large a proportion of the population as possible as 'abnormal'.[221] Genetic susceptibility to disease is an additional means of classifying a significant percentage of the general 'well' population in this way. The proportion of individuals classified as genetically susceptible to particular types of disease seems likely to rise dramatically in the future. The availability of genetic tests, some of which are already advertised and may be purchased directly by the consumer in the US, has grown.

Pre-emptive treatment of 'predisposed individuals' is likely to target the healthy in Western countries, to promote the use of supplements, lifestyle advice or preventative medication and increase the proportion of the population taking medicines regularly. Roche is the world leader in the market of medical tests. It already plans to market a genetic test for heart attack risk in the next 2-3 years.

Additional fears surrounding genetic testing include causing a reduction in positive lifestyle changes in the absence of 'genetic susceptibility'. For example, smokers tested for a predisposition to smoking-related disease (such as lung cancer or chronic obstructive pulmonary disease) who receive negative results may be persuaded that they need not give up. Worryingly:

The sheer number of genetic variations and the large number of spurious published associations means that it is virtually impossible for most medical professionals to make their own assessments of the clinical validity or utility of genetic tests.[222]

PATIENT ORGANISATIONS

260. Over 200 national patient organisations and support groups exist in the UK today. Such groups provide information and a range of services to their members and the general public and often campaign for increased access to particular treatments. A goal of many patient organisations is to influence healthcare policy for the benefit of patients; as the MS Society described, this aim often coincides with that of the pharmaceutical industry:

The Society and the Industry share the common goal of increasing the resources available for the treatment and management of MS. There are circumstances in which the Society will wish to work with the Industry to influence the policy of government and the NHS, or the attitudes and practices of the professions.[223]

261. Pharmaceutical companies may provide direct funding of a charity or valuable contributions in kind, such as distributing leaflets to GPs' surgeries. CancerBACUP, for example, stated:

Over the last 12 months, more than 75,000 cards and 35,000 posters giving details of the helpline have been distributed to cancer centres, GPs' surgeries and pharmacies across the UK by sales representatives from 10 major companies. There is no branding…this has helped a greater number of people gain access to CancerBACUP's information and support than the charity would have been able to reach without this assistance.[224]

262. Most charities claim that they remain independent despite involvement with the pharmaceutical industry, but stress that they simply could not survive without financial input from this source. According to Depression Alliance: "The simple fact is that the strength of the mental health charity is its independence. Without that independence, our voice would hold no sway."[225]

263. The Long-term Medical Conditions Alliance (LMCA) indicated the advantages of close contact between industry and patient groups. In particular, it argued, it ensures that the information needed by patients is provided by the manufacturers of the products in question. Charities are able to influence the workings of the pharmaceutical industry through identifying patient-centred outcomes, ensuring treatment regimes meet patients' needs and that information provided by manufacturers is balanced and appropriate for users of the product.[226]

264. The benefit to the industry of close associations with patient groups was illustrated in a survey of US executives from 14 pharmaceutical and biotechnology companies: 75% of respondents cited patient education as the top-ranked marketing activity necessary to bring a brand to number 1.[227] Drug companies benefit further when charities agree to endorse their products by allowing their logo to appear alongside an advertisement for the drug or details of a sponsored disease awareness campaign.

265. However, many witnesses told us of the disadvantages of close relationships between patient groups and the industry. We received evidence that some groups receive substantial sums from the industry and campaign to increase the availability of medicines for their members in the absence of strong supporting evidence. Dr Tim Kendall, from the Royal College of Psychiatrists, commented:

I am aware that there are some…like Depression Alliance, which have very substantial funding at times from drug companies. They do lobby for an increased accessibility to drugs which the drug companies are selling to these patient organisations. They are persuading them that these are the drugs they must have, with very little evidence to support it^.[228]

266. Charities can be harmed by working closely with the industry. Dr Ike Iheanacho, the Editor of the DTB, told us:

The example I would suggest is GlaxoSmithKline's involvement with a small charity called Allergy UK. That involved producing a book, a little "Mr Men" book based on the children's character - here it is - and it is a very ordinary Mr Men book until you get to the back, where you find some advertising for some of the company's products. This book was in fact illegal and is no longer available; it had to be withdrawn. The law makes it very clear that children cannot be used as a promotional vehicle in this kind of way. In terms of the charity, the charity did not know about the problem, that this was bad behaviour, until they were alerted by the media, who pointed it out: "What is going on here? This isn't the done thing." So the charity was in a very embarrassing position because they had been acting in good faith but essentially they had been taken in by the company.

267. Paul Flynn MP described fears that pharmaceutical companies use patient organisations as "conduits to promote their products in a subtle form of marketing". This leads to a situation in which, instead of representing the interests of patients, groups "become marketing tools for the pharmaceutical companies".[229] Referral by the pharmaceutical industry to patient organisations as "ground troops" for lobbying Government to increase access to new drugs is further evidence of this.[230]

268. The need for charities' relationship with the industry to be transparent was repeatedly made. At present, however, there is no requirement for such groups to declare to the general public the names of donors or the type or amount of support received. A report by Health Which? found that, of 125 patient organisation websites, donors were listed on 32. Only two groups (Diabetes UK and the Alzheimer's Society) explained their funding policy.[231] Furthermore, links between charities and industry may be interpreted differently by patients and the charities themselves, with the sponsors products seen as, "preferable by the charity associating itself with the company".[232]

269. The LMCA publishes guidelines for patient groups on issues relating to relationships with the pharmaceutical industry. These cover the primacy of patients' interests, transparency regarding funding, the expectation of benefit to both sides, and the need for equality between both partners. In addition, limits on the amount or proportion of funding from any individual source, the importance of diluting the influence of any one donor by accepting donations from different commercial organisations, and commitments not to endorse specific products (or to do so only in specified circumstances) are stressed.

270. The Charity Commission also monitors charities' financial activities and requires that all charities make their accounts available on request to the public. The Commission may take action if it feels that undue commercial influence over a charity was giving rise to financial, reputational or governance issues. However there is no common definition for what would constitute "undue commercial influence".[233]

271. The pharmaceutical industry's promotional efforts are relentless and pervasive. The evidence presented showed the lengths to which the industry goes to ensure that promotional messages reach their targets, and that these targets include not only prescribing groups, but patients and the general public.

272. There is an urgent need for a comprehensive and informative PIL, preferably one which indicates the role of the drug in overall management of the disease. We were advised that patients themselves should be involved in the process of developing such a PIL. The MHRA's Patient Information Working Group is addressing this issue but the group is dominated by professional interests.

273. DTCA is inappropriate and unnecessary in the UK. The evidence reviewed above on the targeting of prospective patients, and the central emphasis on emotional appeals, leads us to believe that great caution should be exercised in any relaxation of the rules relating to provision of consumer drug information by drug companies.

274. The existing guidelines on disease awareness campaigns are weak and unmonitored. Drawn up after limited public consultation, they make no strict demands apart from a requirement not to mention brand names. The effectiveness of future guidelines will depend on interpretation, monitoring and enforcement.

