Patients and public deserve changes in evaluation of drugs

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The drug industry has an image problem, and big changes are needed to restore public confidence. The reasons why it has got itself a bad name are well rehearsed. They include research agendas distorted by priorities that are important to industry but not to patients; inappropriately restricted study populations that exclude patients with multiple health problems and children; uninformative trial designs that fail to assess whether new drugs are better than existing treatment options; outcome measures that ignore the effects of treatments on morbidity and mortality or on the quality of life; biased under-reporting and over-reporting, not only of whole studies, but also of outcomes within published reports of research; and specious promotion of drugs, including disease mongering.

Industry makes much of the expense of bringing a new drug to market. In fact, directly and indirectly, the public provides most of the support for developing and evaluating new drugs. The public provides most of the academic infrastructure supporting much of the relatively high risk basic research underpinning drug development. It donates to medical research charities that fund much of this basic research and subsidises charities because charities attract tax relief. And through taxes, health insurance premiums, and direct payments for medicines, the public reimburses industry for its costs in a situation in which a true market does not exist. We believe that patients and health services are getting a poor return on this investment. If they are to reap better dividends in terms of better health at lower cost, major changes are needed in the way that drugs are evaluated.

Whose interests?

In countries where drug manufacturers are major contributors to the national economy no government can afford to ignore the industry's commercial wellbeing. In the United Kingdom, for example, pharmaceuticals and armaments are the last two remaining major elements of manufacturing industry, so it is unsurprising that successive governments have been at pains to support both of them.

An inevitable tension confronts all governments that try to balance the interests of patients and health services against the interests of industry and national economies. Within the UK, the drug industry currently interacts mainly with the Department of Health rather than with the Department of Trade and Industry. We believe that this is appropriate because drugs are made for patients.

However, the European Medicines Evaluation Agency (EMEA) is answerable to the Directorate General for Enterprise and Industry. This shows that European governments are currently prepared to encourage a view that drugs should be seen as consumer goods, rather than as agents for promoting and protecting health. The activities of EMEA are paid for by industry and are surrounded by secrecy, so the agency's decisions cannot be scrutinised by outsiders. In addition, when EMEA's Committee on Human Medicinal Products does not unanimously approve a drug, the reasons expressed by the minority are not made public. The European public assessment report and the summary of product characteristics are drafted in collaboration with industry, with no critical scrutiny from stakeholders representing the interests of patients and the public.

The US Food and Drug Administration is more transparent than the EMEA in several aspects. For instance, the FDA makes available the register of ongoing and completed clinical trials, the reports submitted by drug companies for marketing authorisation, the adverse drug reactions database, and the minutes of advisory meetings on pharmacovigilance.

We do not underestimate the balancing act that European governments face, but their continued support of the current situation, with all its conflicted interests and in the knowledge of its adverse consequences for patients and health services, will continue to attract opprobrium from those who believe that patients are getting a raw deal. Below, we suggest four ways in which governments could alter the balance of their support in favour of patients and health services: involving patients in shaping the therapeutic research agenda, making transparency in drug evaluation a legal requirement, requiring and resourcing independent evaluation, and requiring proof of added value for all new drugs.

Involve patients in shaping the therapeutic research agenda

The people who have most to lose from industry's dominance in drug evaluation are patients and those caring for them. The changes that are needed to ensure that patients' views are taken into account are unlikely to occur unless there is much greater public awareness of the problems and active engagement of patients and carers in confronting the powerful institutions and individuals who will wish to maintain the current situation. This presents a considerable challenge because so many patient groups are funded by industry or are in direct collusion with it.

One example of a British initiative to highlight unanswered questions about the effects of treatments is the James Lind Alliance (www.lindalliance.org). Drawing on uncertainties harvested for and published in the Database of Uncertainties about the Effects of Treatments (www.library.nhs.uk/duets), the alliance promotes working partnerships and collaborations between patients and clinicians to identify and promote shared priorities for therapeutic research. Asthma was the first health problem it tackled. After considering over 300 uncertainties about the effects of asthma treatments, the alliance selected 10 for referral to research funding organisations. The most important concern relates to uncertainties about the possible adverse effects of long term use of drugs for asthma.

Require transparency in drug evaluation, by law

The public has become increasingly aware that some unfavourable research findings of relevance to the safety and wellbeing of patients have remained inaccessible to them and to prescribers. After nearly two decades of ineffective lobbying by some academics for prospective registration of clinical trials, industry has voluntarily taken some important steps towards greater transparency, both by prospective registration of clinical trials and by commitment to publishing results. But dependence on voluntary trial registration and publication is not enough. Mandatory, prospective publication of trial protocols should now be required by law because, in addition to biased reporting of whole studies, there is also biased reporting of outcomes within studies. All of the confidentiality that surrounds clinical research and the activity of the regulatory agencies, including EMEA, should be abolished. After all, the data used by EMEA have been contributed by patients, and this information should be made publicly available to protect the interests of patients.

