One of the critical steps in developing new pharmacotherapies is the clinical trial. However, sometimes during this phase unforeseen toxicities may emerge which cause the trial to fail. In fact, one resource asserts that failures in the early stages of drug development associated with toxicity account for 75% of all the costs during development (Marchetti & Schellens, 2007). However, there are other reasons why a clinical trial may fail. A trial may fail at any point, beginning with phase 0 and up through phase IV, and for several reasons. These include problems with animal models and animals, such as failure of the compound to behave in a predictable manner during animal trials; failure of sufficient positive responders; adverse drug reactions; and minimal efficacy.
Animal testing has long been a means of testing many potential medical interventions for human medicine. A critical component of drug development, particularly in designing and developing trials, is to identify appropriate animal models to help determine the safety of the compounds in question (Blass, 2015). Marchetti & Schellens (2007) note that it is important to have “a sufficient number of animals to guarantee reliable interpretation of the results should be treated” (p. 578). Therefore, if a sufficient number of animals is not used, reliable interpretation of the results cannot be made, meaning that progression through the rest of the levels of trial is not possible. Additionally, it is common when comparing animal and human doses to expect that any possible toxic responses will be similar or equal between animals and humans (Collins, 2009). It is possible that the toxic responses of animals may be more intense or less intense, and that this difference in responses contributes to unpredicted responses in human trials, resulting in failure of the trial. Hoering, LeBlanc, and Crowley (2011) insist that even if an agent has proven safe in animal models, one cannot take this for granted; researchers should be quite certain prior to exposing humans to the agent.
Similar to the need for sufficient animal results for meaningful interpretation, sufficient positive human responders are also required to make meaningful interpretation of findings. The dose-effect relationship is important, since the “intensity and duration of a drug’s effects are a function of the drug dose and drug concentration at the effect site” (Balis, 2009). The main dose-effect parameters are potency and efficacy (Balis, 2009); efficacy will be addressed more in-depth later in this paper. Potency is “the sensitivity of an organ or tissue to the drug” being studied (Balis, 2009). If a drug is not sufficiently potent or is too potent, its safety and utility in treatment is compromised. It can also compromise the response of human participants. Blass (2015) notes that when a predetermined number of patients who positively respond to a new treatment is reached this signals the transition of the trial from one phase to the next. However, if that predetermined number is not reached, this can halt the trial (Blass, 2015). If in repeated attempts a sufficient number of positive responders is not achieved, this can cause the trial to fail.
While toxicity is perhaps the most common adverse drug reaction (ADR), it is not the only one. An ADR is a patient’s “response to a drug that is noxious and unintended and that occurs as doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function” (Calis, 2009). Therapeutic failures, overdoses, substance abuse, noncompliance, and errors in medication (dosage, administration, etc.) are not typically included in this category of response (Calis, 2009). This could include unanticipated allergic responses in patients, which would be an unintended and unpredictable but technically preventable (Calis, 2009). There are three classifications of ADRs: onset, severity, and type (Calis, 2009). Onset can be acute (within an hour of administration); sub-acute (1-24 hours); and latent (occurring 48 hours or more after administration) (Calis, 2009). Acute responses would, undoubtedly, bring a trial to a grinding halt, as the cause would have to be investigated to determine if it was related immediately to the medication or to factors unrelated to the medication. While theoretically patients participating in clinical trials will comply with instructions, human nature can be unpredictable, and all possibilities cannot always be accounted for. Nevertheless, such compromises of clinical trials, even in a single patient, could potentially cause a clinical trial to fail. Additionally, even rare responses by patients could cause problems, especially if they could result in long-term effects (Ye, 2008). This, too, would cause a trial to fail, especially since researchers must weigh the short-term benefits with long-term effects.
Earlier, the two parameters for dose-effect were mentioned, and potency was addressed. Efficacy is the other one, which is the maximum possible effect of the agent (Balis, 2009). Determining efficacy is usually one of the main tasks of phase I clinical trials (Rosenberger & Haines, 2002). There are two schools of thought regarding what qualifies as the maximum tolerated and therefore efficacious dose (Rosenberger & Haines, 2002). One school regards the maximum dose as an amount that can be statistically derived and computed using data; this means the amount is identified (Rosenberger & Haines, 2002). This method tends to employ a trial-and-error approach to testing dosing, which seems unsafe. Enough individuals experience negative effects (either cytotoxicity or other ADRs), and it may be impossible to recruit sufficient participants to make this approach work. If there are insufficient participants to determine the efficacious dose, it is not possible to advance the rest of the trials. This could cause the trial to fail.
The clinical trial process is critical for drug development. However, there are many elements which could be considered. These elements could at any phase cause a trial to fail.
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