Newly licensed drugs

Should be on probation until their value is demonstrated

The Medicines Act 1968 set up a licensing authority that grants a marketing authorisation (product licence) for a medicinal product only if it is effective and safe and of good quality. Once licensed, a drug can usually be prescribed by any doctor under the NHS. But general use of a newly licensed drug may be undesirable.

Firstly, the licensing process cannot define uncommon adverse effects. It is easier to measure common therapeutic benefits than rare, but important, reactions. The numerical problem is daunting. If n patients have been treated, and none has suffered a particular adverse effect, then we can be 95% sure that the true incidence of that adverse effect is between 0/n and 3/n.1 Licensing decisions are based on trials involving on average around 1500 patients,2 so at the time of licensing, a serious reaction that affects as many as 1 in 500 patients could be undetected, and undetectable. Britain's Committee on Safety of Medicines asks for “yellow card” reports of any reactions to newly licensed medicines, marked with an inverted black triangle. A post marketing surveillance scheme, which monitors prescriptions and adverse events, exists only in general practice. Both schemes rely on the good will of prescribers rather than systematic study, and only a fraction of all important reactions is notified.

Secondly, relative efficacy plays no part in licensing decisions, though the licensing authority presumably considers relative safety. Most early studies of new medicines are performed against placebo rather than an established active agent. This makes it difficult to be sure of a new drug's true utility.

Thirdly, prescribers are not constrained to use drugs rationally and cost effectively. Rational prescribing should consider both the benefit and, in its broadest sense, the cost of a treatment. The cost of profligate use of new antibacterial agents, for example, is not simply the money wastefully spent but also the cost of increasing bacterial resistance.3 Local mechanisms, such as practice and hospital formularies, and drugs and therapeutics committees, can have some effect, but the contributors to different formularies are likely to differ in expertise and in freedom from external influences, and they will not be privy to the information on which licensing decisions are based.

Licensing decisions are now made both by the UK Licensing Authority through the Medicines Control Agency and by the European Medicines Evaluation Agency, which runs in parallel with national agencies. The licensing authority is not a drugs wholesaler. It would anyway be unreasonable to hold a Dutch auction, in which a pharmaceutical company reduced the price of its product until the licensing authority would take it. But the NHS is interested in money, and it should see that newly licensed medicines be prescribed at NHS expense only if there are proportionate benefits.

Interferon beta-1b, which has recently been licensed through the European Medicines Evaluation Agency, is an example (see pp 1159, 1195). It probably reduces hospital admission by one day every three years on average in selected patients with multiple sclerosis but has no demonstrable effect on disability.4 The published data concern just 124 patients receiving the 8 million unit dose of the drug. Treatment for one patient costs around £10 000 per year. The NHS might reasonably ask for evidence that the money should be spent on the drug, rather than on other services for patients with multiple sclerosis, or other patients. Several new agents for multiple sclerosis, such as copolymer 1, will pose similar problems.

The newer antiepileptic drugs provide another example where licensed drugs might have been treated more circumspectly by the NHS. Two papers (pp 1169, 1184) and an editorial (p 1158) in this week's BMJ cast considerable doubt on their long term value.5 6 7 As Marson et al say, “the gold standard to determine future use of new drugs will be actively controlled studies”5: trials of relative efficacy by another name.

One answer would be to introduce a form of probation for newly licensed medicines, in which they are subject to careful scrutiny before they become available for all doctors to prescribe. A possible way to do this in Britain would be to allow the licensing authority to operate as before, but to decide separately whether a drug should be available for prescription within the NHS. That decision would necessarily require the manufacturer to show, on the basis of randomised clinical trials, that a drug was at least as effective as standard treatment. It would also permit the NHS to conduct its own trials into the costs and benefits of a newly licensed treatment, within the framework of NHS research.8 This would need some integration, since cost effectiveness is a matter for the health service, and safety a matter for the licensing authority, but that should be possible. Prescribing outside the trials would be prohibited or discouraged by a ban on general prescription within the NHS. The Pharmaceutical Benefits Advisory Committee, which advises the Australian Minister of Health about which drugs should be available under the national pharmaceutical benefits scheme, is a useful model.9

The NHS might also wish to see evidence of cost effectiveness before agreeing to support major changes in the use of established licensed drugs. For example, using lipid lowering agents such as pravastatin in the primary prevention of coronary heart disease10 could be examined.11

The Committee on Safety of Medicines has a good record of protecting the public from frankly dangerous medicines, while allowing potentially useful drugs to be marketed. More careful monitoring after a drug has been marketed would make it easier to detect “rogue” drugs like benoxaprofen (Opren). Local controls on prescribing have been less successful in ensuring that drugs are used rationally. The NHS should not be obliged to pay for new drugs unless they are at least as good as older ones, nor for expensive drugs whose benefits are uncertain. A good starting point would be a trial of the costs and benefits of interferon beta-1b before patients are exposed haphazardly to unknown risks, and before large sums of money are spent for poorly quantified benefits.