By some estimates, more than 90% of drug candidates never make it into consumer hands. That number shouldn’t come as a surprise to anyone who has spent time in pharma R&D, but thankfully most of those failed compounds fail early and relatively cheaply. What’s more surprising, though, is that a significant percentage of even safe and effective compounds fail during later clinical phases, sometimes due to operational issues rather than inherent issues with the drug in terms of safety or efficacy.
In doing research for our trial rescue white paper, we were distraught to find that more than 30% of active clinical trials were significantly protracted over the course of their execution. These overruns weren’t caused by bad science, but by bad project management. To us here at Biorasi, that’s inexcusable – science is iterative and failure is part of the process, but this shouldn’t be the case with project management.
We’ve put together this helpful guide to identify issues that may indicate your clinical trial needs rescue, giving you as the study manager plenty of opportunity to correct any missteps:
1. Minor Deadlines Are Missed with No Warning
It’s obvious that a trial is in danger when major deadlines are being missed. Regulatory approvals granted late, patient recruitment deadlines missed, database not locked on time – these are clear signs that all is not going to plan. Less clear are small deadlines missed and minor promises broken in day to day interactions with your CRO. Emails not being sent when they should be, study documents arriving late, trainings constantly pushed back with little warning and no explanation. These minor missed steps can pile on top of one another, eventually leading to missing a major study milestone, which could have implications across the board from quality issues, study funding, and of course having to defend the performance of the study when your boss begins asking questions. A lack of clear communication about these small delays only compounds the problem by causing the real issues to remain hidden until it is too late.
- Missing a couple small deliverables may seem like a small enough issue to overlook, but this is actually symptomatic of larger problems in the study and the CRO/Sponsor relationship. It’s important to pay them close attention to these details and fix the “leak” before it becomes a big flood.
2. Site Activation is Delayed
Enrollment is probably the most noticeable and telling issue that study managers will encounter as a cue to dangers ahead. What is just as important, often overlooked, and directly tied to enrollment, though, is site activation. You can’t screen a single subject until you have properly initiated and activated the study site. And, in our experience rescuing many clinical studies, delay in site activation and/or the failure to initiate the number of sites that were originally planned is one of the most pervasive issues we have encountered. It is important to establish a clear plan for site activation, including when the first site activation should take place, as well as a plan for how many sites should be activated each week or month, and when all sites should be active and screening subjects. Then, tracking your progress against this plan, you will be able to easily identify when or if you are behind your schedule. Caught early enough, you may be able to correct for the gap by adding a couple extra sites in order to get back to your original goals for Last Subject In.
- Because site activation is a leading indicator of enrollment issues, this is one of the most important red flags to keep in your inventory as a study manager.
3. Enrollment Is Significantly Below Projections
On-time enrollment, or the lack thereof, will absolutely make or break a trial. After ensuring data quality and subject safety, getting patients in the door and screened is THE most important job of a CRO. So when enrollment begins to significantly lag behind projections, especially if it does so repeatedly and consistently, you may well have serious issues with your trial. Aside from the obvious problems that under enrolling presents – budget overruns as you attempt to open more sites or spend more per patient for recruitment, delays in study completion, etc. – failing to meet projections for enrollment is a sign that the planning on the CRO’s end may not have been as thorough and detailed as it should have been. Either they vastly overestimated enrollment rates or they are not properly managing the sites to achieve desired performance, or worse still they are simply failing to follow through on their initial enrollment plans.
4. Queries Are Not Being Responded to in a Timely Fashion
Obtaining clean data that tells an accurate and compelling story about the safety and efficacy of a drug candidate is the goal of any trial. Querying the data is an integral part of getting clean, accurate results. When these queries back up, though, they become increasingly difficult to resolve successfully. Every week that passes on an open query makes it that much harder to answer, and having an excessive amount of these open queries is a sign that things are not on track for success.
- Excessive open queries after Last Patient Out are an even bigger problem, as they can significantly throw off the schedule for database lock. Any great CRO partner should have plans in place to deal with excessively-tardy queries, and should act on the plan long before it becomes an obvious issue. The CRO should be cleaning the database as the data comes in, and allow transparency into this process so that the Sponsor can track their progress, before it becomes a major issues at the close of the trial.
5. Your CRO Partner is Not Responsive
A fantastic project manager will pick up your phone call at 3 AM and be able to sleepily answer any questions you may have about the progress of your trial from memory. A good project manager will return your call first thing the next morning. But when your calls and emails are not being addressed after many days, or the response you get is to be passed around from one person to another with no answer in sight, you may have problems.
- A lack of responsiveness from your CRO partner is one of the clearest signs that your trial may not be their top priority. As complex as clinical trials are, being the second or third item on a PMs agenda can easily result in mistakes that can tank a trial, or even an entire program.
Above is obviously not a comprehensive list of red flags and signs that your trial may be in trouble, but a brief overview of some of the most common ones we run across when working with sponsors we rescue or running our rescue assessment for potential sponsors. For a more detailed list, check out our white paper “3 Measures to Overcome Operational Failures”