Researchers in Canada and France have raised concerns about substantial inconsistencies in a basic aspect of the way Phase-I and Phase-II cancer clinical trials are designed.

Speaking at the 35th Congress of the European Society for Medical Oncology (ESMO) in Milan, Italy, Dr Benoit You from Hospices Civils de Lyon in France and Dr Eric Chen from Princess Margaret Hospital in Canada reported finding unexpectedly large differences in the lists of drugs that trial designers say participants should not be given to avoid potentially dangerous drug-drug interactions.

Phase I and II clinical trials are designed to assess the pharmacological features, safety and efficacy of new experimental drugs. The outcomes of these trials – and patient safety – may be affected by interactions between the new drug being studied and other pharmaceuticals administered at the same time.

Some drugs commonly prescribed to cancer patients are particularly prone to these interactions, especially drugs that are inducers, inhibitors or substrates of liver enzymes involved in drug metabolism, or drugs that can induce risk of heart conduction problems.

?Lists of cautioned or prohibited drugs are important because cancer patients frequently experience complications and symptoms that require medicines prescribed concurrently with study drugs,? explained Dr You. ?As a consequence, investigators and trial nurses have to be guided when they have to choose drugs so that they do not prescribe medicines that could induce drug-drug interactions and thus compromise study outcomes and patient safety.?

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The researchers reviewed the protocols of 100 Phase-I and Phase-II clinical trials conducted in North America between 2004 and 2009. Of these 77 included lists of cautioned or prohibited drugs, most of which were drugs that affect the hepatic cytochrome (CYP) system, where most drug-drug interactions take place.

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The results were surprising. ?To be honest, we expected heterogeneity among protocols because this issue has been raised by the clinical staff in our team for a long time. However we did not expect the inconsistency would be so large.?

For example, in 37 trials involving study drugs that were substrates of the liver enzyme CYP3A4, the lists of prohibited or cautioned drugs ranged in size from one drug up to 152 drugs.

Even among drug safety protocols written by the same drug company, the list of prohibited or cautioned CYP3A4 inducers or inhibitor ranged in length from 5 drugs, up to 152 drugs.

?Moreover, 20% of the protocols reviewed included sources of confusion such as contradictions in drug lists, drug name misspellings or mistakes regarding drug effects on CYP enzymes,? Dr You said.

?We believe that inconsistency among lists of drugs may introduce a source of heterogeneity in patient eligibility, in management of study patient symptoms and thereby in outcomes of phase I trials,? Dr You said. ?As a result, it might impact on the comparability of different trials.?

From a practical point of view, this inconsistency also contributes to a risk of confusion for clinical teams, the researchers say. Long lists of prohibited agents can also significantly reduce the number of drugs available to deal with study patient symptoms such as nausea and vomiting.

?Inconsistency among lists of cautioned and prohibited drugs is unlikely to have harmed patient safety, but it may have significantly reduced the overall quality of new drug development,? Dr You said. ?The development of realistic consensual standardized lists of cautioned and prohibited drugs lists is warranted.?

“This specific aspect of research, especially within early clinical trials, is often underestimated,” noted Fortunato Ciardiello, Professor of Medical Oncology at the Second University in Naples, Italy. “However, although it doesn’t have a direct impact on individual patients, it can have a significant impact on drug development as well as on the evaluation of drug interactions and long-term effects, once these drugs are available on the market and regularly used in the clinical setting.”

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