275. We often do not know what funds or support in kind patient groups receive from pharmaceutical companies. Limiting or legislating against such support is not appropriate; this would disadvantage both the charities that rely on industry funding and the industry itself, by cutting off a source of valuable feedback from the eventual consumers of its products. Measures to limit the influence of industry on patient groups are needed, however. Patient groups should declare all significant funding and gifts in kind and the Government should seek to make appropriate changes to charity law to ensure this. It would in any case be greatly preferable if patient groups were funded by companies' charitable arms, rather than by companies themselves.

The drug regulatory system

276. The presence of a strong, independent drug regulatory system, committed to improved health outcomes, is not only vital to the public interest, but is also fundamental to the development of a healthy pharmaceutical industry. Without an effective regulator in place, licensing standards and operating procedures will not be maintained and inadequately tested medicines will enter the market. The pharmaceutical industry is a business, with obligations to its shareholders. The regulator should expect it to use any legal means to provide a return on investment.

277. The UK regulator, the MHRA, is in a potentially powerful position. Companies need to market new drugs, and benefit from drug approval. The industry has previously expressed concerns that excessive drug regulation and slow approval procedures are impediments to drug innovation, but we heard no strong complaint from its representatives on this score. The evidence presented to us indicated that the UK-based industry has confidence in the MHRA, and vice versa.

278. The pharmaceutical industry in turn exerts a strong influence on drug regulatory policy and process. This influence can be expected to increase because the EU will take more responsibility for drug licensing and because of the trend to global development of regulatory standards and protocols.

279. Globally, the ICH is becoming increasingly important. Its secretariat is run by the International Federation of Pharmaceutical Manufacturers & Associations. ICH standards which are adopted by the EU become binding on the MHRA, and determine the procedures and standards applied by the MHRA. Importantly, these may include restrictions on regulatory scrutiny. During the first oral evidence session, Prof Kent Woods was questioned about one such restriction. A recently introduced ICH requirement prevents the MHRA from accessing the audit report required with each clinical trial - a critical document in assessing standards of compliance with GCP, including the quality of patient care. Under ICH-generated regulations, the MHRA may request sight of an audit report only if it suspects "serious non-compliance", otherwise it receives only a certificate confirming that the audit has taken place. This amounts to a Catch 22 position: the primary evidence of serious non-compliance would be in the audit report, but regulators may ask to see that report only if they suspect serious non-compliance. Surprisingly, the MHRA expressed no concerns about the issue. [234]

280. In its own interests, the Agency needs to keep a close eye on its market share of regulatory business: increasingly it competes with other European drug regulatory agencies to scrutinise drug licence applications. Like any other regulatory agency, the MHRA walks something of a tightrope, trying to strike a balance between support for the industry and effective medicines control. The MHRA Chairman, Prof Sir Alasdair Breckenridge emphasised:

You have to balance each of these…systems of funding which we do have against the [health] incentives … it is clearly terribly important that we retain and advance our position in Europe not only from a UK plc point of view but also from the funding point of view of our Agency[235]

281. There was little doubt that, even in the best-resourced regulatory bodies, the pressure on individual employees may become intense when problems arise. While our inquiry was taking place, Dr David Graham, Associate Director for Science and Medicine in the FDA's Office of Drug Safety, gave relevant evidence to the US Senate Committee on Finance in hearings following the withdrawal of Vioxx[236] and subsequently spoke about the relationship between regulators and industry:

The FDA has become an agent of industry. I have been to many, many internal meetings and, as soon as a company says it is not going to do something, the FDA backs down. The way it talks about industry is 'our colleagues in industry'… it is rather because the body is entirely geared towards concentrating on approving drugs, doing little once they are on the market[237]

282. The relationship between the industry and the MHRA is naturally close. There are regular interchanges of staff, common policy objectives, agreed processes, shared perspectives and routine contact and consultation. Many of the senior staff of the MHRA have previously worked with the industry, the main exception being Prof Woods, who became chief executive of the MHRA in 2004. Overwhelmingly, the different parties appeared to speak the same language, with companies determined to observe the letter of the law and the regulators determined to uphold it. Dr Herxheimer stated:

…when the agency was hived off from the Department of Health…the culture became confirmed that the industry is the client and the client must be looked after: quick service, good service, easy contact, etcetera - so it is a closed community in a sense.[238]

283. Such closeness provides the basis of the trust that the MHRA said it relied on as an integral part of the regulatory process.[239] The MHRA Chairman suggested that trust underpinned the stance of the MHRA towards the companies they regulate. We inferred that this extended to the routine acceptance of companies' summaries of the results of tests on their drugs as true reflections of the raw data on which they were based.

284. Trust is critical in the relationship between regulators and industry. However, at the heart of this inquiry are the concerns of those who believe that the MHRA is too trusting. Trust should be based on robust evidence; it should be earned rather than presupposed. The evidence indicated that the MHRA examined primary (raw) data on drug effects only if it suspected some misrepresentation in the summary data supplied. It was argued that such trust in regulated companies goes too far: reliance on company summaries is neither sufficient nor appropriate, in the absence of effective audit and verification of data that companies provide. The secrecy surrounding this information is also unacceptable, as Sir Iain Chalmers commented:

Denial of access to information held by the [MHRA] puts the interests of pharmaceutical companies ahead of those of patients and prescribers. This is particularly indefensible in the light of evidence that regulatory agencies, supposedly established to protect the public, are acquiescing in biased later publication of the information they hold.[240]

285. Regulatory inertia was clearly illustrated through publication of the findings of the UK's first ever public investigation into a drug safety problem: the December 2004 report of the CSM's Expert Working Group (EWG) into the safety of SSRI antidepressants. The Group's main findings pointed to lack of evidence of risk (rather than risk itself) not least because a number of essential studies had never been performed. Some 10-15 years after licensing the major SSRIs, and in spite of several earlier reviews of the same drug problems, the MHRA had received no convincing evidence of:

• Drug efficacy in mild depression, accounting for some two-thirds of all SSRI prescriptions in the UK;[241]
• Any benefit to be gained with most SSRIs from increasing the dose above the recommended daily dose;
• The incidence of SSRI withdrawal reactions, a common and sometimes disabling side effect and the subject of much complaint.

REPUTATION OF THE REGULATOR

286. The formal aims and objectives of the MHRA set out the commitment to "support industry and scientific innovation" but otherwise give little indication of the extent to which collaboration with the pharmaceutical industry affects the style and content of the Agency's work. The MHRA describes its responsibilities as:

…protecting and promoting public health and patient safety by ensuring that medicines, healthcare products and medical equipment meet appropriate standards of safety, quality, performance and effectiveness, and are used safely^.[242]

287. The reference to "promoting health", and ensuring drugs are "used safely" implies some recent and significant shift in the definition of regulatory responsibilities or, at least, the determination to communicate that public confidence in the present regulatory system is justified. A report by the National Audit Office (NAO) in January 2003[243] highlighted the lack of public profile and impact of the MHRA and stated that it ought to strengthen these aspects in order to fulfil its mission to provide information to contribute to the safe and effective use of medicines.[244] It is clear that some progress has been made in this regard. The new emphasis on the safe use of drugs both alters the Agency's regulatory interpretation and departs from the long-established tradition of not challenging the clinical freedom of prescribing doctors.

