Make Clinical Trials Shorter and Sexier, Study Suggests



PARIS – Clinical trials can show meaningful results after 5 weeks, and many trials should include more women, according to findings from the NEWMEDS program.

NEWMEDS, which is short for Novel Methods Leading to New Medications in Depression and Schizophrenia, is a consortium of scientists from around the world. The consortium is funded by the Innovative Medicines Initiative, a large-scale partnership between the European Union (represented by the European Commission) and the pharmaceutical industry (represented by the European Federation of Pharmaceutical Industries and Associations), according to the NEWMEDS website.

A primary goal of NEWMEDS is to look at ways of addressing the bottleneck that often slows drug development, said Jonathan Rabinowitz, Ph.D., who presented results of NEWMEDS research at the annual congress of the European College of Neuropsychopharmacology.

To date, the NEWMEDS repository of data from randomized controlled trials of antipsychotics in patients with schizophrenia includes 60 studies: 59 industry-sponsored studies from 5 drug companies and 1 from the National Institute of Mental Health (NIMH). The industry-sponsored studies included 29 placebo-controlled trials and 30 active comparator trials for a total of 23,401 patients. The NIMH trial added an additional 1,493 patients, reported Dr. Rabinowitz of Bar Ilan University in Ramat Gan, Israel.

The NEWMEDS team has reviewed 29 of these studies (including 6,971 patients on active treatment and 2,200 on placebo), with the goal of addressing four questions:

• Can clinical trials be shorter?

• What outcomes might predict treatment success?

• Do clinical trials have an overrepresentation of "eligibility creepers," meaning patients who don’t quite meet eligibility criteria?

• Do eligibility creepers have treatment responses that are different from those of patients who fall within the eligibility criteria?

The studies included in the review were sponsored by AstraZeneca, Janssen, Lilly, Lundbeck, and Pfizer.

In 37% of the studies lasting 6 weeks or longer, the effects of the week 5 results were larger than those at week 6, based on the LOCF (last observation carried forward) differences in Positive and Negative Syndrome Scale (PANSS) scores between the placebo and active patients. And in about half of the studies, at least 80% of week 6 effects were detectable at week 3, Dr. Rabinowitz said.

To determine whether certain subgroups of patients would show a stronger active treatment response, the NEWMEDS team examined variables, including sex, age, race, body mass index, age at disease onset, number of previous psychiatric hospitalizations, and the region where patients lived.

A review of study demographics showed that, on average, 71% of the participants in schizophrenia clinical trials were male, Dr. Rabinowitz said. However, "females had considerably less placebo response and slightly more treatment response than males," based on PANSS scores, he said.

Also of interest was the finding that patients in Eastern Europe showed a 19% greater active treatment response than did those in North America, Dr. Rabinowitz said. However, the reasons for this difference remain unclear and require further study, he added.

In addition, "people aged 30 years and older with 4 or more years of illness showed considerably better treatment response," Dr. Rabinowitz said.

A total of 20 of the 29 studies reviewed had specific eligibility criteria, and these were analyzed for eligibility creep, which was defined as patients who were within 6 points of the minimum eligibility criteria at the time of initial screening (for example, if a minimum PANSS score was 70, patients with scores of 70-75 could be eligibility creepers).

The researchers found that eligibility creepers were not overrepresented in the studies they reviewed, although there was an 18% less difference in active treatment response in this group, compared with the rest of the study cohort, Dr. Rabinowitz said.

Based on the findings, he presented three recommendations:

• Efforts should be made to dramatically increase the number of women in studies. Assuming a standard deviation of 19, a study that is 50% women would require 85 patients per treatment arm.

• Placebo-controlled efficacy trials could be shortened by 1 to 2 weeks.

• Sensitivity analysis should be included in a statistical analysis to reanalyze data after removing patients who fall within 6 points of the inclusion criteria.

The next step in the process would be a trial simulator including these elements, he said.

Dr. Rabinowitz has received research grant support and/or travel support and/or speaker fees and/or consultancy fees from Janssen, Johnson & Johnson, Lilly, Pfizer, BiolineRx, F. Hoffmann-La Roche, and Newron Pharmaceuticals.

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