International incidents

I've had a couple of days in Rome this week. I stayed at the 'English' Hotel (d’Inghilterra) near the Spanish Steps in a meeting with a German, a Uruguayan, an American, several people from Switzerland and a single Italian who was from Sicily. We were discussing a clinical trial in which the majority of patients came from France, Poland and Russia, but in fact patients came from all over Europe and even New Zealand and Canada. We considered whether we should open it up to Brazil and Argentina. No-one should doubt that medicine is now truly international.

‘International participation in clinical trials is a bonus and it demonstrates the rigor of the pharmaceutical companies that they go to the expense of establishing data-collection services in so many countries to ensure that the data are truly representative.’

Or is it just that some countries seize on new drugs before they are licensed based on flimsy phase 2 results, making it impossible to conduct clinical trials in those countries?

Recently, the FDA has issued an alert about the risk of progressive multifocal leukoencephalopathy (PML) in patients with systemic lupus erythematosus in patients treated with rituximab. PML (which hematologists take as an abbreviation for promyelocytic leukemia) is in fact a fatal brain disease caused by reactivation of the JC virus (a polyoma virus) in immunodeficient individuals (especially in AIDS in which 5% of patients eventually succumb to it) and there have been 20+ cases in people on rituximab. The same facts did not prompt the European regulator to issue a similar warning, but the FDA were incensed that so much rituximab is used off-license. In fact over 60% of prescriptions for rituximab in the US are for unlicensed indications (principally CLL). No wonder the drug is worth $2.6 billion.

Rituximab is so widely used in America that it is often known as vitamin R. Many of the uses are without any evidence of benefit, and although I think it is a good drug that is likely to be of value both in B cell lymphomas and autoimmune disease, formal evidence for benefit in most indications has not been demonstrated. The worst offence is to do giant phase 2 trials without a comparator. This seems to be an excuse to profit from an unlicensed drug under the guise of ‘science’. Phase 2 trials seldom need to accrue more than 40 patients and should then be followed by randomized trials comparing the new treatment with the previous best. Had this been done with FCR for CLL then we should know for certain by now whether it was better than FC or FR. As it is, it is likely to be 2010 before we know. Comparisons with historical controls frankly do not cut the mustard.

Trials comparing FCR and FC, both as first line and salvage therapy, are currently being conducted. These trials will contain hardly any American patients; indeed, like the chlorambucil v Campath trial many of the patients will have come from Eastern Europe where medical conditions are not always to the standard of Western Europe and North America, and where the financial inducements to participate in trials may weigh more heavily than natural caution in selecting patients.