288. The MHRA claims to have made other changes and we received some convincing evidence of this. The MCA's original leadership responsibilities were defined, not in relation to health outcomes, but in terms of organisation. Dr Keith Jones, the MCA's previous director, has stated: "My role is primarily that of a medically, scientifically informed manager: I am there to oversee the running of the MCA and since July 1991, to advise Ministers on matters of medicines control."[245] However, in evidence to this inquiry, the MHRA Chairman emphasised the changes that had recently taken place, to distance the new MHRA from its predecessor.[246] Sir Alasdair stated:

…if someone who worked in the Agency even in the early part of the 2000s came back and looked at the work that we are doing now, they would find huge changes.[247]

289. The MHRA's proposed reorganisation of the Advisory Committee structure, for example, has signalled its awareness of the need to take greater account of patient and consumer perspectives and to avoid conspicuous potential conflicts of interest. The decision to accept reports from patients of suspected ADRs and publication on the Internet of this and other information gleaned from the Yellow Card Scheme is also notable. Such developments represent a significant advance on policies favoured only a few years ago.

290. In addition, a new Director of Communications and additional staff were appointed in February 2005 in response to implementation of the Freedom of Information Act and other pressure to improve levels of transparency and access to drug information:

…setting up communications…is absolutely critical for an agency like ours. In the past, the old Medicines Control Agency and Medical Devices Agency, working in a different time, did not see this as one of their main purposes. Now it is quite clear, and we are determined, that this is one of ours.[248]

291. For all such evidence of commitment to change, however, the reputation of the regulator ultimately stands or falls on its success in avoiding problems, especially those leading to drug withdrawals and giving rise to adverse publicity. Since it was formed, in April 2003, the MHRA has been involved in a succession of problems and seen unprecedented levels of concern (See Table 2, below).

292. The major safety problems related to SSRI antidepressants (notably Seroxat) and COX-2 inhibitors (notably Vioxx). Publicity has subsequently focused not only on the drugs involved, but on the quality of the regulatory system and its relationship with the pharmaceutical industry.

Date 2003 04-Apr 10-Jun 08-Aug 19-Sep 03-Dec 10-Dec 2004 09-Mar 11-Mar 09-Jun 30-Sep 14-Oct 18-Nov 06-Dec 17-Dec 21-Dec 22-Dec 2005 31-Jan 03-Feb 17-Feb 18-Feb

MHRA safety-related announcements Oral contraceptives and cervical cancer Safety of Seroxat in children and adolescents Hormone replacement therapy (HRT) and breast cancer Safety of Efexor (venlafaxine) in children and adolescents Use of HRT in the prevention of osteoporosis Use of SSRIs in children and adolescents with major depressive disorder   Atypical antipsychotic drugs and stroke Seroxat: reminder to use the recommended dose New prescribing advice for the 40mg dose of Crestor (rosuvastatin) Immediate withdrawal of Vioxx Chiron flu vaccine: quality and safety concerns lead to closure of major vaccine plant Updated guidance on the use of Depo-provera contraceptive SSRI antidepressants: findings of the CSM Expert Working Group New data on cardiovascular risk with celecoxib (Celebrex) Advice on the use of Celebrex and other selective Cox-2 inhibitors in light of concerns about cardiovascular safety Dynastat (parecoxib) and Bextra (valdecoxib): new information on cardiovascular safety and serious skin reactions   Co-proxamol to be withdrawn from the market (dangers of overdose) MHRA issues new advice (relating to liver problems) on use of Strattera (atomoxetine) MHRA issue updated advice on the safety of selective COX-2 inhibitors MHRA highlights its recent advice on SSRIs

Table 2.

293. The timing of these problems was unfortunate for the reputation of the MHRA. It might be claimed that they were simply inherited from the old MCA, but the basis of drug licensing and regulation remains essentially unchanged. The new MHRA and old MCA do not differ in core regulatory activities, but, we are told, are rather concerned with image, reputation and questions of presentation.[249]

294. There was evidence of change in the CSM/MHRA report on the safety of SSRI antidepressants. For the first time, the regulators publicly summarised the clinical trial evidence on which their recommendations were based, and systematically identified the extent of data missing. We were told that the MHRA had taken prompt and effective action to investigate this case, whereas the MCA had repeatedly failed to do so. However, we also had significant concerns about the resulting conclusions and recommendations, including several unresolved issues.[250]

295. In setting up the review of SSRI antidepressants, the MHRA/CSM responded to another long-standing concern about regulatory activity: the possible conflicts of interest of regulators. Members of the EWG, which was set up in May 2003, were required to have no personal interests in any of the companies being investigated. This was the first time this requirement had applied; in previous investigations, conflicts of interest were not debarred, but were required to be disclosed. In future, Lord Warner assured us, the merged Medicines Commission and CSM will require "the chairs and members of the commission and the new statutory committees to have no financial interest in the industry," and "a stronger code of practice on declarations of interest".[251]

POST-MARKETING SURVEILLANCE

296. The MHRA puts its main regulatory emphasis on scrutiny of pre-marketing data. It was argued that it gives too little attention to post-marketing surveillance to evaluate the effects of medicines in normal clinical settings. Sir Richard Sykes told us:

There has got to be a process of making sure you have enough information to give an approval to have the drug into the clinic, but then there have got to be very clear monitoring processes for seeing that drug operate in a true market place, where now you are not selecting the patient who receives the drug but patients of a great genetic diversity are now receiving that drug. That, by definition, will produce adverse events.[252]

297. Both companies and regulators overwhelmingly rely on pre-licensing data, based on industry-sponsored clinical trials that measure drug effects in selected populations of patients in tightly controlled settings. Because these data are regarded as scientific, they routinely 'trump' much of the data collected through post-marketing surveillance, most of which is regarded as anecdotal. The net result is that data from clinical trials may provide the bedrock of understanding of a drug's benefit : risk profile, often years after approval.

298. Lord Warner appeared to dismiss concerns about weakness in the post-marketing surveillance system. He pointed out the "good track record" of the CSM on taking serious post-licensing evidence of drug safety issues:

You could argue that some of the high profile examples [e.g. SSRIs] which you have mentioned are demonstrations that the licensing system does work, that there is a good post-licensing system for picking up problem areas and dealing with them.[253]

299. Others questioned whether waiting for 10 years before undertaking a thorough review of SSRIs represented a good track record. Prof Healy argued:

In actual fact here in the UK we track the fate of parcels through the post one hundred times more accurately than you track the fate of people who have been killed by SSRI or other drugs.[254]

300. There was perhaps a degree of complacency in the Minister's view of the Yellow Card Scheme.[255] This system is widely considered to be failing and was described to us as "worthless"[256] and "bit of a pup"[257], but Lord Warner maintained:

I do not think there was any evidence from [the review of the system] or from any other work that I have seen that the yellow card system did not feed in as an alert to ensure that the regulator accumulated information about particular areas causing concern.[258]

301. In addition, the 5-year renewal procedure has not been used to good effect, and appears to have become an automatic process focussing on safety issues rather than an opportunity to review both efficacy and safety data rigorously.

