Select Committee on Health Fourth Report


4  From drug development to prescription

44. A medicine progresses 'from bench to bedside' over a period of many years —from initial development in the laboratory, through clinical testing, licensing, promotion to doctor and patient, and final prescription. The rationale for the very existence of major pharmaceutical companies is their ability to bring new and useful drugs to market. According to the ABPI, it takes an average of 12 years and over £500 million investment to bring one new drug to patients.[42] This cost has increased greatly over the years (see Figure 3).

Figure 3. Cost of developing a new medicine

Data supplied by the ABPI.

Drug development and the conduct of medical research

45. A drug innovation is generally defined as the discovery, development and bringing to market of a new molecular entity (NME). Drug discovery involves trying to match understanding of disease with an NME which might promise some therapeutic effect. For example, the search for NMEs may take the form of mimicking and/or building on what is known about the body's natural hormones, the activity of natural products from plants and computer-aided design of molecules. Often the NMEs discovered are original but relatively minor molecular modifications of existing drugs; sometimes, they are radically new creations, such as the first H2-antagonist (cimetidine) which was a major breakthrough in the treatment and prevention of peptic ulcers. When discovered, the novelty of NMEs can be legally and commercially protected by patents.

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

Figure 4. Development of a drug from target identification to post-launch product review[
43]

47. Pre-clinical studies are investigations that generally precede product testing in humans. Virtually all pre-clinical and non-clinical testing is conducted by pharmaceutical industry scientists either within the company developing the product or in industry-funded contract research organisations (CROs). This process typically takes about three years. Pre-clinical studies include chemical, pharmacological and toxicological studies in human cells, animal tissues and whole animals. Not all animal testing is completed before human trials begin. For example, long-term animal studies to test for the carcinogenicity of NMEs are generally not completed until after healthy volunteers and/or some patients have been exposed. These long-term tests in mice or rats are particularly important because human trials do not screen for carcinogenicity. This is partly for ethical reasons, but also because the interval between testing for the effects of most carcinogens and the onset of cancer may be many years - far longer than any clinical trial would run. For this reason the long-term carcinogenicity tests in rodents last for about two years in order to approximate the lifespan of the animals, and thus act as a model for cancer induction in humans.

48. A major problem in early stage drug development is uncertainty about the predictive value of results found in cells, tissues or whole animals. Findings in these pre- or non-clinical tests often cannot be extrapolated to human beings and many NMEs which are discovered fail to reach the market because of problems in the development stage. According to Cancer Research UK, failure rates in taking cancer drugs to market are around 95%.[44] There are no UK data, but information from the US Food and Drug Administration (FDA) shows that drug innovation has been declining steadily over the last 10 years (see Figure 5). At the same time, the cost of innovation is high and rising.

Figure 5: New Molecular Entities approved in the US, 1996-2003

FDA website at www.fda.gov/cder/rdmt/NMEapps93-03.htm

49. On the other hand, it is argued that, as approaches to disease change with results from the Human Genome Project and advances in biotechnology increase, so the drug discovery and hence innovation process will be enhanced. Improvements in the techniques used in drug discovery and increased understanding of disease mechanisms at a molecular level that have taken place over the last decade may also bring about a rise in medicines innovation in the future. [45]

50. The clinical stage of research (that involving humans) is traditionally separated into four phases, although in practice they often overlap. Phases I, II and III are carried out before a licence to market the new medicine is sought, and Phase IV trials are carried out after a licence has been granted. It may take as long as 10 years for a product that is eventually successful to progress from Phases I to III. A significant proportion of compounds fail to progress to the next stage with the highest failure rate being observed in Phase I. It is estimated that of every 100 drugs entering Phase I, 70 will go into Phase II, 33 into Phase III, 25 to regulatory submission and 20 to final approval.[46]

51. Phase I trials involve healthy adults. Until quite recently, this work was only carried out by academic clinical pharmacology units, but in recent years CROs have taken over that role almost entirely because, according to the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), they:

…provide an efficient, effective and high-quality service that enables companies to plan and execute the early clinical development of their drugs to tight timelines.[47]

52. Between 100 and 200 healthy volunteers usually take part in Phase I trials, which are essentially performed to determine whether the product is safe for use in humans and whether it is likely to work in a particular patient group. Phase I trials examine the additional effects of the product on the body and look at how the body's reaction to the drug changes its properties. Patient age, gender or external influences such as food or the presence of other medications may alter the action of the drug and it is important to determine this early on.

