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CNS Trial Failure Rates High As Need for New Drugs Grows

The failure rate of CNS drugs in Phase 2 and 3 clinical trials is approximately 85%, second only to oncology. Because of the blood-brain barrier, the development of drugs for CNS indications presents particular challenges, as compounds need to be lipophilic in order to pass through that barrier.

Over the past decade many larger pharmaceutical companies divested their CNS research because of the low rate of success associated with bringing those products to the market, and as a result it has fallen to small- and mid-size biopharma companies to fill the void.

The need for drugs to treat neurodegenerative diseases and other CNS disorders is huge. Estimates vary but it’s likely more than 10 million people live with Parkinson’s disease globally; in the US alone at least 5.5 million people live with Alzheimer’s disease. And anxiety disorders are the most common mental disorder in the US affecting around 40 million adults per year.

In the face of this massive need for both disease-modifying and symptomatic treatments in CNS, we need to carefully evaluate the issues most often associated with trial execution leading to poor outcomes. Avoidable trial failure not only deprives patients of a new treatment that they desperately need, but compounds the cost of the failed trial, the cost of all prior trials and the opportunity cost of not pursuing viable alternatives. Those costs of failure become particularly acute for smaller sponsors that may lack the financial safety net to survive that failure.

Trial Design and Endpoint Protection: Crucial Choices that Directly Impact Success

Poor study design is the number one reason for trial failure. The endpoints in CNS trials are usually subjective and not objective. We rely on the reporting of symptoms by the trial participant and on observational reporting by the clinical investigator.  In some diseases, such as Alzheimer’s and pediatric illnesses, we also rely heavily on the caregiver for their assessment of how the trial participant is thinking, feeling, and acting.

Endpoint protection is a crucial part of study design.  In 2009, Acadia conducted a trial in Parkinson’s Disease Psychosis using central raters in the US for the SAPS-PD scale but used site raters ex-US. The results are shown below. The US central raters found statistically significant separation for the 40 mg dose at week two and a trend towards significance at week six, but the ex-US site raters found no separation at any dose.

As a result, Acadia used central raters globally for their Phase 3 trial and they saw strongly positive efficacy signals across multiple measures – most importantly, primary endpoints and prospectively defined secondary endpoints. Thus, they eliminated a potential false negative and showed separation of test drug and placebo. The results are shown below.

Based on these compelling results, FDA cancelled the need for a confirmatory Phase 3 trial and fast-tracked the submission based on the robust centrally rated results.

Placebo response represents another issue in CNS trial design. The presentation of a strong placebo response—subjects who psychologically believe they are receiving benefits from the investigational drug even though they are unknowingly assigned to the trial’s placebo arm—can adversely affect results. Placebo response in CNS trials appears to be increasing over time1.

“The placebo response is more a problem in clinical [trials] with subjective endpoints rather than objective endpoints,” explains Nathaniel Katz, Adjunct Associate Professor of Anesthesia, Tufts University School of Medicine, and founder of WCG’s Analgesic Solutions.

The sites you choose directly impact your outcomes – a finely balanced decision

Ineffective site selection is the second factor as a reason for trial failure. In CNS trials there is a fine balance to achieve between sites who have extensive CNS trial experience and those who have less experience. Extensive trial experience may be an indicator for success but has the risk of competitive trials and trial participants who may have participated in multiple trials (“professional patients”) or may even be participating in multiple trials (“trial shopping”). Less experienced sites may need more support but have untapped patient pools and fewer competitive studies.

CNS trial complexity puts undue pressure on sites and participants

The third reason for trial failure is poor recruitment.  CNS trial participants and their caregivers need exceptional support to enter and remain in clinical trials.

In pediatric studies and other studies with a caregiver, retention truly starts with recruitment and experience shows that parent/caregiver inclusion in every aspect of the process is key. If the patient and caregiver are not recruited correctly, then the rest of the downstream process is flawed, and the trial will not recruit successfully. 

CNS trials have specific needs to enable them to have optimal outcomes. The reliance on subjective endpoints is a challenge and use of centralized rating for completion of scale assessments, and training to mitigate placebo response, are tactics that can positively affect outcome. Site selection remains a balance between experience, competition, and site resources. Being able to access a large selection of sites, understand their prior experience and success in delivery, as well as assessing the competitive landscape at those sites, are key to making informed site selection decisions. Furthermore, we need to help alleviate the burden on both sites and trial participants due to the complex nature of CNS trials. Sites find it increasingly difficult to keep up with the demands that sponsors place on them resulting in delays recruiting patients, processing trial data, and inadequate time to support participants resulting in poor retention. Trials with a genetic testing component compound this situation. Augmenting site resources and the use of specialized genetic counselling support can overcome these obstacles.

Let’s discuss how you can improve signal detection on your CNS study

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