When clinical trials fail, not only the sponsors but also the patients lose something. The average overall likelihood of approval (LOA) by the FDA from Phase 1 of clinical trials was only 9.6% [1]. Only one out of ten trials make it to approval and commercialization. In addition, the estimated amount of clinical trial cost ranges from $800 million to $1.4 billion [2]. If a trial fails, sponsors face immense financial losses, and patients lose hope of getting new treatment options for their medical conditions.
As carefully enumerated in the research paper “Why 90% of Clinical Drug Development Fails and How to Improve It” written by Sun, Gao, Hu, and Zhou (2021) , some of the most common causes of oversight in clinical trials that lead to their shutdown are lack of safety and poor strategic planning [3]. In addition to the two aforementioned probable causes, the clinical trial’s study design can also greatly contribute to its demise. According to a journal article published on the Oxford Academic website titled “Protect Us From Poor-Quality Medical Research” (2018), 85% of the studies failed because of faulty study design, flawed execution, and irrelevant endpoints [4]. From these findings, it can be inferred that failures in clinical trials can come from different areas of the study.
Lack of Safety
According to a paper published by David Fogel in 2018, clinical trial failures can come from a lack of safety [5]. In a study that Fogel cited, 17% of failed trials were due to safety. In the study, it says that patients reported concerns about different adverse effects that aren’t in accordance with what the physicians are concerned about. This deviation can influence the outcome of the study.
To further emphasize the effect of adverse effects, a paper written by Singh and Loke in 2012 mentioned that inconsistencies in adverse effects can pose challenges in clinical trials [6]. When the outcomes are collected from the patients in a spontaneous manner rather than systematic data gathering, misclassification can occur. Singh and Loke cited an example wherein patients with chronic obstructive pulmonary disease may have an increased risk of pneumonia when they inhaled corticosteroids. In the study example, pneumonia was not an outcome of interest for the researchers, but it was classified as a serious adverse effect in the trial. Like in this case, if there was more harm than benefit done, the failure of a clinical trial is inevitable.
Many clinical trials before having approval and commercialization are being described in superlatives during the course of the study. But no matter how optimistic it looks to the public; medicinal breakthroughs are actually rare. In the comprehensive study “Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results” conducted by Hwang, et. al. (2016), failure in clinical trials can mainly be attributed to a lack of safety and efficacy which comprises almost 75% of the total number of study subjects [7].
In the previously mentioned study, Hwang and his colleagues found out that many of the failed trials that they were able to obtain through data set from 2 commercial databases namely Pharmaprojects and Adisinsight demonstrated reversed results than what has already been observed from initial investigations. Some of the results that the researchers pointed out in terms of clinical trial failures due to safety are increased risk of fatality and serious side effects such as cancer, stroke, and sepsis. Because of these grave issues with safety and efficacy, most clinical trials conducted were halted.
Inadequate Study Design
A paper authored by Scott Evans, Ph.D., called “Fundamentals of Clinical Trial Design” (2010), states that most errors in clinical trials are brought by poor planning [8]. Even though foresight is one key element in conducting clinical trials, it is the quality that is often overlooked. Thus, even fancy statistical methods can’t save the study design fault. Once this occurs, it is already too late.
One common mistake study designers and clinical operations staff make are not formulating the appropriate research questions for the study. As also stressed in the article written by Carla Brown titled “5 Major Pitfalls in Clinical Trial Design and How To Avoid Them” (2020) , the problem in making research questions is the temptation of developing many research questions that are irrelevant to the primary inquiry that the study is trying to answer [9]. A study might encounter trouble during its clinical operations due to wrong research questions that were implemented at the initial stages of the trial.
Other factors that can be attributed to inadequate study design are wrong sample sizes, the complexity of trial design, and the sheer execution of the planned trial design.
Eligibility Criteria
In principle, the eligibility criteria should produce a study population that corresponds perfectly with what kind of subjects the trial needs. However, having a perfect set of respondents is only possible in a perfect world. In reality, study designers and the clinical operations recruitment staff should take into consideration particular conditions such as existing comorbidities. Failure to realize diverse initial patient conditions might lead to severe adverse effects or premature withdrawal of patients in a trial.
As Fogel (2018) reported in his paper, the categories in which the inclusion and exclusion of patients depend should be directly related to the expected effect on recruitment. Furthermore, he underlined the effect of inclusion and exclusion criteria on the study’s duration and cost. Not only that, but he also mentioned that the aforementioned factors also dictate the success of reaching the ideal recruitment rate, patient retention, and the opportunity to meet a statistical endpoint.
But there are two problems with eligibility criteria that can lead to the clinical trial’s failure. The first one is if the inclusion rate is too specific, it can cause major problems in finding the right patient candidate. Fogel explained that if the inclusion criteria are too narrow, it could lead to a significant delay in recruitment and a dramatic change in the study protocol. Hence, contributing more to the probability of a study’s failure. For the second reason, the exclusion criteria might be set in place without explicit justification [5]. According to the author, this happens when participants might not show noticeable improvement against an endpoint. It could be because their health is too poor or too good. The problem with this is that when someone would review the exclusion criteria of a clinical study, he or she might not find sufficient grounds and explanation for why certain criteria had been put in place and may tag it as personal bias.
Conclusion
On a lighter note, the failure of a clinical trial isn’t a wasted opportunity. Future researchers can learn something from studying what went wrong in failed trials. By doing this, the clinical science industry and even the whole scientific community will be much wiser & systematic in handling future research. After all, as the famous line says, “experience is a great teacher.”
References
- Clinical development success rates 2006-2015 [Internet]. Bio.org. 2016 [cited 2022 Oct Available from: https://www.bio.org/sites/default/files/legacy/bioorg/docs/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf
- The high price of failed clinical trials: Time to rethink the model [Internet]. Clinicalleader.com. [cited 2022 Oct 1]. Available from: https://www.clinicalleader.com/doc/the-high-price-of-failed-clinical-trials-time-to-rethink-the-model-0001
- Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B [Internet]. 2022;12(7):3049–62. Available from: https://www.sciencedirect.com/science/article/pii/S2211383522000521
- ESHRE Capri Workshop Group, Ioannidis JPA, Bhattacharya S, Evers JLH, van der Veen F, Somigliana E, et al. Protect us from poor-quality medical research. Hum Reprod [Internet]. 2018 [cited 2022 Oct 1];33(5):770–6. Available from: https://academic.oup.com/humrep/article/33/5/770/4956366
- Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun [Internet]. 2018 [cited 2022 Oct 1];11:156–64. Available from: http://dx.doi.org/10.1016/j.conctc.2018.08.001
- Singh S, Loke YK. Drug safety assessment in clinical trials: methodological challenges and opportunities. Trials [Internet]. 2012;13(1):138. Available from: http://dx.doi.org/10.1186/1745-6215-13-138
- Hwang TJ, Carpenter D, Lauffenburger JC, Wang B, Franklin JM, Kesselheim AS. Failure of investigational drugs in late-stage clinical development and publication of trial results. JAMA Intern Med [Internet]. 2016 [cited 2022 Oct 1];176(12):1826–33. Available from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2565686
- Evans SR. Fundamentals of clinical trial design. J Exp Stroke Transl Med [Internet]. 2010 [cited 2022 Oct 1];3(1):19–27. Available from: http://dx.doi.org/10.6030/1939-067x-3.1.19
- Brown C. 5 major pitfalls in clinical trial design and how to avoid them [Internet]. Anjusoftware.com. [cited 2022 Oct 1]. Available from: https://www.anjusoftware.com/about/all-news/about/all-news/insights/clinical-trial-design
