UK Medicines Resource Centre*

Physicians are subject to continuous pressure to prescribe new drugs. Such drugs are undoubtedly the lifeblood of the pharmaceutical industry and some are essential to the continuing development of medicine. A careful, critical approach to their use ensures appropriate treatment for patients.

This article examines the prescribing of new drugs: the pressures involved, the guarantees (if any) provided by their licensing and the points for consideration before their use. Although it is based on a UK context, many of the principles are relevant globally.

What are the pressures?

Pressure to prescribe new drugs comes from many quarters, but largely from a pharmaceutical industry keen to sell a product it has spent years developing. Increasingly, "patient awareness" is being used as a potent marketing tool alongside the more traditional promotional methods of advertisements, direct mailing and visits by representatives.

Recently, articles in newspapers, general interest magazines and television programmes have preceded or accompanied new drug launches. These articles sometimes mention drug names and often draw attention to the alleged inadequacies of current therapy or the high incidence of the particular condition to be treated. This creates the perception that something better is needed and is on the way.

Self-assessment symptom questionnaires have also appeared in physicians' waiting rooms as educational "services to medicine" sponsored by the company marketing a new product. These never use the drug name but may employ the logo, colours and typefaces used in the product's promotional literature. The effect may be to urge the identification of symptoms and encourage consultation with the doctor. Matching promotional material reminds the prescriber that there is a new drug available for the patients' condition.

What is the drug?

The first thing to ask is whether the product is a new chemical entity and a truly novel medicine, or an addition to an existing therapeutic class - a so-called "me-too" product. Market pressures mean, however, that it is unlikely in the future that there will be, say 20 drugs in a new therapeutic class, as there were in previous decades with $-blockers or benzodiazepines.

New formulations of existing drugs are also called new products, and while some combination medicines, and modified-, sustained- or controlled-release preparations have advantages over standard formulations, many are merely "line-extensions" aimed at prolonging product sales-life through brand loyalty.

What is it for?

The question is whether or not the licensed indications for a product define its appropriate place in therapy. A licence for first line use does not necessarily equate with its use as first choice. Diuretics, $-blockers, ACE inhibitors and calcium antagonists are all licensed for first line use in hypertension, but opinions differ widely as to which are first and second choice for particular patients.

In the UK, the Medicines Control Agency (MCA), the regulatory authority, determines what therapeutic claims can be made in the light of the pre-clinical and clinical data submitted by the company. This includes data on safety relative to other therapies, and on efficacy (but not relative efficacy). The MCA must also be satisfied with the adequacy of the information to be provided to prescribers (data sheet) and also, where appropriate, to patients (patient information leaflet). Where a drug has a special advantage, but also a special risk, restrictions on its promotion and use can be imposed1.

How effective is it?

The efficacy of the drug for the intended condition, and the quality of the evidence for its efficacy are important separate considerations here. The true benefits of a new drug may be difficult to discern from claimed benefits originating in poor quality clinical trial evidence. The quality of the evidence dictates the interpretation of how effective the drug is.

Clinical trials need to be constructed to exclude bias as far as possible. They should ideally:

! have a precise question to answer;

! be randomised;

! be double blind;

! be comparative (with other agents rather than just a placebo; comparator drugs should be effective and relevant, not outmoded and defunct. Appropriate doses should have been used);

! use equivalent groups of patients as controls;

! have sufficient numbers of patients;

! interpret results correctly;

! reflect the population in which the drug is to be used.

Since few trials are conducted in general practice, careful consideration of the patient groups, the drugs used for comparison, and the clinical environment is therefore needed in order to interpret the therapeutic evidence and evaluate the drug's place in therapy.

How safe is it?

The final test of a new drug's safety starts when the first prescription for that drug is written and continues throughout the drug's lifetime2. Critical evaluation of therapeutic efficacy (benefit) balanced against the chance of causing side-effects (risk) is essential to prescribing decisions. This benefit/risk assessment needs to be applied to every drug prescribed for every patient.

Another viewpoint recently voiced is that: "however thorough the licensing authority, and no matter how rigorous its scrutiny of clinical trial data, problems can and will arise. The reason for this is simple: most problems that have led to the withdrawal of drugs from the market could not have been uncovered through studies prior to licensing because the number of patients involved was too small3".

A review of UK product licence applications for new active substances between 1987 and 1989, quoted median numbers of volunteers and patients exposed during pre-marketing studies4. The figures for the successful applications are:

! healthy volunteers: 92 (range 0-819);

! efficacy studies 1,126 (range 122-4,906);

! safety database: 1,480 (range 129-9,400).

This means that the number of subjects who have taken the drug before marketing may only be between 1,000 and 3,000 (at most). Clinical trials will characterise common side-effects but not those occurring more rarely (an incidence of less than one in 250 patients treated)5. A serious adverse reaction with an incidence of one in 5,000 may be enough to cause removal of the drug from the market. Clearly, pre-marketing clinical trials cannot hope to demonstrate such rare events.

Only licensing allows sufficient patients to be treated to uncover a rare but serious adverse event. The recent withdrawal of the quinoline antibiotic temafloxacin showed that such events can affect single members of a therapeutic group and that experience with other drugs in the group is not necessarily a predictor of future safety with similar compounds.

The situation has been well summarised3: "the take-home message for prescribers in all of this is that a product licence does not and cannot provide a safety guarantee. Doctors who prescribe new products are taking part in an extended clinical trial and must be aware of and prepared to accept the extra vigilance that is needed".

