Components Of The Clinical Trial

Before discussing some of the problems that can arise during clinical trials, a brief review of some of the basic components constituting a clinical trial is in order. Figure 7 illustrates the study periods providing the framework for any clinical trial.

Prestudy activities include design and setup of the study, and poststudy activities include data entry, analysis, and report generation. Inclusion and exclusion criteria are determined early in the clinical development process, during the screening period. Before entry into the study, baseline determinations are made to which all subsequent changes will be compared. The heart of a trial is the treatment phase, which consists of drug safety modules and auxiliary modules (Fig. 8), many of which will repeat measurements made at the time of the initial screening or baseline. For Phase II and Phase III trials, specific parameters of efficacy will be assessed. The posttreatment period is the stage at which final measurements are made for safety; it is also the time to assess the effect of withdrawal of drug relative to elimination of the disease state or a return toward the baseline state.

Complex problems reach the decision filter at every stage of drug development, even in the early clinical pharmacology phase (Fig. 9). To delineate the pharmacokinetics of the compound in humans, it is common during Phase I to

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Figure 7 Primary clinical data modules in clinical trials.

Figure 8 Primary clinical data modules in clinical trials.
Figure 9 Investigational drug development.

measure blood concentrations of the test drug as dosage is increased. Sometimes the pharmacokinetic data of a study can illuminate problems inherent within the study. A case in point is the development of a drug in which three similar Phase III studies were conducted. In one of the studies, no patients in the active group had measurable concentrations. The placebo group's samples were then analyzed and it was discovered that the randomization scheme was reversed for this study. A second case in point is a Phase I bioequivalence study in which two patients with similar initials each had a single sample that drastically deviated from their expected profile. When the concentrations were transposed to each other's profile, they seemed to make sense, pharmacokinetically. Reanalysis confirmed the concentrations. The Phase I unit, which used bar-coded wristbands, emphatically denied that there could have been a mixup. A battery of tests was conducted on the remaining samples and proved that the samples had been switched. Several pages of the pharmacokinetic report discussed this issue, and, convincingly, the bioequivalence analysis was then conducted on the samples belonging to the appropriate subjects. The products were bioequivalent. Without moving the data to their appropriate places, the products were not bioequivalent.

A final case in point relates a problem that occurred during Phase I testing of an antidepressant compound. It illustrates that no matter how prepared you think you are, the unexpected or unanticipated can happen. The incident took place during a double-blind, placebo-controlled, dosage-titration trial in normal volunteers. Both plasma and urine samples were being collected for quantitative analysis of drug levels. Results demonstrated detectable levels of drug in all of the volunteers at the lowest dosage given. However, at the highest dosage administered, much to everyone's surprise, drug was not detected in some of the volunteers. Many possible explanations exist, including the following:

1. The drug is inhibiting its own absorption at higher dosages. Even if this phenomenon were true, detectable levels should exist in all volunteers.

2. The assay was not working properly. The appropriate amount of drug was recorded from spiked samples randomly distributed throughout the test samples; this procedure made assay problems less likely.

3. The drug is inducing its own metabolism. Even so, although levels of drug at higher dosages might be lower, they should not be undetectable.

4. Some volunteers failed to ingest drug. The test site used elaborate procedures to ensure that volunteers ingested the test drug. This type of problem was endemic when prisoners were commonly used as volunteers. They would swallow the drug, then go to the bathroom and induce vomiting.

5. Placebo and active drug are mixed. Such a situation could arise either before dosing (packaging error), or after dosing (sampling or labeling error after blood and urine are collected). If blood and urine specimens were mislabeled, some instances might occur in which detectable drug existed in blood but not in urine, or vice versa. In no instance, however, did this situation occur. Because blood and urine samples were collected from the placebo volunteers to keep the study double-blind, those specimens were analyzed. In some cases, drug was detected, with both urine and blood samples correlating positively or negatively. Finally, drug was analyzed that had been packaged for backup volunteers in case of dropouts. An absence of drug was demonstrated in some of the ''active'' volunteers, and drug was detected in some of the ''placebo'' volunteers.

Because an elaborate system of checks and crosschecks was in place to guard against the possibility of drug mispackaging, it was impossible to think about such a wholesale mixup. After considerable inquiry, an almost impossible reason surfaced. A disgruntled employee had deliberately sabotaged the packaging by intentionally mixing drug and placebo.