302. Several witnesses expressed concerns not only about the relatively weak emphasis on post-marketing investigations, but also about possible conflicts of interest that might arise when the same Agency is responsible for both pre- and post-marketing drug evaluation: if problems arise once a drug is on the market, it might indicate flaws in the original assessment and require the regulators to examine their own earlier failings. Such concerns have also been expressed in the US. Witnesses forcefully argued for more robust post-marketing drug surveillance, proper assessment of the extent and cost of drug-induced illness, and the need to avoid basic conflicts of this kind.[259]

THE PATIENT VOICE

303. The MHRA paid the price of the MCA's earlier failures to get to grips with the problem of SSRI antidepressants. During six previous investigations, user reports of often serious problems had been systematically discounted or ignored. The MHRA has since responded to this problem, but the users' voice in the drug regulatory system as a whole remains very weak. The MHRA's proposal to set up a patients' committee in its new structure was welcomed, but previous experience gives rise to concern that it will not fundamentally change the situation. Richard Brook, who was one of two lay members originally on the EWG examining SSRI antidepressants, told us:

I seemed to be the lone voice on this expert committee saying, "This is of concern", and the response I would get is from the Chairman or the officials, "Yes, this is very worrying, but it is going to have to be formally investigated", and it seemed to go, in my view, into a black hole and remains there to this day despite questions on the floor of the House and questions elsewhere.[260]

304. The MHRA is seeking to communicate more effectively with the public. Sir Alasdair Breckenridge admitted that communication had been poor in the past, but that better standards were now in place. Lord Warner also stated that it will become more common for evidence supporting the MHRA licensing decisions to be placed in the public arena:

Certainly I am very keen and the Agency knows that the Government is keen, that that information is put in the public arena so there is no doubt about why the balance was struck…People will be more convinced that the judgments have been fairly made, if the supporting evidence for their judgment is clearly in the public arena.[261]

305. Witnesses stressed that improved communication must involve publication of all benefit : risk assessments produced by the MHRA and documents relating to the withdrawal of medicines.[262]

5. Problems with Seroxat and other SSRIs

Prozac and Seroxat are the best-known examples of SSRI and related antidepressants, but others are widely used. The introduction of SSRIs led to a threefold increase in antidepressant prescriptions between 1990 and 2000. Prescriptions for antidepressants now match those of the benzodiazepine tranquillisers at their peak, 25 years ago.

Almost from the outset, there was concern about two main problems with SSRIs. First, there was suspicion (initially centred on Prozac) that these drugs could induce suicidal and violent behaviour - infrequently, but independently of the suicidal thoughts that are linked to depression itself. There was also concern (centred on Seroxat) about a risk of dependence; some users found it impossible to stop taking SSRIs because of severe withdrawal symptoms.

The MCA/CSM formally reviewed these problems on several occasions. The suicidality problem was first investigated in 1990/1; withdrawal reactions were investigated in 1993, 1996 and 1998. In 2002, the MCA organised a further intensive review of both problems. This review was abandoned in April 2003, following criticism about conflicts of interest involving key figures on the review team.

Expert Working Group report on SSRI safety

The MHRA set up another enquiry in May 2003, an independent review by an Expert Working Group (EWG) of the CSM. None of its members had personal interests in companies whose drugs were under investigation, and they included two consumer representatives. The appointment of lay members was unprecedented; their contribution to the work of the EWG was subsequently warmly acknowledged. However, one of the two lay members left soon after the review began. The other was Richard Brook, the chief executive of Mind, who resigned in protest half way through. A third lay member was appointed to the EWG eight months later, by which time the report was virtually complete.

In evidence to this Committee, Mr Brook expressed concerns about the influence of the industry on drug regulation, specifically the perceived threat by MHRA staff of legal entanglement resulting from regulatory action:

…every time we made difficult decisions there was always this issue of: 'We have got to be very careful because the pharmaceutical companies will sue us if we get this wrong; they will take us to court and take us through legal processes'; and it was very clear that the MRHA officials were very mindful the whole time of that dimension, to my view, more than the dimension of public health and public responsibility of the public.[263]

The EWG was originally expected to report within three months. In the event, the EWG held 20 meetings over as many months and its final report was released in December 2004. This initiative was overtaken by events from the outset.

Very soon after the appointment of the EWG, GSK submitted evidence to the MHRA to support a licensing application for Seroxat use in children. Suspecting a problem, the MHRA requested further data from GSK and, in June 2003, unexpectedly issued a warning to advise against the use of Seroxat in children. A similar warning was issued for another antidepressant, Efexor, three months later and, in December 2003, the warning against use in children was extended to all of the drugs reviewed bar Prozac. The underlying reason was not only the evidence of a small but statistically significant increased risk of drug-induced suicidal behaviour, but lack of evidence of effectiveness.

The EWG was therefore unable to focus on its original brief, relating to withdrawal problems and possible suicidality in adults, until the end of 2003. Its final report identified a significant lack of important data, a clear and substantial risk of sometimes severe withdrawal reactions, and no clear evidence of a greater risk of SSRI-induced suicidal behaviour compared with older drugs (notably tricyclic antidepressants). The final report concluded that the benefit : risk profile of SSRIs was positive in adults; it also somewhat softened the earlier warnings about using SSRIs for children.

There appears to have been a lack of effective warnings relating to the frequency of withdrawal symptoms experienced with Seroxat. Both the manufacturers[264] and the regulators[265] claimed they had acted promptly and appropriately in this respect. However, working papers seen by the EWG state that the original licence application recorded Seroxat withdrawal reactions in 30% of patients. The regulators denied this. Three separate reviews conducted by the MCA/CSM in the 1990s were all based on Yellow Card counts, and produced misleadingly low estimates of the risk level:

John Austin: But up until 2003, both the MHRA and the manufacturers were saying that the incidence of withdrawal reactions was rare and that has now been revised, so 10 years after, when all this surveillance has been going on, that estimate has been raised to 25 to 30 per cent.

Professor Sir Alasdair Breckenridge: When a drug is licensed and for the first few years until there is good clinical trial evidence, one cannot say what the incidence of an adverse reaction is. You cannot tell that from yellow card reports ... [266]

The MHRA/CSM failed to warn of the lack of evidence (since the early 1990s) of SSRI effectiveness in mild depression, suggesting that most users might expect minimal benefit when exposed to significant risks.[267]

There was a lack of basic data identified in the EWG, and a number of other shortcomings:

• The data on Prozac suicide-related events provided by Eli Lilly excluded large numbers of controlled trials performed outside the US. The EWG report commented: "Lilly have provided a proposal for retrieving these data, but this cannot be completed in the required time-frame for the report. Report to be updated when data are available."
• The Dutch company, Organon, "excluded many seemingly relevant studies" from the data on suicidality with Zispin (mirtazepine). The report notes that Organon "has been requested to provide these data. A response is awaited."
• Three companies (Lilly, Solvay, Wyeth) were unable to produce any clinical trials specifically designed to establish the prevalence and severity of withdrawal reactions.