53. Initially, single doses of the drug, in increasing sizes, are given to participants. Repeated doses are then given and the safety and tolerability are assessed and compared to results from animal studies. This phase also determines the dosage for subsequent trials. If it appears that the product is likely to be effective in the target patient group, it progresses to the next stage of testing.

54. Phase II trials usually take place in a hospital and may be co-ordinated by a dedicated Clinical Trials Unit within that hospital. It is at this stage that the manufacturing company begins to involve limited numbers of the medical profession outside the company (typically in hospitals) in a major way. Notably by this stage the patenting process is generally completed so the manufacturer's crucial intellectual property protection is in place. Phase II trials involve individuals affected by the target condition and are designed to determine its safety and efficacy in the relevant patient group. Between 200 and 500 individuals with the target disease usually take part in this phase of testing. If the product proves acceptably safe and appears to be efficacious in this relatively small group, tests are then undertaken in a larger group in a subsequent trial.

55. Phase III trials involve larger groups of patients (2-3,000 approximately) although cohort size depends on the condition as some rarer diseases may necessarily involve a smaller group of patients. Phase III trials determine safety and efficacy of the product on a larger scale and either compare the product to a drug that is already on the market to treat the target condition or, more usually, a placebo. These trials form the basis of licence applications.

56. Human trials tend to have limited predictive value due to problems of extrapolation to routine clinical practice. Typically, only a small sample of the prospective population to be exposed to the drug can be studied in clinical trials. Furthermore, those patients who will probably be exposed to the drug if it is marketed may be excluded from clinical trials because they have multiple pathologies or take a number of different medicines. These co-morbidities and the presence of other drugs in the body might affect the drug being investigated and not allow accurate comparison with a placebo or comparator drug.

57. Phase IV, post-marketing trials, may be conducted by the industry to assess the safety and efficacy of medicines in the long term and in routine clinical practice. Drug companies are obliged to report all adverse effects to the MHRA. Other groups may also conduct Phase IV testing, but comparative studies of the drug against the market leader or involving combinations of products are more likely to be performed by non-industry groups.

Medicines licensing

58. Drug approval and licensing systems worldwide are based on detailed requirements and elaborate processes, the scope of which is constantly changing. However, the core elements of drug control remain essentially unchanged. The primary focus is on the evaluation of pre-licensing (non-clinical tests and Phase I-III trials) data generated or commissioned by companies to obtain approval.

59. The executive arm of the UK Licensing Authority is the Medicines and Healthcare products Regulatory Agency (MHRA), which is also responsible for approving clinical trials[48]. The MHRA is assisted by the Committee on the Safety of Medicines (CSM), and the Medicines Commission. These latter two organisations are due to be merged into one over-arching body, the Commission for Human Medicines. Medicines may be licensed for use in the UK either on a national basis (directly through the MHRA), through a centralised approval system of the European Medicines Agency (EMEA) or through a procedure for 'mutual recognition'. Under the centralised scheme, companies apply for a licence directly to the EMEA. The centralised approval system is already compulsory for biotechnology products and has expanded in scope to cover drugs for AIDS, cancer, neurodegenerative diseases and diabetes. Alternatively, a company may designate one EU country to approve a drug licensing application, and then receive marketing authorisation in various EU countries, provided these other countries agree. Under this 'mutual recognition' procedure, all EU countries in which marketing permission is sought receive the full drug licence application, and any objections are considered and resolved through EMEA's oversight body, the Committee on Human Medicinal Products (CHMP). Details for the arrangements for medicines licensing, regulation and post-licensing surveillance are discussed in Part 5.

