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This step-by-step guide is supported by handy checklists and extracts from submitted protocols. Experienced author and consultant Phillip I. Good incorporates humorous yet instructive anecdotes to illustrate common pitfalls. Based on the proven industrial formula of planning, implementing, and finally performing essential checks, the book's three sections -- "Plan," "Do," and "Check" -- include the following material: Staffing for success. Designing trials and determining sample size. Budgeting. Exception handling. Recruiting and retaining patients and physicians. Data management. Monitoring the trials. Data analysis and review. Executive and managerial professionals involved in the design and analysis of clinical experiments, along with clinical research associates, biostatisticians, and students in public health will find A Manager's Guide to be an indispensable resource.
|1||Cut Costs and Increase Profits||3|
|3||Prescription for Success||15|
|4||Staffing for Success||19|
|9||Recruiting and Retaining Physicians and Patients||95|
|10||Computer-Assisted Data Entry||109|
|12||Are You Ready?||141|
|13||Monitoring the Trials||145|
|14||Managing the Trials||155|
From the outset of the study, we are confronted with the need to make a large number of decisions, including, not least, "should the study be performed?" A clinical trial necessitates a large financial investment. Once we launch the trials, we can plan on tying up both our investment and the work product of several dozen individuals for at least the next two to six years. Planning pays.
Seven major design decisions that must and should be made before the trials begin are covered in the present chapter:
1. Should the study be performed?
2. What are the study's objectives?
3. What are the primary and secondary response variables?
4. How will the quality of the information be assured?
5. What types of subjects will be included in the study?
6. What is the time line of the study?
7. How will the study be terminated?
Five somewhat more technical design decisions are covered in the chapter following:
1. What experimental design will be utilized?
2. What baseline measurements will be made on each patient?
3. Will it be a single-blind or a double-blind study?
4. What sample size is necessary to detect the effect?
5. How many examination sites will we need?
We deal in Chapter 7 with the large number of minor details that must be thought through before we can concludeour preparations.
SHOULD THE STUDY BE PERFORMED?
We should always hesitate to undertake extensive trials when a surgical procedure is still in the experimental stages, or when the cross-effects with other commonly used drugs are not well understood. A cholesterol-lowering agent might well interfere with a beta blocker, for example.
If your study team is still uncertain about the intervention's mode of action, it may be advisable to defer full-scale trials till a year or so in the future and perform instead a trial of more limited scope with a smaller, more narrowly defined study population. For example, you might limit your trial to male nonsmokers between 20 and 40 who are not responding to current medications.
No full-scale long-term clinical trials of a drug should be attempted until you have first established both the maximum tolerable dose and the anticipated minimum effective dose. (In the United States, these are referred to as Phase I and Phase II clinical trials, respectively.) You should also have some ideas concerning the potential side effects.
I'm constantly amazed by the number of studies that proceed well into the clinical phase without any clear-cut statement of objectives. The executive committee has decreed "the intervention be taken to market" and this decree is passed down the chain of command without a single middle manager bothering or daring to give the decree a precise written form.
Begin by stating your principal hypothesis such as:
An increase in efficacy with no increase in side effects
A decrease in side effects with no decline in efficacy
No worse than but less costly and/or less invasive
For Motrin(tm), for example, the principal hypothesis was that Motrin would provide the same anti-inflammatory effects as aspirin without the intestinal bleeding that so often accompanies continued aspirin use.
Keep the package insert in mind. For naproxen, another anti-inflammatory, the package insert reads: "In patients with osteoarthritus, the therapeutic action of naproxin has been shown by a reduction in join pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease.
"In clinical studies ... naproxin has been shown to be comparable to aspirin and indomethacin ... but the frequency and severity of the milder gastrointestinal adverse effects ... and nervous system adverse effects were less in naproxin treated patients than in those treated with aspirin and indomethacin."
The objectives of your study should be stated as precisely as possible. Consider the following: "The purpose of this trial is to demonstrate that X763 is as effective as aspirin in treating stress-induced headaches and has fewer side effects."
Not very precise, is it? Here is a somewhat more informative alternative: "The purpose of this trial is to demonstrate that in treating stress-induced headaches in adults a five-grain tablet of X763 is as effective as two five-grain tablets of aspirin and has fewer side effects." This is a marked improvement, though it is clear we still need to define what we mean by "effective."
A more general statement of objectives that may be used as template for your own studies takes the following form. "The purpose of this trial is to demonstrate that:
in treating conditions A, B, C
with subjects having characteristics D, E, F
an intervention of the form G
is equivalent to/ as effective as/ as or more effective than an intervention of the form H
and has fewer side effects."
Again, we still need to define what we mean by "effective" and to list some if not all of the side effects we hope to diminish or eliminate.
PRIMARY END POINTS
Our next task is to determine the primary end points that will be used to assess efficacy. Here are a few guidelines:
Objective criteria are always preferable to subjective.
True end points such as death or incidence of strokes should be employed rather than surrogate response variables such as tumor size or blood pressure. The latter is only appropriate (though not always avoidable) during the early stages of clinical investigation when trials are of short duration.
The fewer the end points the better. A single primary end point is always to be preferred as it eliminates the possibility that different end points will point in different directions. On the other hand, as we will see in Chapter 14 on data analysis, sometimes more effective use of the data can be made using a constellation of well-defined results.
The obvious exceptions are when (1) surrogate end points are employed and a change in a single factor would not be conclusive, (2) your marketing department hopes to make multiple claims, (3) competing products already make multiple claims.