Further concerns, relating to the MHRA's reliance on company summaries of data, rather than raw data are discussed elsewhere. The EWG did not make clear to what extent its findings were based on re-examination of data held by the regulators for years. To a significant extent this appears to be the case.

The EWG working papers suggested that companies may not comply with requests for relevant information, and that the MHRA is often in no position to require them to. One example involved GSK, the Marketing Authorisation (MA) Holder, arguing first, that it had fully investigated Seroxat withdrawal problems, then later resisting the regulators' proposal to warn that Seroxat withdrawal appeared particularly troublesome, on the grounds that no clinical trials had been done to establish this. From October 2003:

The MA holder considers that the clinical trials already conducted … have allowed the nature, frequency and severity of withdrawal reactions to be comprehensively characterized. They do not consider that further studies would add appreciably to the knowledge of events and consequently do not plan to conduct any further studies in this area.[268]

From February 2004:

They are of the opinion that there are no data from well designed, comparative clinical trials that would support the conclusion that the true frequency of withdrawal reactions is higher for paroxetine than other SSRIs as a class and that such statement in the SPC should not be based on spontaneous reporting data.[269]

All the available evidence pointed to a singular risk with Seroxat, but the warnings eventually proposed by the MHRA/CSM did not mention it.

Wider significance of the SSRI experience

The antidepressant controversy is not yet over, but it has already had a profound effect on shape of drug regulation as well as on the reputation of the industry. The lasting impact of the antidepressant controversy relates to greater recognition of:

• The limitations of clinical trials in predicting the benefits and risks of drugs in routine clinical practice;
• The prevalence and significance of bias resulting from non-publication of negative trial results;
• The limitations of existing post-marketing surveillance systems, and of lack of data relating to the effects of drugs in routine use;
• The essential importance of feedback on drug effects from users, and the importance of the Internet in facilitating this;
• The significance of intensive drug promotion and PR management in shaping perceptions of drug benefit and risk;
• The pervasiveness of conflicts of interest of all kinds, and their significance as factors that affect the quality of drug prescribing; and
• The need for greater transparency of data and clarity in regulatory warnings and communications.

We look forward to hearing the results of the investigation into the withholding of information by the manufacturers of Seroxat, currently underway by the MHRA.[270]

MEDICINES RECLASSIFICATION

306. We heard evidence of "serious concerns", notably from Which? and the DTB, about the MHRA's current programme of de-regulation of prescription-only medicines (POMs), making them available over-the-counter. For a description of the reclassification procedure see Part 6.

307. There was a reasonable number of POM to P switches throughout the 1990s, but due to some regulatory hurdles, the frequency decreased. Numbers of POMs being reclassified has accelerated following the agreement between the industry and Government reached in PICTF. The two parties "agree[d] that a market for medicines not reimbursed by the NHS, which involves NHS prescribers, should be developed."[271] To this end, Government made commitments for "streamlining the processes for reclassifying medicines", and quickly introduced new legislation to do so. Government would also gain from this, because only prescription drugs are reimbursed by the NHS. In its 2001 annual report, the MCA said that the new law had:

…resulted in a complete redesign of the process by which medicines are reclassified …cut dramatically the time taken between an application and a product reaching the shelves, while maintaining essential safeguards.[272]

308. These changes were introduced following public consultation. The consultation document began by saying: "Within the NHS Plan the government aims by 2002 to make more medicines available over the counter to widen access and patient choice…" Comparing this to the previous statement by PICTF suggests that the MHRA has been giving out different messages to different stakeholders, honed to what the regulators perceive to be the stakeholders' particular preferences and needs.

309. Evidence from Which? proposed that the process of selecting and approving medicines for reclassification "is driven by inappropriate targets and without due consideration to public health need or a satisfactory level of safety and efficacy data".[273] The DTB emphasised this was not a wholesale objection, however:

There are many drugs which are available over the counter which do bring great benefits to patients, but … could the reclassification process as it stands lead to ineffective or less effective medicines being promoted to patients without their knowing? Yes, is the answer.[274]

310. The efficacy of some reclassified drugs is questionable but the MHRA's reclassification procedure makes no provision for taking efficacy alone into account. Oral Buscopan (hyoscine butylbromide) was mentioned in this respect. This medicine, which has recently been reclassified from P to GSL status, was mentioned by Dr Iheanacho when he was asked for examples of a drug that had been reclassified and for which there was essentially no evidence of efficacy for the condition it was licensed to treat:

I suppose the most prominent example of a drug which has undergone reclassification … is a drug called hyoscine or Buscopan, which is a treatment for a condition known as irritable bowel syndrome…. If you want an example of a drug which is ineffective, or at least appears to be ineffective for the reason its reclassification is being proposed, that is a very good example.[275]

311. In their evidence, Which? also suggested that there were both safety and efficacy concerns about the drug Zocor, whose reclassification from POM to P status was approved by the Secretary of State for Health in 2004. A key issue was that the indications for the use of the product in the doses provided OTC relied on the extrapolation of trial data generated using higher doses in individuals at high risk of developing coronary heart disease. No large scale trials of the drug as a preventative in individuals at 'moderate risk' of coronary heart disease have been conducted and there is some uncertainty about the risks of these drugs in this population; yet the drug is now available for individuals to purchase if they are at moderate risk.

312. Post-marketing surveillance in the UK is inadequate. This has several causes: the lack of effective post-marketing investigation of drug benefits and harms in real life situations, and institutional indifference to the experience and reports of medicine users. In addition, the focus on drug licensing and on the safety profiles of individual drugs has contributed to a dearth of information about the overall impact of drug-induced illness in the community.

313. The reputation and credibility of the MHRA depends on its ability to communicate uniformly with its different stakeholders. These diverging messages contribute to confusion between health and trade priorities.

6. Generic medicines

Generic medicines are an important resource for the NHS and cost much less than branded drugs. We heard allegations that, over the past decade, major companies have developed, and now systematically employ, a range of product- and legal-based strategies intended to subdue or delay competition from generic manufacturers (known as 'life cycle management'). Strategies to extend the life of branded products include:

a)  Direct entry into the generics markets or developing an exclusive partnership with an existing manufacturer;

b)  Seeking reclassification to obtain OTC status;

c)  Defensive pricing strategies;

d)  Intensified promotion before patent expiry to enhance brand name 'outreach, compliance and retention';

e)  Longer times to process licence applications for generics compared to brand-name products; and

f)  A variety of minor product modifications, collectively known as product 'evergreening'.

Evergreening involves extending the patented life of a branded product, typically by reformulating the drug, for instance by using a different drug delivery system, changing a dosage form, or presentation (e.g. from tablet to capsule). Evergreening, in one common form, occurs when the brand-name manufacturer stockpiles patent protection by obtaining separate patents on multiple attributes of a single product. These patents can cover everything from aspects of the manufacturing process to tablet colour, and may extend to intermediate compounds produced in the body when the drug is ingested and metabolised. The significance of evergreening is underlined by the increased range of drug attributes eligible for patent protection. In the 1980s, the list of relevant drug properties was relatively limited. In the 1990s, the list extended protection in relation to range of use, methods of treatment, mechanism of action, packaging, delivery profiles, dosing route, regimen and range, drug combinations, screening and analytical methods, drug chirality, biological targets and field of use.

