Method of randomizing patients in a clinical trial

Details Method of randomizing patients in a clinical trial Method of randomizing patients in a clinical trial

1999-11-01

2002-09-17

Shaver, Kevin (Department: 3736)

Surgery

Diagnostic testing

C128S920000, C128S925000, C205S067000

Reexamination Certificate

active

06450954

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates generally to predictive instruments for computing a probability of a medical outcome.
One important application of statistical methods to medicine is the evaluation of the efficacy of treating diseases, and the use of statistical models to determine the likelihood of a particular patient's response to a treatment regimen. Some statistical methods include the use of so-called regression models that relate clinical variables gathered from patients being treated for a disease with the probable treatment outcomes of those patients. Logistic regression models are used to estimate the probability of defined outcomes as impacted by associated information.
A number of predictive instruments have been developed to use logistic regression equations to model the probability of mortality for a patient suffering from an acute cardiac condition. The probability of mortality refers to the probability of imminent death for the patient. That is, it is a short term, as opposed to a long term, probability of mortality which does not necessarily have a precisely defined period of time associated with it. One such predictive instrument for determining the probability of mortality of a cardiac patient is described in U.S. Pat. No. 4,957,115 to Dr. Harry P. Selker. Another predictive instrument, described in U.S. Pat. No. 4,998,535, evaluates the efficacy of administering a particular treatment—thrombolytic therapy (TT)—to a patient with a heart condition by comparing a computed first probability of mortality for the patient assuming that thrombolytic therapy is not administered and a second computed probability of mortality for the patient assuming that thrombolytic therapy is administered.
Acute myocardial infarction (AMI) is one of the most common causes of death in the United States. Therefore, the outcomes of its treatment and optimal care setting are of the. upmost importance. It is well understood that re-establishing coronary perfusion at the earliest possible time is a critical part of treatment. There are two general modes of coronary “reperfusion therapy”: 1) thrombolytic therapy (TT); and 2) percutaneous transluminal coronary angioplasty(PTCA). TT can be given by any emergency department or physician in either a hospital or field setting. In contrast, PTCA requires a trained interventional cardiologist in a specialized setting with surgical support in the event of a complication.
Although TT remains the standard of care in reperfusion treatment for AMI, limited clinical studies suggest that PTCA may be substantially superior to TT in reducing mortality, at least in certain settings such as high-volume primary PTCA cardiac centers. To properly test the efficacy of PTCA, a more comprehensive PTCA effectiveness trial is performed. Such a trial could involve the random assignment of patients to either a local community hospital or to referral cardiac center. That is, some patients would be sent to a local hospital, while others would be transferred from the local hospital to a regional care center or the local hospital would be by-passed in favor of the regional cardiac center. In either case, there would be a delay associated with the extra time required to transport the patient beyond the local hospital (where care is readily available) to the more distant cardiac care center. Since time from the onset of AMI until treatment is a crucial determinant of medical outcome regardless of the reperfusion strategy employed, bypassing nearby community hospitals in favor of cardiac centers is not without risk. Thus, randomization under such conditions may be problematic.
SUMMARY OF THE INVENTION
In one aspect of the invention, to determine if a patient may be randomized to a treatment option, data are received for a patient experiencing symptoms of the type that may be treated by either of two treatment options including a first treatment option and a second treatment option. The first treatment option has an associated first time-to-treatment and the second treatment option has an associated second time-to-treatment that is greater than the first time-to-treatment by a given delay time. The second treatment option is estimated to be more effective than the first treatment option. The received data are used to compute a benefit value for the first treatment option at the first time-to-treatment. The received data and the computed benefit value associated with the first treatment option are used to compute for the second treatment option an allowable delay time during which a second benefit value for the second treatment option is no less than the first benefit value. Randomization information is produced based on the computed allowable delay time. The randomization information indicates whether or not the patient may be randomized to one of the two treatment options.
Embodiments of the invention may include one or more of the following features.
The first treatment option can be thrombolytic therapy (TT) and the second treatment option can be percutaneous transluminal coronary angioplasty (PTCA).
The first treatment option may be available at a local hospital and the second treatment option may be available at a more distant treatment center. The given delay time may correspond to the additional time required to transport a patient to the more distant treatment center.
The randomization information can be produced by determining if the given delay time is less than or equal to the allowable delay time and indicating that the patient may be randomly allocated to either the first or the second treatment option if the given delay time is determined to be less than or equal to the allowable delay time.
The randomization information can be produced by sending the computed allowable delay time to an output device for display.
In another aspect of the invention, benefit values are computed for the treatment options and confidence intervals associated with the computed benefit values are used to determine when randomization may occur. An overlap of the confidence intervals indicates that randomization is permissible.
In yet another aspect of the invention, probability of medical outcome values are computed for the first and second treatment option. A determination is made as to whether or not the computed probability of medical outcome values are equal. If equal, an indication that the patient may be randomly allocated to either the first or the second treatment option is provided.
The randomization mechanism of the present invention offers several advantages. It better enables clinicians to make critical treatment decisions involving trade-offs between the proximity of a cardiac center and the benefits associated with the care provided by such a cardiac center. Therefore, it provides for the use of randomization techniques when a delay in time-to-treatment has a critical impact on medical outcome for a patient. The randomization process can be used in clinical trials to further develop models for alternative treatment therapies such as PTCA. In addition, the randomization process can serve as an on-site decision aid for treatment of patients with AMI. As an on-site decision aid, it can be used by EMS providers and hospital emergency room physicians alike to predict which patients are likely to obtain the most incremental benefit from PTCA and to optimize the delivery of acute cardiac services. While the process is advantageous in applications in which time is a critical factor, it may be useful in clinical trials in general. For instance, it could applied in the administration of an on-location clinical trial, e.g., experimential drug testing.


REFERENCES:
patent: 4457315 (1984-07-01), Bennish
patent: 4679144 (1987-07-01), Cox et al.
patent: 4998535 (1991-03-01), Selker et al.
Brooks, Maria, “Predictors of Mortality and Mortality from Cardiac Causes in the Bypass Angioplasty Revascularization Investigation (BARI) Randomized Trial and Registry”, American Heart Association, Inc., Jan. 4, 2000, pp. 2682-2689.
Brooks et al., Predictors of Mortali

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