A packaging error such as the one described is extremely costly. In this case, the study had to be repeated, with the following consequences:

1. Volunteers had to be reexposed to the test drug and associated procedures.

2. The cost of doing the Phase I trial doubled.

3. The development of the drug was delayed for 3 months.

A new drug can potentially reach sales of hundreds of millions of dollars in its first year. The ultimate dollar cost of a 3-months' delay is obvious, in addition to the fact that patients are denied the use of the drug for 3 months. The

Figure 10 Investigational drug development.

situation above in the Phase I trial describes a tribulation that can occur at any point in clinical drug development. However, many issues specific to Phases II and III also must be anticipated. As seen in Fig. 10, different types of efficacy studies may be undertaken (see Chapter 6). Special studies, such as tests for addictive potential or studies allowing compassionate use of the drug (see Chapter 9), occur during these phases.

As already shown in Fig. 8, information regarding safety is collected in every study. An attempt is always made to determine any adverse events that may be caused by the drug. The process is especially difficult in patients, because illness itself is defined by a grouping of adverse events. The critical question when any adverse event occurs during a clinical trial is, ''Why did it occur?'' Did the event occur spontaneously, or as a result of an underlying disease, or as a result of a procedure conducted? Or was it caused by the drug?

What data are needed to answer those questions? Figure 11 depicts points along the course of a clinical trial at which data must be gathered to make an assessment. Figure 12 lists some of the numerous information points required before an accurate judgment can be made.

If Figures 11 and 12 seem unnecessarily complex and unduly detailed relative to the assessment of causality for an adverse event, consider the study of an antidepressant. A probe was made at baseline just before initiation of treatment


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Figure 11 Information required for reporting adverse experiences.

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Figure 11 Information required for reporting adverse experiences.

(see Fig. 11) to determine the clinical status of the depressed individuals who were about to enter into the study. As seen in Table 4, an impressive background of complaints existed before any drug medication. In a 6-week study, multiple probes will be performed to detect adverse events. Consider, then, if headache is reported as an episode during treatment (Fig. 11), it will be extremely difficult to assign causality relative to baseline when more than half the patients reported headache at baseline.

The symptoms listed in Table 4 afflict all of us from time to time, but assessments of causality for more serious events should not require the detailed data reporting depicted in Fig. 12, right? Wrong! Table 5 lists serious adverse events not present at baseline but occurring during placebo treatment. If these events had taken place during active therapy, it would have been very difficult to avoid assigning causality to the drug (see Chapter 14).

Any type of adverse event must then flow through the decision filter. The tribulations associated with assessing causality can be multiplied if case report forms (CRFs) are improperly designed. Poorly designed CRFs during Phase II will compound and multiply the problems encountered in Phase III. Proper design of CRFs at the start of clinical trials will create a firm foundation for passing through the multiple decision filters on the way to new drug approval.

A type of tribulation that occurs more in Phase II, and particularly in Phase III trials, involves adherence to the drug regimen. Drug adherence is loosely described as the number of dosages actually taken by a patient compared with the number prescribed. Alas, as with most things in life, further reflection reveals a far more complex subject. Were dosage administrations properly spaced, were they taken with meals (if required) or without food (if required), were they taken with forbidden concomitant medications? With larger Phase III outpatient studies, the variability of adherence is exaggerated. Adherence is further hindered by prolonged or complex prescriptions. It can destroy the statistical validity of an otherwise carefully controlled trial.

Consider the extreme example of a 71-year-old patient who was admitted to the intensive care unit after being found unconscious at home. Because of his





baseline to episode episode

Serious adverse everts (SAEs) Intensity

Status at start of episode Causal relationship

Test agent administration

Dose start or number of days taken

Route of administration


At onset

Stopped temporarily? Permanently discontinued'.' Date

Concomitant medications Max dosage

Dosage—start of episode Nondrug therapy

Intercurrent illnesa'complicationis)

(Detailed sequence of events)

Time or time range from start of test agent (including hours/minutes, if required)

Test agent dosage and dosage changes SAEs Name

Countermeasures Outcome

Other medications Test procedures/results Comments

Death—autopsy/biopsy, etc.

SAEs summary SAE name(s) Date of onset Max intensity Seriousness Test agent dosage Countermeasures Dechallenge R (¡challenge Outcome

Causal relationship Narrative summary-investigation Sponsor's evaluation

Figure 12 Information required for assessing adverse experiences.

Table 4 Observed Adverse Events at Baseline


Percent of patients

Insomnia Tiredness/fatigue

92 74 59 54

Anorexia Headache deteriorating condition, he had been prescribed 13 different medications at one time or another, but no one had ascertained whether he had adhered to his dosage regimen. The ambulance staff found 46 bottles containing 10,685 tablets for 13 different medications in his room (6)!

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