Report: Why do clinical trials fail? 

Overview

Clinical trials are time consuming, costly, and often onerous on patients. Clinical trials can fail for many reasons. [1]This report examines many of these reasons and presents insights on opportunities for improving the possibility of creating and executing successful clinical trials.

Clinical trials for pharmaceuticals and medical devices offer numerous opportunities for failure. Failures can arise from a lack of efficacy, a deficiency in funding or issues with safety[1]. Similarly there are other factors such as failing to maintain good manufacturing protocols, not following MHRA guidance, or there are problems with patient recruitment, enrolment, and retention.[2] Generating accurate and sufficient results to determine whether or not there is value in continuing is important in the clinical trial process. The investments of resources, time, and funding grow with successive stages, from pre-clinical through phase 3.[3] Therefore if a phase 3 fails, there is a huge financial loss as it relates to all previous trials, as well as the time spent looking into alternatives. This report describes some of the points of contention and issues that have come to light on the failures of clinical trials.

Factors associated with clinical trials that fail:

Eligibility criteria: Exclusion and Inclusion criteria

If there are too many exclusion criteria it becomes problematic, this is because they limit the number of patients, but also have a negative impact on the drug approval and will prevent the sponsor from “gaining knowledge in important patient populations”[1] before registration. It has been noted that in some cases this act of limitation in phase II of clinical development in particular, is justified by reducing variability;[2] on the other hand there is no published evidence that increasing patient population with other criteria will inevitably increase the variability of the primary endpoint.[3]

The inclusion and exclusion criteria should result in a population that matches the general patient population, the criteria must also be chosen in light of effect on recruitment.[4] However inclusion criteria may vary across studies therefore providing a lack of guidance to sponsors. As well as this, having specific inclusion criteria can lead to problems in finding the best and most suitable participants. Having inclusion criteria too narrow could lead to longer recruitment times, it was stated that 16% of protocol amendments are due to changes in inclusion or exclusion criteria,[5] this can lead to differences in the patient populations before and after the amendments.

Failing to demonstrate efficacy or safety

A way in which trials are ill designed is captured in the concept of efficacy, effectiveness and safety. Efficacy demonstrates how well a drug works in model conditions and its effectiveness on how well the drug works with patients. One of the primary sources of trial failure has been with the lack of efficacy[6] . It was determined that out of 640 phase 3 trials with novel therapeutics, that 57% of those that failed was due to inadequate efficacy[7]

Study design

A poor study design can lead to trial failures, for instance selecting the wrong patients or the wrong endpoint, not to mention bad data, can lead to problems in the trial.[1] However data sources can help sponsors be sure that the right patients are then recruited as well as choosing the proper and correct sites and countries to enhance the likely hood of success.

Another common cause of failure in clinical research is based on not being able to meet criteria that have been predetermined by the MHRA. As well as this, it is important to recognise that a sponsor is necessary to move a drug or device forward in the clinical trial process. If studies are rushed into phase 3 after a successful phase 2 it could lack time for reflection on how to address safety in phase 3[2].

Financial impact

It has been noted that of the phase 3 studies that failed, 22% of them failed due to a lack of funding[3]. This financial burden also leads to ethical issues regarding the patients that are involved in the trial, patients are under the impression that their involvement would lead to the advancement of the trial and its successful completion.[4] Therefore underfunded trials are likely to lack the enrolment needed to demonstrate efficacy.

Financial risks

There are risks at all stages of development, however the cost that is associated with having to re-do studies or even delays will escalate the cost further. However taking steps that will identify and address risks early on in the development process is key. But there are many companies that do not carefully monitor for risks, and sometimes don’t even identify problems until much further down the line when it is then difficult to address them cost-effectively.[5] On the other hand this comes from the hesitation of companies to terminate a project prematurely. It was noted that in a study of 842 molecules and 637 development program failures, it was evident that the companies that took time to identify problems early on and stop development on an imperilled trial, then have a much better likelihood of reaching the market with their drug.[6]

Other factors that can result in trial failure include; how funding is misspent, lack of a correct design study, not enough funding designated from the offset, which in turn shows costing is not accurately calculated.[7] As well as this dropout rates effect the financial stability of trials and difficulties with treatment adherence such as side effects, or a lack of follow ups will also contribute to the financial impact of clinical trials.

