Why Drugs Fail in Late Stages of Development: Case Study Analyses from the Last Decade and Recommendations

Abstract

New drug development is both resource and time intensive, where later clinical stages result in significant costs. We analyze recent late-stage failures to identify drugs where failures result from inadequate scientific advances as well as drugs where we believe pitfalls could have been avoided. These can be broadly classified into two categories: 1) where science is mature and the failures can be avoided through rigorous and prospectively determined decision-making criteria, scientific curiosity, and discipline to follow up on emerging findings; and 2) where problems encountered in Phase 3 failures cannot be explained at this time, as the science is not sufficiently advanced and companies/investigators need to recognize the possibility of deficiency of our knowledge. Through these case studies, key themes critical for successful drug development emerge-understanding the therapeutic pathway including receptor and signaling biology, pharmacological responses related to safety and efficacy, pharmacokinetics of the drug and exposure at target site, optimum dose, and dosing regimen; and identification of patient sub-populations likely to respond and will have a favorable benefit-risk profile, design of clinical trials, and a quantitative framework that can guide data-driven decision making. It is essential that the right studies are conducted early in the development process to answer the key questions, with the emphasis on learning in the early stages of development, whereas Phase 3 should be reserved for confirming the safety and efficacy. Utilization of innovative technology in identifying patients based on molecular signature of their disease, rapid assessment of pharmacological response, mechanistic modeling of emerging data, seamless operational processes to reduce start-up and wind-down time for clinical trials through use of electronic health records and data mining, and development of novel and objective clinical efficacy endpoints are some concepts for improving the success rate.

Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

“…Multiple phase 3 failures of agents that aim to reduce beta-amyloid plaques caused researchers to abandon the singular focus on amyloid cascade model. Indeed, if patients with high amyloid levels participate in trials for amyloid clearing drugs and they show no cognitive benefits, it is reasonable to suggest that other or additional pathophysiological substrates need to be targeted [11,12].…”

“…The underlying mechanism is probably related to vascular amyloid deposits (congophilic amyloid angiopathy), present in nearly all patients with AD. The need for vascular repair and regeneration during Aβ immunotherapy is another argument for early treatment and subtle clearance over a long period of time [9,11,12]. Valuable experience gained from several negative phase 3 trials of the first agents of this class, bapineuzumab [19] and solanezumab [20] paved the way for great insights in mAbs research.…”

An Alternate View of Neuroprotection with Peptides in Alzheimer’s Disease

“…Both compounds joining the list of lessons learnt from BACE1 inhibitors, along with Lanabecestat, Atabecestat and Verubecestat. All of which proved excellent in reducing Aβ; however, translation into clinical trials was not as smooth, lacking efficacy or displaying off-target effects [56].…”

Reasons for Failed trials of Disease-modifying Treatments for Alzheimer Disease and their Contribution in Recent Research

“…Μultiple phase 3 failures of agents that aim to reduce beta-amyloid plaques made researchers to abandon the singular focus on amyloid cascade model. Indeed, if patients in anti-amyloid trials are initially positive for high levels of amyloid and although the anti-amyloid drug clears amyloid while finally there is no cognitive benefit, it is reasonable to suggest that pathology or pathophysiology other than singular amyloid needs to be selected as a target [9,10].…”

“…The lack of efficacy observed in previous phase 3 trials raised the question whether treating AD patients once they become symptomatic may be too late to reverse the progress of neurodegeneration. It is hypothesized that presymptomatic intervention may halt or delay the progression of the disease [10].…”