60. Once licensed, the drug itself is under patent protection for 10 years, although in certain circumstances this may be extended. Once the period of patent protection has expired, the originating company is deemed to have been rewarded for risks of innovation and generic versions of the drug may enter the market. A generic medicine contains the same active ingredients as an original product that has been researched and developed by a pharmaceutical company. Regulatory standards for safety and efficacy are the same for generic medicines as for branded products and marketing authorisation must be obtained from the MHRA before the drug is allowed on to the market. Additional clinical data is not required. The manufacturers of generic medicines need prove only that their products are effectively identical to the original branded product, implying that they have identical effects on patients.

Post-licensing evaluation, including value for money assessments

61. The initial marketing authorisation lasts for five years, at which time the company must apply to the MHRA for a further, essentially permanent, licence if it wishes the product to remain on the market. The legal criteria for re-licensing are the same as those for the original assessment (safety, efficacy and quality) but in reality scrutiny is much less stringent and would rarely involve the CSM. Efficacy is rarely considered. There is no specific policy regarding the continuing evaluation and safety assessment of medicines.

62. The MHRA is also charged with conducting more general post-marketing surveillance. This may involve scrutiny of Phase IV trials, which include patients in a more typical clinical setting, as well as monitoring published medical literature and evaluation of spontaneous reports of suspected adverse drug reactions (ADRs), for instance though the Yellow Card Scheme.[49] Controls over drugs on the market extend also to the testing of medicines (for compliance with quality standards), inspection (e.g. of manufacturing facilities, record-keeping, pharmacovigilance inspections, and quality control) and enforcement (including control of promotional activities and other legal requirements).

63. Drug companies may conduct their own Phase IV studies, comparing the efficacy of their drugs to others, but there is no mandatory requirement for the industry to investigate the long-term effects of their medicines in the community. European legislation sets out requirements for proactive management of pharmacovigilance matters, however, and the MHRA is likely to review this at the time of company pharmacovigilance inspections.

64. After licensing, some drugs may be subject to a review by the National Institute for Clinical Excellence (NICE), which will affect the extent to which they are used in the NHS. Uptake of new medicines is therefore controlled not only by licensing through the MHRA but also through NICE guidance on the provision of novel drugs.

Figure 6. Percentage market share for products launched in the last five years (2003)

UK: United Kingdom; J: Japan; It: Italy; Fr: France: CH: Switzerland; D: Germany; Aus: Australia; Can: Canada; E: Spain; US: United States. Data supplied by the ABPI

65. It should be noted that the UK has one of the slowest uptake rates of new drugs in Europe, less than France and Germany. The industry stated that patients suffer as a result of this, for example:

On average, other major European countries treat more than twice as many [breast cancer] patients with Herceptin per head of population compared with the UK, while Switzerland treats more than three times as many patients.[50]

The provision of medicines information

66. The bulk of the information about medicines which is available to patients and healthcare professionals is provided by the pharmaceutical industry. This information may take several forms: that which must, under law, be given out as part of the licensing process; that which is given in order to educate prescribers or the public; and that which is designed to promote the prescription or use of particular medicines over others. There is a degree of overlap between these groups.

67. Legislation requires that pharmaceutical companies must provide information on their products on request from healthcare professionals. This obligation continues once medicines come off-patent and does not apply to generic companies. Large companies in the UK may each receive 15-30,000 requests for information annually. As an example, Pfizer, the largest supplier of prescription medicines to the NHS, pays over £1 million annually to cover the cost of providing this information service.[51]

INFORMATION TO PRESCRIBERS

68. A Summary of Product Characteristics (SPC) is issued to prescribers and other healthcare professionals for every new drug. The detail of content, style, layout and format are closely defined and approval is part of the licensing process.

69. The British National Formulary (BNF), which is published biannually, also provides information to prescribers. The BNF is published jointly by the British Medical Association (BMA) and the Royal Pharmaceutical Society of Great Britain (RPSGB). It provides information on the prescription, dispensing, administration and cost of medicines.

