By the time the drug development process gets to Phase 3, it seems reasonable to assume that the chance of failure is relatively low. After all, the entire early-development process is at least partially designed to reduce the risk of failure of the longer and more expensive clinical trials. The knowledge gained from the data collected in the previous phases should position the drug for Phase 3 success.
However, despite looking promising in the early stages, the FDA has reported that as many as 75% of drugs in development never make it out of Phase 3. There are several identifiable reasons for Phase 3 failures, and there are steps sponsors can take to manage the process in a way that delivers better outcomes.
Common Phase 3 Failure Points
Throughout the drug development process, the FDA is primarily concerned with the safety and efficacy of the drug. Perhaps at no other time in the process are these two factors more important than in this confirmatory phase. Regardless of the type of drug being developed, there are three overarching categories of actions that can lead to failure in Phase 3.
Flawed Clinical Study Design
Sometimes the design of the study protocol is flawed from the start. It may call for an insufficient sample size. It may not provide for the optimal dosage. The patient population definition may have changed from Phase 2 to Phase 3. The selected endpoint may not be one that the FDA believes is therapeutically meaningful. Problems at the design stage can doom the trial.
Flawed Data Collection & Analysis
The study protocol outlines what assessments will be conducted, what data will be collected, and how the data will be reviewed and analyzed. Even though the protocol may have been properly planned, there still may be concerns over how data was actually collected and analyzed. Perhaps data was missing, maybe the data had been biased in some way, or the wrong statistical tests were conducted. Complications in these areas call into question both the safety and efficacy of the drug.
Flawed Study Operations
The way the trial was carried out may raise concerns about the integrity of the data as well as the safety and efficacy of the drug. For instance, there may have been issues with recruitment or participant dropouts. Or, the trial may have been unintentionally un-blinded. Whenever there are deviations from Good Clinical Practices a red flag goes up and the entire trial is jeopardized.
Avoiding Phase 3 Failure
There are steps that a sponsor can take that can lessen the impact of the common Phase 3 failure points or avoid them altogether.
Obtain a Special Protocol Assessment
Typically, sponsors draft a study protocol to the best of their ability and submit it to the FDA for review. The Agency has 30 days to review the protocol. Because this process does not commit it to provide any guidance, the FDA does not have to issue an official response. This lack of response means that the sponsor can proceed with the study as planned. Consequently, if there are flaws in the protocol, the study will likely be flawed in some way.
One of the best ways to position a Phase 3 trial for success is to get feedback and buy-in from the FDA using a Special Protocol Assessment (SPA). This is a process during which sponsors may request to meet with the FDA to reach agreement on the design and size of the clinical trial to determine if the proposed protocol adequately addresses scientific and regulatory requirements.
According to guidance issued by the FDA, as a part of the SPA process, sponsors submit specific questions about protocol design as well as scientific and regulatory requirements. After the FDA completes the SPA review, it issues a SPA Letter that includes an assessment of the protocol, agreement or non-agreement with the proposed protocol, and answers to the sponsor’s questions.
An SPA agreement indicates concurrence by the FDA with the adequacy and acceptability of specific critical elements of the overall design of the protocol such as entry criteria, dose selection, endpoints, and planned analyses. These elements are critical to ensuring that the trial conducted under the protocol has the potential to support a future-submitted application’s ability to meet regulatory requirements for approval.
Engage a Reliable Contract Research Organization (CRO)
The success of a Phase 3 clinical trial can depend heavily on the CRO selected by the sponsor to help with the management of the trial. That’s why it is important that the sponsor fully understands the CRO’s capabilities and their experience level regarding studies comparable to the one they will be contracted to manage.
Follow Good Clinical Practices
While it is important to work with a CRO that has relevant experience, it is also important that they are committed to following Good Clinical Practices (GCPs). FDA’s decisions regarding drug safety and efficacy are based on the demonstration of study integrity, so the sponsor must be comfortable with the CRO’s ability to employ reliable quality assurance plans and behaviors throughout the duration of the trial.
Get the Help You Need to Succeed in Phase 3
You are in the driver’s seat when it comes to moving your drug through the long development process. The decisions you make determine the outcomes. The best way to conduct a successful Phase 3 trial is to start by working with a consulting partner that understands the common failure points and has the experience to help you avoid them.
Here at The Weinberg Group, we’ve organized our company as a drug development unit. We have all the major disciplines in place to take a holistic, 360-degree perspective on your program. So, when communicating with the FDA about your study protocol, we are able to speak scientist-to-scientist regarding every aspect of your Phase 3 trial.