From bench to bedside

Manique Wijesinghe explains how new drugs become licensed and how the pharmaceutical industry ensures a good return from its investment

Pharmaceutical innovations in the past several decades have accounted for vast improvements in public health the world over. In 2003, 650 million prescription items were dispensed in the United Kingdom. And the pharmaceutical industry has been described as “a jewel in the crown of the UK economy.”¹ The NHS spent more than £7bn ($13bn; a10bn) on drugs in 2003, and branded drugs accounted for 80% of this figure (box).¹

Drug development

Drug research and development is a costly and uncertain process. Many new molecular entities fail stringent tests for safety and efficacy (figure 2).

Phase I, II, and III trials are done before a marketing licence is granted, but phase IV trials form a postmarketing surveillance system. Adverse drug reactions in this time should be reported to the country’s drug licensing authority—in the UK, the Medicines and Healthcare Products Regulatory Agency (MHRA) and in the United States, the Food and Drug Administration.¹ About half of new drugs have serious adverse effects that are detected only after approval.² In 2004, the Food and Drug Administration reported 375000 adverse reactions—more than twice as many as a decade ago.²

Regulatory authorities

The UK government created the Medicines Control Agency in 1989.³ From 1 April 2003, this agency (together with the Medical Devices Agency) was replaced by the MHRA.⁴

Some important areas of MHRA responsibility include:⁴

• Assessing the safety, quality, and efficacy and authorising medicines sold or supplied in the UK
• Operating postmarketing surveillance and other systems for reporting, investigating, and monitoring adverse reactions to medicines
• Regulating clinical trials of medicines and medical devices.

An MHRA spokesperson explained: “Control of medicines in Europe is based on a licensing system, whereby companies are legally required to obtain a ‘marketing authorisation’ before placing their products on the open market. In the UK, manufacture, sale, and supply of medicines were previously controlled by the medicines act of 1968, which has now been largely superseded by European directives implemented into national legislation. Directive 2001/83/EC (as amended) currently forms the backbone of European medicines legislation. However, this is a dynamic and continually evolving area and the directive is due to be replaced later this year.”

The MHRA is an executive agency of the Department of Health and has an annual income of £65m derived entirely from licensing fees paid by drug companies.¹ “The agency’s independence and ability to carry out its regulatory functions are determined by UK and [European Union] legal requirements, not by the way they are funded,” the MHRA spokesperson said, pointing out that “most leading medicines regulators worldwide are funded substantially or exclusively by user fees.”

A parliamentary report has strongly censured the agency, stating that the MHRA “has failed to adequately scrutinise licensing data and its postmarketing surveillance is inadequate.”¹ The report further notes that the licensing authority “has been too close to the [pharmaceutical] industry, a closeness underpinned by common policy objectives… frequent contact… and interchange of staff.”¹

“The working relationship which the agency needs to have with the industry does not inhibit the scientific and regulatory independence of the MHRA,” countered the MHRA spokesperson. The spokesperson, although admitting that “a significant proportion” of their staff is recruited from, or have been previously employed in, the drug industry, goes on to argue that this is in fact advantageous “because, in fields such as assessment and inspection, an intimate knowledge of industry and its working methods are necessary for effective regulation.”

Healthcare business

Given the nature of their products, drug companies have weighty public health responsibilities. But they are commercial enterprises, the primary aim of which is profitability. Striking the right balance between public health responsibilities and commercial concerns in a way that benefits all stakeholders—the regulators, governments, prescribers, patients, and the companies themselves—is an important challenge.

One of the main difficulties facing drug companies today is the rising cost of drug development. According to the Association of the British Pharmaceutical Industry, it cost an average $897m and took 12 years to develop each new drug in 2003.¹ The staggering cost of drug development is due partly to the difficulty of discovering new compounds, with only one in 13 drugs entering preclinical trials and ultimately entering the market.⁵ Compounding the issue is the cost and other difficulties of doing trials in developed countries: manufacturers are increasingly opting to do large scale trials in eastern Europe and India.¹

Distortion of the evidence

Sixty five per cent of medical research and development is done by the drug industry.¹ Although 75% of papers published in three selected major journals were found to be funded by the drug industry,¹ a study in the BMJ in 2003 concluded that “systematic bias favours products which are made by the company funding the research.”⁶ This situation can lead to distortion of the evidence base of health care.⁷ “The explanations… is not that sponsored science is bad science but rather that the scientific questions reflect the self interest of the sponsor,”⁷ Ray Moynihan wrote in the BMJ.