It is essential that, in countries where there is an adverse drug reaction report system, "innovative prescribers" accept their responsibilities and report all (not just serious) suspected adverse reactions to new drugs. In the UK this is done through the Committee on Safety of Medicines "yellow card" reporting system. New drugs are annotated with a black triangle (?) in the British National Formulary data sheet and in the Monthly Index of Medical Specialties (MIMS).

When did you hear about it?

It has been said that innovatory prescribing must proceed as something of an act of faith6. The question then becomes: which sources of information available to the doctor are sufficient to inspire such faith7?

Pharmaceutical marketing uses a continuous stream of advertisements, direct mailing and representative visits. While perhaps 10% of UK general practitioners have "see no reps." policies, no single source of prescribing information exceeds the influence of the medical representative upon the prescribing of GPs8. Figures from 19879 indicate that an estimated 1.93 million visits to UK doctors are made by sales representatives every year. This equates to 62 visits per GP every year10. In an average four-week period a GP sees about 6 representatives, but some see considerably more11.

In the UK the behaviour of medical representatives and the content of promotion material are self-regulated. However in a highly competitive market the benefits of a new drug are emphasised more strongly than the known side effects. Representatives should be questioned thoroughly on the data they present, in order to elucidate the whole picture12.

Evaluation of primary research material is difficult, time consuming, not possible for prescribers in many parts of the world, and generally not a priority for a busy primary health care physician.

Ideally all prescribers should at least have access to a national formulary, treatment guidelines and a source of objective data on the comparative efficacy of different drug therapeutic regimes such as that provided by an independent bulletin. In the UK, for example, the Drug and Therapeutics Bulletin and the MeReC Bulletin are circulated nationally and provide independent, evaluated advice and information on medicines and wider issues.

Information sharing between medical colleagues and community pharmacists is a useful educational exercise. Discussion using the above information sources facilitates agreement on the adoption or rejection of new drugs. This also enables their appropriate place in therapy to be defined: should they replace or add to existing formulary drugs; should they be used for specific classes of patient; or should additional data be awaited?

What does it cost?

Cost/benefit and cost/effectiveness arguments are increasingly used by companies in order to promote product uptake. Recently, premium pricing of new pharmaceuticals has been seen on an increasing scale. New products have not been priced to reflect profit and research and development expenditure (past and future) alone, but to reflect what the company thinks the "customer" should pay. At the same time, pharmacoeconomic data are used to argue that the price is still less than the costs of alternative treatments and/or the consequences of a non-treatment or treatment failure. Non-commercial sources of drug information, such as independent information bulletins, need to develop expertise in evaluating such health economic arguments. The implications for prescribing can then be included in the overall assessments in these publications.

Conclusion

New product introductions present an opportunity to review current prescribing practices. Careful assessment prior to prescribing, using reliable information, allows a place in therapy to be defined. This minimises inappropriate prescribing, ensures proper use of resources and is in the interests of good patient care.

* MeReC is a national centre funded by the Department of Health which provides professional advice and information for all general practitioners in England on medicinal products and matters relating to prescribing practice. The emphasis is on encouraging rational, safe and cost-effective prescribing. MeReC issues a monthly bulletin which is available free of charge to UK prescribers.

Articles are circulated for comment to expert clinicians in the relevant field and to other medical and pharmaceutical advisers throughout England. This helps to ensure that the advice and information given is accurate, practical and up-to-date.

For further information contact: Medicines Resource Centre, Hamilton House, 24 Pall Mall, Liverpool L3 6AL, UK.

References

1. Laurence DR, Bennett PN. Clinical pharmacology. 7th Edition. London: Churchill Livingstone, 1992

2. International Drug Surveillance Department, Glaxo Group Research. Drug safety - a shared responsibility. London: Churchill Livingstone, 1991

3. Dean T. Safety and new drugs. Prescriber 1992; 3: 11

4. Rawlins MD, Jeffreys DB. Study of United Kingdom product licence applications containing new active substances, 1987-89. BMJ 1991; 302: 223

5. International Drug Surveillance Department, Glaxo Group Research. Drug safety - a shared responsibility. London: Churchill Livingstone, 1991

6. Mapes REA. Physicians' drug innovation and relinquishment. Soc. Sci. & Med. 1977; 11:619

7. Peay MY, Peay ER. Differences among practitioners in patterns of preference for information sources in the adoption of new drugs. Soc. Sci. & Med. 1984; 16: 1019

8. Greenwood J. Marketing medicines - what works and why. London: Remit Consultants Limited, 1991

9. UK Sales rep coverage data. Scrip 1987; (1211): 3

10. Greenwood J. Marketing medicines - what works and why. London: Remit Consultants Limited, 1991

11. Swailes R, Western R. Making targeting work. Pharmaceutical Marketing 1992; 4: 27

12. Getting good value from drug reps. Drug and Therapeutics Bulletin 1983; 21: 13

KEY QUESTIONS WHEN PRESCRIBING NEW DRUGS

What is the drug?
Is it a truly novel medicine or a "me-too" product?
Is it simply a "line-extension"?
What is it for?
What are the licensed indications?
Does first-line mean first choice?
How effective is it?
Can the claims for it be substantiated?
Has it been compared with existing drugs?
How does it compare?
How safe is it?
Are there any comparative safety data?
Has it been widely used in other countries?
Are you familiar with the data sheet?
Who should not receive it?
Are there any contraindications or precautions in the data sheet
relating to particular groups of patients?
Where did you hear about it?
Have you only heard of it from the manufacturer?
Have you read any independent information on it?
What does it cost?
How does its price compare with existing therapies?
Is there any evidence that it is more cost-effective?
What is its place in therapy?
Should it replace an existing drug, or does it fill a gap, in the
practice formulary?
Are there some patients for whom it might be particularly suitable?
Is there a problem with existing therapies?