70. A range of alternative sources of independent information is available, including the Drug and Therapeutics Bulletin (DTB) that is published by Which? and distributed by the Department of Health to all doctors,[52] the Cochrane Collaboration and the James Lind Library. Medical journals provide a variety of specialist and non-specialist data relating to clinical trials or basic scientific studies. Industry produced or sponsored information is also provided to prescribers, in the form of journal supplements, reprints and other literature.

INFORMATION TO PATIENTS

71. Patient Information Leaflets (PILs), which are legally required documents written in accordance with EU regulations and approved by the MHRA, are printed and distributed alongside medicines by pharmaceutical companies to inform patients of how to take their medicine most effectively and to warn them of possible risks and side-effects. Like the SPC, they are approved as part of the licensing process; however, the regulations are not so prescriptive for PILs, allowing limited variation in their content and appearance. The PIL must correspond to the SPC. In response to long-standing criticisms, the MHRA set up a Patient Information Working Group in 2003, to review the design, content and utility of PILs. The work of this group is continuing.[53]

72. In addition to the PIL, patients (and carers) may receive industry-produced pamphlets or written instructions through their doctor or other healthcare professional. Patients can also access large amounts of information and promotional material on the Internet. The variable quality of this information has caused concern to both the pharmaceutical industry and charities/patient groups.

PROFESSIONAL AND PATIENT EDUCATION

73. Doctors are required to continue their education after they have qualified by taking part in accredited activities. These may take the form of attendance at training days or workshops. Industry funds over half of all postgraduate education and training for doctors in the UK, often meeting the travel and accommodation costs of attendance. The pharmaceutical industry also funds a significant amount of training for nurses. In 2003, for instance, GSK funded 235 nursing diplomas in respiratory disease management and 199 diplomas in diabetes management.[54]

74. Education for patients is provided in a variety of ways, including disease awareness campaigns, which are discussed in detail in Part 8. Such campaigns are designed to increase awareness among the general public of particular conditions that may be under-reported or under-diagnosed and to encourage people to seek treatment. Often, such campaigns are sponsored by a drug company and may bear a company's logo; they may be also endorsed by a charity or patient organisation and/or supported by a celebrity.

75. Guidelines for disease awareness campaigns, developed jointly between the MHRA and the ABPI, were published in April 2003. The guidelines state that educational materials may highlight the availability of treatment but may not focus on, or name, any single intervention.

THE PROMOTION OF DRUGS

76. Worldwide, there has been a marked trend to substantially increased expenditure on marketing. In the US, major pharmaceutical companies spend of the order of 24% to 33% of sales on marketing, about twice as much as on R&D.[55] Exact comparisons are complicated because of uncertainties about the dividing line/overlap between marketing and related activities, notably provision of drug information and professional education programmes. We have not been presented with UK figures, but direct promotional expenditure in this country is proportionately lower than in most European countries, reflecting the dominance of the NHS as the major drug purchaser and the terms of the Pharmaceutical Price Regulation Scheme (PPRS, see Paragraph 113)

77. Prescription-only medicines may be promoted only to healthcare professionals, except in very specific cases such as Government-endorsed vaccination programmes. Promotion to prescribers may take many forms:

a)  Drug company representatives. Approximately. 8,000 drug company representatives operate in the UK and play an important role in information provision and medicines promotion. Many doctors cite them as one of the main sources of information on the use of new drugs.[56]

b)  Sponsored attendance at industry-organised events or medical conferences. Travel and accommodation costs are often met by the company. Other forms of hospitality are also provided.

c)  Journal articles and supplements supporting use of the company's drug. These are distributed free to prescribers and are available at conferences and on the Internet.

d)  Direct advertising. Advertisements are placed in medical journals and magazines. Direct mailing to healthcare professionals often takes the form of informing prescribers of changes in drug delivery systems or the availability of new drug formulations. Approximately 80% of medicines advertising is aimed at doctors, with an increasing amount targeting nurses with new prescribing powers.[57]

78. Public relations and marketing agencies are often used by the pharmaceutical industry to assist with the promotional activities described above. 'Medical communications' play an important role in the marketing of medicines. The main aim is to improve sales figures and there are dedicated agencies that often form part of enormous, multinational PR and communications companies, such as Ogilvy, Burson-Marsteller, Edelman and Ketchum. Medical communications agencies may be involved in all or some of the following:

a)  Pre-marketing of drugs;

b)  Identification of disease areas;

c)  Disease awareness campaigns;

d)  Consumer education and marketing;

e)  Publications and papers;

f)  Conferences, meetings and hospitality;

g)  'Product lifecycle management';

h)  Regulatory and policy issues;

i)  Grassroots communications;

j)  Key opinion leader development; and

k)  The production of 'educational' materials aimed at prescribers.

