Getting more out of inclusion criteria
Julie Nelson returned from her morning walk with Candy, an 8-year-old Rottweiler. These walks had become progressively slower as Candy’s limp worsened, and Julie winced as Candy haltingly climbed the few steps into the kitchen. She resolved to call Dr Thompson later that day. But, right now, she needed her morning coffee. She filled her mug, grabbed the paper, and settled into her favorite chair. About halfway through the paper, Julie’s eyes fell on an ad for a clinical trial aimed at canine lameness. Candy’s symptoms seemed to fit the study’s requirements, and Dr Thompson’s clinic was listed as a study site. Julie called as soon as they opened.
“Good morning, Mrs Nelson,” said Nicole, the clinic’s receptionist. “How’s Candy?” “Fine,” answered Julie, “except for a worsening limp. It started a few weeks ago, and now it’s pretty bad. I see from the paper that Dr Thompson is part of a clinical trial. I think Candy is a perfect candidate!” “That’s awesome, Mrs Nelson! Enrollment just started! Let me get the appointment book… how’s tomorrow at 3 o’clock?” Julie was relieved to get such a prompt appointment.
When Julie arrived, Nicole weighed Candy and saw that she was three pounds over the study maximum. Julie promised to decrease Candy’s food so she could be included in the study. Hoping Candy’s weight would not exclude her, Nicole continued the screening interview. All of Julie’s other answers met the criteria.
Before Dr Thompson came in to examine Candy, a clinic technician drew blood and took radiographs. As she waited for Dr Thompson, Julie remembered the clinic’s previous owner, Dr Parker, who had cared for Candy since she was puppy and operated to repair a broken hind leg. Julie liked Dr Thompson and the new staff, but she missed Dr Parker.
“Good afternoon, MrsNelson,” said Dr Thompson, as he breezed into the examining room. “I hear Candy has a limp.” “Yes, and it getting worse,” said Julie. “I’m excited that she can be in your study.” “Hmmm,” said Dr Thompson, as he studied the radiographs. “When did Candy break her leg?” “About six years ago. She slipped off our deck chasing a squirrel. Dr Parker fixed it.” “Did you tell Nicole that?” Dr Thompson asked. “No; she didn’t ask about Candy’s history. I assumed she knew all about Candy from her records.” “Ahhh,” moaned Dr Thompson. “When I bought the practice from Dr Parker, we converted to electronic records. However, some of the older files didn’t get scanned. Nicole should have pulled Candy’s old folders from the storeroom before scheduling your visit. The study criteria exclude any dog with a prior fracture. So, unfortunately, Candy doesn’t qualify. I’m very sorry.”
Sponsors spend a lot of time and money designing their clinical trials and training investigators to perform the required activities in accordance with the protocol. Then, once the trial starts, the real spending begins. So, focusing most of their efforts on what happens from first subject-first visit to last subject-last visit makes perfect sense. However, paying more attention to what happens before first subject-first visit, and to anyone involved in that, offers opportunity for significant cost savings.
We learned this lesson the hard way in some of our early trials. When we analyzed the results of those studies, we found that, on average, slightly more than 94% of all enrolled subjects completed their respective visit schedules. About 4% terminated early for a variety of reasons, and almost 2% of the cases were discarded due to data quality. The big revelation was the large numbers of additional animals we had screened to enroll the required number of subjects for each study. We found screening failure rates of 20% to 35%! When we added the cost of screening failures to that of other unusable cases, we discovered that screening failures accounted for almost 60% of the total cost of “lost” subjects!
This experience taught us several things:
1. When reviewing the protocol, be sure that the inclusion/exclusion criteria are unambiguous.
2. Train everyone involved with subject recruitment in the inclusion/exclusion criteria.
3. Monitor screening failure rates and provide remedial training as soon as they start to rise.
Such extra effort will pay handsome dividends throughout your next study.