Drug doses 'set too high'

A drug often takes more than a decade to develop

Drug companies often have to reduce the recommended doses of their new drugs for safety reasons - and the trend is increasing, say researchers.

One recently-published study suggested that more than one-in-five drugs undergo "post-marketing dose changes".

Another found that the bulk of these involved cutting the maximum recommended dose rather than increasing it.

Some of the original doses were eventually cut in half for safety reasons.

In the UK, there is a well-established system for doctors to report any problems which may be due to side-effects from medicines.

New medicines have to go through a lengthy testing process often involving thousands of patients to make sure they are safe before they hit the market.

No guarantee

However, even with clinical trials of this kind, it is impossible to completely rule out the chance that new side-effects or dose problems will show up once the drug is being given to even more patients.

These "adverse reactions" can be reported to the Medicines Control Agency, which collates information and then decides if there is a need for the drug to be given in different doses.

The pharmaceutical industry says the figures prove the present drug safety system is working well.

However, the lead researcher on one of the studies, Dr James Cross from the Center for Drug Evaluation and Research, at the US Food and Drug Administration, said his findings suggested a "systematic flaw" in the way pharmaceutical companies worked out dosages.

Very often, he said, there was pressure to work out a dose very early in the testing process, and final clinical trials often involved giving patients what appears to be the "maximum tolerated dosage" (MTD).

He wrote: "Although the MTD approach may enable efficient demonstration of effectiveness, it has led, as our data shows, to frequent post-marketing dosage reductions due to inadequate pre-marketing dose optimisation."

Changes needed

His study found that 21% of drugs given a licence in the US between 1980 and 1999 needed dose changes later.

Three-quarters of these involved reducing the dose - 80% of these were sparked by safety concerns.

Moreover, between 1980 and 1999, the number of dose changes per year trebled, although the average time delay dropped.

The other study, carried out at the Utrecht Institute for Pharmaceutical Sciences in the Netherlands, looked at changes in recommended daily doses in drugs licensed between 1982 and 2000, and again found that the vast majority of changes involved reductions in dose.

The most commonly changed drugs were cardiovascular medicines, including ACE inhibitors and beta-blockers.

The author of the second study, Dr Eibert Heerdink, said that it was possible regulatory authorities were getting better at picking up drugs licensed at unsafe doses.

'No problem'

The Association of the British Pharmaceutical Industry is convinced that the present alert system is working well.

A spokesman said: "It's a situation that will be closely monitored in future."

The Medicines Control Agency also feels that the current system of checks and balances is sufficient.

A spokesman said: "it is reassuring to know that the pharmaceutical industry is vigilant in monitoring its product's usage throughout its commercial life."