Until recently, governments have not supported such changes. However, the recent US act forcing publication of trial results has created expectations that other governments will take similar steps to protect patients. The UK government seems to be shifting its position after realising that GlaxoSmithKline could not be prosecuted for non-disclosure of trial data that showed it was unsafe for children under 18 to take the antidepressant paroxetine.

Require and resource independent drug evaluation

The monopoly that the drugs industry has in evaluating its own products, and the secrecy surrounding this process, leads to biased evidence that is currently only rarely questioned by independent studies. Independent clinical research to evaluate new drugs is not a new idea. In the 1950s, for example, the British Tuberculosis Association established a Clinical Trials Organisation to act as an interface between companies developing new drugs for chest diseases and clinicians treating these conditions. The Clinical Trials Organisation paid all the necessary expenses from the association's funds, and the companies then refunded the association. No fees of any sort were paid to individuals, and the organisation reserved the right to publish the results of trials that were unfavourable to the drugs tested.

There are similar arrangements today. The Italian Agency for Drugs (AIFA) is responsible for drafting the list of drugs reimbursable through the Italian health service. A recent Italian law requires all drug companies operating in Italy to pay 5% of their promotional expenses to the agency to support independent clinical research on the efficacy of orphan drugs, comparisons of drugs for the same indication, observational outcome studies, and pharmacovigilance.

The Italian precedent has already been emulated by the Spanish drug regulatory agency. Public investment in independent studies has also increased in the UK through the National Institute for Health Research and the US through the National Institutes of Health. For example, the National Eye Institute has launched a trial to assess whether ranibizumab (at $2000 a dose) confers any advantage over bevacizumab (at $40-70 a dose) in age related macular degeneration.

Require demonstration of added value for all new drugs

The evaluations of the European Medicines Evaluation Agency currently do not have to establish whether a new drug represents a real advance: no comparison is required with existing drugs or other (non-drug) forms of treatment. Authorising the marketing of drugs that may be less effective or more toxic, or both, than treatments already available is only in the interests of the market, and certainly not of patients and health services. By making it compulsory to show added value for all new drugs, governments could make clear to the public that they are prepared to deal with current conflicts of interest and ensure that patients and health services receive better value for their investment. European governments could signal this change of emphasis by supporting a transfer of responsibility for drug licensing and evaluation to the EU Directorate General for Health and Consumer Affairs. Furthermore, it would be important for regulatory authorities to require drug companies to have at least one pivotal phase III trial conducted by independent scientific organisations.

How might the proposed changes benefit the drug industry?

Why should policy makers within government and industry take any of these suggestions seriously as long as their current strategies continue to yield acceptable profit margins? Firstly, particularly after forced disclosures of suppressed information about adverse effects of its products, the industry has become concerned about its image. Adopting these changes will help restore public confidence.

Secondly, they could help improve returns from investment in research and development, which have been mediocre in terms of real advances in drug treatment. Of 12 sectors examined in terms of the yield of US patents per £10m spent on research and development, only telecommunications did worse than the drug sector. Furthermore, predictions about the economic future of the industry are anything but reassuring. For example, there is a high and increasing failure rate of potential new drugs in phase II studies. The industry is concerned that failure to report disappointing results of phase I studies may be one of the causes of this. Tim Mant, a director of a major contract research organisation, has acknowledged how frustrating it is to be commissioned to organise a clinical trial that he knows is going up a scientific blind ally because he has been there previously with another company but cannot divulge information that is commercially confidential (Academy of Medical Sciences meeting on experimental medicine, 24 April 2006). Science is believed to function most effectively through open exchange of ideas. Perhaps rather more openness might help to transform an industry that is not performing well and begin to deliver better value for the investments made by the public. To compensate industry for the requirement to make qualitative and quantitative improvements in carrying out clinical trials, governments could extend patent time.

We believe that, if informed and consulted, the public would support the changes we have proposed. It remains to be seen how far governments are prepared to go in promoting changes designed to serve the interests of patients and health services more effectively, and how far the drug industry is prepared to go in acknowledging that its current ways of working are not as effective as they might be, scientifically or financially.

This article is based on a joint presentation made by the authors at the Rome Science Festival, 20 January 2008. We thank Hilda Bastian, Donald Light, Aubrey Sheiham, Paolo Carminati for helpful comments on an earlier draft.

Contributors and sources: IC has a longstanding interest in the evaluation of healthcare interventions and in trying to persuade the research community to address questions of importance to patients and clinicians. SG has always been interested not only in the mechanism of action of drugs but also in the approval of new drugs. He has been a member of the Committee on Human Medicinal Products for seven years.

Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.

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Cite this as: BMJ 2009;338:b1025

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