The British Generic Manufacturers Association (BGMA) listed five examples in which the originating company had employed evergreening methods, resulting in little or no therapeutic gain, but at a cost to the NHS estimated between £164m and £369m.[276]

NICE

314. The relationship between NICE and the pharmaceutical industry is one in which some degree of conflict is inevitable. NICE acknowledges this:

The Institute is conscious of the conflict of interest that manufacturers of health technologies have when engaging with us - that their desire, ultimately, is to ensure a market for their products and a return for their shareholders. [277]

315. The fact that manufacturers do not attend meetings of the technology appraisals advisory committee, whereas patient and carer groups and healthcare professionals are present at these meetings, in NICE's view is, "an important part of minimising the risks associated with the potential conflict of interest".[278]

316. NICE has great influence on the industry. A key problem articulated by witnesses from the industry was that an evaluation by NICE of the comparative value of a new drug treatment might not be completed until several years after the drug is launched.[279] Furthermore, implementation remains patchy and slow. Industry stressed that this presented a significant additional cost in marketing medicines in the UK. GSK, among others, told us that it was, "disappointed to date by the lack of progress" in delivering the goals of "faster, more equitable access to improved treatments, the need to address postcode prescribing and the promotion of the longer-term interest of the NHS in the development of innovative new treatments."[280] There are many factors which may contribute to this time lag, including:

a)  Lack of relevant data before a drug is licensed and widely used;

b)  Lack of access to such clinical data before a drug is licensed;

c)  Lack of NICE resources to undertake fast-tracked evaluations; and

d)  Delays resulting from the evaluation process (including time needed for consultation with stakeholders).

317. As we have previously indicated, the UK has one of the slowest uptake rates of new drugs in the world. We do not know the health significance of this slow uptake, but several submissions from the industry argue that patients suffer as a result of "NICE blight", in which uptake is slowed until NICE guidance is compiled or medicines not evaluated by NICE are not prescribed. Further concerns about NICE regulation were expressed by the BioIndustry Association (BIA):

NICE has an emphasis on mainstream drugs, whereas the bioscience industry often has niche products where the patient numbers involved fall below NICE's economic threshold.[281]

318. In our review of the organisation in 2002, we urged the MHRA to provide NICE with the confidential information held by pharmaceutical companies. We also recommended that NICE publish all the information on which it based its decisions, a recommendation which was reiterated by the WHO in its review of NICE published in 2003. According to NICE, an agreement between NICE and the ABPI in May 2004, "acknowledge[d] the importance of putting relevant information into the public domain to ensure the credibility of NICE guidance" but that unrestricted access to and publication of all relevant data for the development of guidance has yet to be achieved.[282]

319. The industry therefore also influences NICE, through access to its information. It provides the data on which the Institute bases its guidelines. The creation of such guidelines and algorithms may be compromised by publication bias and the proportion of articles that are ghost-written. A consistent lack of reporting of drug safety effects in the literature means that such effects will not show up in reviews and will therefore not be highlighted in the guidelines. Management of the medical literature may result in a drug that has not been proven to be more efficacious than its older (cheaper) rivals, being preferentially prescribed, which imposes a financial cost on the NHS and might put patients at risk.

320. Industry also influences the topics that are chosen for NICE review. Cancer Research UK stressed its concern over the influence of the industry on the topics considered by NICE for appraisal and suggested a need for increased transparency in this area and in the process by which certain drugs are prioritised by the Institute.[283]

321. Several improvements were suggested by witnesses. The BIA argued that a system for the provisional licensing of drugs should be introduced to provide early access (and reimbursement) to drugs where real need exists and no alternative is available. Such a scheme exists, for example, in France (the Autorisation temporaires d'Utilisation system) where medicines deemed highly likely to be effective are available often before the completion of Phase III clinical trials. AIDS, some types of cancer and neurological diseases are the conditions most commonly involved.

322. NICE could play a role in determining the research agenda by defining targets for new treatments in a limited number of disease areas. For example, it could prospectively define the type and size of benefit in the treatment of heart failure that would be considered an advance likely to merit inclusion in a local formulary, and fast-track subsequent guidance. Prof Patrick Vallance argued:

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.[284]

323. The need for closer working and ongoing dialogue between NICE and drug manufacturers was reiterated by the industry, "to reduce duplication of effort and to accept regulatory evidence".[285]

324. Improved and transparent communication between the MHRA and NICE and the pharmaceutical industry at an early stage in medicines development would encourage the provision of truly innovative and beneficial treatments to the public. The regulators could, for example, outline the type of clinical trial and size of patient benefit proven that would be likely to lead to marketing approval or positive NICE guidance While many of the criticisms that have been levelled against both industry and the regulators have involved perceived 'cosiness' and exclusion of the public, the public would not be served by forcibly separating these entities. Instead, we urge transparency in process and access to data for all.

Government

325. Government has a number of areas of responsibility for medicines. It must act as sponsor for UK-based drug companies to encourage a thriving and competitive industry, it must maintain oversight of the regulatory system and ensure that mechanisms and incentives are in place so that the industry acts in a way that is consonant with the Government's public health aims.

326. In particular, the Government must ensure that areas of research that are not addressed by the pharmaceutical industry are resourced. Non-drug approaches, for example, are rarely investigated. Sir Iain Chalmers told us that most clinical trials relating to osteoarthritis of the knee are commercial studies of drugs whereas patients, rheumatologists, physiotherapists and GPs have made clear that what they need, instead of more drug trials, are rigorous evaluations of physiotherapy, surgery and educational/coping strategies.[286]

327. Government has been slow to see the importance of these areas, perhaps because the pharmaceutical industry funds such a great proportion of other medical research. The industry cannot be expected to fully fund areas of research that are not directly in its interest, however, and so it falls to Government to address areas of need such as non-drug treatments, combination studies and iatrogenic illness.

328. Areas of research that are not of direct interest to the pharmaceutical industry but may significantly benefit patients, such as non-pharmacological treatments, should be funded by Government.

329. The Government is in a position to determine the ultimate balance between the interests of the industry and its requirement to look after health, but its task in doing this must be seen in the context of the growing influence of the industry.

330. The industry's influence internationally is underlined by the growing intensity of world trade; through strong support for companies by governments of the leading drug producing nations; and by the developing trend to Public-Private Partnerships. The close connection between the industry and Government is strong in the EU, where the European Commission's directorate for trade (DG Enterprise), not the directorate for health (DG Sanco), is responsible for drug policy and the operation of the EMEA. At the invitation of DG Enterprise, industry representatives were directly and prominently involved in the recent, major review of EU pharmaceutical regulation.