The end point can be determined in two ways:
1. Duration of the symptom or disease.
2. Severity of the symptom or disease at some fixed point after the start of treatment. This latter can be expressed either in terms of (a) a mean value or (b) the proportion of individuals in the study population whose severity lies below some predetermined fixed value.
For a blood-pressure lowering agent such as metoprolol, the primary end point is diastolic blood pressure. For an anti-inflammatory such as Motrin, it might be either the duration or the extent of the inflammation. For a coronary-stenosis reducing surgical procedure or device, it might be the percentage of stenosis or the percentage of the population with less than 50% stenosis (termed "binary restenosis").
An exact quantitative definition should be provided for each end point. You also will need to specify how the determination will be made and who will make it. Subjective? Objective? By the treating physician? Or by an independent testing laboratory? Is the baseline measurement to be made before or after surgery?
In a study of several devices for maintaining flow through coronary arteries, the surgeon who performed the operation made the initial determination of stenosis. But it was decided that the more accurate and "official" reading would be made from an angiogram by an independent laboratory.
How much give in dates is permitted?-patients have been known not to appear as scheduled for follow-up exams. What if a patient dies during the study or requires a further remedial operation? How is the end point of such a patient to be defined?
Don't put these decisions off till some later date; make them now and make them in writing lest you risk not collecting the data you will ultimately need.
Secondary End Points
Secondary end points are used most often to appraise the safety of an intervention.
For a blood-pressure lowering agent like metoprolol these might include dizziness and diarrhea. But the systolic blood pressure would also be of interest.
For an anti-inflammatory, the most important are intestinal bleeding and ulcers. How does one detect and measure intestinal bleeding? Two ways, by self-evaluation and by measuring the amount of blood in the stool. Data relating to both must be collected.
For a coronary-stenosis reducing surgical procedure or device, the primary concern is with other procedure- and condition-related adverse events including death, myocardial infarctions, and restenosis severe enough to require further operations.
To ensure that you will collect all the data you need, a careful review of past clinical and pre-clinical experience with the present and related interventions is essential. For example, suppose that extremely high doses of your new agent had resulted in the presence of abnormal blood cells in mice. While such abnormal cells may be unlikely at the therapeutic dose you are using in the trials, to be on the safe side, blood tests should be incorporated in the trial's follow-up procedure.
During the trial and afterward, you will probably want to record the frequency of all adverse events, of specific adverse events, and of those events directly related to the intervention that exceed a certain level of severity.
You should also determine how the adverse event data are to be collected. By use of a checklist-"Since your last appointment, did you experience fever? nausea? dizziness?" Or a volunteered response-"Have you had any problems since your last visit?" Elicited responses tend to yield a higher frequency of complaints. To be on the safe side, use both methods. Of course, hospitalizations, emergency treatment, and phoned-in complaints between visits must always be recorded.
Some secondary end points may also concern efficacy. For example, in a study of sedatives, you might be interested in how rapidly the patient obtained relief.
Tertiary End Points. Tertiary end points such as costs may or may not be essential to your study. Don't collect data you don't need. When in doubt, let your marketing department be your guide.
You will need to specify what baseline data should be gathered prior to the start of intervention and how it will be gathered-by interview, questionnaire, physical examination, specialized examinations (angiograms, ultrasound, MRI), and/or laboratory tests. Baseline data will be used both to determine eligibility and, as discussed in the next chapter, to stratify the patients into more homogeneous subgroups.
Be comprehensive. Unexpected differences in outcome (or lack thereof) may be the result of differences in baseline variables. What isn't measured can't be accounted for.
WHO WILL COLLECT THE DATA?
One further step involves grouping the questions in accordance with the individual who will be entering the data, for example, demographics and risk factors by the interview nurse with review by the physician, and laboratory results by the lab itself or by the individual who receives the report. These groupings will form the basis for programming the case report forms (see Chapter 10).
Finally, I would recommend you charge specific individuals with the responsibility of addressing each of the points raised in the preceding sections. The design committee can then function as a committee should in reviewing work that has already been performed.
The secret of successful clinical trials lies in maintaining the quality of the data you collect. The most frequent sources of error are the following:
Protocol deviations that result when the intervention is not performed/administered as specified
Noncompliance of patients with the treatment regimen
Improperly labeled formulations
Improperly made observations
º Inaccurate measuring devices
º Inconsistent methods of observation, the result of
* Ambiguous directions
* Site-to-site variation
* Time-period to time-period variation
º Fraud (sometimes laziness, sometimes a misguided desire to please)
Improperly entered data
Improperly stored data
Among the more obvious preventive measures are the following:
1. Keep the intervention simple. I am currently serving as a statistician on a set of trials where, over my loudest protests, each patient will receive injections for three days, self-administer a drug for six months, and attend first semiweekly and then weekly counseling sessions over the same period. How likely are these patients to comply?
2. Keep the experimental design simple (see Chapter 6).
3. Keep the data collected to a minimum.
4. Pretest all questionnaires to detect ambiguities.
5. Use computer-assisted data entry to catch and correct data entry errors as they are made (see Chapter 10).
6. Ensure the integrity and security of the stored data (see Chapter 11).
7. Prepare a highly detailed procedures manual for the investigators and investigational laboratories to ensure uniformity in treatment and in measurement. Provide a training program for the investigators with the same end in mind.
This manual should include precise written instructions for measuring each primary and secondary end point. It should also specify how the data are to be collected. For example, are data on current symptoms to be recorded by a member of the investigator's staff, or by the self-administering patient?
8. Monitor the data and the data collection process. Perform frequent on-site audits.
Excerpted from A Manager's Guide to the Design and Conduct of Clinical Trials by Phillip I. Good Excerpted by permission.
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Posted February 17, 2010
No text was provided for this review.