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Summary in Thirty Seconds
Clinical trial failures are common and costly, yet they can teach us important lessons.
While failures are under-reported in publications, four common reasons for trial failures can be identified: poor efficacy/safety issues; funding concerns; protocol design problems; and patient enrollment shortcomings.
The most preventable but common of these reasons is enrollment issues, which can be driven by eligibility criteria, recruitment costs, and patient concerns.
All four reasons for trial failures can exacerbate and drive each other, increasing the risk of failures resulting in delays in/barriers to introducing potentially life-changing treatments.
A good CRO can help anticipate and overcome patient enrollment issues through a variety of creative and proactive steps.
Failure Under-reporting
Over the past decade, the cost and complexity of clinical trials have increased, particularly in new drug development for precision medicines targeting difficult, rare, and chronic conditions.[1] So when a trial fails, tremendous financial costs are not only incurred to sponsors but also to patients in need of life-changing and possibly life-saving treatments. However, trials that fail to complete are likely under-reported in the scientific literature because they are rarely published in journals; and even for successful trials, publications aren’t frequent. One study found less than one in five cancer clinical trials registered at clinicaltrials.gov resulted in a peer-reviewed journal publication.[2] Almost two-thirds of these publications reported positive results. Another study found that trial failures for non-commercial reasons were reported 40% of the time in peer-reviewed journals and only 8% of those that failed for commercial reasons were published.[3] Nevertheless, there are lessons to be learned from clinical trial failures.
Reasons for Clinical Trial Failures
A review of the reasons for clinical trial failures identified at least four causative factors:[4]
Efficacy/Safety—a study of 640 Phase III novel therapeutic trials found a 54% failure rate. 57% of those failures were secondary to poor efficacy while 17% failed for safety/serious adverse events.[5] This study additionally found that cancer compounds and agents sponsored by small- and medium-sized pharmaceutical companies were less likely to obtain FDA approval.
Funding—in the study of 640 trials cited above, 22% of studies failed for commercial reasons/lack of funding. Estimates of costs to bring a drug to market provide a range of results. A 2020 study in JAMA estimated the median cost of bringing 63 new medicines to market at $1.6 billion, with cancer drugs costing a median of $2.8 billion.[6] Another study evaluated costs for the development of 106 drugs to approval and found a cost of $2.6 billion[https://www.lighthouse.bio/post/the-patient-journey-of-people-with-cancer7], while another review of 17 studies provided an estimate as high as $6 billion for research and development to release a new drug.[8] Such huge costs may lead to underfunded trials, questions of return on investment, concern over positive outcomes, and a variety of other factors which may lead sponsors or funding entities to stop underwriting a clinical trial.
Protocol design—a review of cancer clinical trials found that two factors raising the risk of failing to complete were single-center trials and studies centered in only one country.[9] Studies involving a longer follow-up time have been associated with lower patient accrual.[10] Additionally, when studies have complex protocols, patients are twice as likely to drop out. [11],[12]
Enrollment—falling short of patient enrollment targets and timelines is a chronic problem in clinical trials and can result in trial failure. Up to 80% of trials fail to meet enrollment timelines,[13] and as many as 30% of trials are terminated for not meeting enrollment goals.[14] Research of 114 trials in the UK found only 31% met enrollment targets,[15] and a review of over 7,000 cancer clinical trials found 20% failed to complete enrollment, leaving almost 48,000 patients enrolled in trials that were terminated.[16] Studies of less common/rare diseases have been associated with poorer patient accrual rates.[17] Four specific causes of enrollment problems are:
a. Eligibility issues—inclusion/exclusion criteria may suppress patient enrollment. Such criteria involve inclusion criteria such as identifying and recruiting participants with very specific molecular variants (i.e., biomarkers),[18] while excluding those comorbidities, unstable/progressing disease, prior treatments, outside age ranges, etc.[19] Inclusion/exclusion issues can increase the duration and cost of a trial[20] and lead to protocol amendments,[21] which also complicate study timelines, costs, and success rates. One study found that across 3,400 trials, 40% amended protocols before the first patient visit, which delayed trial starts by an average of 4 months.[22]
b. Recruitment-associated costs—often, clinical trials offer remuneration to cover participants’ time and expenses, which would seem more likely to increase enrollment likelihood; however, larger payouts can be linked to a perception of higher risks for participating in a trial, thus suppressing enrollment.[23] Financially incentivizing providers to recruit patients has shown benefits, while participant perceptions that providers are disinterested in or unsupportive of a clinical trial can suppress recruitment and retention.[24]
c. Patient concerns—patients are less willing to enroll when they are concerned about being assigned to a control/placebo group, and part of this concern may be due to misinformation/limited knowledge about placebos.[25] Concerns about side effects[26] and financial burdens[27] can also suppress enrollment.