When asked to comment, Mike Sankey, head of regulatory affairs at Merck, said, “To obtain a marketing authorisation from the regulatory authorities it is essential that the pivotal clinical trials comply with all the relevant international guidelines.” Given the requirement to do these trials in compliance with existing regulatory advice and that all results will be examined by the regulators “it is difficult to see how, for these trials at least, you could end up with something which was intentionally and unacceptably ‘systematically biased.’”

Food, flattery, and friendship

BAYER
I was working in the lab,late one night

Drug companies spend large sums on marketing their products to prescribers. In the US, companies reportedly spend $12bn-$15bn a year or 24-33% of sales on marketing.^18 Direct marketing expenditure is proportionately less in the UK compared with other European countries, as the NHS is the largest drug purchaser.¹

Drug company promotional activities may take many forms, from visits from company representatives to gifts of equipment, hospitality, sponsored meals, and the ubiquitous pens and notepads emblazoned with drug names or company logos. In the UK, more than half of all postgraduate medical education and training is funded by the pharmaceutical industry.¹

Studies show that such interactions with drug companies influence the prescribing habits of doctors,^7-9 despite “professional self delusion” that they do not.¹⁰

Commenting on the practice, Sankey said, “Merck’s business interests are to sell its products and get a satisfactory return on its investment. Our business is not giving away free gifts or pens.” He went on to explain, “The cost of such items is very carefully controlled in the UK both by law and the code of practice, and in many other countries, such as France, it is not permitted to provide such free gifts to prescribers.”

Today, there is increased awareness of the pitfalls of accepting gifts from drug companies and the conflict of interests that this could create. The American Medical Student Association supports the view that “the only practical approach” is “for physicians not to accept anything of financial value, no matter how trivial, from drug companies.”⁸

“I am sure many companies would be very pleased if all doctors refused such items and we no longer had to compete in this way,” said Sankey. Merck spent a280.3m on research and development in the first half of this year alone, and “clearly there is no point in investing such huge sums… without also trying to maximise the sales of the resultant product.” However, he said, “If some medical students are anticipating being showered with expensive gifts and free holidays by pharmaceutical companies they are like[ly] to be severely disappointed.”

It is important that medical students receive guidance on appropriate relationships with drug companies during their training. The House of Commons Health Committee reported that the “quality of teaching on evaluation of clinical trial data and drug marketing techniques seems to be highly variable… prescribers often lack the time or skills to distinguish between weak and strong clinical studies and to evaluate critically the claims made.”¹ The committee also recommends that prescribers record all gifts, honoraria, or hospitality received from drug companies in a public register.¹

The drug industry is an important partner in health care and is largely responsible for continued therapeutic advances. It is therefore crucial that the relationship between the industry and prescribers is fostered. The terms of this relationship, however, do need to be regulated to ensure appropriate, informed, and unbiased prescribing and thus public safety.

Fig 2:From the laboratory to a chemist near you

Manique Wijesinghe, third year medical student, University of Southampton
Email: manique_w@hotmail.com


studentBMJ 2005;13:309-352 September ISSN 0966-6494

1. House of Commons Health Committee. The influence of the pharmaceutical industry. London: Stationery Office, 2005. www.parliament.the-stationery-office.co.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf (accessed 15 Aug 2005 ).
2. Okie S. Safety in numbers: monitoring risk in approved drugs. N Engl J Med 2005;352:1173-6.
3. Abraham J. The pharmaceutical industry as a political player. Lancet 2002;360:1498-502.
4. Medicines and Healthcare Products Regulatory Agency. About the MHRA. London, MHRA, 2005. www.mhra.gov.uk/aboutmhra/aboutmhra.htm (accessed 15 Aug 2005).
5. Oberholzer-Gee F, Inamdar SN. Merck’s recall of rofecoxib: a strategic perspective. N Engl J Med 2004;351:2147-9.
6. Lexchin J, Bero JA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003;326:1167-76.
7. Moynihan R. Who pays for the pizza? Redefining the relationships between doctors and drug companies. 1: Entanglement. BMJ 2003;326:1189-92.
8. Blumenthal D. Doctors and drug companies. N Engl J Med 2004;351: 1885-90.
9. Studdert DM, Mello MM, Brennan TA. Financial conflicts of interest in physicians’ relationships with the pharmaceutical industry: self-regulation in the shadow of federal prosecution. N Engl J Med 2004;351:1891-900.
10. Godlee F. Say no to the free lunch.[Editor’s choice] BMJ 2005;330:0.