331. The close contact between the UK Government and the pharmaceutical industry in formulating health policy was illustrated by Ms Margot James:

When the national service frameworks came out we would make sure that we were very much in touch with the advisors to the Government on those implementation task forces. Where vaccine policies are concerned we would make sure that we are in touch with advisors so that we know where Government priority is going to be and that way we can advise our clients

…[if our clients] have anything that would be really beneficial in helping the Government attain those targets then obviously there will be a pay off for the company as well. It is a case of getting intelligence and using it appropriately.[287]

332. Lord Warner mentioned that he had been struck by the "detachment" of health ministers from other EU countries regarding issues concerning the pharmaceutical industry, but added that "we have kept the balance pretty well" between public health interests and the interests of the pharmaceutical industry,[288] arguing against the separation of responsibility for the two within the Department of Health:

Chairman: Cross-dressing in politics is apparently quite fashionable, but you seem to be in an impossible cross-dressing position in the role you have… What would be the impact if the commercial aspects, the competitive task force aspects of your role were actually within DTI and the regulatory remained within Health? ….

Lord Warner: Once you separate those two functions it would be far more difficult to get the right balance. You set up a scope for conflict departmentally within government if you go down that path.[289]

333. Yet a distinguished witness with a wealth of experience in the industry and in academic life argued that the DTI would be much better placed than the Department of Health to promote the industry's commercial interests. He suggested the main reason for the present arrangements was more to do with the perceived threat of abuse arising from the monopoly power of the NHS in purchasing drugs:

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![290]

334. Other witnesses have forcefully argued that the right balance between health and trade interests has not been achieved. The UK Government has established PICTF, which is not concerned with health yet is co-chaired by the health minister responsible for the MHRA and drug licensing. The lack of national medicines policy, as recommended by the WHO, is also a source of concern, despite Lord Warner's acceptance of the need for a policy of this kind:

There is a lot in what the WHO are saying and one of the things which we are going to do is to see whether we cannot have, what we are calling at the moment, a Futures Forum, which starts to look ahead, tries to be a bit more anticipatory about some of the areas where we might try to get the science applied faster where there is clear human need. What we have in mind here is that the [UKCRC]…which brings together industry, the research community, the charitable sector, patient interest, we might ask them on a regular basis to discuss where medicines policy might be directed more and relate it more to the progress of science in scientific knowledge.[291]

335. The interests of patients, the NHS and industry can be at odds and we have no confidence that the Department is capable of achieving the balance required. The 'cross-dressing' role of the Department in this regard does not serve the public as well as it should.

7. Over promotion and prescription of drugs: Vioxx

The COX-2 inhibitor Vioxx was launched in 1999 and was widely promoted and prescribed to arthritis patients in the UK and elsewhere. It was withdrawn by its manufacturers (Merck) in September 2004 following the revelation that it had probably caused many thousands of heart attacks and strokes. A report in The Lancet in January estimated that there are 140,000 people with serious heart disease in the US caused by use of the drug.[292]

There have been suggestions that Merck might have been aware of potential heart problems with the drug much earlier, but that the results of these trials were not publicised. The 1999 Vioxx Gastrointestinal Outcomes Research study of 8,000 patients, for example, showed heart attacks to be five times as common in patients taking Vioxx compared to a conventional, non-selective non-steroidal anti-inflammatory drug (NSAID). This was attributed by the company to the protective effect of the NSAID, however.[293] A 1998 trial (Study '090') involved 978 patients. Serious cardiovascular events were found to be approximately six times more common in patients taking Vioxx than in patients taking another arthritis drug or a placebo.[294] This study was never published. A recent meta-analysis comparing Vioxx to another arthritis drug or placebo in 20,742 patients has showed increased risk of heart attack in both short- and long-term trials. The Swiss and UK researchers concluded that Merck should have withdrawn the drug when this data was first available, in 2000 (four years earlier).[295]

Another COX-2 selective inhibitor, Celebrex, manufactured by Pfizer, has also similarly been linked with cardiovascular problems, although it remains on the market. Pfizer originally stated in October 2004 that no completed study had shown an increased risk of heart attack or stroke. A colon cancer prevention study, released in December 2004, however, showed a higher risk of heart attacks and strokes compared to placebo. A study conducted in 1999 showed a 3.6-fold increase in cardiovascular problems in older patients with Alzheimer's compared to those receiving a placebo. This latter study was not published and was submitted to the FDA only in June 2001.[296] Questions have also been raised about the validity of licensing Celebrex based on 6-month safety data because no significant advantage over comparator NSAIDs was observed in the same group at 12 months.[297]

A statement to the effect that heart problems were associated with Celebrex was issued by the MHRA in December 2004. In the statement, the Agency made it clear that it had not seen the actual data from the drug company but that its advice was based on information from Pfizer's website.

A promotional letter sent to healthcare professionals in November 2004 regarding the safety of Celebrex was the subject of a complaint investigated by the MHRA. The complainant argued that the information given was not balanced or accurate. The complaint was upheld by the regulator and a corrective statement, highlighting the limitations of the research previously cited, was to be sent to the original letter's recipients. However, in the interim period, updated safety advice from the CSM on Vioxx and other selective COX-2 inhibitors was issued by the MHRA, publication of which would have coincided with the corrective letter from Pfizer. The MHRA therefore decided "health professionals would be aware of current advice on prescribing celecoxib and that a further corrective letter would not serve a useful purpose."[298]

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102   Q517 Back

103   PI 27 Back

104   PI 27 Back

105   PI 35 Back

106   PI 106 Back

107   Q9 Back

108   PI 01 Back

109   PI 27 Back

110   PI 19 Back

111   PI 19 Back

112   PI 59 Back

113   PI 106, 47 Back

114   PI 81 Back

115   PI 19 Back

116   Q1006 Back

117   See Paragraph 48 Back

118   Q261. Dr Richard Nicholson suggested that under 10% of drugs licensed are truly innovative. Back

119   PI 33  Back

120   Q680 Back

121   PI 106 Back

122   Q253, Q 471, Q 527 Back

123   This issue was discussed during our visit to Pfizer in Sandwich. Back

124   Q98 Back

125   PI 28 Back

126   PI 51 Back

127   PI 35 Back

128   Lexchin JR. Published online, 23 Oct 2004, www.theannals.com Back

129   Qq29-32 Back

130   PI 104, PI 77, Q195, 503 Back

131   Q172 Back

132   Q37, 38. This area was also explored during our visit to Pfizer in Sandwich. Back

133   Q253 Back

134   PI 77 Back

135   PI 65 Back

136   PI 29 Back

137   PI 59 Back

138   PI 22, PI 106, Q408, Q508 Back

139   PI 22 Back

140   Q408, Q432, Q439 Back

141   Q408 Back

142   PI 29 Back

143   PI 59 Back

144   Intellectual property protection need not be a barrier to transparency. Sir Richard Sykes commented that "the whole point about intellectual property is to make it available to everybody so that everybody can see what you are doing" (Q416) Back

145   Q186 Back

146   See http://www.oag.state.ny.us/press/2004/aug/aug26a_04_attach2.pdf Back

147   Q769 Back

148   PI 35 Back

149   Q117, Q566  Back

150   PI 77 Back

151   PI 77 Back

152   The use of a medicine to treat a condition other than that for which it was approved  Back

153   Q533 Back

154   Q689 Back

155   Q696 Back

156   Originally published in Current Medical Research & Opinion 2003;19:149-154 Back

157   The European Medical Writers Association have also recently issued guidelines for medical 'ghost-writers', which are published in Current Medical Research & Opinion 2005, 21:317-21 Back

