Challenges in Drug Development
High Costs and Low Success Rates
Despite significant advancements in basic research, the creation of new drugs continues to be a labor-intensive process characterized by low success rates. A recent commentary highlights the reasons behind these failures, based on the analysis of notable case studies. The journey of bringing a new drug to market can cost billions of dollars and take over a decade, with high attrition rates primarily driven by escalating expenses throughout various development stages.
Critical Phase 3 Trials
The third phase of clinical research is particularly crucial, as it assesses the large-scale efficacy, effectiveness, and safety of the drug. Failure to demonstrate any of these essential characteristics can prevent regulatory approval and market access. Although drug candidates may be discarded at any point during development, failures during Phase 3 are especially concerning due to the substantial financial investments already made.
Sources of Drug Development Failure
Avoidable Errors
In earlier phases of drug development, specifically Phases 1 and 2, a drug candidate’s safety and efficacy should be well established. However, a lack of efficacy remains the predominant reason for failures in Phase 3. Researchers from Janssen and the University of California San Francisco examined prominent cases of failed drugs to identify the sources of late-stage failures, which they classified into avoidable and unavoidable errors.
Avoidable errors stem from insufficient scientific rigor. Examples include suboptimal experimental designs, such as incorrect dosing, treatment regimens, or patient populations. In some cases, doses for Phase 3 trials are chosen based on their potential to achieve superior statistical significance rather than optimizing patient benefits and risks. While broad population doses are desirable, they may lead to adverse effects in more sensitive subgroups, particularly for drugs with narrow therapeutic indices. Failing to establish dosing and endpoint rigorously in Phase 2 can carry forward errors to later, more costly stages. For instance, small sample sizes in subjective conditions like depression can result in false positives during Phase 2, which may not be replicated in Phase 3.
Unavoidable Errors
Unavoidable errors arise from limitations in scientific advancement. A drug may lack sufficiently predictive models for safety and efficacy, which are essential for identifying potential safety issues in earlier development stages. This is especially relevant for liver toxicity, neurotoxicity, and oncology-related concerns. Drug-induced liver injury remains a significant cause of late-stage failures, as biomarkers may not effectively predict toxic effects in later phases. Neurological disorders, such as Alzheimer’s disease, present unique challenges due to their complex nature, variable manifestations, and gradual progression, necessitating long-term trials.
Recommendations for Improvement
Precision Medicine Approach
To mitigate avoidable errors, the authors recommend selecting patient populations for studies using a precision medicine approach that incorporates genotypic, phenotypic, and molecular data. Drugs that do not demonstrate efficacy in broad populations may still be effective for specific subgroups. For instance, the heart failure drug BiDil was ineffective in mixed-race trials but proved effective for African-Americans, leading to its targeted approval.
Enhanced Trial Design
Well-structured Phase 2 trials with thorough dose-ranging are crucial for subsequent Phase 3 success. Trial designs should be adaptive, allowing for modifications based on data collected during the trial.
Regulatory Strategies
Utilizing specific regulatory pathways, such as the FDA’s Breakthrough Therapy Designation, can accelerate approval processes by enhancing regulatory guidance and involvement. The authors emphasize the need for a balance between efficiency and scientific rigor, aiming to streamline the drug approval process and reduce the likelihood of failures.
Written by Agustin Dominguez Iino, BSc
Reference: Parasrampuria DA, Benet LZ, Sharma A. Why Drugs Fail in Late Stages of Development: Case Study Analyses from the Last Decade and Recommendations. AAPS J. 2018 Mar 13;20(3):46. doi: 10.1208/s12248-018-0204-y.