Clinical trials are a fundamental part of developing and approving new medicines. These research studies involve human volunteers to determine if a new drug, device, or treatment is both safe and effective. They move promising therapies from laboratory research and animal studies into real-world patient populations. Despite rigorous preclinical work and substantial investments, a significant number of investigational drugs do not succeed. Approximately 90% of drug candidates entering clinical trials ultimately fail to gain approval.
Insufficient Efficacy
A primary reason for clinical trial discontinuation is the investigational drug’s failure to demonstrate sufficient efficacy in human subjects. This means the drug does not produce the intended therapeutic effect, or it fails to offer a meaningful advantage over existing treatments or a placebo. Lack of efficacy accounts for a substantial portion of clinical trial failures, ranging between 40% to 50%. This outcome can occur even after a drug shows promising results in preclinical studies, highlighting the complexities of human biology compared to simplified laboratory models.
Preclinical studies often utilize cell cultures and animal models, which provide valuable initial insights into a drug’s potential. However, the intricate physiological systems and disease mechanisms in humans can differ considerably from these models. A drug that effectively targets a disease pathway in an animal might not produce the same beneficial response in humans due to variations in drug metabolism, absorption, or target interaction. Consequently, a drug might reach the later stages of development, such as Phase 3 trials, only to fail because it cannot provide a statistically significant or clinically relevant benefit to patients.
Unacceptable Safety Profiles
Another major factor contributing to clinical trial failure is the emergence of unacceptable safety profiles in human subjects. Even if a drug demonstrates some efficacy, severe or frequent adverse events can halt its development. Safety is a primary concern throughout all phases of clinical trials, and unforeseen toxicities can manifest only when tested in larger human populations. Approximately 30% of clinical trial failures are attributed to unmanageable toxicity or side effects.
The relationship between the dose of a drug and the body’s response, known as the dose-response relationship, is carefully studied to establish a therapeutic window. This window represents the range of doses that can produce desired effects without causing undue harm. However, some drugs may exhibit a narrow therapeutic window, where the dose needed for efficacy is too close to the dose that causes toxicity. Furthermore, some adverse reactions, such as organ toxicity or immunological responses, might only become apparent in a diverse human population during later-phase trials, even after extensive preclinical safety testing.
Methodological and Design Deficiencies
Flaws in the methodology or design of a clinical trial can also lead to its failure, irrespective of the drug’s inherent properties. Poor study design can yield inconclusive or misleading results, preventing a clear determination of a drug’s potential. For instance, an inadequate sample size may prevent the trial from having enough statistical power to detect a true treatment effect, even if one exists.
Challenges in patient recruitment and retention frequently undermine trial integrity. Many studies struggle to enroll enough participants who meet the specific eligibility criteria, or they experience high dropout rates. This can delay trial timelines, increase costs, and compromise the generalizability of the findings. Additionally, issues such as inappropriate selection of study endpoints, lack of blinding, or poor patient adherence to the study protocol can introduce bias or render the results unreliable, leading to trial failure.
Translational Science Gaps
Translational science gaps refer to the challenges encountered when attempting to translate promising findings from preclinical research into successful human treatments. This “bench-to-bedside” gap often results from a lack of validated biomarkers that accurately predict human response or an incomplete understanding of disease pathophysiology. The distinct genetic makeup, physiological processes, and disease progression in humans mean a drug effective in an animal model may not show the same efficacy or safety profile in people. Addressing these fundamental biological and scientific differences is an ongoing challenge in drug development, directly impacting the success rate of therapies moving from early-stage discovery to clinical application.