d. Low awareness—if patients aren't aware of clinical trials, they won't enroll. A 2022 survey by the National Cancer Institute (NCI) Health Information National Trends Survey (HINTS) found that 41% of Americans reported knowing nothing about clinical trials.[28a]
These four reasons can exacerbate and play into each other; for example, poor efficacy in preliminary analyses can drive funding decisions, or low enrollment can lead to costly fixes or the underpowering of a protocol’s statistical efficacy analysis. Regardless of the specific cause(s), delays and failures result in increased clinical trial costs as well as delays in/barriers to introducing potentially life-changing treatments to people in desperate need of new therapies.
What Failures Teach Us
The purpose of a clinical trial is to determine the efficacy and safety profile of an investigative compound or treatment;[28] thus, trial failure due to efficacy or safety issues can be expected as part of the process. In commercial trials, financial considerations/profitability issues drive many decisions.[29] Beyond these two factors, protocol design and patient enrollment issues can often be anticipated and ideally addressed before starting a trial or at least at the outset of the trial. A quality CRO can help advise sponsoring agencies on a variety of patient enrollment topics that can lead to a higher likelihood of clinical trial success, including:
setting up multi-site and international trials, including having connections within the international field to set up and assist in a new clinical trial;
identifying patients who signal their interest/need for a clinical trial based on their digital activity;
raising awareness of clinical trials, particularly in rare diseases;
raising the awareness of health practitioners about biomarkers and emerging technologies to identify them;
conducting high-quality, efficient, and accurate screening of potentially eligible patients;
using nurse navigators and medical liaisons to further screen patients and help guide participants through the clinical trial process;
providing doctor discussion guides understandably written to help potential patients understand the risks and benefits of participating in a clinical trial as well as concepts such as placebos, finances, etc.
Lessons learned through clinical trial failures can teach us how to proceed more intelligently. William A. Ward said, “Failure should be our teacher, not our undertaker. It is delay, not defeat. It is a temporary detour, not a dead-end street.”
[1] Nat Rev Drug Discov. 2017; 16(5):307 [2] Oncologist. 2008; 13(9):925-929 [3] JAMA Intern. Med. 2016; 176:1826–1833 [4] Contemp Clin Trials Commun. 2018; 11: 156–164 [5] JAMA Intern. Med. 2016; 176:1826–1833 [6] JAMA. 2020; 323(9):844-853 [7] J. of Health Econ. 2016; 47:20-33 [8] Inquiry. 2021; 58:00469580211059731 [9] J. Natl. Cancer Inst. 2012; 106(9):dju229 [10] J. Natl. Cancer Inst. 2016; 108(2):djv324 [11] J. Natl. Cancer Inst. 2017; 109(3):djw233 [12] Retention in Clinical Trials: Keeping Patients on Protocols - Advarra [13] Clin Investig. 2015; 5(5):491–9 [14] Clin Trials. 2015; 12(1):77–83 [15] Fam. Pract. 2009; 26:391–397 [16] J. Natl. Cancer Inst. 2012; 106(9):dju229 [17] J. Natl. Cancer Inst. 2016; 108(2):djv324 [18] Radiology. 2002; 224:157-163 [19] BMJ Evidence-Based Medicine 2019; 24:92-94 [20] World J. Meth. 2014; 4:109–122 [21] Drug Inf. J. 2011; 45:265–275 [22] ibid [23] Soc. Sci. Med. 2010; 70:455–464 [24] Trials. 2013; 14:389 [25] J. Med. Ethics. 2017; 43(12):867-870 [26] AJOB Prim Res. 2012; 3:10-23 [27] Oncology. 2015; 20(6):572-575