The FDA’s Center for Drug Evaluation and Research (CDER) is ramping up efforts to make certain that clinical trials include wide enough breadths of patient populations, and don’t unnecessarily keep out subjects with multiple chronic conditions (MCCs) who could turn up important data that would otherwise be missed.
Robert Temple, deputy director of clinical science at CDER, led a conference call with reporters last week and talked about “Good Review Practice: Clinical Review of Investigational New Drug Applications,” a 108-page memo issued in December.
The effort to be inclusive has been in place “for a very long time, since really 1982, when we first proposed guidance on including the elderly in trials,” Temple said, but it’s getting special attention lately.
In order to see which types of people were getting excluded from trials, the FDA analyzed 147 clinical experiments involving more than 115,000 participants. The findings showed that 71 percent of the studies denied subjects on the basis of a psychiatric disorder, 66 percent on the basis of a heart disorder, 55 percent because of atherosclerosis and 38 percent due to diabetes.
The psychiatric bias is “a particular problem, because some drugs – weight loss drugs and things like that, and anti-epileptic drugs – have been found to cause increased rates of depression,” Temple said. “You want to know whether that’s worse in people who have a history of depression or not. It’s important information.”
The FDA’s guidance on including more of the elderly came out in 1989. In 1994, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use released its recommendations, also urging that more elderly patients – defined as those 65 years of age and beyond – be allowed spots in clinical studies.
“Interestingly, [they] modified it in 2012, to say, ‘We made a mistake saying the elderly were people over 65. You should really pay attention to people over 75 and even older,’” Temple said. “We don’t yet know what the impact of that is going to be.”
The “elderly” category is of special interest as would-be trial participants who are turned away because of MCCs tend to be in that group – “conditions accumulate as you get older,” in Temple’s words.
Reads the December memo: “Data collected from elderly subjects can be of particular value because elderly subjects are more likely to have organ impairment, take a larger number of concomitant medications, and be susceptible to certain drug-related toxicities. In general, subjects over 65 years of age are considered elderly for the purposes of data evaluation, but it is particularly important to have data on subjects 75 years of age and older.”
But it’s not just the elderly. Drug developers are “encouraged to conduct major efficacy trials in demographically heterogeneous patient populations and in patients with a wide range of concurrent illnesses and treatments to ensure that the results are reasonably generalizable,” the memo said. “Within those trials, subset analysis can help identify important differential treatment effects.”
Temple said sponsors should be ready to answer questions about broad inclusion at the end-of-Phase II meeting.
“That’s before you cause the most severe patient exposure, and it’s the time when you can do something about it,” he said. Protocol design is another juncture at which inclusion is scrutinized.
“Since the mid-1980s, every new drug application has had to include integrated summaries of effectiveness and safety information,” he pointed out, and those figures are broken down by various demographics. “You had to look at age, gender and race. We’ve recently looked at how people are doing with that. In fact, those analyses are always carried out.”
As part of big trials such as those in heart failure and hypertension, “there’s almost invariably an examination of pertinent subsets in what are called forest plots,” Temple said. Such factors as demographics, concomitant illness and weight are used to examine subset variances and examine pharmacokinetic differences.
“This has become much more common over the last 20 years or so,” he said. Now, it seems, the agency will be looking to ensure that even more diversity in trial enrollment and analysis is done, and in more therapeutic areas.
Some trial designers may worry that wider inclusion could increase discontinuation rates, Temple acknowledged, “but many chronic conditions don’t mean you’re going to drop out. The presence of arthritis or a history of depression – I’m not sure there’s any good evidence that it makes dropouts more likely,” nor should statistical analysis, or trials in general, be made more difficult.
“I don’t think it makes them harder,” he said, noting that research by Oxford, UK, scientists has indicated that bigger, simply executed trials are superior. “Their concept of a simple trial was to have less exclusion,” Temple said.