Patient recruitment

There are various reasons why patient recruitment results in the failure of clinical trials. Firstly, there are too many companies using the same, preferred trial site thus chasing going after too few subjects. The targeted disease may be rare and so the number of subjects is too small to begin with. The failure to enrol a sufficient number of patients is a long standing problem with a UK study of 114 trials 10 indicated that only 31% met enrolment goals.[1] 

Patient difficulties

Only another aspect of this is that patients who are ill cannot travel so easily to designated hospitals. There has been some companies trying to address this problem by potentially bringing the trial to people’s homes, however this could present further issues.[2] As well as this, some studies offer certain remunerations to patients to cover expenses in the hope that recruitment could be improved. However this step has not provided any evidence that paying patients to participate in said trials generate better recruitment.[3] Although financial incentives did not result in better recruitment, it was reported that financial incentives did increase participant’s response to questionnaires for the trial.[4]

Additional costs

There are additional costs with patient recruitment which can be difficult to estimate and become highly variable. It is evident that marketing strategies such as advertisement can play an important role in the financial viability of a trial.[5] As well as this, healthcare providers can significantly impact patient recruitment, the aspect of recruitment and retention can potentially suffer when staff are unavailable or just perceived to be, or if there is a constant rotation of new staff and no relationship is able to develop between staff and the patient. Establishing this communication and trust may lead to better participation.

All of these patient recruitment problems have an effect on the trial and cause massive delays in some cases. There are only 6% of clinical trials completed within the time frame given, with a further 80% of trials delayed by at least a month.[6] These delays affect study costs but also subsequent sales causing high potential loss. As costs are high there is potential for money to be lost, therefore there are massive gains to be made by improving the rate of recruitment and retention[7]

Unethically designed trials

It cannot be assumed that everyone understands the value of honesty, or is sensitive to it. Breaches occur, and ethical issues introduce a high risk of trial failure, severely damaging the reputation of all parties involved, i.e. the pharmaceutical company, the CRO and the pharmaceutical physicians.[1] Too many industry cases illustrate that alleged short-term gains can rapidly turn into long-term losses.[2]

Patient risk

The general problems with the ethics of clinical trials come from the fact that participants bear the risk and burden. Participation in a clinical trial has an increased level of risk; this is because of the exposure to effects of new treatment. These risks however are not “offset by a prospective clinical benefit”[3], this is because the goal of the trial is not to treat trial participants but to produce generalised medical knowledge


References:

Saberwal, Gayatri. “Biobusiness in Brief: What Ails Clinical Trials?” Current Science, vol. 115, no. 9, Current Science Association, 2018, pp. 1648–52, https://www.jstor.org/stable/26978474.

Pharmafile “clinical trials and their patient”  https://www.pharmafile.com/news/511225/clinical-trials-and-their-patients-rising-costs-and-how-stem-loss (2016)

Chris Plaford “why do most clinical trials fail” https://www.clinicalleader.com/doc/why-do-most-clinical-trials-fail-0001#_ftn1 (2015)

  Hwang T.J., Carpenter D., Lauffenburger J.C., Wang B., Franklin J.M., Kesselheim A.S. Failure of investigational drugs in late-stage clinical development and publication of trial results. JAMA Intern. Med. 2016;176:1826–1833.

 Tukey, John W. “Use of Many Covariates in Clinical Trials.” International Statistical Review / Revue Internationale de Statistique, vol. 59, no. 2, [Wiley, International Statistical Institute (ISI)], 1991, pp. 123–37, https://doi.org/10.2307/1403439.

Worrall, John. “<em>What</Em> Evidence in Evidence‐Based Medicine?” Philosophy of Science, vol. 69, no. S3, [The University of Chicago Press, Philosophy of Science Association], 2002, pp. S316–30, https://doi.org/10.1086/341855.

Altman, Douglas G. “Size Of Clinical Trials.” British Medical Journal (Clinical Research Edition), vol. 286, no. 6381, BMJ, 1983, pp. 1842–43, https://www.jstor.org/stable/29511193.

Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018;11:156-164. Published 2018 Aug 7. doi:10.1016/j.conctc.2018.08.001

Jansen, Lynn A. “The Problem with Optimism in Clinical Trials.” IRB: Ethics & Human Research, vol. 28, no. 4, Hastings Center, 2006, pp. 13–19, https://www.jstor.org/stable/30033204.

Chris Plaford “why do most clinical trials fail” https://www.clinicalleader.com/doc/why-do-most-clinical-trials-fail-0001#_ftn1 (2015)

Kobak Kenneth “why do clinical trials fail? Journal of Clinical Psychopharmacology: February 2007 – Volume 27 – Issue 1 – p 1-5 doi: 10.1097/JCP.0b013e31802eb4b7

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