Time sensitivity has long been a defining characteristic of clinical research, and is especially so today. Many of the innovations that have bolstered recent clinical trials – eSource, mobile health apps – are aimed at responding to sponsors’ concerns over study timelines, a concern sparked by rising study costs and growing markets for certain classes of drugs and other treatments. Opportunities to reduce timelines exist in all study phases. But certain inefficiencies are particular to Phase I, as are certain time-saving strategies. Here are three of them.
Phase I site negotiations
Money paid to sites that host clinical trials can comprise a significant chunk of a trial’s R&D budget. The more money that is at stake, the more meticulous sponsors and sites may be in negotiating prices. This can lead to prolonged negotiations and, ultimately, prolonged trials. This dilemma appears to be particularly acute in Phase I. Late last year, Applied Clinical Trials reported that the median time spent on site negotiations decreases as a compound moves through Phases I – IV. The median negotiation time for Phase I trials is 46 days, almost 60% longer than Phase II and more than double the 20-day maximum negotiation period considered, by many sponsors, to be ideal1.
One of the fundamental factors in this inefficiency is study protocol. Site negotiations, of course, occur before dosing even begins, and as this is early in the research process, protocols are most vulnerable to uncertainty and change. During this period of abstraction, it is difficult to offer a confident forecast of study duration, which complicates negotiations over site payments. Limiting site negotiations, then, can mean making protocols as well-established as possible. This brings us to the next point.
Phase I protocol amendments
Changes made to study protocols are one of the most notorious causes of delays2. These changes can occur for a variety of reasons, and a single one can set researchers back months and significantly raise the price tag on a study. And, perhaps most frustratingly, they are often avoidable3.
According to a 2008 study by Tufts University, most major protocol amendments do not occur in Phase I, but in Phases II and III4. However, there are some Phase I trials, such as oncology trials, that may, in fact, have higher rates of protocol amendments. Many amendments stem from challenges in patient recruitment or changes to eligibility criteria3; most Phase I patients are healthy volunteers and are thus relatively easy to deem eligible, but in Phase I oncology trials, which enroll sick patients, the right demographic can be more difficult to find and enroll. These trials have also been associated with higher dropout rates.
While Phase I trials may, overall, have a lower rate of protocol amendments than other phases, some of the strategies for addressing amendments may be particular to Phase I. The Tufts study found that most Phase I protocol amendments occurred before the enrollment of the first patient, whereas the majority of amendments in later phases took place after the start of dosing. Phase I sponsors, therefore, may benefit from putting extra focus on establishing protocol in the pre-enrollment stage. In general, more thorough planning and review early on could minimize protocol amendments, or at least better equip researchers to respond to them when they do occur.
Patient satisfaction in Phase I
In Phase I studies, another major cause of delays is difficulty with enrollment3. Part of this challenge is not recruitment itself, but rather patient retention. In studies with healthy volunteers, patients can feel unmotivated to continue their participation due to a lack of medical necessity. Phase I oncology patients may drop out if they feel the treatment regimen in the study isn’t moving as quickly as their advanced condition often demands.
Significant time savings can come from working to keep patients enrolled. And the best way to do this may be, simply put, to keep them engaged. Many sponsors and CROs are already striving to take a patient-centric approach to clinical trials, listening to patients’ needs and priorities and making sure the study is as convenient as possible for them. In some studies, patients are even playing a role in study design5. This could go a long way toward not only enrolling patients, but retaining them. In oncology trials, given the time sensitivity of many patients, catering to patients’ needs may mean working with general efficiency; investing in more thorough and technologically advanced preclinical research could catalyze Phase I trials by equipping researchers with stronger predictions of how a treatment will affect humans before the first patient is dosed.
Phase I clinical trials are unique in numerous ways. The origins of the delays that affect them, and the strategies for overcoming those delays, are part of their distinction. By focusing on the duration of site negotiations, the creation of well-established protocols, and the comfort and convenience of patients, sponsors and CROs can get closer to the efficiency and timeliness that today’s healthcare landscape demands.
1 Glass, Lucas Miller; Speeding Negotiations with Investigator Sites; Applied Clinical Trials; 06 November 2015
2 Minimize Phase I Clinical Trials Delays With Early CRO Communication; Cutting Edge Information; 2016
3 Getz, Kenneth A.; Protocol Amendments: a Costly Solution; Applied Clinical Trials; 01 May 2011
4 Getz, Kenneth A.; Acknowledging Cycle Time Impact from Protocol Amendments; Applied Clinical Trials; 01 April 2016
5 Marcus, Amy Dockser; Design Power: Patients Play Researchers in Drug Trials; Wall Street Journal; 29 September 2014