79. A critical element of the work of medical communications companies is the recruitment and training of key opinion leaders (KOLs), who are usually 'authoritative third parties' such as physicians at the top of their field. These individuals may be paid to speak and write on behalf of the sponsoring pharmaceutical company. They attend medical conferences, for example, and may present research papers, take part in panel debates or field questions in oral sessions. The 'development' of KOLs, we were told, is a well-worked process involving all types of doctors (hospital consultants, clinical academics and GPs).

80. A major part of the work of medical communications agencies involves liaison with the lay media and a significant proportion of their activities may be directed towards building relationships with journalists.

81. In addition to building relationships between KOLs and journalists, medical communications agencies commonly have links with patient organisations. Such groups provide information to their members and the general public and often campaign for increased access to a particular medicine or procedure. Many are powerful lobbying groups, working both through the lay media and in specialist settings. As such, their interests may coincide to some degree with those of the pharmaceutical industry, and the communications company may be used as a mediator in the relationship between the two.

82. PR companies and communications agencies have expanded their work in recent years. They are increasingly involved with research and the design of clinical trials. A well-documented trend is for large medical communications groups to buy into the infrastructure of drug testing by taking over CROs that conduct clinical trials and generate evidence for licensing approval.

83. Increasingly creative methods are used in the promotion of drugs by Industry. Which? cited a financial donation made by the manufacturers of Cipralex (escitalopram, an antidepressant manufactured by Eli Lilly) to Depression Alliance when GPs completed and returned a feedback leaflet relating to their drug[58] and a spoof Mr Man book ('Mr Sneeze') that was sponsored by a drug company and carried information about its anti-allergy product.[59]

84. The direct advertising of prescription drugs to patients is prohibited. Direct-to-consumer advertising (DTCA) of prescription-only medicines is permitted only in the US and New Zealand. Moves towards extending DTCA to Europe proposed by the European Commission were quashed by the European Parliament in October 2002 by a majority of 494 to 42. Only over-the-counter (OTC) medicines may be advertised to the UK general public. The Medicines (Advertising) Regulations 1994, amended in 1999, govern the advertising of these medicines. There are specific regulations relating to promotional methods that could lead to the unnecessary or excessive use of medicines.

85. Complaints regarding advertising material are handled by a variety of bodies. The Proprietary Association of Great Britain (for OTC medicines), the Prescription Medicines Code of Practice Authority (PMCPA, for prescription-only drugs) and the Advertising Standards Authority operate as self-regulatory schemes and take responsibility for handling advertising complaints alongside the MHRA. Corrective statements are rarely mandatory, although a recent increase in the number of such statements required by the MHRA has been observed.


42   PI 35 Back

43   PI 51 Back

44   PI 59 Back

45   PI 33 Back

46   ABPI Report of Seminar 2 Nov 2000 Medicines; Tried and tested - or an unknown risk? http://www.abpi.org.uk/amric/tried_&_tested.pdf  Back

47   PI 107 Back

48   Q39 Back

49   See Paragraph 104 Back

50   PI 17  Back

51   PI 28 Back

52   The Department provides a grant to cover this service. Back

53   http://medicines.mhra.gov.uk/aboutagency/regframework/csm/piwg/patinfowg.htm  Back

54   PI 51 Back

55   Health Affairs 2001; 20(5): 136; http://www.eaepc.org/parallel_trade/threats.php?n=2; http://www.abpi.org.uk/statistics/section.asp?sect=3  Back

56   PI 35 Back

57   Q784 Back

58   PI 53 Back

59   Q150 Back


 
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