158   Q423 Back

159   Q134 Back

160   PI 05, PI 30, PI 112,  Back

161   PI 51 Back

162   PI 19 Back

163   Krzyanowska MK, et al. Journal of the American Medical Association. 2003;290:495-501. This study showed that late-phase industry sponsored trials were as likely to be published as non-sponsored trials. Back

164   PI 59 Back

165   PI 33b Back

166   See Paragraphs 187-188 Back

167   PI 108 Back

168   Q587 Back

169   Q588 Back

170   PI 103 Back

171   PI 53 Back

172   PI 33 Back

173   Q93 Back

174   PI 66 Back

175   Q810. See Recommendation at Paragraph 380 Back

176   Q948 Back

177   Q200 Back

178   Q200 Back

179   Information derived from Q740 and Public Expenditure Questionnaire 2004 Back

180   PI 05 Back

181   This evidence was presented to the Committee in Australia, by Dr David Henry of the University of Newcastle, New South Wales. Back

182   Staff numbers may have risen by as much as 59%, according to Dr Richard Smith, ex-editor of the BMJ: http://www.websee.org/documentacion/conf_richard_smith.ppt  Back

183   PI 125 Back

184   PI 126, PI 128, PI 129, PI 130, PI 131, PI 132, PI 133 Back

185   PI 126, PI 128, PI 129, PI 130, PI 131, PI 132, PI 133 Back

186   PI 126, PI 128, PI 129, PI 130, PI 131, PI 132, PI 133 Back

187   PI 65 Back

188   PI 53 Back

189   PI 35 Back

190   Q596 Back

191   See: http://medicines.mhra.gov.uk/ourwork/advertpromed/complaints/zocor_nov04.htm Back

192   Information supplied by UCL to the Committee. Back

193   Q101, Q137, Q200, PI 27 Back

194   HC Deb 31 March 1988, Cols 657-8W; 27 February 1990, 121-2W  Back

195   PI 64 Back

196   PI 27 Back

197   PI 33 Back

198   Q283 Back

199   PI 127 Back

200   PI 16e. Direct-to-consumer advertising (DTCA) of prescription medicines: third quarterly update - July to September 2002, Colin Meek November 2002. Commissioned by the RPSGB. Back

201   Q609 Back

202   PI 53 Back

203   The Henry J. Kaiser Family Foundation, Daily Health Policy Report, 21 March 2005 Back

204   Q619 Back

205   PI 35 Back

206   PI 53, Q250, PI 16i: Letter to MCA from RPSGB in July 2002, commenting on draft disease awareness campaign guidelines: "One of the problems with [disease awareness campaigns] is that if there is only one product (or a clear brand leader) to treat a particular condition then promoting the condition equates to promoting the product." Back

207   Q92 Back

208   Q651 Back

209   PI 05 Back

210   Q91 Back

211   PI 103a Back

212   See boxed text after Paragraph 305 Back

213   PI 05, Q89, Q651 Back

214   PI 16 Back

215   PI 125 Back

216   Q560 Back

217   PI 125 Back

218   Q562 Back

219   PI 22 Back

220   PI 18 Back

221   PI 19 Back

222   PI 18 Back

223   PI 25 Back

224   PI 07 Back

225   PI 54 Back

226   PI 36 Back

227   The Pharmaceutical Journal 2004, 272: 635-636 Back

228   Q296 Back

229   PI 38 Back

230   This reference was made in an article , 'The Mark of Zorro', published in Pharmaceutical Marketing in May 2000. It cited the need to, "employ ground troops in the form of patient support groups, sympathetic medical opinion and healthcare professionals. This will have the effect of weakening political, ideological and professional defences."  Back

231   Health Which? April 2003 Back

232   PI 36 Back

233   PI 38 Back

234   Qq24-25 Back

235   Q862 Back

236   US Senate Committee on Finance. Hearings: FDA, Merck and Vioxx: Putting Patient Safety First? 18 November, 2004. See: http://finance.senate.gov Back

237   Griffiths K; The Interview - Drug tsar who took on the system: David Graham, FDA whistleblower. The Independent, 12 February 2005 Back

238   Q169 Back

239   Q822 Back

240   PI 29 Back

241   Martinez et al, BMJ 2005; 330:389-393 Back

242   See http://www.mhra.gov.uk Back

243   NAO, Safety, Quality, Efficacy: Regulating Medicines in the UK Back

244   PI 27 Back

245   See http://www.bseinquiry.gov.uk/files/ws/s447.pdf  Back

246   Qq775-776, Q779, Qq808-809 Back

247   Q779 Back

248   Q778 Back

249   Q778 Back

250   See boxed text after Paragraph 305 Back

251   Q915 Back

252   Q434 Back

253   Q914 Back

254   Q168 Back

255   See Paragraph 104 for a description of the Yellow Card Scheme Back

256   Q168 Back

257   Q168, 403 Back

258   Q953 Back

259   PI 19, PI 65, PI 113, Q102, Q189, Q434 Back

260   Q162. Mr Brook was commenting on the late submission of information regarding the anti-depressant Efexor to the MHRA. Back

261  Q931  Back

262   PI 29, Q195, Q439 Back

263   Q162 Back

264   Q713 Back

265   Qq801-803, Qq806-808 Back

266   Q802 Back

267   Qq798-799 Back

268   Risk:Benefit Evaluation of Paroxetine (Article 31 Referral), October 2003, p 53 Back

269   Article 31 Referral for paroxetine - Assessment of the MAH's response to the list of outstanding issues, February 2004, p 23 Back

270   Q987 Back

271   PICTF, section 2.61, March 2001 Back

272   This information is taken from the MHRA's annual report, available at http://medicines.mhra.gov.uk/aboutagency/annualreports/2001/maintaining.pdf  Back

273   PI 53 Back

274   Q110 Back

275   Q114 Back

276   PI 48 Back

277   PI 32 Back

278   PI 32 Back

279   Q729, PI 33, PI 35 Back

280   PI 51 Back

281   PI 47 Back

282   PI 32 Back

283   PI 59 Back

284   PI 106 Back

285   PI 28 Back

286   Q408 Back

287   Qq643-644 Back

288   Q912 Back

289   Q998 Back

290   Q454. Sir Richard later explained that the pharmaceutical industry are "the chickens" and the NHS "the fox" due to its power as monopoly purchaser. Back

291   Q917 Back

292   Graham D et al. The Lancet 2005; 365: 475-81 Back

293   Bombardier C et al. New England Journal of Medicine. 2000 Nov 23;343:1520-8 Back

294   FDA memorandum. http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf Back

295   Juni et al, The Lancet online, published 5 November 2004; http://www.thelancet.com Back

296   Public Citizen's Health Research Group, http://www.citizen.org/hrg Back

297   PI 49  Back

298   http://medicines.mhra.gov.uk/ourwork/advertpromed/complaints/celebrex_1204.htm Back

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Prepared 5 April 2005